Publications du service de Pédiatrie Générale (depuis 1999) 2007 ABADIE V. Phenylketonuria, from neonatal screening to adulthood. Archives Pédiatrie, 14 (6), 607-609, 2007 ; (Facteur d'Impact 2006 : 0,258) (Services cités : Pédiatrie Générale) BAALA L., ROMANO S., KHADDOUR R., SAUNIER S., SMITH U.M., AUDOLLENT S., OZILOU C., FAIVRE L., LAURENT N., FOLIGUET B., MUNNICH A., LYONNET S., SALOMON R., ENCHA-RAZAVI F., GUBLER M.C., BODDAERT N., de LONLAY P., JOHNSON C.A., VEKEMANS M., ANTIGNAC C., ATTIE-BITACH T. The Meckel-Gruber Syndrome Gene, MKS3, Is Mutated in Joubert Syndrome. Amer. J. Hum. Genet., 80 (1), 186-194, 2007 ; (Facteur d'Impact 2006 : 12,629) (Services cités : Pédiatrie Générale, Génétique Médicale Pédiatrique, Radiologie Pédiatrique, U574, U781, Métabolisme) Joubert syndrome (JS) is an autosomal recessive disorder characterized by cerebellar vermis hypoplasia associated with hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The association of retinal dystrophy and renal anomalies defines JS type B. JS is a genetically heterogeneous condition with mutations in two genes, AHI1 and CEP290, identified to date. In addition, NPHP1 deletions identical to those that cause juvenile nephronophthisis have been identified in a subset of patients with a mild form of cerebellar and brainstem anomaly. Occipital encephalocele and/or polydactyly have occasionally been reported in some patients with JS, and these phenotypic features can also be observed in Meckel-Gruber syndrome (MKS). MKS is a rare, autosomal recessive lethal condition characterized by central nervous system malformations (typically, occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. Since there is obvious phenotypic overlap between JS and MKS, we hypothesized that mutations in the recently identified MKS genes, MKS1 on chromosome 17q and MKS3 on 8q, may be a cause of JS. After mutation analysis of MKS1 and MKS3 in a series of patients with JS (n=22), we identified MKS3 mutations in four patients with JS, thus defining MKS3 as the sixth JS locus (JBTS6). No MKS1 mutations were identified in this series, suggesting that the allelism is restricted to MKS3. BRADAI M., PISSARD S., ABAD M.T., DECHARTRES A., RIBEIL J.A., LANDAIS P., de MONTALEMBERT M. Decreased transfusion needs associated with hydroxyurea therapy in Algerian patients with thalassemia major or intermedia. Transfusion, 47 (10), 1830-1836, 2007 ; (Facteur d'Impact 2006 : 3,278) (Services cités : Biostatistique, Pédiatrie Générale, Biothérapie) BACKGROUND: Studies of evolution of transfusion requirements in thalassemic patients treated with hydroxyurea have produced somewhat conflicting results, especially in patients with thalassemia major. Our aims were to determine the proportion of good responders to hydroxyurea in a population of transfusion-dependent thalassemic patients and to identify the factors

associated with a decrease of transfusion needs. STUDY DESIGN AND METHODS: Hydroxyurea treatment was initiated in 9 patients with thalassemia intermedia (TI) and 45 with thalassemia major (TM). Patients received transfusions when their hemoglobin (Hb) levels dropped below 6 g per dL. A decrease in annual transfusion requirements greater than 70 percent defined a good response, between 40 and 70 percent a partial response, and smaller than 40 percent no response. RESULTS: The response was good in 8 (90%) patients with TI and 20 (44.5%) with TM, partial in 9 (20%) patients with TM, and absent in 1 (10%) with TI and 16 (35.5%) with TM. In TM patients, transfusion needs decreased by 56 percent over the first year of hydroxyurea treatment. By univariate analysis, a better response to hydroxyurea was associated with older age at the first transfusion (p = 0.02), higher prehydroxyurea Hb (p = 0.0004), codon 6(-A) mutation (p = 0.002), TI (p = 0.03), and history of splenectomy (p = 0.05). Xmn1-/- was associated with a worse response (p = 0.0001). By multivariate analysis, a better response was associated with the Xmn1 polymorphism (p = 0.008). CONCLUSION: Hydroxyurea may be an alternative to transfusions for TI patients as well as for TM patients in countries that have limited blood supplies. BRANCATI F., BARRANO G., SILHAVY J.L., MARSH S.E., TRAVAGLINI L., BIELAS S.L., AMORINI M., ZABLOCKA D., KAYSERILI H., AL-GAZALI L., BERTINI E., BOLTSHAUSER E., D'HOOGHE M., FAZZI E., FENERCI E.Y., HENNEKAM R.C., KISS A., LEES M.M., MARCO E., PHADKE S.R., RIGOLI L., ROMANO S., SALPIETRO C.D., SHERR E.H., SIGNORINI S., STROMME P., STUART B., SZTRIHA L., VISKOCHIL D.H., YUKSEL A., DALLAPICCOLA B., VALENTE E.M., GLEESON J.G. CEP290 Mutations Are Frequently Identified in the Oculo-Renal Form of Joubert Syndrome-Related Disorders. Amer. J. Hum. Genet., 81 (1), 104-113, 2007 ; (Facteur d'Impact 2006 : 12,629) (Services cités : Pédiatrie Générale) Joubert syndrome-related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Loken syndrome (JSRD-SLS phenotype). Here, we performed comprehensive CEP290-mutation analysis on two nonoverlapping cohorts of JSRD-affected patients with a proven MTS. We identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only two patients. The data suggest that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies. BURTON B.K., GRANGE D.K., MILANOWSKI A., VOCKLEY G., FEILLET F., CROMBEZ E.A., ABADIE V., HARDING C.O., CEDERBAUM S., DOBBELAERE D., SMITH A., DORENBAUM A. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-

label, screening study. J. Inherit. Metab. Dis., 30 (5), 700-707, 2007 ; (Facteur d'Impact 2006 : 1,574) (Services cités : Pédiatrie Générale) This study aimed to evaluate the response to and safety of an 8-day course of sapropterin dihydrochloride (6R-tetrahydrobiopterin or 6R-BH4) 10 mg/kg per day in patients with phenylketonuria (PKU), who have elevated blood phenylalanine (Phe) levels, and to identify a suitable cohort of patients who would respond to sapropterin dihydrochloride treatment with a reduction in blood Phe level. Eligible patients were aged > or = 8 years, had blood Phe levels > or = 450 micromol/L and were not adhering to a Phe-restricted diet. Suitable patients were identified by a > or = 30% reduction in blood Phe level from baseline to day 8 following sapropterin dihydrochloride treatment. The proportion of patients who met these criteria was calculated for the overall population and by baseline Phe level (< 600, 600 to < 900, 900 to < 1200 and > or = 1200 micromol/L). In total, 485/490 patients completed the study and 20% (96/485) were identified as patients who would respond to sapropterin dihydrochloride. A reduction in Phe level was observed in all subgroups, although response was greater in patients with lower baseline Phe levels. Wide variability in response was seen across all baseline Phe subgroups. The majority of adverse events were mild and all resolved without complications. Sapropterin dihydrochloride was well tolerated and reduced blood Phe levels across all PKU phenotypes tested. Variability in reduction of Phe indicates that the response to sapropterin dihydrochloride cannot be predicted by baseline Phe level. CAVAZZA F., PERRIN A. Les soins aux enfants drépanocytaires au sein d'un réseau de santé. Soins Pédiatr. Puéric. (234), 27-31, 2007 ; (Facteur d'Impact 2006 : X) (Services cités : Pédiatrie Générale) COUILLARD S., BENKERROU M., GIROT R., BROUSSE V., FERSTER A., BADER-MEUNIER B. Steroid treatment in children with sickle-cell disease. Haematologica, 92 (3), 425-426, 2007 ; (Facteur d'Impact 2006 : 5,032) (Services cités : Pédiatrie Générale) Given the controversy concerning the effects of steroids in patients with sickle cell disease (SCD), we evaluated the tolerability of long-term steroid treatment in 16 children with SCD and autoimmune and/or systemic diseases. The steroid treatment was poorly tolerated. DE MONTALEMBERT M. Échanges érythrocytaires chez les patients drépanocytaires. Hématologie, 13 (4), 243-249, 2007 ; (Facteur d'Impact 2006 : X) (Services cités : Pédiatrie Générale) La drépanocytose associe une anémie hémolytique chronique et une hyperviscosité sanguine. La transfusion a pour but soit de corriger une aggravation de l’anémie chronique, soit d’apporter des hématies déformables afin de délivrer l’oxygène aux tissus anoxiés. Il importe de ne pas dépasser une valeur d’hématocrite autour de 35 % pour ne pas majorer excessivement la viscosité. L’association d’une saignée à une transfusion, procédure qui définit un échange transfusionnel, permet de diminuer le pourcentage d’HbS sans élever l’hématocrite. Un échange peut être

effectué par voie manuelle, en remplaçant le sang total du malade par des concentrés érythrocytaires, ou à l’aide d’un séparateur de cellules, qui réinjecte au patient son propre plasma. Les procédures automatisées sont appelées érythrocytaphérèses. Les échanges transfusionnels peuvent être nécessaires en urgence, lors d’une occlusion vasculaire (accident vasculaire cérébral (AVC), syndrome thoracique aigu, défaillance viscérale brutale). Ils peuvent s’intégrer aussi dans des programmes mensuels. Les indications les plus fréquentes des programmes chroniques chez les enfants sont les vasculopathies cérébrales, les échanges pouvant être indiqués en prévention d’un premier AVC chez un enfant dont une ou des artères cérébrales ont un flux, mesuré par doppler trans-crânien, accéléré ils peuvent être aussi indiqués pour prévenir une récidive chez un enfant ayant déjà fait un AVC. les échanges mensuels sont plus fréquemment pratiqués chez les adultes pour prévenir des récidives de crises douloureuses ou de syndromes thoraciques aigus, ou pour enrayer l’évolution d’une défaillance viscérale progressive. L’hydroxyurée est aussi parfois proposée dans ces indications, et il n’existe pas d’étude randomisant cette molécule à la transfusion chronique dans ce type d’indications. Les transfusions érythrocytaires peuvent être compliqués d’allo-immunisation dans les pays où les donneurs et les receveurs de sang sont d’origines ethniques différentes. Le risque résiduel de transmettre une infection virale a été très considérablement réduit dans les pays industrialisés. On dispose maintenant d’un nouveau chélateur du fer administrable par voie orale, le déférasirox. Enfin, une large proportion de patients régulièrement transfusés nécessitent l’insertion de chambres implantables, qui représentent un risque infectieux accru chez les malades drépanocytaires. DE MONTALEMBERT M., TSHILOLO L. Is therapeutic progress in the management of sickle cell disease applicable in sub-Saharan Africa ? Méd. Trop., 67 (6), 612-616, 2007 ; (Facteur d'Impact 2006 : X) (Services cités : Pédiatrie Générale) The life expectancy of patients with sickle cell disease has improved in the United States and Europe thanks to the use of penicillin prophylaxis, appropriate immunizations, neonatal screening, implementation of a quality transfusional policy, hydroxyurea therapy, detection and treatment of cerebral vasculopathy, recognition of situations that can benefit from allogenic marrow transplantation, and improvements in bone marrow transplantation techniques. The cost of almost all these techniques is far beyond the means of health care systems in Africa where they cannot be used. However at least three, i.e., penicillin, vaccines, and hydroxyurea, could be easily accessible in the framework of defined therapeutic strategies. If daily penicillin and pneumococcal vaccine Pneumo 23 are required, it would likely be necessary to select a conjugated vaccine other than Prevenar that does not provide protection against all strains present in Africa. Neonatal screening is still a rare procedure in sub-Saharan countries. Periodic transfusion is steadily improving but exchange transfusion programs aimed in particular at preventing neurological complications are still unfeasible. Indications for hydroxyurea therapy in Africa are more common due to the lack of access to chronic transfusion and must be based on consensus decision. Use of bone marrow transplantation, i.e., the only currently available curative treatment, is still possible only in northern hemisphere countries where it is still restricted to children with severe forms and an HLA-compatible family donor. DE MONTALEMBERT M., AGGOUN Y., NIAKATE A., SZEZEPANSKI I., BONNET D.

Endothelial-dependent vasodilation is impaired in children with sickle cell disease. Haematologica, 92 (12), 1709-1710, 2007 ; (Facteur d'Impact 2006 : 5,032) (Services cités : Cardiologie Pédiatrique, Pédiatrie Générale) Impairment of endothelial-dependent vasodilation has been demonstrated in adults with sickle cell anemia (SCA). We enrolled 21 SCA children, mean age 10.4+/-3.3 yrs, and 23 Afro-Caribbean controls. We examined flow-mediated (FMD) and nitroglycerine-mediated (GTNMD) dilation of the brachial artery, using echotracking techniques, and measured intima-media thickness (IMT) and mechanical properties of the common carotid artery. FMD was significantly decreased in SCA children vs controls (5.6+/-0.2 vs 8.0+/-0.2%, p=0.008), while IMT, stiffness of the common carotid artery, and GTNMD were comparable. In conclusion, endothelial dysfunction is present as early as childhood in SCA patients. EDELMAN A., SERMET-GAUDELUS I., ROUSSET J.P. Genetic testing to provide targeted treatment for cystic fibrosis patients. Pharmacogenomics, 8 (9), 1101-1104, 2007 ; (Facteur d'Impact 2006 : 3,603) (Services cités : Pédiatrie Générale, U845 (AE)) GERMANAUD D., HADJ-RABIA S., PARSY C., ABADIE V. Neonatal subcutaneous fat necrosis with hypercalcemia: efficiency of a low dose of corticosteroids. Archives Pédiatrie, 14 (2), 167-169, 2007 ; (Facteur d'Impact 2006 : 0,258) (Services cités : Dermatologie, Pédiatrie Générale) We report the case of a newborn with macrosomia, extensive subcutaneous fat necrosis and symptomatic hypercalcemia. Low doses of prednisone were efficient, while dietary intervention, hyperhydratation and furosemide were not. Treatment of hypercalcemia in this specific neonatal condition are discussed. GERMANAUD D., SERMET-GAUDELUS I. Parvovirus B19: importance of diathesis in the clinical expression of a common infection. Rev. Prat., 57 (10), 1049-1055, 2007 ; (Facteur d'Impact 2006 : X) (Services cités : Pédiatrie Générale) Symptomatic manifestations of parvovirus B19 infection range from harmless conditions such as 5th disease of the child or arthropathy of the middle-aged woman to life threatening disease such as transient aplastic crisis during sickle cell disease, chronic anaemia in immunodeficiency states or hydrops foetalis during pregnancy. Increasing knowledge of parvovirus B19 has led to a better understanding about how a single and unvariant erythrovirus causes such a variety of diseases. The importance of age, hematopoietic and immune status has been raised and besides, effective diagnostic assays, treatments and possibly vaccine have been developed that can be rationally used at the light of this knowledge. HOFMANN M., de MONTALEMBERT M., BEAUQUIER-MACCOTTA B., de VILLARTAY P., GOLSE B.

Posttraumatic stress disorder in children affected by sickle-cell disease and their parents. Amer. J. Hematol., 82 (2), 171-172, 2007 ; (Facteur d'Impact 2006 : 1,882) (Services cités : Pédiatrie Générale, Pédo-Psychiatrie) Children affected with sickle-cell disease experience painful crises that may be life threatening, or felt as if they were. We evaluated by semistructured interviews and questionnaires the presence of posttraumatic stress disorder in 11 children affected by sickle-cell disease and having suffered at least one hospitalization for a painful crisis, and in their parents (10 mothers, 1 father). Three children (27%) and four parents (40%) were diagnosed with the disorder. It was not correlated to the disease severity but, in parents, to a feeling of powerlessness over the child's illness (P = 0.04). Am. J. Hematol., 2006, (c) 2006 Wiley-Liss, Inc. OGIER de BAULNY H., ABADIE V., FEILLET F., de PARSCAU L. Management of Phenylketonuria and Hyperphenylalaninemia. J. Nutr., 137 (6), 1561.S-1563.S, 2007 ; (Facteur d'Impact 2006 : 4,009) (Services cités : Pédiatrie Générale) Hyperphenylalaninemia (HPA) is the most frequently inherited disorder of amino acid metabolism (prevalence 1:10,000). In France, a nationwide neonatal screening was organized in 1978 to control its efficacy and patient follow-up. Phenylketonuria (PKU) was diagnosed in 81.6% of screened patients, the remaining affected with either non-PKU HPA (17.2%) or with cofactor deficiency (1.1%). French guidelines were established to specify the minimal diagnosis procedures and optimal treatment of patients. A low-phenylalanine diet must be started within the first days of life for all newborns whose blood phenylalanine levels are above 10 mg/dL (600 mumol/L). The dietary control must keep the phenylalanine levels between 2 and 5 mg/dL (120 and 300 mumol/L) until 10 y of age. Thereafter, a progressive and controlled relaxation of the diet is allowed, keeping levels below 15 mg/dL until the end of adolescence and below 20 mg/dL (1200 mumol/L) in adulthood. A lifelong follow-up is recommended for PKU women to prevent for maternal PKU. PISSARD S., de MONTALEMBERT M., BACHIR D., MAX-AUDIT I., GOOSSENS M., WAJCMAN H., BADER-MEUNIER B. Pyruvate kinase (PK) deficiency in newborns: the pitfalls of diagnosis. J. Pediat., 150 (4), 443-445, 2007 ; (Facteur d'Impact 2006 : 3,991) (Services cités : Pédiatrie Générale) Pyruvate kinase (PK) deficiency is asymptomatic in heterozygotes, but it can lead in homozygous neonates to a severe neonatal hemolysis, sometimes life-threatening. We report five cases, with a 1- to 17-month delayed diagnosis, highlighting the need to measure PK activity in neonates and parents in case of an hemolysis at birth. REINERT P., BENKERROU M., de MONTALEMBERT M., LESPRIT E., ABADIE I., BERNAUDIN F., DOIT C., BINGEN E., TETELBOUM R., BONNET E. Immunogenicity and Safety of a Pneumococcal Conjugate 7-Valent Vaccine in Infants With Sickle Cell Disease. Pediat. Inf. Dis. J., 26 (12), 1105-1109, 2007 ; (Facteur d'Impact 2006 : 3,215) (Services cités : Pédiatrie Générale)

OBJECTIVES:: To evaluate safety and immunogenicity of the pneumococcal 7-valent conjugate vaccine (PCV7) when administered to infants with sickle cell disease (SCD) at 2, 3, and 4 months of age with a booster dose of a 23-valent pneumococcal polysaccharide vaccine (PS-23) at 15 to 18 months of age. METHODS:: This open-label multicenter study in France enrolled 2-month-old infants with SCD. Blood samples for the determination of antibody concentrations to vaccine serotypes were obtained immediately before and 1 month after the primary immunization, and before and 1 month after the PS-23 booster. Local and systemic reactions were recorded on diary cards. RESULTS:: Of the 51 infants enrolled, 49 received primary immunization and 46 received the booster dose. After primary immunization >/=95% of the subjects had antibody titers >/=0.35 mug/mL for the 7 serotypes. After boosting, geometric mean concentrations were high for all serotypes, ranging from 6.32 mug/mL (serotype 18C) to 29.49 mug/mL (serotype 4). Except for 1 case after administration of the booster dose, all fevers reported were less than 39 degrees C. No vaccine-related serious adverse events were reported. CONCLUSIONS:: PCV7 administered at 2, 3, and 4 months of age in infants with SCD was well-tolerated, highly immunogenic, and primed for immune memory as indicated by the dramatic response to the PS-23 dose administered at 15-18 months in this study. However, the current recommended schedule is to boost with the PCV7 at 12-15 months of age and for these high-risk children, to enlarge the protection with a subsequent PS-23 dose at 2 years of age. ROBERTS I., de MONTALEMBERT M. Sickle cell disease as a paradigm of immigration hematology: new challenges for hematologists in Europe. Haematologica, 92 (7), 865-871, 2007 ; (Facteur d'Impact 2006 : 5,032) (Services cités : Pédiatrie Générale) SAUDUBRAY J.M., RABIER D. Biomarkers identified in inborn errors for lysine, arginine, and ornithine. J. Nutr., 137 (6), 1669.S-1672.S, 2007 ; (Facteur d'Impact 2006 : 4,009) (Services cités : Biochimie Métabolique, Pédiatrie Générale) Inborn errors of lysine, arginine, and ornithine metabolism are very rare: only a few patients affected with these disorders have been carefully investigated, and very few reports on long-term outcome are available. These rare data make it difficult to define safety limits of these amino acids and useful biomarkers from these disorders. Only 4 disorders give rise to an important increase of the plasma amino acid concentration proximal to the metabolic block: lysine in 2-aminoadipic semialdehyde synthase deficiency, arginine in arginase deficiency, ornithine in ornithine amino transferase deficiency, and hyperammonemia hyperornithinemia homocitrullinuria syndrome. There is an obvious discrepancy between the important physiological role of these amino acids in cell metabolism and nutrition and the clinical consequences that are actually observed in these disorders. SEDEL F., BARNERIAS C., DUBOURG O., DESGUERRES I., LYON-CAEN O., SAUDUBRAY J.M. Peripheral neuropathy and inborn errors of metabolism in adults.

J. Inherit. Metab. Dis., 30 (5), 642-653, 2007 ; (Facteur d'Impact 2006 : 1,574) (Services cités : Pédiatrie Générale, Métabolisme) Although they are classically viewed as paediatric diseases, it is now recognized that inborn errors of metabolism (IEMs) can present at any age from childhood to adulthood. IEMs can involve the peripheral nervous system, mostly as part of a more diffuse neurological or systemic clinical picture. However, in some cases, the neuropathy can be the unique initial sign. Here, based on our personal experience and on a comprehensive literature analysis, we review IEMs causing neuropathies in adults. Diseases were classified according to the predominant type of neuropathies into (1) acute neuropathies, (2) mononeuropathy multiplex, (3) chronic axonal polyneuropathies, (4) chronic demyelinating polyneuropathies, (5) small-fibre neuropathies, and (6) lower motor neuron disease. SERMET-GAUDELUS I., GIRODON E., HUET F., ABOUTAAM R., BUI S., DENEUVILLE E., GUILLOT M., VRIELYNCK S., LENOIR G., EDELMAN A. Nasal potential difference in cystic fibrosis diagnosis of very young children. J. Pediat., 150 (3), e34-e35, 2007 ; (Facteur d'Impact 2006 : 3,991) (Services cités : Pédiatrie Générale, U845 (AE)) SERMET-GAUDELUS I., RENOUIL M., FAJAC A., BIDOU L., PARBAILLE B., PIERROT S., DAVY N., BISMUTH E., REINERT P., LENOIR G., LESURE J.F., ROUSSET J.P., EDELMAN A. In vitro prediction of stop-codon supression by by intravenous gentamycin in patients with cystic fibrosis; a pilot study. BMC Med., 5 (1), 5, 2007 ; (Facteur d'Impact 2006 : X) (Services cités : U845 (AE), ORL & Chirurgie Cervico-Faciale, Pédiatrie Générale) ABSTRACT: BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, which acts as a chloride channel activated by cyclic AMP (cAMP). The most frequent mutation found in 70% of CF patients is F508del, while premature stop mutations are found in about 10% of patients. In vitro aminoglycoside antibiotics (e.g. gentamycin) suppress nonsense mutations located in CFTR permitting translation to continue to the normal termination of the transcript. Pharmacologic suppression of stop mutations within the CFTR may be of benefit to a significant number of patients. Our pilot study was conducted to determine whether intravenous gentamycin suppresses stop codons in CF patients and whether it has clinical benefits. METHODS: A dual gene reporter system was used to determine the gentamycin-induced readthrough level of the most frequent stop mutations within the CFTR in the French population. We investigated readthrough efficiency in response to 10 mg/kg once daily intravenous gentamycin perfusions in patients with and without stop mutations. Respiratory function, sweat chloride concentration, nasal potential difference (NPD) and CFTR expression in nasal epithelial cells were measured at baseline and after 15 days of treatment. RESULTS: After in vitro gentamycin incubation, the readthrough efficiency for the Y122X mutation was at least 5 times higher than that for G542X, R1162X, and W1282X. In 6 of the 9 patients with the Y122X mutation, CFTR immunodetection showed protein at the membrane of the nasal epithelial cells and the CFTR-dependent Cl- secretion in NPD measurements increased significantly. Respiratory status also improved in these patients,

irrespective of the gentamycin sensitivity of the bacterias present in the sputum. Mean sweat chloride concentration decreased significantly and normalized in 2 patients. Clinical status, NPD and sweat Cl- values did not change in the Y122X patients with no protein expression, in patients with the other stop mutations investigated in vitro and those without stop mutations. CONCLUSION: Suppression of stop mutations in the CFTR gene with parenteral gentamycin can be predicted in vitro and is associated with clinical benefit and significant modification of the CFTR-mediated Cl- transport in nasal and sweat gland epithelium. Trial registration: ClinicalTrial NCT00376428. SERMET-GAUDELUS I., SOUBERBIELLE J.C., ELADARI D., RUIZ J.C., MALLET E. Pediatric bone health: Starting at the beginning. Pediat. Pulm., 42 (Suppl.30), 187-188, 2007 ; (Facteur d'Impact 2006 : 1,965) (Services cités : Pédiatrie Générale, U845 (AE)) SERMET-GAUDELUS I., SOUBERBIELLE J.C., RUIZ J.C., VRIELYNCK S., HEUILLON B., AZHAR I., CAZENAVE A., LAWSON-BODY E., CHEDEVERGNE F., LENOIR G. Low bone mineral density in young children with cystic fibrosis. Amer. J. Respir. Crit. Care Med., 175 (9), 951-957, 2007 ; (Facteur d'Impact 2006 : 9,091) (Services cités : Pédiatrie Générale, Explorations Fonctionnelles) Rationale: Low bone mineral density (BMD) is a frequent problem for adult patients with cystic fibrosis (CF). Only limited information is available for young patients. Objectives: The aim of this study was to evaluate BMD of children with CF younger than 6 years. Methods: BMD was measured at the lumbar spine (LS) after adjustment for height, sex, and pubertal status in 25 children with CF younger than 6 years, 53 prepubertal children aged 6 to 10 years, and 36 adolescents aged 11 to 18 years. Nutritional status, body composition, pulmonary disease severity, corticosteroid usage, dietary calcium, caloric intake, and vitamin D status were evaluated as potential correlates of BMD. Measurements and Main Results: The mean LS z score in the youngest group was significantly lower than normal (-0.96; SEM, 0.3). It did not differ significantly from that of children aged 6 to 10 years (-0.91; SEM, 0.2) or adolescents (-1.4; SEM, 0.2). LS z score was positively correlated with fat-free mass in multiple regression analysis. LS z score was less than -1 in 34% of the patients with mild pulmonary disease and normal nutritional status. Conclusions: These data suggest that the origin of CF bone disease in early childhood may be independent of nutritional status or disease severity. VRIELYNCK S., ROQUES C., SERMET I., EMOND S., LENOIR G. Cervical tumefaction in a teenager with cystic fibrosis. Archives Pédiatrie, 14 (10), 1210-1212, 2007 ; (Facteur d'Impact 2006 : 0,258) (Services cités : Pédiatrie Générale, Radiologie Pédiatrique) Lobular emphysema and soft-tissue emphysema can exceptionally complicate malnutrition. We report the case of a teenager presenting malnutrition with cystic fibrosis and anorexia nervosa with soft-tissue emphysema.

2006 BAGHDADLI A., BEUZON S., BURSZTEJN C., CONSTANT J., DESGUERRE I., ROGE B., SQUILLANTE M., VOISIN J., AUSSILLOUX C. Clinical guidelines for the screening and the diagnosis of autism and pervasive developmental disorders. Archives Pédiatrie, 13 (4), 373-378, 2006 (Services cités : Département de Pédiatrie) Autism is the best defined category among PDD. Its high prevalence, its onset in very young children and its persistence in adulthood arise many questions about early screening and early diagnosis. The aim of the study was to identify professional best practices about screening and diagnosis of autism in order to propose clinical guidelines and actions for the future. Scientific experts and parents take part to this procedure. Literature and previous guidelines were analyzed, experts in various fields were interviewed, a national study about the medical practices of the diagnosis of autism was made and questionnaires were send to 1600 psychiatrists and pediatricians. Guidelines built around 2 levels were proposed about screening and diagnosis. CONCLUSION: Diagnosis needs a multidisciplinary approach, validated instruments and more communication between professionals and parents. Finally one of the more important aims of the diagnosis of autism is to facilitate intervention program. BARNERIAS C., GIURGEA I., HERTZ-PANNIER L., BAHI-BUISSON N., BODDAERT N., RUSTIN P., ROTIG A., DESGUERRE I., MUNNICH A., de LONLAY P. Respiratory chain deficiency in a female with Aicardi-Goutieres syndrome. Dev. Med. Child Neurol., 48 (3), 227-230, 2006 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique, Radiologie Pédiatrique, U781) Aicardi-Goutieres syndrome (AGS) is an early-onset progressive encephalopathy characterized by calcifications of the basal ganglia, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis, and/or a raised level of CSF interferon (INF)-alpha. We report a female with mitochondrial respiratory chain deficiency fulfilling the criteria of AGS. Disease onset was in the first year of age with seizures and psychomotor regression. To date, at 4 years of age, she presents a severe encephalopathy, increased INF-alpha in the CSF, and calcifications of basal ganglia on computerized tomography. Cerebral magnetic resonance imaging showed bilateral and symmetric hypersignal of the posterior white matter. A complex I deficiency of the mitochondrial respiratory chain was found in skeletal muscle, which was associated with a complex IV deficiency in cultured skin fibroblasts. The question of whether this oxidative phosphorylation deficiency is primary or secondary in AGS is open to debate. We suggest giving consideration to systematic evaluation of the mitochondrial respiratory chain in skeletal muscle and skin fibroblasts of other AGS patients. BERGWITZ C., ROSLIN N.M., TIEDER M., LOREDO-OSTI J.C., BASTEPE M., ABU-ZAHRA H., FRAPPIER D., BURKETT K., CARPENTER T.O., ANDERSON D., GARABEDIAN M., SERMET I., FUJIWARA T.M., MORGAN K., TENENHOUSE H.S.,

JUPPNER H. SLC34A3 Mutations in Patients with Hereditary Hypophosphatemic Rickets with Hypercalciuria Predict a Key Role for the Sodium-Phosphate Cotransporter NaPi-IIc in Maintaining Phosphate Homeostasis. Amer. J. Hum. Genet., 78 (2), 179-192, 2006 (Services cités : Département de Pédiatrie) Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare disorder of autosomal recessive inheritance that was first described in a large consanguineous Bedouin kindred. HHRH is characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histological evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption. We performed a genomewide linkage scan combined with homozygosity mapping, using genomic DNA from a large consanguineous Bedouin kindred that included 10 patients who received the diagnosis of HHRH. The disease mapped to a 1.6-Mbp region on chromosome 9q34, which contains SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaP(i)-IIc. Nucleotide sequence analysis revealed a homozygous single-nucleotide deletion (c.228delC) in this candidate gene in all individuals affected by HHRH. This mutation is predicted to truncate the NaP(i)-IIc protein in the first membrane-spanning domain and thus likely results in a complete loss of function of this protein in individuals homozygous for c.228delC. In addition, compound heterozygous missense and deletion mutations were found in three additional unrelated HHRH kindreds, which supports the conclusion that this disease is caused by SLC34A3 mutations affecting both alleles. Individuals of the investigated kindreds who were heterozygous for a SLC34A3 mutation frequently showed hypercalciuria, often in association with mild hypophosphatemia and/or elevations in 1,25-dihydroxyvitamin D levels. We conclude that NaP(i)-IIc has a key role in the regulation of phosphate homeostasis. BUSEYNE F., SCOTT-ALGARA D., CORRE B., PORROT F., MONCHATRE E., BELLAL N., BURGARD M., ROUZIOUX C., BLANCHE S., RIVIERE Y. Poor recognition of HIV-1 Nef protein by CD8 T cells from HIV-1-infected children: impact of age. Virology, 354 (2), 271-279, 2006 (Services cités : Département de Pédiatrie, Laboratoire de Microbiologie) Recognition of various HIV proteins by CD8 T cells from HIV-infected children was determined by two functional assays. First, using an Elispot assay, we show that 80% of patients recognized Gag, 77% recognized Pol, 61% recognized Env, 44% recognized Nef and 29% recognized Vif. Frequencies of Gag-, Pol-, and Env-specific IFN-gamma producing CD8 T cells were higher than frequencies of Nef and Vif-specific CD8 T cells. The poor recognition of Nef by ex vivo CD8 T cells was confirmed by CTL assays performed in HAART naive children: 25% of children had positive response against Nef versus 44, 63 and 62% for Env, Gag, and Pol, respectively. Memory Gag-specific CTL were positively correlated with age, whereas Nef-specific CTL were negatively correlated with age. The poor Nef-specific CD8 T cell response in HIV-infected children contrasts with dominance of Nef-specific responses in infected adults. CHALOUHI C., BARNERIAS C., ABADIE V. Afebrile seizures in gastroenteritis: a japanese peculiarity. Archives Pédiatrie, 13 (3), 266-268, 2006

(Services cités : Métabolisme-Neurologie, Pédiatrie Générale) Febrile seizures appearing during acute gastroenteritis have been described in japanese populations. These convulsions are not related to clinical signs of dehydration or electrolyte disorder. This entity was called CwG, benign Convulsions with mild Gastroenteritis. We report the case of a 19 month-old japanese boy who presented with a CwG. We described the characteristic clinical features of this entity and we reviewed the cases reported in literature. The evolution of the CwG is always simple without relapse or side effects. Better understanding will help pediatricians make more accurate diagnosis and avoid treatment even though initial signs might be severe. DE LONLAY P., SIMON-CARRE A., RIBEIRO M.J., BODDAERT N., GIURGEA I., LABORDE K., BELLANNE-CHANTELOT C., VERKARRE V., POLAK M., RAHIER J., SYROTA A., SEIDENWURM D., NIHOUL-FEKETE C., ROBERT J.J., BRUNELLE F., JAUBERT F. Congenital Hyperinsulinism: Pancreatic [18F]Fluoro-L-Dihydroxyphenylalanine (DOPA) Positron Emission Tomography and Immunohistochemistry Study of DOPA Decarboxylase and Insulin Secretion. J. Clin. Endocrinol. Metabol., 91 (3), 933-940, 2006 (Services cités : Anatomo-Pathologie, Chirurgie Pédiatrique, Département de Pédiatrie, Explorations Fonctionnelles, Radiologie Pédiatrique) Context: Congenital hyperinsulinism (HI) is characterized by hypoglycemia related to inappropriate insulin secretion. Focal and diffuse forms of hyperinsulinism share a similar clinical presentation, but their treatment is dramatically different. Preoperative differential diagnosis was based on pancreatic venous sampling, a technically demanding technique. Objective: Positron emission tomography (PET) after injection of [(18)F]fluoro-l-DOPA (l-dihydroxyphenylalanine) has been evaluated for the preoperative differentiation between focal and diffuse HI, by imaging uptake of radiotracer and the conversion of [(18)F]fluoro-l-DOPA into dopamine by DOPA decarboxylase. We propose to validate this test by immunohistochemical approach. Patients and Methods: Pancreatic surgical specimens of four focal and three diffuse HI were studied, using anti-DOPA decarboxylase and proinsulin antibodies. The effect of an inhibitor of DOPA decarboxylase (carbidopa) on insulin secretion was evaluated in vivo and in cultured INS-1 cells. Results: Immunohistochemical detection of DOPA decarboxylase showed diffuse staining of Langerhans islets in the whole pancreas in all diffuse cases, in contrast with dense focal staining in all focal cases. Staining of Langerhans islets outside the focal lesion was diffusely but weakly positive. We correlated the localization of DOPA decarboxylase and proinsulin in normal pancreas and in both diffuse and focal HI tissues. The diffuse PET uptake found before treatment in one child with diffuse HI disappeared completely after carbidopa administration, suggesting in vivo that pancreatic cells can take up amine precursors and contain DOPA decarboxylase. The insulin secretion measured in the supernatant was the same whether INS-1 cells were treated by dopamine or Lodosyn or untreated. Conclusion: We validate PET with as a consistent test to differentiate diffuse and focal HI. DE MONTALEMBERT M., GIROT R., GALACTEROS F. Sickle cell disease in France in 2006: results and challenges. Archives Pédiatrie, 13 (9), 1191-1194, 2006 (Services cités : Pédiatrie Générale) Sickle cell disease is currently recognized as the most frequent genetic disease screened in the

neonatal period in France, and begins to be funded by Public Health Authorities. Despite these issues, SCD is still largely unknown, in particular by general public and practitioners, and education about the disease has to be intensified. Respective roles of proximate and reference centres have to be better defined. Screening of heterozygous patients remains to be organized. Limits of definition of a severe form, and therapeutic options need to be debated. DE MONTALEMBERT M., BROUSSE V., ELIE C., BERNAUDIN F., SHI J., LANDAIS P. Long-term hydroxyurea treatment in children with sickle cell disease: tolerance and clinical outcomes. Haematologica, 91 (1), 125-128, 2006 (Services cités : Biostatistique, Pédiatrie Générale) Two hundred twenty-five SCD children have been enrolled in a study assessing the tolerability of hydroxyurea treatment. Mean age at inclusion was 9.2+/-4.4 years, median duration of treatment was 3.8 years. Ten and 75 patients have been treated respectively for more than 10 and 5 years. No severe side effect was related to hydroxyurea treatment, which was discontinued in 81 children mainly for treatment failure (30 cases) or non-compliance (17 cases). Treatment was also withdrawn in 5 of 6 children who had developed hypersplenism, in 3 because of a pathological transcranial Doppler, and in 2 after a stroke. DE MONTALEMBERT M., BACHIR D., HULIN A., GIMENO L., MOGENET A., BRESSON J.L., MACQUIN-MAVIER I., ROUDOT-THORAVAL F., ASTIER A., GALACTEROS F. Pharmacokinetics of hydroxyurea 1,000 mg coated breakable tablets and 500 mg capsules in pediatric and adult patients with sickle cell disease. Haematologica, 91 (12), 1685-1688, 2006 (Services cités : CIC 9303, Pédiatrie Générale) Little is known about the pharmacokinetics of hydroxyurea in patients with sickle cell disease (SCD). Our aims were to evaluate bioequivalence between standard hydroxyurea capsules and a new formulation of 1,000 mg coated breakable tablets in adults and to compare pharmacokinetic parameters in adults and children with SCD. Fifteen adults received hydroxyurea capsules and tablets in a randomized cross-over study. Eleven children received hydroxyurea tablets. The results showed bioequivalence between capsules and tablets in adults. Pharmacokinetic parameters were not significantly different between adults and children. Considerable inter-individual variability was noted. DELNATTE C., SANLAVILLE D., MOUGENOT J.F., VERMEESCH J.R., HOUDAYER C., BLOIS M.C., GENEVIEVE D., GOULET O., FRYNS J.P., JAUBERT F., VEKEMANS M., LYONNET S., ROMANA S., ENG C., STOPPA-LYONNET D. Contiguous Gene Deletion within Chromosome Arm 10q Is Associated with Juvenile Polyposis of Infancy, Reflecting Cooperation between the BMPR1A and PTEN Tumor-Suppressor Genes. Amer. J. Hum. Genet., 78 (6), 1066-1074, 2006 (Services cités : Anatomo-Pathologie, Département de Pédiatrie, E 0210, Génétique Médicale Pédiatrique) We describe four unrelated children who were referred to two tertiary referral medical genetics units between 1991 and 2005 and who are affected with juvenile polyposis of infancy. We show that these children are heterozygous for a germline deletion encompassing two contiguous genes,

PTEN and BMPR1A. We hypothesize that juvenile polyposis of infancy is caused by the deletion of these two genes and that the severity of the disease reflects cooperation between these two tumor-suppressor genes. DELNATTE C., SANLAVILLE D., MOUGENOT J.F., STOPPA-LYONNET D. Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes. M S-Méd. Sci., 22 (11), 912-913, 2006 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique) FERRONI A., VU-THIEN H., LANOTTE P., LE BOURGEOIS M., SERMET-GAUDELUS I., FAUROUX B., MARCHAND S., VARAIGNE F., BERCHE P., GAILLARD J.L., OFFREDO C. Value of the chlorhexidine decontamination method for recovery of nontuberculous mycobacteria from sputum samples of patients with cystic fibrosis. J. Clin. Microbiol., 44 (6), 2237-2239, 2006 (Services cités : Département de Pédiatrie, Laboratoire de Microbiologie, Pneumologie-Allergologie Pédiatrique) The chlorhexidine method was compared to the N-acetyl-l-cysteine-NaOH-oxalic acid decontamination method currently recommended for the recovery of nontuberculous mycobacteria (NTM) from patients with cystic fibrosis. Sputum samples (n = 827) treated with chlorhexidine yielded twice as many NTM-positive cultures as those treated by the reference method (54 [6.50%] versus 27 [3.25%]; P < 0.0001) despite a higher contamination rate (20% versus 14.2%; P = 0.0017). GIURGEA I., BELLANNE-CHANTELOT C., RIBEIRO M., HUBERT L., SEMPOUX C., ROBERT J.J., BLANKENSTEIN O., HUSSAIN K., BRUNELLE F., NIHOUL-FEKETE C., RAHIER J., JAUBERT F., de LONLAY P. Molecular Mechanisms of Neonatal Hyperinsulinism. Horm. Res., 66 (6), 289-296, 2006 (Services cités : Anatomo-Pathologie, Chirurgie Pédiatrique, Département de Pédiatrie, Radiologie Pédiatrique) Congenital hyperinsulinism (CHI), characterized by profound hypoglycaemia related to inappropriate insulin secretion, may be associated histologically with either diffuse insulin hypersecretion or focal adenomatous hyperplasia, which share a similar clinical presentation, but result from different molecular mechanisms. Whereas diffuse CHI is of autosomal recessive, or less frequently of autosomal dominant, inheritance, focal CHI is sporadic. The most common mechanism underlying CHI is dysfunction of the pancreatic ATP-sensitive potassium channel (K(+)(ATP)). The two subunits of the K(+)(ATP) channel are encoded by the sulfonylurea receptor gene (SUR1 or ABCC8) and the inward-rectifying potassium channel gene (KIR6.2 or KCNJ11), both located in the 11p15.1 region. Germ-line, paternally inherited, mutations of the SUR1 or KIR6.2 genes, together with somatic maternal haplo-insufficiency for 11p15.5, were shown to result in focal CHI. Diffuse CHI results from germ-line mutations in the SUR1 or KIR6.2 genes, but also from mutations in several other genes, namely glutamate dehydrogenase (with associated hyperammonaemia), glucokinase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and insulin receptor gene. Hyperinsulinaemic hypoglycaemia may be observed in several overlapping syndromes, such as Beckwith-Wiedemann syndrome (BWS), Perlman

syndrome, and, more rarely, Sotos syndrome. Mosaic genome-wide paternal isodisomy has recently been reported in patients with clinical signs of BWS and CHI. The primary causes of CHI are genetically heterogeneous and have not yet been completely unveiled. However, secondary causes of hyperinsulinism have to be considered such as fatty acid oxidation deficiency, congenital disorders of glycosylation and factitious hypoglycaemia secondary to Munchausen by proxy syndrome. Copyright (c) 2006 S. Karger AG, Basel. GIURGEA I., SEMPOUX C., BELLANNE-CHANTELOT C., RIBEIRO M., HUBERT L., BODDAERT N., SAUDUBRAY J.M., ROBERT J.J., BRUNELLE F., RAHIER J., JAUBERT F., NIHOUL-FEKETE C., de LONLAY P. The Knudson's Two-Hit Model and Timing of Somatic Mutation May Account for the Phenotypic Diversity of Focal Congenital Hyperinsulinism. J. Clin. Endocrinol. Metabol., 91 (10), 4118-4123, 2006 (Services cités : Chirurgie Pédiatrique, Département de Pédiatrie, Radiologie Pédiatrique) Background: Congenital hyperinsulinism (CHI) is associated with focal hyperplasia of endocrine tissue in 40-65% of patients. Focal CHI is sporadic and is caused by a germline, paternally inherited, mutation of the SUR1 (ABCC8) or KIR6.2 (KCNJ11) genes (encoding subunits of the pancreatic ATP-dependent potassium channel) together with somatic maternal haploinsufficiency for 11p15.5. Plurifocal or large forms of focal CHI are a cause of apparent failure of surgery, and their underlying mechanism has not been thoroughly investigated. Patients: We here report two patients with bifocal CHI as evidenced by relapsing hypoglycemia after removal of the first focal lesion and the detection of a second, distinct, focal adenomatous hyperplasia during later surgery (patients 1 and 2) and a patient with a giant focal lesion involving the major part of the pancreas (patient 3). Results: In the three patients, a germline, paternally inherited, mutation of SUR1 was found. In patients 1 and 2, haploinsufficiency for the maternal 11p15.5 region resulted from a somatic deletion specific for each of the focal lesions, as shown by the diversity of deletion break points. In patient 3, an identical somatic maternal 11p15 deletion demonstrated by similar break points was shown in two independent lesion samples, suggesting a very early event during pancreas embryogenesis. Conclusion: Individual patients with focal hyperinsulinism may have more than one focal pancreatic lesion due to separate somatic maternal deletion of the 11p15 region. These patients and those with solitary focal lesions may follow the two-hit model described by Knudson. The stage of embryogenesis at which the somatic event occurs may account for the observed histological diversity (early event giant lesion, later event small lesion). GIURGEA I., SANLAVILLE D., FOURNET J.C., SEMPOUX C., BELLANNE-CHANTELOT C., TOUATI G., HUBERT L., GROOS M.S., BRUNELLE F., RAHIER J., HENQUIN J.C., DUNNE M.J., JAUBERT F., ROBERT J.J., NIHOUL-FEKETE C., VEKEMANS M., JUNIEN C., de LONLAY P. Congenital hyperinsulinism and mosaic abnormalities of the ploidy. J. Med. Genet., 43 (3), 248-254, 2006 (Services cités : Anatomo-Pathologie, Chirurgie Pédiatrique, Département de Pédiatrie, Génétique Médicale Pédiatrique, Radiologie Pédiatrique, U781) BACKGROUND: Congenital hyperinsulinism and Beckwith-Wiedemann syndrome both lead to beta islet hyperplasia and neonatal hypoglycaemia. They may be related to complex genetic/epigenetic abnormalities of the imprinted 11p15 region. The possibility of common pathophysiological determinants has not been thoroughly investigated. OBJECTIVE: To report abnormalities of the ploidy in two unrelated patients with congenital hyperinsulinism.

METHODS: Two patients with severe congenital hyperinsulinism, one overlapping with Beckwith-Wiedemann syndrome, had pancreatic histology, ex vivo potassium channel electrophysiological studies, and mutation detection of the encoding genes. The parental genetic contribution was explored using genome-wide polymorphism, fluorescent in situ hybridisation (FISH), and blood group typing studies. RESULTS: Histological findings diverged from those described in focal congenital hyperinsulinism or Beckwith-Wiedemann syndrome. No potassium channel dysfunction and no mutation of its encoding genes (SUR1, KIR6.2) were detected. In patient 1 with congenital hyperinsulinism and Beckwith-Wiedemann syndrome, paternal isodisomy for the whole haploid set was homogeneous in the pancreatic lesion, and mosaic in the leucocytes and skin fibroblasts (hemihypertrophic segment). Blood group typing confirmed the presence of two erythroid populations (bi-parental v paternal only contribution). Patient 2 had two pancreatic lesions, both revealing triploidy with paternal heterodisomy. Karyotype and FISH analyses done on the fibroblasts and leucocytes of both patients were unremarkable (diploidy). CONCLUSIONS: Diploid (biparental/paternal-only) mosaicism and diploid/triploid mosaicism were present in two distinct patients with congenital hyperinsulinism. These chromosomal abnormalities led to paternal disomy for the whole haploid set in pancreatic lesions (with isodisomy or heterodisomy), thereby extending the range and complexity of the mechanisms underlying congenital hyperinsulinism, associated or not with Beckwith-Wiedemann syndrome. GLOYN A.L., DIATLOFF-ZITO C., EDGHILL E.L., BELLANNE-CHANTELOT C., NIVOT S., COUTANT R., ELLARD S., HATTERSLEY A.T., ROBERT J.J. KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. Eur. J. Human Genet., 14 (7), 824-830, 2006 (Services cités : Département de Pédiatrie) Heterozygous activating mutations in the gene encoding for the ATP-sensitive potassium channel subunit Kir6.2 (KCNJ11) have recently been shown to be a common cause of permanent neonatal diabetes. Kir6.2 is expressed in muscle, neuron and brain as well as the pancreatic beta-cell, so patients with KCNJ11 mutations could have a neurological phenotype in addition to their diabetes. It is proposed that some patients with KCNJ11 mutations have neurological features that are part of a discrete neurological syndrome termed developmental Delay, Epilepsy and Neonatal Diabetes (DEND), but there are also neurological consequences of chronic or acute diabetes. We identified KCNJ11 mutations in four of 10 probands with permanent neonatal diabetes and one affected parent; this included the novel C166F mutation and the previously described V59M and R201H. Four of the five patients with mutations had neurological features: the patient with the C166F mutation had marked developmental delay, severe generalised epilepsy, hypotonia and muscle weakness; mild developmental delay was present in the patient with the V59M mutation; one patient with the R201H mutation had acute and chronic neurological consequences of cerebral oedema and another had diabetic neuropathy from chronic hyperglycaemia. In conclusion, the clinical features in these patients support the existence of a discrete neurological syndrome with KCNJ11 mutations. The severe DEND syndrome was seen with the novel C166F mutation and mild developmental delay with the V59M mutation. These features differ markedly from the neurological consequences of acute or chronic diabetes.European Journal of Human Genetics (2006) 14, 824-830. doi:10.1038/sj.ejhg.5201629; published online 3 May 2006. HERTZ-PANNIER L., DECHAUX M., SINICO M., EMOND S., CORMIER-DAIRE V.,

SAUDUBRAY J.M., BRUNELLE F., NIAUDET P., SETA N., de LONLAY P. Congenital disorders of glycosylation type I: a rare but new cause of hyperechoic kidneys in infants and children due to early microcystic changes. Pediat. Radiol., 36 (2), 108-114, 2006 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique, Radiologie Pédiatrique, Explorations Fonctionnelles) BACKGROUND: There are numerous causes of bilateral hyperechoic kidneys. Congenital disorders of glycosylation (CDGs) are a rapidly growing family of inherited disorders due to defects in the synthesis of the glycans of glycoproteins or other glycoconjugates. OBJECTIVE: To describe renal sonographic abnormalities in CDG type I in infants and children. MATERIAL AND METHODS: A retrospective study of renal US in 12 infants and children: 8 CDG-Ia (6 multivisceral forms, 2 neurological forms), 2 CDG-Ib, and 2 CDG-Ix, with detailed functional renal tests in 6. Histology of the kidneys of one 35-week fetus with CDG-Ia was available. RESULTS: Renal US was normal in the two children with the neurological form of CDG-Ia. All patients with the multivisceral form of CDG-Ia or with CDG-Ib showed increased cortical echogenicity, and/or abnormal pyramids (small +/- hyperechoic). The two patients with CDG-Ix showed predominant involvement of the medulla, with inverted corticomedullary differentiation in one. Kidney size was normal in all but two patients. The fetal kidneys exhibited diffuse microcysts arising from the distal tubules. CONCLUSIONS: Hyperechoic kidneys are common in CDG-I patients, contrasting with grossly preserved renal function. The US pattern seems to differ slightly according to the type of CDG-I, and is consistent with microcystic changes of the renal parenchyma, which occur prenatally, and may be due to ciliary dysfunction secondary to altered glycosylation of tubular glycoproteins. CDG-I, which remains largely underdiagnosed at present, should be added to the causes of hyperechoic kidneys in children, especially in cases of multivisceral involvement, after ruling out other more frequent causes. JINNAH H.A., VISSER J.E., HARRIS J.C., VERDU A., LAROVERE L., CEBALLOS-PICOT I., GONZALEZ-ALEGRE P., NEYCHEV V., TORRES R.J., DULAC O., DESGUERRE I., SCHRETLEN D.J., ROBEY K.L., BARABAS G., BLOEM B.R., NYHAN W., de KREMER R., EDDEY G.E., PUIG J.G., REICH S.G. Delineation of the motor disorder of Lesch-Nyhan disease. Brain, 129 (Pt 5), 1201-1217, 2006 (Services cités : Biochimie Médicale, Département de Pédiatrie, Métabolisme-Neurologie) Lesch-Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study includes the results of a multi-centre international prospective study of the motor disorder in the largest cohort of patients studied to date. A total of 44 patients ranging from 2 to 38 years presented a characteristic motor syndrome that involved severe action dystonia superimposed on baseline hypotonia. Although some patients also displayed other extrapyramidal or pyramidal signs, these were always less prominent than dystonia. These results are compared with a comprehensive review of 122 prior reports that included a total of 254 patients. Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia.

JUGIE M., CANIONI D., LE BIHAN C., SARNACKI S., REVILLON Y., JAN D., LACAILLE F., CERF-BENSUSSAN N., GOULET O., BROUSSE N., DAMOTTE D. Study of the Impact of Liver Transplantation on the Outcome of Intestinal Grafts in Children. Transplantation, 81 (7), 992-997, 2006 (Services cités : Anatomo-Pathologie, Département de Pédiatrie, U793, Biostatistique, Chirurgie Pédiatrique, Gastroentérologie Pédiatrique, U580) BACKGROUND.: Successful small bowel transplantation remains a challenge due to the septic and immune content of the gut. The possible beneficial role of the liver was assessed in pediatric recipients of isolated intestinal and liver intestinal combined transplantation, receiving the same immunosuppressive therapy. METHODS.: Fifteen children who underwent small bowel transplantation (seven SbTx) or combined liver-small bowel transplantation (eight LSbTx) at a single center between 1994 and 1998 were retrospectively reviewed and compared with fifteen controls (eight normal and seven appendicitis as inflammatory control). Transplant and patient survival, acute rejection episodes were analyzed and compared. Epithelial apoptotic body counts (ABC) and NF-kB (p65), Caspase-3 and Bax intestinal immunostaining from days 0 to 20 after transplantation were assessed. RESULTS.: Graft and patient survivals at 5 years were respectively 75% and 75% in LSbTx; 43% and 57% in SbTx (NS). Histological analysis showed higher ABC in LSbTx intestinal mucosa (P=0.05 on day 5, P<0.01 thereafter). Immunostaining of biopsies on day 0 after reperfusion showed different expression of NF-kB, Caspase-3 and Bax on endothelial (P<0.05 for NF-kB and Bax), mononuclear (P<0.05 for Bax) and epithelial cells in LSbTx and SbTx. CONCLUSIONS.: Our results suggest a protective role of the liver toward intestinal transplantation even in absence of significative difference, probably due to the small number of children. Early changes in NF-kB immunostaining in the biopsies sampled on day 0, pointed to a possible beneficial effect of the liver in the very early phase following transplantation, perhaps through the differential control of ischemia-reperfusion. KA A.S., BROUSSE V., DIAKHATE I., SERMET-GAUDELUS I., LENOIR G., IMBERT P. Tuberculous cold abscess of the chest wall in children: a report of 3 cases. Archives Pédiatrie, 13 (9), 1265-1266., 2006 (Services cités : Pédiatrie Générale) MITANCHEZ D., WALTER-NICOLET E., SALOMON R., BAVOUX F., HUBERT P. Congenital chylothorax: what is the best strategy ? Arch. Dis. Child. Fetal Neonat. Ed., 91 (2), F153-F154, 2006 (Services cités : Réanimation Pédiatrique - Néonatalogie, Département de Pédiatrie) MOHNIKE K., BLANKENSTEIN O., CHRISTESEN H.T., de LONLAY J., HUSSAIN K., KOOPMANS K.P., MINN H., MOHNIKE W., MUTAIR A., OTONKOSKI T., RAHIER J., RIBEIRO M., SCHOENLE E., FEKETE C.N. Proposal for a standardized protocol for 18F-DOPA-PET (PET/CT) in congenital hyperinsulinism. Horm. Res., 66 (1), 40-42, 2006 (Services cités : Chirurgie Pédiatrique, Département de Pédiatrie) REYNOLDS W.F., SERMET-GAUDELUS I., GAUSSON V., FEUILLET M.N.,

BONNEFONT J.P., LENOIR G., DESCAMPS-LATSCHA B., WITKO-SARSAT V. Myeloperoxidase promoter polymorphism -463G is associated with more severe clinical expression of cystic fibrosis pulmonary disease. Mediat. Inflamm., . (7), 36735, 2006 (Services cités : Biochimie Médicale, Pédiatrie Générale, U507) The severity of cystic fibrosis (CF) pulmonary disease is not directly related to CFTR genotype but depends upon several parameters, including neutrophil-dominated inflammation. Identification of agents modulating inflammation constitutes a relevant goal. Myeloperoxidase (MPO) is involved in both microbicidal and proinflammatory neutrophil activities. The aim of this study was to evaluate whether the -463GA MPO promoter polymorphism is linked to clinical severity of CF-associated pulmonary inflammation. This polymorphism significantly affects the level of MPO gene expression in leukocytes and the G allele is more expressing than the A allele. We show that MPO genotype significantly influences the severity of pulmonary disease in early stages, prior to the development of chronic lung infections, with GG genotype being associated with more severe CF disease. Our findings indicate that the level of MPO gene expression influences the CF pathogenesis, presumably reflecting cellular damage by MPO-generated oxidants or other activity of MPO in airway inflammation. SERMET-GAUDELUS I., ROUSSEL D., BUI S., DENEUVILLE E., HUET F., REIX P., BELLON G., LENOIR G., EDELMAN A. The CF-CIRC study: a French collaborative study to assess the accuracy of Cystic Fibrosis diagnosis in neonatal screening. BMC Ped., 6 25, 2006 (Services cités : Pédiatrie Générale, U806) BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR) protein, which acts as a chloride channel after activation by cyclic AMP (cAMP). Newborn screening programs for CF usually consist of an immunoreactive trypsinogen (IRT) assay, followed when IRT is elevated by testing for a panel of CF-causing mutations. Some children, however, may have persistent hypertrypsinogenemia, only one or no identified CFTR gene mutation, and sweat chloride concentrations close to normal values. In vivo demonstration of abnormal CFTR protein function would be an important diagnostic aid in this situation. Measurements of transepithelial nasal potential differences (NPD) in adults accurately characterize CFTR-related ion transport. The aim of the present study is to establish reference values for NPD measurements for healthy children and those with CF aged 3 months to 3 years, the age range of most difficult-to-diagnose patients with suspected CF. The ultimate goal of our study is to validate NPD testing as a diagnostic tool for children with borderline results in neonatal screening. METHODS/DESIGN: We adapted the standard NPD protocol for young children, designed a special catheter for them, used a slower perfusion rate, and shortened the protocol to include only measurement of basal PD, transepithelial sodium (Na+) transport in response to the Na+ channel inhibitor amiloride, and CFTR-mediated chloride (Cl-) secretion in response to isoproterenol, a beta-agonist in a Cl- free solution. The study will include 20 children with CF and 20 healthy control children. CF children will be included only if they carry 2 CF-causing mutations in the CFTR gene or have sweat chloride concentrations > 60 mEq/L or both. The healthy children will be recruited among the siblings of the CF patients, after verification that they do not carry the familial mutation. DISCUSSION: A preliminary study of 3 adult control subjects and 4 children older than 12 years with CF verified that the new protocol was well tolerated and produced NPD measurements that did not differ significantly from those

obtained with the standard protocol. This preliminary study will provide a basis for interpreting NPD measurements in patients with suspected CF after neonatal screening. Earlier definitive diagnosis should alleviate parental distress and allow earlier therapeutic intervention and genetic counseling. VUILLAUMIER-BARROT S., LE BIZEC C., de LONLAY P., MADINIER-CHAPPAT N., BARNIER A., DUPRE T., DURAND G., SETA N. PMM2 intronic branch-site mutations in CDG-Ia. Mol. Genet. Metab., 87 (4), 337-340, 2006 (Services cités : Département de Pédiatrie) Congenital Disorders of Glycosylation (CDG, OMIM#212065)-Ia is an autosomal recessive disorder, characterized by central nervous system dysfunction and multiorgan failure associated with mutations in the PMM2 gene. We report two patients who are compound heterozygotes with respect to two new intronic mutations that affect a highly conserved adenosine in a consensus branch-site sequence. The mutations, one in intron 7: c.340 -23A > G (IVS7 -23A > G) and the other in intron 2: c.179 -25A > G (IVS2 -25A > G), are associated with the c.422G > A (R141H) and c.193 G > T (D65Y) mutations, respectively. The c.179 -25A > G and the c.340 -23A > G changes cause exon 3 and exon 8 to be lost at the RNA level, respectively. This kind of mutation can cause a problem in molecular diagnosis of CDG-Ia if intronic primers are not correctly chosen, and if molecular diagnosis is not performed at both the DNA and mRNA levels. WEIL-OLIVIER C., ANGOULVANT F., CHEVALLIER B., de MONTALEMBERT M., GAUDELUS J., QUINET B., LABRUNE P., DUCLOS A., DUNAIS B., MAITRE M. Influenza vaccination coverage rate in children with underlying chronic disorders in 7 French paediatric wards. Archives Pédiatrie, 13 (10), 1287-1293, 2006 (Services cités : Département de Pédiatrie) In France, annual influenza vaccination is recommended and free of charge for children with chronic disease (chronic lung, heart or kidney disease, diabetes, haemoglobinopathy, immune deficiency). The national goal is to reach 75% influenza vaccination coverage by 2008, but data on coverage in high risk children are limited. OBJECTIVES: To estimate the influenza vaccination coverage in children with an underlying chronic health condition in the Paris region, during in- or out-patient visit at hospital. METHODS: A multicentre cross-sectional descriptive study was carried out over 2 months before the 2004-2005 flu vaccination campaign in 7 French paediatric hospitals (Paris region). Inclusion criteria for this survey were: children aged 6 months to 18 years, with an underlying chronic disease requiring annual influenza vaccination, with a vaccination card available, so as to check their vaccination status. Reasons for non vaccination were recorded. RESULTS: Data from 239 children were analysed. 56% of patients were males (mean age: 8.1 years). Two patients had 2 separate underlying chronic disorders; 69% had a haemoglobinopathy, 16.3% had a chronic respiratory disease, and 7.5% had diabetes. The influenza vaccination rate for 2003-2004 was 43.7% (haemoglobinopathy: 55.5%; chronic respiratory diseases: 12.8%). This rate increased from 20.4% to 43.7% between 1999 and 2003. Less than 16% of parents remembered having received a voucher for free vaccination from the National Health Insurance Agency. CONCLUSION: Efforts are still needed to achieve the 2008 objectives of 75% coverage. 2005

ABADIE V., BERTHELOT J., FEILLET F., MAURIN N., MERCIER A., OGIER de BAULNY H., de PARSCAU L. Management of phenylketonuria and hyperphenylalaninemia: the french guidelines. Archives Pédiatrie, 12 (5), 594-601, 2005 (Services cités : Département de Pédiatrie) Phenylketonuria (PKU) is an inherited metabolic disease affecting about one birth out of 15 000. From 1978, a national systematic neonatal screening was set up in France with a regional organisation. French rational and guidelines have been established by the national PKU group with the collaboration of all the physicians responsible for the regional centres. These guidelines specify the minimal diagnosis procedures leading to an optimal treatment of all patients. A low-phenylalanine diet must be started as soon as possible in the neonatal period for all newborns whose phenylalanine levels are above 10 mg/dl. The dietary control must keep the phenylalanine plasma levels between 2 and 5 mg/dl until 10 years of age. After this age, several data argue for a progressive and controlled relaxation of the diet, keeping the phenylalanine level below 15 mg/dl until the end of the adolescence and below 20 to 25 mg/dl in adulthood. All PKU patients must be followed up for life, in order to screen those who may not bear the diet relaxation and in order to strictly prevent maternal PKU deleterious consequences. BENSALEM N., VENTURA A.P., VALLEE B., LIPECKA J., TONDELIER D., DAVEZAC N., DOS SANTOS A., PERRETTI M., FAJAC A., SERMET-GAUDELUS I., RENOUIL M., LESURE J.F., HALGAND F., LAPREVOTE O., EDELMAN A. Down-regulation of the Anti-inflammatory Protein Annexin A1 in Cystic Fibrosis Knock-out Mice and Patients. Mol. Cell. Proteomics, 4 (10), 1591-1601, 2005 (Services cités : U467, Département de Pédiatrie, U370) Cystic fibrosis is a fatal human genetic disease caused by mutations in the CFTR gene encoding a cAMP-activated chloride channel. It is characterized by abnormal fluid transport across secretory epithelia and chronic inflammation in lung, pancreas, and intestine. Because cystic fibrosis (CF) pathophysiology cannot be explained solely by dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR), we applied a proteomic approach (bidimensional electrophoresis and mass spectrometry) to search for differentially expressed proteins between mice lacking cftr (cftr(tm1Unc), cftr(-/-)) and controls using colonic crypts from young animals, i.e. prior to the development of intestinal inflammation. By analyzing total proteins separated in the range of pH 6-11, we detected 24 differentially expressed proteins (>2-fold). In this work, we focused on one of these proteins that was absent in two-dimensional gels from cftr(-/-) mice. This protein spot (molecular mass, 37 kDa; pI 7) was identified by mass spectrometry as annexin A1, an anti-inflammatory protein. Interestingly, annexin A1 was also undetectable in lungs and pancreas of cftr(-/-) mice, tissues known to express CFTR. Absence of this inhibitory mediator of the host inflammatory response was associated with colonic up-regulation of the proinflammatory cytosolic phospholipase A(2). More importantly, annexin A1 was down-regulated in nasal epithelial cells from CF patients bearing homozygous nonsense mutations in the CFTR gene (Y122X, 489delC) and differentially expressed in F508del patients. These results suggest that annexin A1 may be a key protein involved in CF pathogenesis especially in relation to the not well defined field of inflammation in CF. We suggest that decreased expression of annexin A1 contributes to the worsening of the CF phenotype. BOUDJEMLINE Y., AGNOLETTI G., MERCKX J., OUACHEE-CHARDIN M.,

CHALOUI C., BONNET D., SIDI D. Reperméabilisation des gros troncs veineux supérieurs : un nouveau défi pour la cardiologie interventionnelle pédiatrique. Archives Pédiatrie, 12 (4), 420-423, 2005 (Services cités : Anesthésie Réanimation, Cardiologie Pédiatrique, Département de Pédiatrie, Immuno-Hématologie Pédiatrique) The use of long-term central venous catheters is a routine in chronic pediatric diseases. Thrombotic complications progressively reduce the central venous capital and hamper the long-term management of these patients. Observation. - We report two cases of obstruction of the central upper venous system and discuss of the techniques used to repermeabilize venous axes before the placement of a new central line. Conclusion. - The control of the permeability of the central veins should be performed before any withdrawal of central catheters, repermeabilization of the venous axes being simpler when the central catheter is kept in place in the occluded vessel. BUSEYNE F., LE CHENADEC J., BURGARD M., BELLAL N., MAYAUX M.J., ROUZIOUX C., RIVIERE Y., BLANCHE S. In HIV type 1-infected children cytotoxic T lymphocyte responses are associated with greater reduction of viremia under antiretroviral therapy. AIDS Res. Hum. Retroviruses, 21 (8), 719-727, 2005 (Services cités : Département de Pédiatrie) The evolution of the HIV-specific CD8+ T cell response in patients receiving potent combination therapy has been well documented in adult patients. However, no study reported whether baseline HIV-specific CD8+ T cell response is linked to treatment outcome. The aims of this study were to investigate both the impact of baseline memory cytotoxic T lymphocytes (CTL) on treatment outcome and the effect of potent therapy on memory HIV-specific CTL in HIV-1-infected pediatric patients. The study group comprised 30 children who started a first-line combination treatment including at least three drugs from two different classes and were longitudinally followed during treatment. Their memory HIV-specific responses were measured at baseline and during treatment, as well as their plasma viremia and CD4+ levels. The intensity of memory Gag-specific CTL and the breadth of the CTL response at the beginning of treatment were significantly correlated with lower plasma viral load during treatment, independently of baseline plasma viral load, CD4+ counts, and age. Children with partially controlled viral replication had enhanced Gag-specific CTL compared to their baseline value. This improvement of antiviral responses during treatment was not observed when viral replication was either fully suppressed or uncontrolled. In conclusion, our results show that higher baseline HIV-specific CTL are linked to lower viremia under combination therapy. This result adds further support to the hypothesis that cooperation between the antiviral immune response and antiviral drugs could be helpful for therapeutic management of HIV-infected patients. BUSEYNE F., CATTEAU A., SCOTT-ALGARA D., CORRE B., PORROT F., ROUZIOUX C., BLANCHE S., RIVIERE Y. A vaccinia-based elispot assay for detection of CD8+ T cells from HIV-1 infected children. J. Immunol. Method., 298 (1-2), 105-108, 2005 (Services cités : Département de Pédiatrie, Laboratoire de Microbiologie) HIV-specific CD8+ T lymphocytes participate in the control of viral replication in infected patients. These responses are of low intensity in young infants and are decreased by antiretroviral therapy. In the present study, we report on a recombinant Vaccinia virus (rVV)-based Elispot

assay for the detection of HIV-specific CD8+ T cells immediately after isolation of peripheral blood mononuclear cells (PBMC). The rVV-based assay was highly sensitive; 48 out of 50 children had a positive response against the rVV encoding HIV Env-Gag-Pol antigen. Interferon-gamma was produced by CD8+ T cells, and CD14+/15+ cells were the main cell subset presenting antigens expressed by rVV. We observed that the cell input per well had a critical influence on the sensitivity of the assay. Results from the ex vivo Elispot assay correlated poorly with those of the (51)Cr release assay performed after expansion of PBMC in vitro; thus, both assays gave information on different subsets and/or functions of the HIV-specific T cell response. BUSEYNE F., SCOTT-ALGARA D., BELLAL N., BURGARD M., ROUZIOUX C., BLANCHE S., RIVIERE Y. The Frequency of HIV-Specific Interferon- gamma -Producing CD8 T Cells Is Associated with Both Age and Level of Antigenic Stimulation in HIV-1-Infected Children. J. Infect. Dis., 192 (10), 1781-1786, 2005 (Services cités : Département de Pédiatrie, Laboratoire de Microbiologie) Ex vivo interferon (IFN)- gamma -producing CD8 T cells specific for human immunodeficiency virus (HIV) Env, Gag, and Pol antigens were measured in the peripheral blood of 55 children not receiving highly active antiretroviral therapy (HAART) and 70 children receiving HAART. In children not receiving HAART, the frequency of HIV-specific IFN- gamma -producing CD8 T cells was positively correlated with age and was not associated with plasma viral load or CD4 T cell levels. In children receiving HAART, the frequency of HIV-specific IFN- gamma -producing CD8 T cells was directly correlated with plasma viral load, and its association with age remained significant. In conclusion, the frequency of HIV-specific IFN- gamma -producing CD8 T cells in children is primarily determined by both age and plasma viral load. CATALANO-PONS C., QUARTIER P., LERUEZ-VILLE M., KAGUELIDOU F., GENDREL D., LENOIR G., CASANOVA J.L., BONNET D. Primary cytomegalovirus infection, atypical Kawasaki disease, and coronary aneurysms in 2 infants. Clin. Infect. Dis., 41 (5), e53-e56, 2005 (Services cités : Cardiologie Pédiatrique, Département de Pédiatrie, Immuno-Hématologie Pédiatrique, Laboratoire de Microbiologie, U550) We describe 2 infants who developed atypical Kawasaki disease and coronary aneurysms during primary cytomegalovirus infection. These observations suggest that children with coronary aneurysms and Kawasaki-like disease should be tested for cytomegalovirus. Conversely, children with unusually severe primary cytomegalovirus infection should be tested for coronary aneurysms. CLAIRICIA M., LENOIR G. L'autonomie des patients. L'expérience du Centre de Formation au Traitement à domicile de l'enfant (CFTDE). Rev. Mal. Resp., 22 (3), 518-520, 2005 (Services cités : CFTDE, Département de Pédiatrie) CRETOLLE C., de LONLAY P., SAUVAT F., BRUNELLE F., RAHIER J., SAUDUBRAY J.M., NIHOUL-FEKETE C. Hyperinsulinisme persistant du nouveau-ne et du nourrisson : traitement chirurgical des lesions

pancreatiques focales dans 60 cas. Archives Pédiatrie, 12 (3), 258-263, 2005 (Services cités : Chirurgie Pédiatrique, Département de Pédiatrie, Radiologie Pédiatrique) Congenital hyperinsulinism of infancy is a severe disease that leads to important brain damage. Two different forms of the disease have been identified by pathologists: a diffuse and a focal form. A specific genetic anomaly identified in focal forms has never been described in diffuse ones. However, for most of authors, failure of medical treatment results in near-total pancreatectomy in all cases, which ends in diabetus. The aim of this retrospective study was to assess the results of elective partial pancreatectomy performed in 60 cases of focal form of hyperinsulinism over the last 18 years. Fifty-eight patients were cured with euglycemia at both fasting and hyperglycaemic tests without insulin-dependent diabetes mellitus. One patient is still in hypoglycaemia from unrecognized lesion; insulin-dependent diabetes mellitus occurred in one case nine years after surgery (a near-total pancreatectomy has been performed because of unknown focal form, in 1985). DE LONLAY P., GIURGEA I., SEMPOUX C., TOUATI G., JAUBERT F., RAHIER J., RIBEIRO M., BRUNELLE F., NIHOUL-FEKETE C., ROBERT J.J., SAUDUBRAY J.M., STANLEY C., BELLANNE-CHANTELOT C. Dominantly inherited hyperinsulinaemic hypoglycaemia. J. Inherit. Metab. Dis., 28 (3), 267-276, 2005 (Services cités : Anatomo-Pathologie, Chirurgie Pédiatrique, Département de Pédiatrie, Radiologie Pédiatrique, U393, Métabolisme-Neurologie) Congenital hyperinsulinism (HI), the most important cause of hypoglycaemia in early infancy, is a heterogeneous disease with two types of histological lesions, focal and diffuse, with major consequences in terms of surgical approaches. In contrast to focal islet-cell hyperplasia, always sporadic to our knowledge, diffuse hyperinsulinism is a heterogeneous disorder involving several genes, various mechanisms of pathogenic mutations and different transmissions: (i) channelopathy involving the genes encoding the sulphonylurea receptor (SUR1) or the inward-rectifying potassium channel (Kir6.2) in recessively inherited HI or more rarely dominantly inherited HI; (ii) metabolic disorders implicating the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) enzyme inrecessi-vely inherited HI, the glucokinase gene (GK), the glutamate dehydrogenase gene (GLUD1) when hyperammonemia is associated, dominant exercise-induced HI with still-unknown mechanism, and more recently the human insulin receptor gene in dominantly inherited hyperinsulinism. Thus, dominant HI disorders always correspond to diffuse HI, where most hypoglycaemia occur in infancy, and are sensitive to medical treatment. Channel causes could be due to dominant negative mutation with one abnormality in channels composed of four Kir6.2 subunits and four SUR1 subunits, leading to a complete destruction of the channel structure or function, or due to haploinsufficiency with only one functional allele, leading to 50% of functional protein, which is not sufficient to obtain enough opened channels to maintain the membrane depolarized. Metabolic causes are due to a gain of function of enzyme activity (deregulated enzymes), except for physical exercise-induced hyperinsulinaemic hypoglycaemia, of still-unknown cause. Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy (Aynsley-Green et al 2000; Cornblath et al 1990; Pagliara et al 1973; Thomas et al 1977). The inappropriate oversecretion of insulin is responsible for profound hypoglycaemia that requires aggressive treatment to prevent severe and irreversible brain damage (Volpe 1995). HI is a heterogeneous disease associated with several genes, various mechanisms of pathogenic mutations and different transmissions (Dunne

et al 2004). DE MONTALEMBERT M., BONNET D., LENA-RUSSO D., BRIARD M.L. Ethical aspects of neonatal screening for sickle cell disease in Western European countries. Acta Paediatr., 94 (5), 528-530, 2005 (Services cités : Cardiologie Pédiatrique, Département de Pédiatrie) Sickle cell disease raises some important ethical questions regarding neonatal screening in Western European countries such as France, England or Belgium, which have already introduced either universal or selective screening. Such screening is aimed at benefiting children affected with major sickle cell syndrome. It also detects heterozygous babies and, in doing so, heterozygous parents. The latter information, which is ignored most of the time, risks making parents feel guilty and can raise fears of stigmatization. Whether it would change their future reproductive decisions requires further studies, for cultural and religious reasons may have a strong negative influence on the request for prenatal diagnosis. Disclosure of the child's illness may oblige the family to remain in the country they have emigrated to because it offers the best chance of treatment. As a result, links between the family and its original community are modified. Parents must more or less sever links with their family in Africa and try to trust and adapt to the public health services in Europe.Conclusion: Neonatal screening of sickle cell disease is highly ethical in facilitating the prevention of the early death of affected children. It also detects heterozygous parents and offers at-risk couples the possibility to perform a prenatal diagnosis during the next pregnancy. Adequate counselling must consider the risk of stigmatization that carrier status represents, especially for women in many cultural beliefs, and the numerous cultural and religious reasons which limit parental uptake for prenatal diagnosis. Disclosure of their child's illness may oblige immigrant families to stay in Europe, where free and adapted healthcare is available. FAYON M., DONATO L., de BLIC J., LABBE A., BECMEUR F., MELY L., DUTAU H. French experience of silicone tracheobronchial stenting in children. Pediat. Pulm., 39 (1), 21-27, 2005 (Services cités : Département de Pédiatrie, Pneumologie-Allergologie Pédiatrique) FERRONI A., SERMET-GAUDELUS I., LE BOURGEOIS M., PIERRE-AUDIGIER C., OFFREDO C., ROTTMAN M., GUILLEMOT D., BERNEDE C., VINCENT V., BERCHE P., GAILLARD J.L. Measurement of immunoglobulin G against Mycobacterial antigen A60 in patients with cystic fibrosis and lung infection due to Mycobacterium abscessus. Clin. Infect. Dis., 40 (1), 58-66, 2005 (Services cités : Pédiatrie Générale, Laboratoire de Microbiologie) FONTAINE K., SEMONIN O., LAGARDE J.P., LENOIR G., LUCOTTE G. A new mutation of the Noggin gene in a French Fibrodysplasia ossificans progressiva (FOP) family. Genet. Counsel., 16 (2), 149-154, 2005 (Services cités : Département de Pédiatrie) A new mutation of the Noggin gene in a French Fybrodysplasia ossificans progressiva (FOP) family: Fibrodysplasia ossificans progressiva (FOP) is a very rare disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of the muscles.

We previously located a FOP gene in the 17q21-22 region and described several mutations of the noggin (NOG) gene (located in 17q22) in lour FOP patients, including the G91C mutation which is transmitted dominantly in a Spanish FOP family. We describe in the present study a new mutation of the NOG gene in a French FOP family. This new mutation is a guanine to adenine change at nucleotide 283 (283G -> A) of the NOG gene, and is transmitted in the family (in the heterozygote form) by the affected mother to her two affected children. At the peptide level this mutation (A95T) substitutes an Alanine residue by a Threonine at position 95 of the Noggin protein. The Alanine mutated residue Is located just adjacent to the myristoylation site of the protein, where all the mutations we described until now are located. GARCIA-CAZORLA A., de LONLAY P., NASSOGNE M.C., RUSTIN P., TOUATI G., SAUDUBRAY J.M. Long-term follow-up of neonatal mitochondrial cytopathies: a study of 57 patients. Pediatrics, 116 (5), 1170-1177, 2005 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique, Métabolisme-Neurologie) OBJECTIVES: We sought to determine the long-term clinical and biochemical outcome of newborns with mitochondrial cytopathies (MCs) and to identify possible prognostic factors that may modify the course of these diseases. MATERIAL AND METHODS: Fifty-seven newborns with MCs were identified in a retrospective review (1983-2002). We defined 2 different outcome categories: clinical (neurologic, hepatic, myopathic, and multiorganic) and biochemical (lactate level normalization or initially normal remaining unchanged, decreased but not normalized, and persistently high). We used 2 different statistical approaches: (1) survival studies depending on the initial symptoms and lactate and enzymatic deficiencies using the Kaplan-Meier method; and (2) the same variables compared with different survival age groups and clinical and biochemical outcome categories using the chi2 test. RESULTS: Thirty-three patients died (57.8%), 12 remain alive (21%), and 12 were lost in the follow-up; 6 of them are currently older than 4 years. Most of the patients manifested multiorganic disease (64.8%) and high lactate level (77.1%) over time. Children surviving to 2.5 to 3 years of age were more likely to survive for a long period of time. Initial neurologic and hepatic presentation increased the risk to develop neurologic disease and severe persistent hyperlactacidemia, respectively. Initial severe hyperlactacidemia and combined enzyme deficiencies were significant risk factors for higher mortality and multiorganic disorders. Two patients with exclusively myopathic outcome are alive and cognitively normal at 12 years of life. CONCLUSIONS: Children with neonatal-onset MCs have very high mortality and poor prospects. However, some with life-threatening presentations may gradually improve, giving rise to less severe diseases. Those with exclusively myopathic symptoms have a better prognosis. GIURGEA I., RIBEIRO M.J., BODDAERT N., TOUATI G., ROBERT J.J., SAUDUBRAY J.M., JAUBERT F., BELLANNE-CHANTELOT C., BRUNELLE F., NIHOUL-FEKETE C., de LONLAY P. Congenital hyperinsulinism in newborn and infant. Archives Pédiatrie, 12 (11), 1628-1635, 2005 (Services cités : Anatomo-Pathologie, Chirurgie Pédiatrique, Radiologie Pédiatrique, Métabolisme-Neurologie, Département de Pédiatrie) Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy. The inappropriate oversecretion of insulin is responsible for profound hypoglycaemias requiring aggressive treatment to prevent severe and irreversible brain damage. Several classifications of

HI can be attempted, based on: 1) the onset of hypoglycemia in the neonatal period or later in infancy; 2) the histological lesion: focal or diffuse; 3) the genetic transmission: sporadic, recessive, or less frequently dominant. The most common underlying mechanism of HI is dysfunction of the pancreatic ATP-sensitive potassium channel (K(+)(ATP)). The 2 subunits of the K(+)(ATP) channel are encoded by either the sulfonylurea receptor gene (SUR1 or ABCC8) or the inward-rectifying potassium channel gene (KIR6.2. or KCNJ11), both located in the 11p15.1 region. Focal CHI has been shown to result from a paternally inherited mutation on the SUR1 or KIR6.2 gene and loss of the maternal 11p15 allele restricted to the pancreatic lesion. Diffuse HI, frequently due to mutations of the SUR1 or KIR6.2 genes of autosomal recessive inheritance is genetically heterogeneous. The distinction between the focal and the diffuse HI is very important, because the treatments are different. To distinguish between focal and diffuse HI, transhepatic catheterisation with pancreatic venous sampling was the reference technique, but will likely be replaced by [(18)F] Fluoro-L-Dopa PET scan, which is easier to perform. In absence of response to the medical treatment (diazoxide) a limited pancreatectomy permits to cure focal HI, while a diffuse HI requires a subtotal pancreatectomy with high risk of subsequent diabetes mellitus. GIURGEA I., MICHEL A., LE MERRER M., SETA N., de LONLAY P. Underdiagnosis of mild congenital disorders of glycosylation type Ia. Pediat. Neurol., 32 (2), 121-123, 2005 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique) Congenital disorders of glycosylation-Ia are the most frequent type of congenital disorders of glycosylation. This condition affects the nervous system as well as other organs. The estimated incidence of congenital disorders of glycosylation-Ia is higher than the number of identified cases, therefore underdiagnosis of this heterogeneous disorder is probable. Neurologic and biologic signs are hallmarks for the identification of patients with congenital disorders of glycosylation-Ia. This report describes two children with congenital disorders of glycosylation-Ia syndrome confirmed by phosphomannomutase gene mutations with normal development and absence of biologic anomalies such as elevated transaminases and altered hemostasis. In conclusion, congenital disorders of glycosylation should be considered in cases of unexplained behavioral symptoms such as hyperactivity and concentration difficulties and mild neurologic signs. Intellectual retardation is often overestimated because of dysarthria and motor difficulties. Psychomotor reeducation might improve quality of life. GOULET O., BAGLIN-GOBET S., TALBOTEC C., FOURCADE L., COLOMB V., SAUVAT F., JAIS J.P., MICHEL J.L., JAN D., RICOUR C. Outcome and long-term growth after extensive small bowel resection in the neonatal period: a survey of 87 children. Eur. J. Pediatr. Surg., 15 (2), 95-101, 2005 (Services cités : Biostatistique, Gastroentérologie Pédiatrique, Pédiatrie Générale) This retrospective study aims to analyze the outcome, the prognosis factors and the long-term growth of children after extensive small bowel (SB) resection in the neonatal period. PATIENTS AND METHODS: 87 children, born between 1975 and 1991 who had undergone extensive neonatal small bowel resection, were followed up over a mean period of 15 years. Anatomical data influencing PN dependency and duration were analyzed. Data on height and weight were collected and compared using growth standards. Final heights were studied for patients who achieved their puberty and compared to predicted height based on Tanner's formula. Patients

were analyzed according to PN weaning and growth: children still receiving PN (group A), patients weaned from initial PN but requiring PN once again or enteral feeding (group B), and children with permanent intestinal autonomy (group C). RESULTS: The overall survival is 89.7 %, depending on the date of birth. The duration of PN-dependency varies according to the intestinal length and the presence of the ileocaecal valve (ICV). All patients who remain PN dependent had less than 40 cm of small bowel and/or the absence of ICV. Patients in group B had a mean small bowel length of 35 +/- 19 cm, resection of the ICV in 50 % of cases, and a PN duration of 47.4 +/- 23.8 months. There was a significant decrease in height and weight gain within the 4 years after cessation of PN, requiring enteral or parenteral feeding. Patients in group C had a mean small bowel length of 57 +/- 19 cm, presence of ICV in 81 % of cases and a PN duration of 16.1 +/- 11.4 months. After PN weaning, they grow up normally with normal puberty and final height as predicted from genetic target height. CONCLUSION: PN duration is influenced by the length of residual SB and the absence of ICV. With good anatomic prognosis factors and short duration of initial PN, normal long-term growth may be predicted. Conversely, poor anatomical factors and protracted initial PN require careful monitoring of growth and may sometimes require nutritional support to be restarted. The last group, permanently dependent on PN, might be candidates for intestinal transplantation. LALLEMAND J.Y., LECLAIRE B., SERMET I., LENOIR G. Cystic fibrosis : Chemical drugs to cure genetic diseases. Bull. Acad. Natl. Méd., 189 (5), 789-795, 2005 (Services cités : Département de Pédiatrie) Cystic Fibrosis is the most common lethal genetic disease among Caucasian population. Despite considerable efforts, no significant progress has been so far achieved by gene therapies approaches. On the basis of a surprising clinical observation, we have developed an approach using anti-cancer drugs promoting the over expression of ABC transporters closely related to the deficient protein CFTR, which seem able to share functions with it and to restore the missing function(s). LE BOURGEOIS M., SERMET-GAUDELUS I., CATHERINOT E., GAILLARD J.L. Nontuberculous mycobacteria in cystic fibrosis. Archives Pédiatrie, 12 Suppl 2 S117-S121, 2005 (Services cités : Pneumologie-Allergologie Pédiatrique, Département de Pédiatrie) Patients with cystic fibrosis are particularly at risk of infection with non-tuberculous mycobacteria (NTM). Prevalence of these infections increases with age to around 15 %. The main species involved are M. abscessus and M. avium, the latter not found in children under 15. Diagnosis relies on clinical, radiological and above all bacteriological criteria defined by the ATS. Identification of the causal species of NTM is essential and requires genetic techniques, some of which are currently evaluated. Treatment depends on the mycobacterial species. For M. avium, combined therapy with rifampicin, clarythromycin and ethambutol must be extended 12 months after negativation. M. abscessus infection is particularly resistant to therapy. Usual treatment is a one month course of intravenous imipenem or cefoxitin plus amikacin followed by oral clarithromicin plus ethambutol for at least 12 months after negativation. In case of local lesions, surgery is an option. LOI C., NAKIB S., NEVEUX N., ARNAUD-BATTANDIER F., CYNOBER L. Ornithine alpha-ketoglutarate metabolism in the healthy rat in the postabsorptive state.

Metabolism, 54 (8), 1108-1114, 2005 (Services cités : Département de Pédiatrie) Abstract To gain further insight into the ability of ornithine alpha -ketoglutarate (OKG) to generate key metabolites, the aim of this work was to study the short-term metabolism, that is, 1 hour after administration, of OKG in plasma and tissues. Particular attention was paid to keto acids ( alpha -ketoglutarate and branched-chain keto acids). Young (3 weeks old) male Wistar rats in the postabsorptive state received either 1.5 g/kg of monohydrated OKG (OKG group, n = 8) diluted in distilled water or an equivalent volume of saline solution at 0.9% (control group, n = 8) by gavage and were killed 1 hour later. Plasma, liver, jejunal and ileal mucosa, and the extensor digitorum longus muscle were removed to analyze amino and keto acid contents. Major metabolites detected after OKG ingestion (ornithine [ORN], alpha -ketoglutarate, proline and glutamate; OKG vs control, P <.05) and the absence of increased arginine (and even a decrease in jejunum and muscle) and citrulline levels suggested that ORN was mainly metabolized by the ORN aminotransferase pathway. In addition, significantly decreased plasma branched-chain keto acids and increased hepatic branched-chain amino acids (OKG vs control, P <.05) were observed upon OKG ingestion. Finally, glutamine accumulation restricted to the intestine, as evidenced in this short-term study, suggests that the effects of OKG on glutamine pools in other tissues in various pathological states after several days of treatment, as observed in previous studies, may be related to a long-term induction of glutamine synthetase. PIERRE-AUDIGIER C., FERRONI A., SERMET-GAUDELUS I., LE BOURGEOIS M., OFFREDO C., VU-THIEN H., FAUROUX B., MARIANI P., MUNCK A., BINGEN E., GUILLEMOT D., QUESNE G., VINCENT V., BERCHE P., GAILLARD J.L. Age-related prevalence and distribution of nontuberculous mycobacterial species among patients with cystic fibrosis. J. Clin. Microbiol., 43 (7), 3467-3470, 2005 (Services cités : Département de Pédiatrie, Laboratoire de Microbiologie) We studied the prevalence and species distribution of nontuberculous mycobacteria (NTM) in relation to age in 385 patients with cystic fibrosis (CF) (mean age +/- standard deviation [range], 12.0 +/- 6.1 [1 to 24] years; sex ratio, 0.53) attending three Parisian centers. The overall prevalence of NTM in sputum was 8.1% (31 out of 385). The following NTM were isolated (n = 33): Mycobacterium abscessus (n = 13, 39.4%), Mycobacterium avium complex (MAC) (n = 7, 21.2%), Mycobacterium gordonae (n = 6, 18.2%), and other (n = 7, 21.2%). Sixteen patients met the American Thoracic Society microbiological criteria for NTM infection, including 11 patients positive for M. abscessus, 4 for MAC, and 1 for MAC and Mycobacterium kansasii. The overall prevalence of NTM was significantly lower in patients under 15 years old than for patients equal to or more than 15 years old (4.8 versus 14.9%, respectively; P = 0.001). M. abscessus was isolated at all ages, while MAC was not recovered before 15 years (prevalence of 0.0 and 5.2% in patients aged 1 to 14 and 15 to 24, respectively; P = 0.001). PINTO G., ABADIE V., MESNAGE R., BLUSTAJN J., CABROL S., AMIEL J., HERTZ-PANNIER L., BERTRAND A.M., LYONNET S., RAPPAPORT R., NETCHINE I. CHARGE Syndrome Includes Hypogonadotropic Hypogonadism and Abnormal Olfactory Bulb Development. J. Clin. Endocrinol. Metabol., 90 (10), 5621-5626, 2005 (Services cités : Département de Pédiatrie, Endocrinologie et Croissance, Génétique Médicale Pédiatrique, Radiologie Pédiatrique)

Context: CHARGE (coloboma, heart defect, choanal atresia, retarded growth and development, genital hypoplasia, ear abnormalities, and/or hearing loss defect) syndrome consists of a combination of congenital malformations including genital hypoplasia and retarded growth. Objective: The objective of the study was to study gonadotropic axis function and growth parameters in CHARGE syndrome. Design: This was a retrospective study. Patients: The study included 32 children with CHARGE syndrome. Results: Nineteen of 20 affected boys had micropenis and/or cryptorchidism, consistent with hypogonadotropic hypogonadism during fetal life. None of the boys was of pubertal age. Seven of nine boys tested before the age of 5 months during the neonatal peak period had extremely low testosterone levels. LH response to GnRH stimulation was variable during the first year of life and not correlated with existing clinical abnormalities. None of the girls over the age of 12 yr (n = 7) had begun puberty spontaneously, and a lack of response to GnRH stimulation was documented in five of them. Olfactory evaluation (n = 10) and magnetic resonance imaging (n = 18) of the forebrain revealed defective sense of smell and abnormal olfactory bulbs in all cases. Cardiorespiratory and nutritional problems were corrected, but the mean height of the 25 children who had reached 5 yr of age was -2 +/- 0.2 sd score. Height was not correlated with birth length or body mass index. GH deficiency was diagnosed in only three children. Conclusion: These findings suggest that CHARGE syndrome includes the main features of Kallmann syndrome, which is defined by hypogonadotropic hypogonadism combined with a defective sense of smell and abnormal olfactory bulb development. This forebrain abnormality, if confirmed in a larger group of patients, could serve as a major new criterion for the diagnosis of CHARGE syndrome. SCOTT-ALGARA D., BUSEYNE F., PORROT F., CORRE B., BELLAL N., ROUZIOUX C., BLANCHE S., RIVIERE Y. Not All Tetramer Binding CD8(+) T Cells Can Produce Cytokines and Chemokines Involved in the Effector Functions of Virus-Specific CD8(+) T Lymphocytes in HIV-1 Infected Children. J. Clin. Immunol., 25 (1), 57-67, 2005 (Services cités : Département de Pédiatrie, Laboratoire de Microbiologie) In the pediatric human immunodeficiency virus type-1 (HIV-1) infection, the presence of cytotoxic T lymphocytes (CTL) is associated with a slow progression to AIDS. The secretion of cytokines by CTLs may be critical in the control of viral infection. We used the combination of cell surface and intracellular staining to study the functionality of tetramer binding CD8(+) T cells recognizing two HIV-1 immunodominant epitopes, in peripheral blood mononuclear cells from HIV-1-infected children. A fraction of tetramer positive CD8(+) T cells produce cytokines (IFN-gamma, TNF-alpha) or chemokines (CCL4, CCL5) after ex vivo stimulation with the cognate peptide. There was a negative correlation between the plasma viral load and the percentage of CD8(+) Tetramer Gag(+) T cells secreting IFN-gamma. This is the first report in the context of pediatric HIV-1 infection showing that only a fraction of HIV-1-specific CD8(+) T cells have the capacity to produce cytokines and chemokines implicated in their antiviral functions. SERMET-GAUDELUS I., DECHAUX M., VALLEE B., FAJAC A., GIRODON E., NGUYEN-KHOA T., MARIANOVSKI R., HURBAIN I., BRESSON J.L., LENOIR G., EDELMAN A. Chloride transport in nasal ciliated cells of cystic fibrosis heterozygotes. Amer. J. Respir. Crit. Care Med., 171 (9), 1026-1031, 2005 (Services cités : CIC 9303, Département de Pédiatrie, U467)

Studying subjects heterozygous for mutations of the cystic fibrosis (CF) gene may help clarify the impact on disease onset of CF transmembrane conductance regulator protein (CFTR-)-dependent chloride secretion. CFTR-mediated chloride transport was evaluated in 52 heterozygous subjects, 32 healthy control subjects, and 77 patients with CF with class I or II mutations. We measured the change in nasal potential difference in response to chloride-free isoproterenol solution for each subject and used a video-imaging fluorescent dye assay to assess the percentage of nasal ciliated cells with cAMP-dependent anion conductance. Our findings did not confirm the standard assumption that heterozygosity implies 50% of normal CFTR function. Half the heterozygous subjects had CFTR-mediated chloride transport levels below 50% of the normal range, and one-third had levels similar to those of the patients with CF. This reduced CFTR function was not associated with an elevated prevalence of CF-like symptoms in heterozygous subjects but was highly related to respiratory status in the patients with CF. These data suggest that CFTR-dependent chloride conductance does not directly modulate disease severity but may be part of a more global defect in patients with CF involving other CFTR functions or currently unknown modulatory factors. SERMET-GAUDELUS I., CHADELAT I., LENOIR G. Temperature measurement in daily practice. Archives Pédiatrie, 12 (8), 1292-1300, 2005 (Services cités : Pédiatrie Générale) The use of rectal mercury thermometer has long been the standard method for measurement of body temperature. The restriction of mercury use since 1996 has led to development of other devices. The liquid crystal strip thermometer held against the forehead has a low sensitivity. The single-use chemical thermometer measures oral temperature. Its accuracy must be evaluated. Infrared ear thermometers are routinely used because it is convenient and fast to use. However, numerous studies have shown that it does not show sufficient correlation with rectal temperature, leading to the risk to miss cases of true fever. Rectal temperature remains the gold standard in case of fever. Rectal temperature measurement with an electronic device is well correlated with the glass mercury standard. Galistan thermometer accuracy must be evaluated because of sterilization of the whole device, which is not the case for the electronic thermometer. A paediatric study is necessary to evaluate the performance of this device in comparison with the electronic thermometer. THOUVENIN B., D'ARC B.F., BAUJAT G., BROUSSE V., ABADIE V. Infantile rumination. Archives Pédiatrie, 12 (9), 1368-1371, 2005 (Services cités : Département de Pédiatrie) Infantile rumination can be defined as self-induced regurgitation of previously swallowed food. Because it can lead to potential somatic complications and because it implies dysfunctional mother-child bonding, both a pediatric and psychiatric approach is needed. The treatment must be somatic (nutritional) and psychological (intensive nursing, mother-baby psychotherapy). Two case studies illustrate this rare but impressive picture. 2004 ABADIE V. Investigation of oral disorder in infants and children. Archives Pédiatrie, 11 (6), 603-605, 2004

(Services cités : Département de Pédiatrie) BAULAC S., GOURFINKEL-AN I., NABBOUT R., HUBERFELD G., SERRATOSA J., LEGUERN E., BAULAC M. Fever, genes, and epilepsy. Lancet Neurol., 3 (7), 421-430, 2004 (Services cités : Département de Pédiatrie) About 13% of patients with epilepsy have a history of febrile seizures (FS). Studies of familial forms suggest a genetic component to the epidemiological link. Indeed, in certain monogenic forms of FS, for which several loci have been reported, some patients develop epilepsy with a higher risk than in the general population. Patients with generalised epilepsy with febrile seizures plus (GEFS+) can have typical and isolated FS, FS lasting more beyond age 6 years, and subsequent afebrile (typically generalised) seizures. Mutations associated with GEFS+ were identified in genes for subunits of the voltage-gated sodium channel and the gamma2 subunit of the ligand-gated GABAA receptor. Screening for these genes in patients with severe myoclonic epilepsy in infancy showed de novo mutations of the alpha1 subunit of the voltage-gated sodium channel. Antecedent FS are commonly observed in temporal-lobe epilepsy (TLE). In sporadic mesial TLE-characterised by the sequence of complex FS in childhood, hippocampal sclerosis, and refractory temporal-lobe seizures-association studies suggested the role of several susceptibility genes. Work on some large pedigrees also suggests that FS and temporal-lobe seizures may have a common genetic basis, whether hippocampus sclerosis is present or not. The molecular defects identified in the genetic associations of FS and epileptic seizures are very attractive models to aid our understanding of epileptogenesis and susceptibility to seizure-provoking factors, especially fever. BONNET D., AGGOUN Y., SZEZEPANSKI I., BELLAL N., BLANCHE S. Arterial stiffness and endothelial dysfunction in HIV-infected children. AIDS, 18 (7), 1037-1041, 2004 (Services cités : Cardiologie Pédiatrique, Département de Pédiatrie, E 0016) BACKGROUND:: The role of antiretroviral therapy in acceleration of atherosclerosis in HIV-infected adults is controversial, partly because of the confounding effects of the involvement of classic cardiovascular risk factors. OBJECTIVE:: To study vascular function in HIV-infected children. DESIGN:: Cross-sectional study of 49 HIV-infected children (34 receiving antiretroviral therapy and 15 never treated) and if 24 age- and sex-matched controls. METHODS:: Automatic, computerized, ultrasonic procedure evaluation of geometric and mechanical properties of the common carotid artery, and of the endothelium-dependent dilation and endothelium-independent dilation. RESULTS:: Relative systolodiastolic variations in diameter of the carotid artery in HIV-infected children were significantly lower than those in controls, but there was no significant difference in intima-media thickness. Cross-sectional compliance and distensibility were also significantly lower. Wall stiffness, assessed as the incremental elastic modulus, was larger in HIV-infected children. Endothelium-dependent dilation was lower in HIV-infected children but non-endothelium-dependent dilation was similar to that in controls. We did not find differences for any of the vascular variables between HIV-infected children receiving antiretroviral therapy and those never treated. All arterial variables were similar in children with and without dyslipidemia. CONCLUSIONS:: HIV-infected children had a vascular dysfunction in the absence of cardiovascular risk factors. In this short series, no additional detrimental effects were observed after a mean of 5 years of antiretroviral therapy.

CLAIRICIA M., POISSON C., LEVRET M., LENOIR G., SCHEINMAN P., ROBERT J.J. La mucoviscidose de l'hôpital au domicile. Soins Pédiatr. Puéric., (218), 31-33, 2004 (Services cités : Département de Pédiatrie, Métabolisme-Neurologie Génétique Pédiatrique, Pneumologie-Allergologie Pédiatrique) DE LONLAY P., GIURGEA I., TOUATI G., SAUDUBRAY J.M. Neonatal hypoglycaemia: aetiologies. Semin. Neonat., 9 (1), 49-58, 2004 (Services cités : Département de Pédiatrie) Diagnosis of glucose status requires knowledge of the homeostatic mechanisms that maintain the blood glucose concentration between the narrow range of 2.5 and 7.5 mmol/l during periods of eating or fasting. Hypoglycaemia occurring within the first few hours after eating is suggestive of hyperinsulinism. Most glucose is subsequently converted into glycogen in the liver, and hypoglycaemia occurring during this phase is suggestive of glycogenosis. During fasting, gluconeogenesis progressively replaces glycogen as the major source of blood glucose, and hypoglycaemia occurring during this period is suggestive of impaired gluconeogenesis or fatty acid disorders. Growth hormone, glucagon, cortisol and insulin-like growth factor 1 deficiencies may also play a role. Other causes of hypoglycaemia have also been identified recently, namely glucose transporter disorders, respiratory chain disorders and congenital disorders of glycosylation. DE MONTALEMBERT M., LENOIR G. Antibiotic prevention of pneumococcal infections in asplenic hosts: admission of insufficiency. Ann. Hematol., 83 (1), 18-21, 2004 (Services cités : Département de Pédiatrie) DE MONTALEMBERT M., MAUNOURY C., ACAR P., BROUSSE V., SIDI D., LENOIR G. Myocardial ischaemia in children with sickle cell disease. Arch. Dis. Child., 89 (4), 359-362, 2004 (Services cités : Cardiologie Pédiatrique, Département de Pédiatrie) BACKGROUND: The heart may be involved in children affected with sickle cell disease (SCD) via several mechanisms. Principally, chronic anaemia increases cardiac output and may cause left ventricular enlargement and cardiac insufficiency. AIMS: To investigate whether the heart also suffers from ischaemia in SCD, as has already been shown for other organs (bone, brain, etc), and to look for risk factors predisposing to this complication. METHODS: Twenty two children with SCD, and chest pain or ECG or echocardiographic signs (left ventricle dilation or hypokinesis) suggesting myocardial ischaemia were subjected to thallium-201 (201Tl) single photon emission computed tomography (SPECT). RESULTS: Eight children had a normal SPECT, 14 an abnormal one. Myocardial perfusion defects were reversible in nine, fixed in five. Patients with perfusion defects tended to be older and have more severe disease. Five had had cardiac symptoms (episodes of cardiac failure in three, ventricular fibrillation in one, angina in one). Myocardial perfusion was reassessed after six months of hydroxyurea treatment in three patients, and was found to be improved. CONCLUSIONS: Myocardial perfusion defects are present in children with SCD and may be demonstrated using SPECT. Hydroxyurea improved perfusion in

three patients. DE MONTALEMBERT M. Sickle cell disease in the neonatal period. J. Gynécol. Obst. Biol. Reprod., 33 (1 Suppl), S12-S14, 2004 (Services cités : Département de Pédiatrie) The prognosis of pregnancy in women with major sickle cell syndromes has improved greatly in recent years. Correction of maternal anemia with programmed transfusion has been a major advance. Rates of preterm birth and intra-uterine growth retardation nevertheless remain high in this population. A newborn affected with sickle cell disease does not develop complications of the disease, because the predominant fetal hemoglobin cannot co-polymerize with sickle hemoglobin. The rate of complications increases as the infant's hemoglobin synthesis switches from fetal to sickle hemoglobin. Neonatal screening of sickle cell disease patients enables early implementation of a comprehensive prevention program (daily antibiotic prophylaxy, immunization, parental education.). A neonatal screening program, targeted with regard to the parents' ethnic background, has been implemented throughout metropolitan France since 1999. In 2002, this program enabled early diagnosis of sickle cell disease in 313 newborns. DE MONTALEMBERT M. Management of sickle cell disease. Rev. Prat., 54 (14), 1557-1564, 2004 (Services cités : Département de Pédiatrie) Hypoxia, hemolysis and infection are more or less associated in patients affected with sickle cell disease. Treatment is based on a programme including regular lifestyle, hydration, folic acid supply, prevention of pneumococcal infections and cerebrovascular events in children, regular follow-up in specialised centres allowing precocious screening and treatment of organ deficiency. Some patients exhibit a severe form and need intensive preventive care, such as chronic transfusion, hydroxyurea or bone marrow transplantation for children and adolescent with an HLA-identical sibling. The choice between these strategies is multifactorial, excepted in patients with a severe cerebral vasculopathy, for whom chronic transfusion or bone marrow transplantation are preferable. We usually propose hydroxyurea as a first line treatment to patients with recurrent pain crises or acute chest syndromes. In cases of refusal, initial or secondary failure (which occur more frequently in adults), or intolerance of hydroxyurea, patients with a severe disease are chronically transfused, which leads them most of the time to necessitate iron chelation. DES ROBERT C., LACAILLE F., CANIONI D., QUARTIER-DIT-MAIRE P., TALBOTEC C., GOULET O. EBV-negative lymphoproliferative disease with hyper-IgA, in a child with combined liver and small bowel transplantation. Pediat. Transplant., 8 (3), 305-307, 2004 (Services cités : Anatomo-Pathologie, Département de Pédiatrie) Des Robert C, Lacaille F, Canioni D, Quartier-dit-Maire P, Talbotec C, Goulet O. EBV-negative lymphoproliferative disease with hyper-IgA, in a child with combined liver and small bowel transplantation. Pediatr Transplantation 2004: 8: 305-307. Copyright 2004 Blackwell MunksgaardAbstract: A 4-year-old boy presented 14 months after liver and small bowel transplantation with fever, diarrhea, elevated liver enzymes, thrombocytopenia and

autoantibodies. Total gammaglobulins level was normal but the level of plasma IgA1 was very high. The blood PCR for Epstein-Barr virus (EBV) was negative. The ileal biopsy disclosed a lymphoplasmacytic infiltration. The EBER probe was negative on the small bowel biopsies. The child was considered as suffering from a non-EBV-induced posttransplant lymphoproliferative disorder (PTLD). The high IgA level was presumed to be secreted by proliferating plasma cells in the transplanted bowel. Immunosuppression was reduced; but the efficacy was incomplete and an anti-CD20 antibody was added. There was complete resolution of symptoms and normalization of the IgA level. As IgA1 is mostly of intestinal origin, this unusual presentation of PTLD should lead to a high suspicion of a small bowel proliferating process. ELEFTERIOU F., TAKEDA S., EBIHARA K., MAGRE J., PATANO N., KIM C.A., OGAWA Y., LIU X., WARE S.M., CRAIGEN W.J., ROBERT J.J., VINSON C., NAKAO K., CAPEAU J., KARSENTY G. Serum leptin level is a regulator of bone mass. Proc. Nat. Acad. Sci. USA, 101 (9), 3258-3263, 2004 (Services cités : Département de Pédiatrie) Leptin is a powerful inhibitor of bone formation in vivo. This antiosteogenic function involves leptin binding to its receptors on ventromedial hypothalamic neurons, the autonomous nervous system and beta-adrenergic receptors on osteoblasts. However, the mechanisms whereby leptin controls the function of ventromedial hypothalamic antiosteogenic neurons remain unclear. In this study, we compared the ability of leptin to regulate body weight and bone mass and show that leptin antiosteogenic and anorexigenic functions are affected by similar amounts of leptin. Using a knock-in of LacZ in the leptin locus, we failed to detect any leptin synthesis in the central nervous system. However, increasing serum leptin level, even dramatically, reduced bone mass. Conversely, reducing serum-free leptin level by overexpressing a soluble receptor for leptin increased bone mass. Congruent with these results, the high bone mass of lipodystrophic mice could be corrected by restoring serum leptin level, suggesting that leptin is an adipocyte product both necessary and sufficient to control bone mass. Consistent with the high bone mass phenotype of lipodystrophic mice, we observed an advanced bone age, an indirect reflection of premature bone formation, in lipodystrophic patients. Taken together, these results indicate that adipocyte-derived circulating leptin is a determinant of bone formation and suggests that leptin antiosteogenic function is conserved in vertebrates. FEILLET F., ABADIE V., BERTHELOT J., MAURIN N., OGIER H., VIDAILHET M., FARRIAUX J.P., de PARSCAU L. Maternal phenylketonuria: the French survey. Eur. J. Pediat., 163 (9), 540-546, 2004 (Services cités : Département de Pédiatrie) We report the French experience regarding pregnancies in maternal phenylketonuria (PKU). In 2001, a questionnaire was sent to each referring PKU specialist in the 20 centres of each region of France, collecting reports on 135 pregnancies in 79 women born between 1958 and 1980. The majority of the 135 pregnancies occurred after 1990. A total of 42 women were informed of the risks of untreated pregnancy, while 26 were not informed (no data for 11). A strict diet was achieved in 83% of informed and in 16% of uninformed mothers prior to conception. Healthy offspring were observed in 43% of the 135 pregnancies, spontaneous abortions in 10.4%, elective abortions in 4.4%, therapeutic abortions in 12.6%, and embryopathies (EP) in 21.5%. In 8.1% of cases, the outcomes (in earliest pregnancies) are unknown. The proportion of healthy children

increased over time and reached 80% of the pregnancies of informed females. There were seven heart defects, all in cases of EP, but although microcephaly and intrauterine growth retardation (IUGR) were almost constant in EP, we also found nine healthy children with IUGR. A continuum between EP and healthy children is suggested. The anthropometric data of the mothers showed that their body mass index (BMI) distribution was shifted to the left compared to women of the general population. This lower BMI and poor weight gain during pregnancy could contribute to the IUGR observed in normal babies whose mothers received a phenylalanine-restricted diet during pregnancy. CONCLUSION:the information and the preconception diet are effective for avoiding embryopathies in maternal phenylketonuria. Nutritional parameters can influence fetal growth and the nutritional state must be closely monitored throughout pregnancies of women with phenylketonuria. FEUILLET-FIEUX M., FERREC M., GIGAREL N., THUILLIER L., SERMET I., STEFFANN J., LENOIR G., BONNEFONT J. Novel CFTR mutations in black cystic fibrosis patients. Clin. Genet., 65 (4), 284-287, 2004 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique) Feuillet-Fieux MN, Ferrec M, Gigarel N, Thuillier L, Sermet I, Steffann J, Lenoir G, Bonnefont JP. Novel CFTR mutations in black cystic fibrosis patients.Cystic fibrosis (CF) is considered as a rare disease in black Africans. In fact, this disease is likely to be underestimated since clinical features consistent with CF diagnosis are often ascribed to environmental factors such as malnutrition. Very little is known about CFTR mutations in affected patients from Central Africa. We report here four novel mutations, i.e., IVS2 + 28 (intron 2), 459T > A (exon 4), EX17a_EX18del (exons 17-18), and IVS22 + IG > A (intron 22), in such patients. An update of CFTR mutations reported in black patients from various ethnies is included. These data might be helpful for genetic counselling regarding CF in black patients. GENEVIEVE D., BAUMANN C., HUBER C., FAIVRE L., SANLAVILLE D., BODEMER C., HADJ-RABIA S., ASSOUMOU A., VERLOES A., RAQBI F., MUNNICH A., CORMIER-DAIRE V. A novel form of syndromic cutis laxa with facial dysmorphism, cleft palate, and mental retardation. J. Med. Genet., 41 (6), E77, 2004 (Services cités : Département de Pédiatrie, Dermatologie, Génétique Médicale Pédiatrique) GIURGEA I., LABORDE K., TOUATI G., BELLANNE-CHANTELOT C., NASSOGNE M.C., SEMPOUX C., JAUBERT F., KHOA N., CHIGOT V., RAHIER J., BRUNELLE F., NIHOUL-FEKETE C., DUNNE M.J., STANLEY C., SAUDUBRAY J.M., ROBERT J.J., de LONLAY P. Acute Insulin Responses to Calcium and Tolbutamide Do Not Differentiate Focal from Diffuse Congenital Hyperinsulinism. J. Clin. Endocrinol. Metabol., 89 (2), 925-929, 2004 (Services cités : Anatomo-Pathologie, Chirurgie Pédiatrique, Département de Pédiatrie, Radiologie Pédiatrique) Congenital hyperinsulinism (CHI) is related to two main histological pancreas anomalies: focal adenomatous hyperplasia and diffuse beta-cell hypersecretion. Pharmacological tests to measure acute insulin responses (AIR) to peripheral iv injections of glucose, calcium, and tolbutamide

have been reported as potential means to distinguish between these histological forms. In patients with defects in ATP-sensitive potassium channels, tolbutamide will fail to induce insulin release in affected portions of the pancreas, whereas calcium gluconate will enhance insulin release through spontaneously active voltage-gated Ca(2+) channels. Consequently, in focal CHI patients, calcium should promote AIRs from the lesion, whereas tolbutamide should act to promote insulin secretion from the healthy region of the pancreas (outside the focal hyperplasia). We therefore studied AIRs to calcium and tolbutamide stimulation tests in 16 children with focal (n = 9) or diffuse (n = 7) CHI before pancreatic surgery. We found hypervariable AIRs to glucose and calcium stimulation in both focal and diffuse CHI patients. AIRs to tolbutamide stimulation were found modest in focal CHI patients, which might account for beta-cell quiescence in the healthy portion of the pancreas of these patients. We conclude that AIRs to calcium and tolbutamide stimulation tests are not sufficient to differentiate the focal from the diffuse CHI patients. LACAILLE F., LESAGE F., de MONTALEMBERT M. Acute hepatic crisis in children with sickle cell disease. J. Pediat. Gastroenterol. Nutr., 39 (2), 200-202, 2004 (Services cités : Département de Pédiatrie) MAHE E., BODEMER C., DUPIC L., HUBERT P., LACAILLE F., GOULET O., LERUEZ-VILLE M., FRAITAG S. Drug-induced hypersensitivity syndrome associated with primary Epstein-Barr virus and human herpesvirus 6 infections in a child intestinal transplant recipient. Transplantation, 77 (3), 479-480, 2004 (Services cités : Anatomo-Pathologie, Département de Pédiatrie, Dermatologie, Laboratoire de Microbiologie, Réanimation Pédiatrique) MONTALEMBERT M.D. Sickle cell disease in the neonatal period. J. Gynécol. Obst. Biol. Reprod., 33 Suppl 1 12-14, 2004 (Services cités : Département de Pédiatrie) The prognosis of pregnancy in women with major sickle cell syndromes has improved greatly in recent years. Correction of maternal anemia with programmed transfusion has been a major advance. Rates of preterm birth and intra-uterine growth retardaion nevertheless remain high in this population. A newborn affected with sickle cell disease does not develop complications of the disease, because the predominant fetal hemoglobin cannot co-polymerize with sickle hemoglobin. The rate of complications increases as the infant's hemoglobin synthesis switches from fetal to sickle hemoglobin. Neonatal screening of sickle cell disease patients enables early implementation of a comprehensive prevention program (daily antibiotic prophylaxy, immunization, parental education.). A neonatal screening program, targeted with regard to the parents' ethnic background, has been implemented throughout metropolitan France since 1999. In 2002, this program enabled early diagnosis of sickle cell disease in 313 newborns. MUNCK A., MALBEZIN S., BLOCH J., GERARDIN M., LEBOURGEOIS M., DERELLE J., BREMONT F., SERMET I., MUNCK M.R., NAVARRO J. Follow-up of 452 totally implantable vascular devices in cystic fibrosis patients. Eur. Respir. J., 23 (3), 430-434, 2004

(Services cités : Département de Pédiatrie) The use and complications of totally implantable vascular access devices (TIVADs) were examined during multiple courses of antibiotics in cystic fibrosis (CF) patients. This retrospective study involved 36 CF centres. Risk factors for removal and septicaemia were sought by survival analysis of censored data. Multivariate Cox models were constructed with removal or septicaemia as the event and the characteristics of TIVADs as explanatory variables. TIVADs (n=452) were implanted in 315 patients. The mean functional time per device was 32 +/- 25 months. Long-term complications occurred with 188 devices (42%); they consisted mainly of occlusion (21%, requiring removal in 77%), infection (9.3% requiring removal in 85%; septicaemia in 7.3%; rate 0.3 per 1,000 days, Candida in 66%), and vascular thrombosis (4.7%, removal in 58%). Multivariate survival analysis showed that removal, whatever the reason, was associated with polyurethane (versus silicone) and routine use of the device for blood sampling (versus never). No risk factors, including heparin lock, were identified for septicaemia or for removal for obstruction. Totally implantable venous access devices appear to be safe and reliable for longterm intermittent venous access. Although retrospective, this study suggests that the characteristics of the material and blood sampling are risk factors for removal. PAPPAS P.A., G TZAKIS A., GAYNOR J.J., CARRENO M.R., RUIZ P., HUIJING F., KLEINER G., RABIER D., KATO T., LEVI D.M., NISHIDA S., GELMAN B., THOMPSON J.F., MITTAL N., SAUDUBRAY J.M. An analysis of the association between serum citrulline and acute rejection among 26 recipients of intestinal transplant. Amer. J. Transplant., 4 (7), 1124-1132, 2004 (Services cités : Génétique Médicale Pédiatrique, Département de Pédiatrie) Small preliminary studies suggest that serum citrulline levels may act as a marker for acute cellular rejection in small intestinal transplant recipients. The results comparing serum citrulline concentrations with biopsy-based grades of rejection are summarized here for an expanded group of 26 isolated intestinal and multivisceral transplant recipients. Other factors considered included patient and donor age and sex, ischemia time, serum creatinine, and type of transplant. Straight-line fits reasonably described how each patient's citrulline levels changed over time. Among 21 patients who demonstrated increasing citrulline levels over time, the estimated median time-to-achieve normal citrulline (>or=30 micromol/L) was 79 days post-transplant. Using stepwise linear regression, two characteristics were associated with a significantly higher maximum grade of rejection after 14 d post-transplant: longer time-to-achieve normal citrulline (using ranks, p < 0.00001) and the patient not receiving a multivisceral transplant (p = 0.0005). Only the latter characteristic was significantly associated with maximum grade of rejection during the first 14 d post-transplant (p = 0.01). Clearly, time-to-normalization of citrulline was delayed by the incidence of rejection, and in some cases with moderate-to-severe rejection, normalization of citrulline levels never occurred. We plan to further examine the use of citrulline as a marker for rejection in larger prospective studies. REY J., AGGETT P., KOLETZKO B. Thirty Years of the ESPGAN/ESPGHAN Committee on Nutrition. J. Pediat. Gastroenterol. Nutr., 39 (5), 474-479, 2004 (Services cités : Département de Pédiatrie) The creation of the Committee on Nutrition of ESPGAN (later ESPGHAN) in 1974 was stimulated by the need to define generally acceptable standards for infant feeding and for dietetic

products for infants. Since the late 1970s the Committee has published a series of widely respected authoritative comments that have provided guidance for pediatricians, regulatory bodies and manufacturers of food products in Europe and other parts of the world. The Committee and its members have also contributed to the development of standards by the Codex Alimentarius Committee of the World Health Organization and of the Food and Agriculture Organization of the United Nations, and of standards in the European Union. Among the further aims of the Committee aims is the stimulation and support of young researchers entering the field of nutrition and metabolism, as well as the lobbying for public and private funding that supports pediatric nutrition research. The strong tradition of 30 successful years with the achievements made, and the appreciation of the vision and determination of the pioneers who had built the Committee, provide a major stimulus to strive for continued excellence in achieving the Committee's mission. ROBERT C.D., LACAILLE F., CANIONI D., QUARTIER-DIT-MAIRE P., TALBOTEC C., GOULET O. EBV-negative lymphoproliferative disease with hyper-IgA, in a child with combined liver and small bowel transplantation. Pediat. Transplant., 8 (3), 305-307, 2004 (Services cités : Anatomo-Pathologie, Département de Pédiatrie) Des Robert C, Lacaille F, Canioni D, Quartier-dit-Maire P, Talbotec C, Goulet O. EBV-negative lymphoproliferative disease with hyper-IgA, in a child with combined liver and small bowel transplantation. Pediatr Transplantation 2004: 8: 305-307. Copyright 2004 Blackwell MunksgaardAbstract: A 4-year-old boy presented 14 months after liver and small bowel transplantation with fever, diarrhea, elevated liver enzymes, thrombocytopenia and autoantibodies. Total gammaglobulins level was normal but the level of plasma IgA1 was very high. The blood PCR for Epstein-Barr virus (EBV) was negative. The ileal biopsy disclosed a lymphoplasmacytic infiltration. The EBER probe was negative on the small bowel biopsies. The child was considered as suffering from a non-EBV-induced posttransplant lymphoproliferative disorder (PTLD). The high IgA level was presumed to be secreted by proliferating plasma cells in the transplanted bowel. Immunosuppression was reduced; but the efficacy was incomplete and an anti-CD20 antibody was added. There was complete resolution of symptoms and normalization of the IgA level. As IgA1 is mostly of intestinal origin, this unusual presentation of PTLD should lead to a high suspicion of a small bowel proliferating process. RUEMMELE F.M., JAN D., LACAILLE F., CEZARD J.P., CANIONI D., PHILLIPS A.D., PEUCHMAUR M., AIGRAIN Y., BROUSSE N., SCHMITZ J., REVILLON Y., GOULET O. NEW PERSPECTIVES FOR CHILDREN WITH MICROVILLOUS INCLUSION DISEASE: EARLY SMALL BOWEL TRANSPLANTATION. Transplantation, 77 (7), 1024-1028, 2004 (Services cités : Anatomo-Pathologie, Chirurgie Pédiatrique, Département de Pédiatrie, Gastroentérologie Pédiatrique) BACKGROUND.: Microvillous inclusion disease (MVID) is a congenital intestinal epithelial cell disorder leading to lifelong intestinal failure. Despite long-term total parenteral nutrition, life expectancy is extremely reduced because of metabolic or septic complications or liver failure. METHODS.: Twelve patients with early-onset MVID were evaluated between 1995 and 2002 for the possibility of small bowel transplantation (SbTx). Three patients died before they could be

placed on the waiting list for SbTx, and one patient is still awaiting SbTx. SbTx was contraindicated in one patient. RESULTS.: Seven of 12 patients (six boys and one girl) underwent transplantation (three SbTxs and four combined liver-SbTxs). Actuarial survival rates were 100% and 75% in the SbTx and combined liver-SbTx groups, respectively, with a mean follow-up of 3 years (1.1-8.5 years). In contrast, the survival rate was only 40% in the subgroup of five patients who did not undergo transplantation. After transplantation, all patients were weaned from parenteral nutrition: the five patients with an additional colon graft were weaned within 36 days as opposed to the others without colonic transplant who obtained full intestinal autonomy several months after transplantation. The only two surviving patients who did not undergo SbTx remain highly dependent on total parenteral nutrition, which is complicated by repeated episodes of metabolic decompensation. CONCLUSIONS.: SbTx alone or in combination with the liver is highly successful in children with MVID, offering them a long-term perspective for the first time. Associated colon grafting markedly improves the outcome and quality of life after SbTx in patients with MVID. SCHULER D., SERMET-GAUDELUS I., WILSCHANSKI M., BALLMANN M., DECHAUX M., EDELMAN A., HUG M., LEAL T., LEBACQ J., LEBECQUE P., LENOIR G., STANKE F., WALLEMACQ P., TUMMLER B., KNOWLES M.R. Basic protocol for transepithelial nasal potential difference measurements. J. Cyst. Fibrosis, 3 (sup.2), 151-155, 2004 (Services cités : Département de Pédiatrie, U467) SERMET-GAUDELUS I., de LA ROCQUE F., SALOMON J.L., LACHASSINE E., LERUEZ-VILLE M., BAUJAT G., TRIOCHE P., VALDES L., PAREZ N., AUJARD Y. Rotavirus nosocomial infection in pediatric units. A multicentric observation study. Pathol. Biol., 52 (1), 4-10, 2004 (Services cités : Département de Pédiatrie) Objective. - Rotavirus nosocomial infection (RNI) is frequent in pediatric units. This study was designed to determine the incidence and the main risk factors of RNI in children aged 3 months-3 years and admitted for at least 48 hours days during the epidemic period. Patients and methods. - A stool sample was obtained within the 24 hours of admission. An additional sample was collected from rotavirus-negative children either the day of discharge, or when they developed abnormal clinical signs. Parents were contacted by phone after discharge. Children initially rotavirus-negative and positive 2 days or more after admission were considered as certain nosocomial cases. In the absence of the second sample, possible nosocomial cases were considered if new symptoms (i.e.; fever and or digestive symptoms) occurred 2 days or more after the first negative sample. Results. - One hundred and seventeen children were included. The incidence was 11.1% for certain NRI, 16.8% for possible hospital-acquired cases and 19.4% for the whole cases. Possible risk factors were the low number of nurses during the weekend, the great number of medicine students in the unit, and no use of individual material. Conclusion. - NRI have a high incidence, whose reality can only be approximated by taking into account the possible NRI occurring at home after hospital-discharge. VILA G., ZIPPER E., DABBAS M., BERTRAND C., ROBERT J.J., RICOUR C., MOUREN-SIMEONI M.C. Mental disorders in obese children and adolescents. Psychosom. Med., 66 (3), 387-394, 2004

(Services cités : Pédo-Psychiatrie, Département de Pédiatrie) OBJECTIVE: To evaluate the type and frequency of psychiatric disorders in obese children and adolescents; to assess the correlation between psychopathology and severity of obesity; to explore the relationship between psychiatric disorders in obese children and obesity and psychopathology in their parents. METHODS: One hundred fifty-five children referred and followed for obesity were evaluated (98 girls and 57 boys; age, 5 to 17 years). Psychiatric disorders were assessed through a standardized diagnostic interview schedule (K-SADS R) and self-report questionnaires completed by the child (STAIC Trait-anxiety and CDI for depression) or his (her) parents (CBCL or GHQ). These obese children were compared with insulin-dependent diabetic (IDDM) outpatient children (N = 171) on questionnaire data. RESULTS: Eighty-eight obese children obtained a DSM-IV diagnosis, most often an anxiety disorder (N = 63). Psychological disorders were particularly pronounced in those obese children whose parents were disturbed. There was no correlation between severity of obesity in the child or his (her) parents and frequency of psychiatric disorders. Compared with diabetic children, they displayed significantly higher internalized and externalized questionnaire scores and poorer social skills. CONCLUSION: These results highlight the importance of including a child psychiatric component in the treatment of obesity, which must engage the whole family. VILLAIN E. Congenital complete atrio-ventricular block. Arch. Mal. Coeur Vaisseaux, 97 (10), 994-999, 2004 (Services cités : Département de Pédiatrie) Congenital complete atrio-ventricular block is a rare condition, the result of an anatomical anomaly of the conduction pathways, or even the trans-placental passage of maternal antibodies causing fetal myocarditis with fibrosis of the conduction tissue. It is not clear whether AV block discovered later in childhood is really "congenital". Whatever the age of the child, the only treatment is pacemaker implantation. Cardiac failure and syncope are absolute indications for implantation. Children whose heart rate is below 50 beats per minute (bpm) represent a group at high risk of syncope or even sudden death and must be paced, even if asymptomatic. Moreover, certain patients with immunological complete AV block have cardiopathy and must also be paced. In our department, the route for pacing is epicardial in younger children, in practice weighing less than 10-15 kg, and endocavitary in older children. The choice is either double chamber pacing, which restores AV conduction initiated by the child's sinus, or ventricular pacing with activity-controlled heart rate. Although worrying complications have been described, such as venous thrombosis, infections related to repeated interventions, and delayed cardiomyopathy, the results of paediatric pacing are generally satisfactory and the great majority of children with congenital complete AV block lead a normal life. 2003 ACAR P., MAUNOURY C., de MONTALEMBERT M., DULAC Y. Abnormalities of myocardial perfusion in sickle cell disease in childhood: A study of myocardial scintigraphy. Arch. Mal. Coeur Vaisseaux, 96 (5), 507-510, 2003 (Services cités : Département de Pédiatrie, Biophysique & Médecine Nucléaire) Ischaemic complications are common in SS homozygotic sickle cell disease in children, but the heart does not appear to be the target organ. The early detection of myocardial ischaemic in these children could prevent cardiac complications. The authors undertook a study of myocardial

perfusion by myocardial scintigraphy in children with sickle cell disease. Twenty-three patients (average age 12 5 years) underwent Thallium 201 myocardial scintigraphy. Exercise on a bicycle ergometer and/or intravenous injection of dipyridamole were carried out depending on the age. The images (on exercise and late recovery period) were analysed in the 3 standard projections of the left ventricle: short axis, long axis and 4-chamber view. The left ventricular ejection fraction was measured by gamma angiography. Myocardial perfusion was abnormal in 14 patients (61%). The perfusion defects were reversible in the late recovery period in 9 patients and irreversible in 5 patients. The average left ventricular ejection fraction was 63 9%. Its value was not related to symptoms, haemoglobin level or the results of myocardial scintigraphy. Four patients with perfusion defects were symptomatic (cardiac failure, angina or ventricular tachycardia); 1 patient died and 3 were treated with hydroxyurea. Myocardial scintigraphy was carried out 6 months later and showed improved perfusion in 3 patients. Abnormalities of myocardial perfusion are therefore common in sickle cell disease. Often asymptomatic in childhood, there is a real risk of ischaemic cardiomyopathy and its complications in adulthood. Specific treatment of sickle cell disease with hydroxyurea should be considered in cases with significant abnormalities of myocardial perfusion. BRADAI M., ABAD M.T., PISSARD S., LAMRAOUI F., SKOPINSKI L., de MONTALEMBERT M. Hydroxyurea can eliminate transfusion requirements in children with severe beta-thalassemia. Blood, 102 (4), 1529-1530, 2003 (Services cités : Département de Pédiatrie) Hydroxyurea (HU) enhances fetal hemoglobin (Hb) production. An increase in total Hb level has been repeatedly reported during HU treatment in patients with sickle cell disease and in several patients with beta-thalassemia intermedia. Effects in patients with beta-thalassemia major are controversial. We now report a marked elevation of total Hb levels with HU that permitted regular transfusions to be stopped in 7 children with transfusion-dependent beta-thalassemia. The median follow-up was 19 3 months (range, 13-21 months). We conclude that HU can eliminate transfusional needs in children with beta-thalassemia major, which could be particularly useful in countries such as Algeria, where supplies of blood or chelating agents are limited. BRIVET M., GARCIA-CAZORLA A., LYONNET S., DUMEZ Y., NASSOGNE M.C., SLAMA A., BOUTRON A., TOUATI G., LEGRAND A., SAUDUBRAY J.M. Impaired mitochondrial pyruvate importation in a patient and a fetus at risk. Mol. Genet. Metab., 78 (3), 186-192, 2003 (Services cités : Maternité, Génétique Médicale Pédiatrique, Département de Pédiatrie) The patient was the first child of healthy consanguineous parents. She presented at birth with hypotonia, mild facial dysmorphism, periventricular cysts, marked metabolic acidosis, hyperlactacidemia with normal lactate/pyruvate molar ratios, normoglycemia, and normal ammonia. Hyperlactacidemia was severe (5-14mmol/l) and not corrected with bicarbonate, thiamine (10mg/d), 2-chloropropionate (100mg/kg/d) and a ketogenic diet. Pyruvate dehydrogenase (PDHC) activity was normal in lymphocytes and fibroblasts. Functional assays were performed in digitonin-permeabilized fibroblasts to measure oxidation rates from radiolabeled pyruvate and malate. The production of [14C]acetylcarnitine or [14C]citric cycle intermediates derived from [2-14C]pyruvate as well as the release of 14CO(2) from [1-14C]pyruvate was severely impaired, whereas decarboxylation of [U-14C]malate was normal. With increasing concentrations of [1-14C]pyruvate, the patient's fibroblasts behave like control

fibroblasts incubated in the presence of alpha-cyano-4-hydroxycinnamate, a specific inhibitor of mitochondrial pyruvate uptake: a progressive increase in 14CO(2) production was observed, likely due to passive diffusion of [1-14C]pyruvate through the mitochondrial membranes. Our results are consistent with a defect of mitochondrial pyruvate transport in the patient. Mutational analysis was precluded as the cDNA sequence of the pyruvate carrier has not been identified as yet in any organism. An affected fetus was recognized in a subsequent dichorionic twin pregnancy using the coupled assay measuring [2-14C]pyruvate oxidation rates on digitonin-permeabilized trophoblasts. After selective feticide, the pregnancy was uncomplicated with delivery at 37w of a healthy female, who is currently 2-month old. BROUSSE V., IMBERT P., MBAYE P., KIEFFER F., THIAM M., KA A.S., GERARDIN P., SIDI D. Evaluation au Sénégal du devenir des enfants transférés pour chirurgie cardiaque. Méd. Trop., 63 (4-5), 506-512, 2003 (Services cités : Département de Pédiatrie, Cardiologie Pédiatrique) The incidence of childhood heart disease in developing countries is high, but access to cardiac surgery is limited. This mismatch has given rise to numerous humanitarian programs aimed at sending children abroad for surgical treatment. However little is available about the long-term outcome of these interventions. In 1999 we conducted a retrospective study of 168 Senegalese children undergoing follow-up at the Principal Hospital in Dakar after being transferred to Europe or the Ivory Coast for surgical treatment thanks to the Terre des Hommes Association. A total of 85 children presented congenital heart disease (CHD) and 83 presented acquired heart disease (AHD). Fifteen patients did not undergo surgery due to either contraindications or preoperative death. At the end of study, 23 children had been lost to follow-up mostly from the CHA group and presumably some were cured. Outcome was verifiable in the remaining 145 patients with a median follow-up of 5.6 years. Ninety-seven patients were cured or undergoing surveillance. Quality of life was better in the CHD group (p = 0.047). Forty-eight patients died including 16 in the CHD group and 32 in the AHD group. Perioperative mortality (n = 19) was lower and late mortality (n = 29) was higher in the AHD group (p = 0.005). In the AHD group compliance with surveillance was better for children with valve prostheses. In children treated for isolated mitral valve insufficiency, late mortality was higher after valve replacement than valve repair (p = 0.04). In absence of comparative study data, high mortality was due in part to the long delay between the decision to send the patient abroad and the actual evacuation. These findings support humanitarian action to promote cardiac surgery in developing countries. DE LEERSNYDER H., BRESSON J.L., de BLOIS M.C., SOUBERBIELLE J.C., MOGENET A., DELHOTAL-LANDES B., SALEFRANQUE F., MUNNICH A. beta(1)-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith-Magenis syndrome. J. Med. Genet., 40 (1), 74-78, 2003 (Services cités : U393, Génétique Médicale Pédiatrique, Département de Pédiatrie, CIC 9303, Explorations Fonctionnelles) DE LONLAY P., GIURGEA I., SAUDUBRAY J.M. Molecular testing in inborn metabolic diseases. Archives Pédiatrie, 70 (Suppl.1), 75S-78S, 2003 (Services cités : Département de Pédiatrie)

DE MONTALEMBERT M. Antibiotic prophylaxis against bacterial infections in the hyposplenic or asplenic child. Presse Médicale, 32 (28), S15-S16, 2003 (Services cités : Département de Pédiatrie) Antibiotic prophylaxis against bacterial infections in the hyposplenic or asplenic child. Risk of infection in splenectomized children: Observations in cohorts of splenectomized patients have led to the conclusion that the risk of bacterial infection is highest among young children, particularly under the age of 2 years, within 2 years of splenectomy and in children with an associated disease. Severity of the infections. According to the Holdsworth study conducted between 1952 and 1987, the rate of postoperative infection in splenectomized children under the age of 16 years is 4.4%, mortality reaching 2.2%. The risk of severe bacterial infection is also high in sickle-cell anemia children and is the leading cause of death in this age group. Basis for antibiotic prophylaxis. Current guidelines concerning antibiotic prophylaxis in asplenic and hyposplenic children are based on several notions: not giving antibiotic prophylaxis is unacceptable due to the major vulnerability of these children to pneumococcal infection and the frequence of pneumococcal colonization in this age group; the antibiotic given should have a narrow spectrum. Guidelines: Antibiotic prophylaxis against infection in asplenic and hyposplenic children is based on daily administration of Oracilline(R) (Penicilline V). Prophylaxis is started at diagnosis in sickle-cell anemia children, i.e. around 2-3 months of age in case of neonatal screening. Oracilline(R) should be given at least 5 years after splenectomy or even longer, and up to the age of 15 years in sickle-cell anemia children who develop frequent ENT/bronchial complications or have a history of pneumococcal infection. FERRONI A., SERMET-GAUDELUS I., ABACHIN E., QUESNES G., LENOIR G., BERCHE P., GAILLARD J.L. Phenotypic and genotypic caracteristics of non fermenting atypical strains recovered from cystic fibrosis patients. Pathol. Biol., 51 (7), 405-411, 2003 (Services cités : Laboratoire de Microbiologie, Département de Pédiatrie) We used partial 16S rRNA gene (16S DNA) sequencing for the prospective identification of nonfermenting Gram-negative bacilli recovered from patients attending our cystic fibrosis center (hopital Necker-Enfants malades), which gave problematic results with conventional phenotypic tests. During 1999, we recovered 1093 isolates of nonfermenting Gram-negative bacilli from 702 sputum sampled from 148 patients. Forty-six of these isolates (27 patients) were not identified satisfactorily in routine laboratory tests. These isolates were identified by 16S DNA sequencing as Pseudomonas aeruginosa (19 isolates, 12 patients), Achromobacter xylosoxidans (10 isolates, 8 patients), Stenotrophomonas maltophilia (9 isolates, 9 patients), Burkholderia cepacia genomovar I/III (3 isolates, 3 patients), Burkholderia vietnamiensis (1 isolate), Burkholderia gladioli (1 isolate) and Ralstonia mannitolilytica (3 isolates, 2 patients). Fifteen isolates (33%) were resistant to all antibiotics in routine testing. Sixteen isolates (39%) resistant to colistin were recovered on B. cepacia-selective medium: 2 P. aeruginosa, 3 A. xylosoxidans, 3 S. maltophilia and the 8 Burkholderia - Ralstonia isolates. The API 20NE system gave no identification for 35 isolates and misidentified 11 isolates (2 P. aeruginosa, 2 A. xylosoxidans and 1 S. maltophilia classified as B. cepacia ). Control measures and/or treatment were clearly improved as a result of 16S DNA sequencing in three of these cases. This study confirms the weakness of phenotypic methods for identification of atypical nonfermenting Gram-negative bacilli recovered from cystic

fibrosis patients. The genotypic methods, such as 16S DNA sequencing which allows identification of strains in routine practice, appears to have a small, but significant impact on the clinical management of CF patients. HURBAIN I., SERMET-GAUDELUS I., VALLEE B., FEUILLET M.N., LENOIR G., BERNAUDIN J.F., EDELMAN A., FAJAC A. Evaluation of MRP1-5 gene expression in cystic fibrosis patients homozygous for the delta F508 mutation. Pediat. Res., 54 (5), 627-634, 2003 (Services cités : U467, Département de Pédiatrie, Biochimie Générale) Cystic fibrosis (CF), due to mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), exhibits a wide range of disease severity, even among deltaF508 homozygous patients, and the mechanisms of this variability have yet to be elucidated. In view of the close structural homology and possible functional overlap between CFTR and Multidrug Resistance-associated Proteins (MRPs), MRPs were investigated as potentially relevant factors in CF pathophysiology. MRP1-5 gene expression was analyzed in nasal respiratory epithelial cells from deltaF508 homozygous patients (n = 19) and control subjects (n = 20) using semiquantitative RT-PCR. Significantly lower MRP1 and MRP5 transcript levels were found in CF patients than in control subjects. MRP1 and MRP5 transcript levels were strongly correlated (r = 0.71). In CF patients, low MRP1 transcript levels were associated with more severe disease as assessed by the Shwachman score. A relation was also observed between MRP1 levels and presence of a cAMP-independent chloride conductive pathway, as determined by a halide-sensitive fluorescent assay. These results suggest that MRPs, especially MRP1, might play a role in CF phenotype and might therefore constitute a target for a novel pharmacotherapy of CF. LACAILLE F. Hepatitis B vaccination and anti-HBc-positive livers in children. Hepatology, 38 (5), 1311, 2003 (Services cités : Département de Pédiatrie) LACAILLE F., SOMMACALE D., BELGHITI J., REVILLON Y. Evaluation of the donor for living-related liver transplantation. Transplant. Proc., 35 (3), 960, 2003 (Services cités : Département de Pédiatrie, Chirurgie Pédiatrique) NABBOUT R., DULAC O. Epileptic encephalopathies : a brief overview. J. Clin. Neurophysiol., 20 (6), 393-397, 2003 (Services cités : Département de Pédiatrie) Epileptic encephalopathies are conditions in which neurologic deterioration is attributable entirely or partly to epileptic activity. It can be due to very frequent or severe seizures and/or to subcontinuous paroxysmal interictal activity. The former mainly consists of Dravet syndrome, in which patients have seizures from the middle of the first year of life and repeat episodes of severe febrile status epilepticus and migrating partial epilepsy in infancy, in which from the first trimester of life, partial seizures affect various areas of the cortex randomly and in a subcontinuous fashion. In Rasmussen syndrome, also, epileptic activity contributes at least partly to the neurologic deterioration. Subcontinuous paroxysmal interictal activity affects newborn

infants with suppression bursts, thus consisting in either Ohtahara syndrome or neonatal myoclonic encephalopathy. In infants, it is either myoclonic epilepsy of nonprogressive encephalopathy or West syndrome. In school-age children, it consists of various types of generalized seizures combined with slow spike waves of the Lennox-Gastaut syndrome, myoclonic-astatic epilepsy, and continuous spike waves in slow sleep combined with various motor or cognitive deficits including negative myoclonus, orofacial dyspraxia, Landau-Kleffner syndrome, and frontal lobe syndrome. Treatment differs for all of these syndromes. It is important to avoid potential drug-induced worsening, and valproate is preferred when a definitive diagnosis is not reached in children and especially infants. RAQBI F., LE BIHAN C., MORISSEAU-DURAND M.P., DUREAU P., LYONNET S., ABADIE V. Early prognostic factors for intellectual outcome in CHARGE syndrome. Dev. Med. Child Neurol., 45 (7), 483-488, 2003 (Services cités : Génétique Médicale Pédiatrique, Département de Pédiatrie) CHARGE syndrome (coloboma, heart disease, atresia of the choanae, retarded growth and mental development, genital anomalies, and ear malformations and hearing loss) is a heterogeneous condition for which early prediction of intellectual outcome is important but difficult. The psychomotor milestones and intellectual outcome of a consecutive series of children with CHARGE syndrome who were observed by the same team from the neonatal period to the time of study were analyzed retrospectively. Twenty-one children (11 males and 10 females, aged from 5 to 12 years, mean 8 years 7 months, SD 2 years 5 months) were included. The influence of 19 early identifiable parameters that could be considered as deleterious for intellectual outcome was recorded. Generally, the main psychomotor milestones (0 to 4 years) were severely delayed, although intellectual outcome (at primary-school age) was satisfactory for half the children in this series. We show that extensive bilateral coloboma resulting in low vision, microcephaly, and brain malformation were the only three parameters that were predictive of poor intellectual outcome. Conversely, severe neonatal medical conditions, such as tracheotomy, conditions requiring long stays in hospital, or cardiac surgery were not predictive of poor intellectual outcome. Severe hearing loss was not found to be negatively correlated with intellectual outcome once coloboma had been taken into account. SARTORATO P., LAPEYRAQUE A.L., ARMANINI D., KUHNLE U., KHALDI Y., SALOMON R., ABADIE V., DI BATTISTA E., NASELLI A., RACINE A., BOSIO M., CAPRIO M., POULET-YOUNG V., CHABROLLE J.P., NIAUDET P., de GENNES C., LECORNEC M.H., POISSON E., FUSCO A.M., LOLI P., LOMBES M., ZENNARO M.C. Different inactivating mutations of the mineralocorticoid receptor in fourteen families affected by type I pseudohypoaldosteronism. J. Clin. Endocrinol. Metabol., 88 (6), 2508-2517, 2003 (Services cités : Néphrologie Pédiatrique, Département de Pédiatrie) We have analyzed the human mineralocorticoid receptor (hMR) gene in 14 families with autosomal dominant or sporadic pseudohypoaldosteronism (PHA1), a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Six heterozygous mutations were detected. Two frameshift mutations in exon 2 (insT1354, del8bp537) and one nonsense mutation in exon 4 (C2157A, Cys645stop) generate truncated proteins due to premature stop codons. Three missense mutations (G633R, Q776R, L979P) differently affect hMR function. The DNA binding domain mutant R633 exhibits reduced

maximal transactivation, although its binding characteristics and ED(50) of transactivation are comparable with wild-type hMR. Ligand binding domain mutants R776 and P979 present reduced or absent aldosterone binding, respectively, which is associated with reduced or absent ligand-dependent transactivation capacity. Finally, P979 possesses a transdominant negative effect on wild-type hMR activity, whereas mutations G633R and Q776R probably result in haploinsufficiency in PHA1 patients. We conclude that hMR mutations are a common feature of autosomal dominant PHA1, being found in 70% of our familial cases. Their absence in some families underscores the importance of an extensive investigation of the hMR gene and the role of precise diagnostic procedures to allow for identification of other genes potentially involved in the disease. SERMET-GAUDELUS I., SOUBERBIELLE J.C., AZHAR I., RUIZ J.C., MAGNINE P., COLOMB V., LE BIHAN C., FOLIO D., LENOIR G. Insulin-like growth factor I correlates with lean body mass in cystic fibrosis patients. Arch. Dis. Child., 88 (11), 956-961, 2003 (Services cités : Département de Pédiatrie) BACKGROUND: A major consequence of malnutrition in cystic fibrosis (CF) patients is the loss of lean body mass (LBM) and the subsequent impairment of respiratory muscle function. AIM: To determine whether insulin-like growth factor I (IGF-I) could be related to the LBM depletion and the evolution of respiratory disease in CF patients. METHODS: LBM was evaluated by dual energy x ray absorptiometry; serum concentrations of IGF-I were measured in 24 CF patients twice with a one year interval. Both values were expressed as SD score (SDS) calculated from normal data for age, sex, and pubertal stage and analysed with respect to anthropometric evaluation and disease related conditions. RESULTS: At the initial evaluation, IGF-I SDS had a mean value of -0.98 (range -3.6 to 3.2) and correlated with weight for age index, LBM SDS, and lung disease related conditions. Multiple regression analysis showed that only LBM remained independently related to IGF-I, suggesting that the relation of IGF-I to LBM was independent of weight and that the correlation between IGF-I and the respiratory conditions was related to the level of LBM. IGF-I SDS at the first evaluation was lower for the patients who lost > or =5% of weight for age index or > or =1 SD of LBM between the two evaluations. CONCLUSION: Low levels of IGF-I could be crucial for clinical outcome by impairing LBM and respiratory function. IGF-I could be a tool for nutritional evaluation by identifying the CF patients at risk of LBM depletion. SERMET-GAUDELUS I., LE BOURGEOIS M., PIERRE-AUDIGIER C., OFFREDO C., GUILLEMOT D., HALLEY S., AKOUA-KOFFI C., VINCENT V., SIVADON-TARDY V., FERRONI A., BERCHE P., SCHEINMANN P., LENOIR G., GAILLARD J.L. Mycobacterium abscessus and children with cystic fibrosis. Emerg. Infect. Dis., 9 (12), 1587-1591, 2003 (Services cités : Pneumologie-Allergologie Pédiatrique, Laboratoire de Microbiologie, Département de Pédiatrie) We prospectively studied 298 patients with cystic fibrosis (mean age 11.3 years; range 2 months to 32 years; sex ratio, 0.47) for nontuberculous mycobacteria in respiratory samples from January 1, 1996, to December 31, 1999. Mycobacterium abscessus was by far the most prevalent nontuberculous mycobacterium: 15 patients (6 male, 9 female; mean age 11.9 years; range 2.5-22 years) had at least one positive sample for this microorganism (versus 6 patients positive for M. avium complex), including 10 with >3 positive samples (versus 3 patients for M. avium

complex). The M. abscessus isolates from 14 patients were typed by pulsed-field gel electrophoresis: each of the 14 patients harbored a unique strain, ruling out a common environmental reservoir or person-to-person transmission. Water samples collected in the cystic fibrosis center were negative for M. abscessus. This major mycobacterial pathogen in children and teenagers with cystic fibrosis does not appear to be acquired nosocomially. SERMET-GAUDELUS I. Treatment of staphylococcal infections in cystic fibrosis. Rev. Mal. Resp., 20 (2Pt2), S91-S99, 2003 (Services cités : Département de Pédiatrie) THIBAULT H., ROLLAND-CACHERA M.F. Prevention strategies of childhood obesity. Archives Pédiatrie, 10 (12), 1100-1108, 2003 (Services cités : Département de Pédiatrie) Considering the high prevalence and the increasing trends, obesity is now considered as a public health problem in numerous countries. The main aim of the National Program of Nutrition and Health is to stop the increasing prevalence of childhood obesity. In this frame work, a group of experts has established a new presentation of the corpulence curves, adapted for clinical practice, to define normal weight and obesity. Weight status is now currently assessed on the basis of weight and height measurements, after computing the Quetelet index or body mass index (BMI) corresponding to weight (m) divided by square of height (weight/height2). As body proportion varies during growth, age must be taken into account. Various curves were published. In 1982, based on the French sample of the international growth study, BMI curves were published. They were revised in 1991. The third and 97th centiles define the normal weight range. Overweight is defined by BMI values greater than the 97th centile. In the year 2000, a new international definition was established. Two centiles were constructed to define overweight and obesity. The new BMI charts adapted for clinical practice, proposed by the French National program of nutrition and health, include the French reference curves plus the centile defining obesity in the international definition. Thus, in the new French charts, the area above the 97th centile is split in two levels (degree 1 obesity and degree 2 obesity). Drawing the BMI curve for each child, like drawing weight and height curves, is a simple act which can be done routinely. The age at adiposity rebound (an indicator predicting the risk of adult obesity) can be read from the curve. It allows to identify an early phase of obesity development, even at the time when overweight is not yet clinically visible. When obesity appears clearly, the identification is easy. The use of BMI curves is particularly useful in two situations: (1) in very young overweight children, the curves allow to identify children who have a real risk of developing obesity. (2) By the age of 6 years, when due to normal physiological variations, clinical assessment can be misleading. The BMI curves allow to identify children at risk. When a child is identified as having a real risk of obesity, simple preventive measures, adapted for each subject, could avoid a development toward massive obesity, which may become difficult to reduce if managed too late. THURET I., LACAILLE F., CANIONI D., ROQUELAURE B., MICHEL G., BLANCHE S. Histopathology of the liver in adolescents co-infected with HIV and hepatitis C virus. AIDS, 17 (15), 2265-2267, 2003 (Services cités : Immuno-Hématologie Pédiatrique, Département de Pédiatrie)

WILLEMOT J.M., SERMET-GAUDELUS I., LENOIR G. New therapeutic approaches to Cystic fibrosis. Ann. Pharm. Fr., 61 (4), 253-258, 2003 (Services cités : Département de Pédiatrie) Since the cloning of the defective gene in cystic fibrosis, much has been learned on the function of CFTR and on the mechanisms regulating its expression. Based on the current understanding of the processes involved in lung disease progression, a number of approaches have been developed using gene therapy and pharmacological agents. Several of these agents have been reported to restitute a function to CFTR with specific mutations. Other molecules act on channels other than CFTR, and may be effective by bypassing CFTR itself. In the present review the various therapeutical strategies currently investigated are discussed. 2002 ABADIE V., MORISSEAU-DURAND M.P., BEYLER C., MANACH Y., COULY G. Brainstem dysfunction: a possible neuroembryological pathogenesis of isolated Pierre Robin sequence. Eur. J. Pediat., 161 (5), 275-280, 2002 (Services cités : Département de Pédiatrie, Stomatologie & Chirurgie Maxillo-Faciale) Pierre Robin sequence (posterior U-shape cleft palate, glossoptosis, retrognathia) (PRS) is a frequent and heterogeneous neonatal condition of obscure origin. We show here that orodigestive and cardiorespiratory functional disorders are very frequent in PRS and that these functional disorders, as well as anatomical and embryological data, argue for the involvement of brainstem dysfunction in the pathogenesis of some cases of isolated PRS. A total of 66 infants consecutively admitted for isolated PRS were followed-up with observations and investigations focused on their orodigestive and cardiorespiratory disorders. Neonatal clinical examination and neonatal anatomical aspects of the three orofacial features of the sequence were evaluated. Feeding difficulties and respiratory disorders were recorded and infants were classified according to three grades of severity. The relation between functional severity grade and neonatal orofacial features was evaluated, as well as the relation between functional severity grade and specific criteria characterising oesophageal and laryngeal motility and cardiac orthoparasympathetic imbalance. In the first weeks of life, sucking and swallowing disorders (100%), excessive regurgitation (94%), upper airways obstruction (50%), and cardiac vagal overactivity (59%) were noted. Correlation of anatomical features with functional severity grades was poor except for extreme forms of glossoptosis and retrognathia. Specific anomalies of oesophageal motility, pharyngolaryngeal tone and parasympathetic cardiac regulation were described. These anomalies were more frequent in children with the two higher grades of functional severity. CONCLUSION: infants with Pierre Robin sequence have early and severe anomalies of orodigestive and cardiorespiratory function which do not appear to be related solely to anatomical features and which require proper medical management. We suggest a prenatal and neonatal brainstem dysfunction as a neuroembryological hypothesis to explain the onset of some cases of Pierre Robin sequence. BARDAKDJIAN-MICHAU J., GUILLOUD-BATAILLE M., MAIER-REDELSPERGER M., ELION J., GIROT R., FEINGOLD J., GALACTEROS R., DE-MONTALEMBERT M. Decreased morbidity in homozygous sickle cell disease detected at birth. Hemoglobin, 26 (3 ), 211-217, 2002

(Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique) In metropolitan France, newborn screening for sickle cell disease has been performed at the Hopital Henri Mondor, Creteil, since 1985. After confirmation of the diagnosis, children are enrolled in a comprehensive medical-care program. Our aim was to evaluate the effectiveness of this program in France where most families are first generation immigrants with cultural and social differences that can interfere with medical follow-up. We compared the complications of sickle cell disease in two populations of homozygous SS children aged more than two years at their last medical visit, and recruited from an initial register of 134 SS children: (1) 38 diagnosed by neonatal screening; (2) 69 controls, diagnosed at a mean age of 24 months. Mean age at the last medical visit is 58 months in both groups. BASTARD J.P., MAACHI M., VAN NHIEU J.T., JARDEL C., BRUCKERT E., GRIMALDI A., ROBERT J.J., CAPEAU J., HAINQUE B. Adipose Tissue IL-6 Content Correlates with Resistance to Insulin Activation of Glucose Uptake both in Vivo and in Vitro. J. Clin. Endocrinol. Metabol., 87 (5), 2084-2089, 2002 (Services cités : Département de Pédiatrie) Obesity and type 2 diabetes are associated with insulin resistance, the mechanisms of which remain poorly understood. A significant correlation between circulating IL-6 level and insulin sensitivity has recently been found in humans. Because adipose tissue could be a significant source of IL-6, we analyzed the relationship between the levels of adipose tissue IL-6 and insulin action in vivo, during a hyperinsulinemic normoglycemic clamp, and in vitro by measuring glucose transport in adipocytes from 12 obese subjects with (n = 7) or without (n = 5) diabetes. We observed an inverse correlation between adipose tissue IL-6 content and maximal insulin-responsiveness measured in vivo (P < 0.02) and in vitro (P < 0.02). Conversely, there was no significant correlation between these two later parameters and adipose tissue leptin or tumor necrosis factor-alpha protein contents. Furthermore, we showed, for the first time, the presence of immunoreactive IL-6 receptors in the plasma membrane of human abdominal sc adipocytes. This suggests that locally secreted IL-6 could act on adipocytes by an autocrine/paracrine mechanism. In conclusion, increased IL-6 production by sc adipose cells might participate to the insulin-resistant state observed in human obesity. BUSEYNE F., LE CHENADEC J., CORRE B., PORROT F., BURGARD M., ROUZIOUX C., BLANCHE S., MAYAUX M.J., RIVIERE Y. Inverse Correlation between Memory Gag-Specific Cytotoxic T Lymphocytes and Viral Replication in Human Immunodeficiency Virus-Infected Children. J. Infect. Dis., 186 (11), 1589-1596, 2002 (Services cités : Fédération de Pédiatrie, Laboratoire de Microbiologie) A previous study showed that, during the first year of life, the presence of cytotoxic T lymphocytes (CTLs) in human immunodeficiency virus (HIV)-infected children is associated with a lack of rapid progression to acquired immunodeficiency syndrome. The goal of the study was to address the role of CTLs in children who survived after age 5 years. Memory HIV-specific CTLs directed against Env, Gag, Nef, and Pol proteins were measured in a group of 47 highly active antiretroviral therapy-naive HIV-infected children. Both Gag- and Pol-specific CTLs were positively correlated with CD4(+) T cell counts. Gag-, Nef-, and Pol-specific CTLs were inversely correlated with virus load. The inverse correlation between virus load and Gag-specific CTLs was independent of CD4(+) T cell counts. In conclusion, this study showed the beneficial

role of HIV-specific CTLs in children who survived after age 5 years. COSGROVE K.E., ANTOINE M.H., LEE A.T., BARNES P.D., de TULLIO P., CLAYTON P., MCCLOY R., de LONLAY P., NIHOUL-FEKETE C., ROBERT J.J., SAUDUBRAY J.M., RAHIER J., LINDLEY K.J., HUSSAIN K., AYNSLEY-GREEN A., PIROTTE B., LEBRUN P., DUNNE M.J. BPDZ 154 activates adenosine 5'-triphosphate-sensitive potassium channels: in vitro studies using rodent insulin-secreting cells and islets isolated from patients with hyperinsulinism. J. Clin. Endocrinol. Metabol., 87 (11), 4860-4868, 2002 (Services cités : Département de Pédiatrie) A novel ATP-sensitive potassium channel (K(ATP)) channel agonist, BPDZ 154 (6,7-dichloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide), was synthesized, and its effects on insulin-secreting cells were evaluated using electrophysiology, (86)Rb(+) and (45)Ca(2+) efflux, and RIA determinations of insulin secretion. BPDZ 154, an analog of diazoxide, inhibited both glucose-induced insulin secretion from isolated perifused islets and the secretion of insulin induced by glucose and tolbutamide. These effects were mediated by the activation of ATP-sensitive potassium channels because BPDZ 154 induced a concentration-dependent increase in channel activity that was inhibited by the sulfonylurea tolbutamide and the imidazoline efaroxan. In beta-cells isolated from patients with either nontypical hyperinsulinism (preserved K(ATP) channel function) or from the control areas of the pancreas of patients with focal hyperinsulinism, BPDZ 154 activated K(ATP) channels and was found to be more effective and less readily reversible than diazoxide. By contrast, it was not possible to activate K(ATP) channels by either diazoxide or BPDZ 154 in beta-cells from patients with hyperinsulinism as a consequence of defects in K(ATP) channel function. In beta-cells isolated from a patient with pancreatic insulinoma, K(ATP) channels were readily recorded and modulated by BPDZ 154. These data suggest that BPDZ 154 or BPDZ 154-like compounds may have therapeutic potential in the treatment of certain forms of hyperinsulinism. DE LONLAY P., CORMIER-DAIRE V., AMIEL J., TOUATI G., GOLDENBERG A., FOURNET J.C., BRUNELLE F., NIHOUL-FEKETE C., RAHIER J., JUNIEN C., ROBERT J.J., SAUDUBRAY J.M. Facial appearance in persistent hyperinsulinemic hypoglycemia. Amer. J. Med. Genet., 111 (2), 130-133, 2002 (Services cités : Anatomo-Pathologie, Chirurgie Pédiatrique, Département de Pédiatrie, Métabolisme-Neurologie Génétique Pédiatrique, Radiologie Pédiatrique, U383, U393) Persistent hyperinsulinism is the most common cause of recurrent hypoglycemia in infancy because of inappropriate oversecretion of insulin by the pancreas. Pancreatic lesions can be either focal or diffuse, and they have distinct molecular bases. We have studied the facial features in 17 unrelated patients presenting with neonatal (n = 8) or infancy-onset (n = 9) hyperinsulinism. Hyperinsulinism was related to focal adenomatous hyperplasia (n = 7), diffuse hyperinsulinism (n = 5), non-operated hyperinsulinism (n = 2), and hyperinsulinism with hyperammonemia (n = 3). SUR1 or Kir6.2 mutations were found in six of seven focal adenomatous hyperplasia and three of five diffuse hyperinsulinism. A loss of the maternal allele from chromosome 11p15 in the lesion was found in all focal adenomatous hyperplasia. GLUD1 mutations were found in all patients with hyperammonemia. Large birth weight (mean > 3,800 g) was consistently observed (11/17) but protruding tongue, exomphalos, or visceromegaly were never noted and Wiedemann-Beckwith syndrome could always be ruled out. All patients presented with high forehead, small

nasal tip, and short columella giving the impression that the nose is large and bulbous, smooth philtrum, and thin upper lip. A square appearance to the face was more obvious in younger patients. These specific facial features, observed in patients with hyperinsulinism of various molecular mechanisms, could be the consequence of fetal intoxication by insulin. However, to date, facial anomalies have not been noted in infants of diabetic mothers and inversely, malformations that are commonly reported in infants of diabetic mothers were not present in our hyperinsulinemic patients. DE LONLAY P., FENNETEAU O., TOUATI G., MIGNOT C., BILLETTE-DE VILLEMEUR T., RABIER D., BLANCHE S., OGIER-DE BAULNY H., SAUDUBRAY J.M. Manifestations hématologiques dans les erreurs innées du métabolisme. Arch. Pediatr., 9 (8), 822-835, 2002 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique, Métabolisme-Neurologie Génétique Pédiatrique) Haematological symptoms can be helpful for the diagnosis of metabolic diseases. A megaloblastic anemia orientates to folate and cobalamine anomalies when associated with homocystinemia and decreased plasma methionine levels, or to congenital oroticuria (hypochromia), Pearson syndrome (sideroblasts and vacuolisation of precursors) and thiamine transporter abnormality (sideroblasts) in the absence of homocystinuria. An hemolytic anemia orientates to anomalies of anaerobic glycolysis, heme synthesis, or iron metabolism, and Wilson disease. A pancytopenia orientates to organic aciduria, lysinuric protein intolerance, mevalonic aciduria and lysosomal storage diseases (Gaucher, Niemann Pick, Wolman) when hepatosplenomegaly is present. Uremic hemolytic syndrome and hemophagocytic lymphohistiocytosis respectively orientate to B12 anomalies, lysinuric protein intolerance, lysosomal storage diseases and organic aciduria. DE LONLAY P., FOURNET J.C., TOUATI G., GROOS M.S., MARTIN D., SEVIN C., DELAGNE W., MAYAUD C., CHIGOT V., SEMPOUX C., MARIE-CLAIRE C.S., LABORDE B.K., BELLANE-CHANTELOT C., VASSAULT A., RAHIER J., JUNIEN C., BRUNELLE F., NIHOUL-FEKETE C., SAUDUBRAY J.M., ROBERT J.J. Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. a series of 175 cases. Eur. J. Pediat., 161 (1), 37-48, 2002 (Services cités : Anatomo-Pathologie, Fédération de Pédiatrie, Radiologie Pédiatrique, Chirurgie Pédiatrique, U383, Biochimie Générale, Métabolisme-Neurologie Génétique Pédiatrique) Hyperinsulinism is a heterogeneous disorder characterised by severe hypoglycaemia due to an inappropriate oversecretion of insulin. In a personal series of 175 patients investigated for hyperinsulinaemic hypoglycaemia over the last 20 years, we review clinical presentations, molecular studies and therapeutic management of hyperinsulinism. There were 98 neonatal-onset patients, including 86 permanent hyperinsulinism and 12 transient forms, 68 with infancy-onset and nine with childhood-onset. Hyperammonaemia was found in 12 out of 69 patients tested, 4 neonates and 8 infants. Neonates were clinically more severely affected than infants. Diagnosis of infancy-onset hyperinsulinism was often delayed because of less profound hypoglycaemia and better tolerance to hypoglycaemia. Neonates required higher rates of iv glucose than infants to maintain normal plasma glucose levels (16 mg/kg per min versus 12 mg/kg per min). Only 16% of neonates were diazoxide-sensitive compared to 66% of the infants. Neonates with hyperammonaemia or transient hyperinsulinism were diazoxide-sensitive. Most neonates were

pancreatectomised whereas 65% of the infants were treated medically. Among surgically-treated patients, 47% had a focal adenomatous hyperplasia (31 neonates and 13 infants) and 53% a diffuse form of hyperinsulinism (39 neonates and 11 infants). Diazoxide-responsiveness in the focal and diffuse forms did not differ in both neonates and infants; it depended only upon the age of onset of hypoglycaemia. One or two mutations, SUR1 or KIR6.2, were found in 41 of 73 neonates who were investigated and in 13/38 infants using polymerase chain reaction-single strand conformational polymorphism analysis of both genes. Almost all patients with SUR1 (38/41) or KIR6.2 (5/7) mutations were resistant to diazoxide. Ten patients with hyperinsulinism-hyperammonaemia syndrome had a mutation in the glutamate dehydrogenase gene (three neonates and seven infants) after reverse transcriptase-polymerase chain reaction and sequence analysis of cDNA. No mutation was found by polymerase chain reaction-single strand conformational polymorphism in the glucokinase gene. Eight of nine patients with childhood onset hyperinsulinism were treated surgically and histological examination confirmed an adenoma in each case. Conclusion: the clinical severity of hyperinsulinism varies mainly with age at onset of hypoglycaemia. The heterogeneity of hyperinsulinism has major consequences in terms of therapeutic outcome and genetic counselling. [References: 27] DE LONLAY P., TOUATI G., ROBERT J.J., SAUDUBRAY J.M. Persistent hyperinsulinaemic hypoglycaemia. Semin. Neonatol., 7 (1), 95-100, 2002 (Services cités : Département de Pédiatrie, Métabolisme-Neurologie Génétique Pédiatrique, U393) Congenital hyperinsulinism (CI) is the most important cause of hypoglycaemia in early infancy. The inappropriate oversecretion of insulin is responsible for profound hypoglycaemias which require aggressive treatment to prevent severe and irreversible brain damage. Hypoglycaemia have a neonatal or infancy onset. Medical treatment with diazoxide is first used to treat CI, but patients who are medically resistant (mostly of neonatal-onset) require pancreatectomy. CI is a heterogeneous disorder with two histopathological lesions, diffuse and focal which are clinically indistinguishable. Only diazoxide-sensitive neonates should be orientated to transient hyperinsulinism or hyperinsulinism-hyperammonemia syndrome. Focal CI is characterized by a sporadic somatic islet-cell hyperplasia. Diffuse CI corresponds to a functional abnormality of insulin secretion in the whole pancreas and involves several genes with different transmissions. The knowledge of both focal and diffuse lesions is very important. Focal lesions are effectively treated by limited pancreatic resection while diffuse lesions which are unresponsive to drug or dietary treatment require extensive pancreatectomy with high risk of diabetes mellitus. DE MONTALEMBERT M. Prise en charge des enfants drépanocytaires : un travail d'équipe. Arch. Pediatr., 9 (11), 1195-2001, 2002 (Services cités : Département de Pédiatrie) Treatment of children with sickle cell disease has been impressively improved during recent years. Neonatal screening is now generalized to all continental France. Coupled with parents' education and a comprehensive care program, it allows a reduction of pneumococcal infections, and of the mortality related to splenic sequenstration, the occurrence of cerebrovascular accidents being also reduced by the use of transcranial Doppler ultrasonography. However, to be effective these measures require a close collaboration not only between parents and the medical team but frequently also between the medical team and social workers, as many affected children living in

France are born from first generation African migrants, for whom it may be difficult to understand and/or to apply the care program. ERNOULT A., AUROY F., BERTIER C., HUE V., SMIT C. A child dies in hospital. How to help parents bereavement ? Arch. Pediatr., 9 (12), 1291-1296, 2002 (Services cités : Département de Pédiatrie) Caring for a child who is dying in an intensive care unit always generates stress for his parents and the medical team. Those last days initiate the griewing and will remain for ever in the parent memories, sometimes in the professional carers memories too. By listening to parents, months after their child's death, we have pointed out facts either positive which help them in their mourning, or negative which prevent them from overcoming their loss. This led us to propose concrete steps, aiming to help parents bereavement after a child's death. In no way these proposals should be considered as "the only way to do things", since each child and each family is unique. Nevertheless, they have proved to be efficient. FAIVRE L., CORMIER-DAIRE V., LAPIERRE J.M., COLLEAUX L., JACQUEMONT S., GENEVIEVE D., SAUNIER P., MUNNICH A., TURLEAU C., ROMANA S., PRIEUR M., de BLOIS M.C., VEKEMANS M. Deletion of the SIM1 gene (6q16.2) in a patient with a Prader-Willi-like phenotype. J. Med. Genet., 39 (8), 594-596, 2002 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique, Histo-Embryologie & Cytogénétique) FERRONI A., SERMET-GAUDELUS I., ABACHIN E., QUESNE G., LENOIR G., BERCHE P., GAILLARD J.L. Use of 16S rRNA Gene Sequencing for Identification of Nonfermenting Gram-Negative Bacilli Recovered from Patients Attending a Single Cystic Fibrosis Center. J. Clin. Microbiol., 40 (10), 3793-377., 2002 (Services cités : Département de Pédiatrie, Laboratoire de Microbiologie, U467) During 1999, we used partial 16S rRNA gene sequencing for the prospective identification of atypical nonfermenting gram-negative bacilli isolated from patients attending our cystic fibrosis center. Of 1,093 isolates of nonfermenting gram-negative bacilli recovered from 148 patients, 46 (4.2%) gave problematic results with conventional phenotypic tests. These 46 isolates were genotypically identified as Pseudomonas aeruginosa (19 isolates, 12 patients), Achromobacter xylosoxidans (10 isolates, 8 patients), Stenotrophomonas maltophilia (9 isolates, 9 patients), Burkholderia cepacia genomovar I/III (3 isolates, 3 patients), Burkholderia vietnamiensis (1 isolate), Burkholderia gladioli (1 isolate), and Ralstonia mannitolilytica (3 isolates, 2 patients), a recently recognized species. HAYEM F. Les fièvres périodiques. Arch. Pediatr., 9 (6), 638-643, 2002 (Services cités : Département de Pédiatrie) Periodic fever is defined as a series of unexplained febrile episodes, most often starting during childhood. The febrile episodes last usually few days, are of fixed or variable duration, and regress spontaneously, the intervals between episodes being asymptomatic. Fever is accompanied

by clinical manifestations affecting peritoneal, pleural and/or mucous membranes, joints and skin. Four different etiologies are presently known. Three are hereditary diseases: familial mediterranean fever and periodic fever with hyperimmunoglobulinemia D which have a recessive autosomal transmission, and TNF receptor associated periodic syndrome or TRAPS which has a dominant autosomal transmission. One is sporadic: periodic fever with aphthous stomatitis, pharyngitis and adenopathy or PFAPA. Other etiologies are yet to be identified as many cases of periodic fever remain unexplained. KAMOUN P., RABIER D., SAUDUBRAY J.M. A risk factor for chronic mild hyperammonaemia. Eur. J. Pediat., 161 (4), 221, 2002 (Services cités : Biochimie Médicale, Département de Pédiatrie, Métabolisme-Neurologie Génétique Pédiatrique) LACAILLE F. Hépatite chronique C chez l'enfant. Arch. Pediatr., 9 (5), 539-542, 2002 (Services cités : Département de Pédiatrie) Peripartum transmission is today the main cause of hepatitis C virus (HCV) infection in children. HCV infection rarely causes a clinical illness during childhood and adolescence, except when it is associated with additional risk factors such as hepatitis B or HIV infection, chemotherapy or immunodeficiency. Present data suggest that between 20 to 50 percent of contaminated infants will become spontaneously non viremic within 15 to 20 years. Studies on treatment with interferon-alpha are limited and show a mean recovery rate of 40%. LACAILLE F., CANIONI D., FOURNET J.C., REVILLON Y., CEZARD J.P., GOULET O. Centrilobular necrosis in children after combined liver and small bowel transplantation. Transplantation, 73 (2), 252-257, 2002 (Services cités : Chirurgie Pédiatrique, Département de Pédiatrie, Gastroentérologie Pédiatrique) BACKGROUND: Centrilobular necrosis is not an uncommon finding after isolated liver transplantation. In this study, we sought to describe hepatic centrilobular necrosis in children after combined liver and small bowel transplantation (LSBT), and to assess the predictive factors, possible causes, and prognosis. METHODS: Six children aged 4 to 11 years, in whom liver biopsy showed centrilobular necrosis at least once, 3 weeks to 2 years after LSBT, were compared with nine children without this pathology. All six children experienced an acute complication in the few weeks preceding the finding of centrilobular necrosis. In addition, one child had an early arterial thrombosis and one, severe colitis 3 years after LSBT. RESULTS: Centrilobular necrosis was associated with centrilobular swelling, dropout, endotheliitis, and inflammation. Fibrosis developed early and worsened on follow-up biopsy in three children. Portal symptoms of acute rejection were not constant, and there was no ductopenia. Biologic abnormalities were responsive to increased immunosuppression, including mycophenolate in four cases. However, follow-up biopsies showed persistent lesions in five patients, mildly inflammatory in four. Baseline immunosuppression had to be maintained at high levels. No viral infections, vascular compromise (except in one), and autoimmunity were found. We compared the two groups of children for initial diagnosis, age at transplantation, time receiving parenteral nutrition, ischemic time, presence of an associated transplanted colon, number of reoperations

and infections, intestinal rejection, and immunosuppression, and found no differences. CONCLUSIONS: This severe manifestation of chronic liver rejection occurred despite the heavy immunosuppression needed for LSBT. The previous acute clinical event could have triggered rejection by modifying the effective immunosuppression at the tissue level. Despite high baseline immunosuppression, histologic lesions persisted and significant fibrosis developed in half the children. We speculate that the lack of induction of tolerance in this particular setting of LSBT could be responsible for constant immune stimulation, thus chronic rejection. The optimal protocol of immunosuppression has yet to be defined to avoid this complication. MARQUIS E., ROBERT J.J., BOUVATTIER C., BELLANNE-CHANTELOT C., JUNIEN C., DIATLOFF-ZITO C. Major difference in aetiology and phenotypic abnormalities between transient and permanent neonatal diabetes. J. Med. Genet., 39 (5), 370-374, 2002 (Services cités : U383, Fédération de Pédiatrie) SAUDUBRAY J.M., NASSOGNE M.C., de LONLAY P., TOUATI G. Clinical approach to inherited metabolic disorders in neonates: an overview. Semin. Neonatol., 7 (1), 3-15, 2002 (Services cités : Département de Pédiatrie, Métabolisme-Neurologie Génétique Pédiatrique, U393) There are almost one hundred inborn errors of metabolism which can start in the neonatal period, but less than 20 are amenable to treatment. In general, an extremely evocative clinical setting is the course of a full-term baby born after normal pregnancy and delivery who, after an initial symptom-free period deteriorates relentlessly for no apparent reason and does not respond to symptomatic therapy. Investigations routinely performed in all sick neonates yield normal results. Emergency treatment must be undertaken in parallel with investigations. Five main presentations can be observed: a neurologic deterioration 'intoxication' type mostly suggests maple syrup urine disease, methylmalonic, propionic, isovaleric acidaemias and urea cycle disorders. Isolated seizures is the revealing symptom of pyridoxine-responsive and folinic acid responsive seizures. A jaundice or a liver failure suggest galactosaemia, fructosaemia, tyrosinaemia type I (after 3 weeks), phosphomannoisomerase deficiency or bile acid synthesis defects. Cardiac failure and heartbeat disorders should first suggest mitochondrial fatty acid oxidation (FAO) disorders. Persistent hypoglycaemia is the presenting sign of glyco/ gluconeogeneis defects, hyperinsulinism and FAO disorders. The first line investigation relies upon the collection at the same time of a few samples including blood gases electrolytes, prothrombin time, transaminases, ammonia and lactic acid, and the search for ketonuria. The storage of plasma, urine and blood (on filter paper) is an important element in the diagnosis. The utilization of these samples should be carefully planned after taking advice from specialists in inborn errors. SERMET-GAUDELUS I., FERRONI A., BROUSSE V., LENOIR G. Staphyloccocal infection in cystic fibrosis: Physiopathological and therapeutic approach. Méd. Mal. Infec., 32 Suppl. 2 131S-133S, 2002 (Services cités : Laboratoire de Microbiologie, Département de Pédiatrie) SERMET-GAUDELUS I., LECOCGUIC Y., FERRONI A., CLAIRICIA M., BARTHE J., DELAUNAY J., BROUSSE V., LENOIR G.

Nebulized antibiotics in cystic fibrosis. Paediatr. Drugs, 4 (7), 455-467, 2002 (Services cités : Département de Pédiatrie) Nebulization is a useful administration route in cystic fibrosis (CF) as it delivers antibiotics directly to the endobronchial site of infection and is associated with decreased toxicity because of limited systemic absorption. It is assumed that the concentration of antibiotics in bronchial secretions should be as high as 10 times the minimum inhibiting concentration to allow penetration of antibiotics into biofilms, suppress inhibitory factors and promote bactericidal effectiveness. However, effective aerosol delivery is compromised by nebulizers with limited capacity to produce particles of a size in the respirable range. Three antibiotics are commonly used for inhalation: tobramycin, amikacin and colistin (colomycin). Placebo-controlled studies evaluating antibiotic aerosol maintenance in stable patients chronically infected with Pseudomonas aeruginosa indicate a significant improvement of lung function and a reduction of the number of hospital admissions for an acute exacerbation of CF. TOBI((R)) is a recently marketed preservative- and sulfate-free formula of tobramycin, specially designed for diffusion in the bronchioles and optimal tolerance. A wide-scope study involving 520 patients compared TOBI((R)) (300mg twice daily; n = 258) with placebo (n = 262) for three 28-day cycles with each cycle separated by a 28-day period of no treatment. Respiratory function was significantly improved as early as in the second week and remained so for the rest of the trial even during periods without aerosol treatment. There was also a parallel decrease in the relative risk of hospitalization, the number of days of hospitalization and the number of days on intravenous antipyocyanic treatment. Toxicity studies carried out so far have shown no renal or ototoxicity with nebulized tobramycin. Introduction or selection of resistant bacteria is relatively rare but remains a matter of concern. Aerosol maintenance treatment with an appropriate antibiotic in a high enough dosage can be recommended for patients with CF who are chronically infected with P. aeruginosa. SERMET-GAUDELUS I., VALLEE B., URBIN I., TOROSSI T., MARIANOVSKI R., FAJAC A., FEUILLET M.N., BRESSON J.L., LENOIR G., BERNAUDIN J.F., EDELMAN A. Normal Function of the Cystic Fibrosis Conductance Regulator Protein Can Be Associated with Homozygous DeltaF508 Mutation. Pediat. Res., 52 (5), 628-635, 2002 (Services cités : CIC 9303, Département de Pédiatrie, U467) Cystic fibrosis (CF) is caused by mutations of the gene encoding for the CFTR (CF transmembrane conductance regulator) protein. The most frequent mutation, the DeltaF508 mutation, results in a defective cAMP-regulated chloride transport in the epithelial cells. The spectrum of clinical manifestations in patients bearing homozygous DeltaF508 mutations can vary considerably, suggesting that, in the patients with a mild disease, CFTR could be partly functional. To test this hypothesis, we explored in nasal ciliated epithelial cells (NCC) of 9 control subjects and 23 DeltaF508 homozygous patients the anion conductive pathway by a halide sensitive fluorescent dye assay SPQ (6-methoxy-N-3'-sulfopropylquinolinium) and the CFTR transcript levels by RT-PCR. As 50% represented the lowest fraction of the control subjects NCC demonstrating a cAMP-dependent conductance, a CF patient was considered as "cAMP responder" if at least 50% of the NCC tested displayed a cAMP-dependent conductive pathway. According to these criteria, 8 of the 23 patients were considered as cAMP responders. They had a significantly less severe disease considering the respiratory function and infectious

status. The amount of CFTR mRNA did not differ between the control subjects and the patients. No statistical correlation could be found between the transcript level and the expression of a cAMP conductive pathway. This cAMP-dependent Cl(-) conductance detected in homozygous NCC could be due to a residual CFTR activity and may explain the mild phenotypes observed in some DeltaF508 homozygous patients. VUILLAUMIER-BARROT S., LE BIZEC C., de LONLAY P., BARNIER A., MITCHELL G., PELLETIER V., PREVOST C., SAUDUBRAY J.M., DURAND G., SETA N. Protein losing enteropathy-hepatic fibrosis syndrome in Saguenay-Lac St-Jean, Quebec is a congenital disorder of glycosylation type Ib. J. Med. Genet., 39 (11), 849-851, 2002 (Services cités : Département de Pédiatrie) 2001 ABADIE V., ANDRE A., ZAOUCHE A., THOUVENIN B., BAUJAT G., SCHMITZ J. Early feeding resistance: a possible consequence of neonatal oro-oesophageal dyskinesia. Acta Paediatr., 90 (7), 738-745, 2001 (Services cités : Département de Pédiatrie, Gastroentérologie Pédiatrique) Paediatricians. frequently find early feeding disorders in neonates and infants that result in poor weight gain and which sometimes have no clear organic basis. For many years, we have observed infants with unexplained poor feeding skills and excessive regurgitation, and since 1992 we have prospectively performed oesophageal manometry in infants hospitalized for retarded growth and "unexplained" feeding disorders. From the group of infants hospitalized for growth failure in the General Paediatric Unit of Necker-Enfants Malades Hospital from 1992 to 1997, we identified 16 children (3%) with abnormal feeding behaviour who had an abnormal oesophageal manometry. The manometric data of these children were compared with those of a group of 16 age-matched children who underwent oesophageal manometry for other reasons, and served as controls. The affected children had precocious feeding skills disorders: prolonged bottle-feeding (75%), bottle refusal (75%), unexplained crying (63%) and excessive regurgitation (94%). Half of them had mild anatomical facial consequences of their poor foetal sucking, and mild pharyngolaryngeal hypotonia, which could not be considered as malformations. Apart from these disorders, their clinical status was normal. At inclusion, their oesophageal manometry was abnormal, showing in 70% of cases specific anomalies: lower oesophageal sphincter hypertonia and/or partial failure to relax. and giant waves of oesophagus body. Their course was good and their feeding difficulties decreased around the end of the first year, with the acquisition of normal voluntary mastication. Conclusion: We suggest that the early feeding resistance of this group of children could be related to an organic and transient neonatal oro-oesophageal dyskinesia. [References: 33] ABADIE V., DEPONDT E., BRESSON J.L., VIDAILHET M. Recommended dietary allowances for pregnant women affected with phenylketonuria. Archives Pédiatrie, 8 (4), 397-406, 2001 (Services cités : Fédération de Pédiatrie) Prevention of embryopathy due to maternal phenylketonuria is possible thanks to a maternal-specific low-phenylalanine diet, which has to be started before conception and followed during the whole gestation. The setup of this diet implies knowing the recommended dietary allowances for normal pregnant women as well as for women with nutritional deficiencies. Women with phenylketonuria must be considered at risk for nutritional imbalance for two main reasons. First,

most adult women with phenylketonuria have been on a vegetarian diet for many years without protein substitutes or medical control. Secondly, the strict diet for pregnant women with phenylketonuria may induce anorexia or nutritional deficits if it is not well tolerated or understood. Protein, iron, calcium, selenium, vitamin B 12 and caloric intakes are the most sensitive parameters. Close cooperation with an experienced medical and dietician team is required. (C) 2001 Editions scientifiques et medicales Elsevier SAS. [References: 67] ABADIE V., BERTHELOT J., FEILLET F., MAURIN N., MERCIER A., de BAULNY H.O., de PARSCAU L. Neonatal screening and long-term follow-up of phenylketonuria: the french database. Early Hum. Dev., 65 (2), 149-158, 2001 (Services cités : Département de Pédiatrie) Background: In France, neonatal screening of phenylketonuria (PKU) started in 1966. A national association was created in 1978 in order to organise the neonatal screening program and to control the efficacy of the screening and patients' follow-up. Aims: To evaluate the results of the French PKU screening program in terms of hyperphenylalaninaemia epidemiology, efficacy of the screening procedure, management and outcome of the patients. Study design: The national database has been filled-up first with the answers to questionnaires that were sent each year by the PKU patients' physicians, and second with the results of an additional inquiry, which was set up in 1994 in order to investigate diagnosis, treatment, and school outcome of all French PKU patients. Results: PKU was diagnosed in 81.6% of patients with hyperphenylalaninaemia (HPA), non-PKU HPA in 17.2% and cofactor deficiency in 1.1%. From 1980, incidence of PKU has been stable: 1 per 17,124 live births. Sensitivity of the screening procedure was 99.3%. Age at diet initiation regularly decreased to reach 14 days as a median in 1996. Until 1990, median age at diet discontinuation was 6 years of age. Later, strict diet was continued longer (at lease up to 8-10 years). PKU patients who entered to secondary school at normal age were characterised by an earlier age at diagnosis and at diet initiation and a later age at diet discontinuation, compared to those who entered 1 year or more behind normal age. Conclusion: These data confirm the benefit of a nationwide organised screening program. They emphasise the importance of an early neonatal diagnosis and diet initiation in PKU patients and are consistent with the benefit of a longer period of strict diet in childhood. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved. [References: 24] ACQUAVIVA C., BENOIST J.F., CALLEBAUT I., GUFFON N., de BAULNY H.O., TOUATI G., AYDIN A., PORQUET D., ELION J. N219y, a new frequent mutation among mut degrees forms of methylmalonic acidemia in caucasian patients. Eur. J. Human Genet., 9 (8), 577-582, 2001 (Services cités : Département de Pédiatrie) Mutations in the MUT locus encoding for the methylmalonyl-CoA mutase (MCM) apoenzyme are responsible for the mut forms of methylmalonic acidemia (MMA). To date, 49 different mutations have been identified in mut MMA. Only two frequent mutations have been reported in the Japanese population and in African-Americans. Here we report a new missense mutation N219Y (731 A --> T) which we found in five unrelated families of French and Turkish descent. All the patients exhibited a severe mut degrees phenotype and three of them were homozygotes for N219Y. Direct involvement of the mutation in the loss of enzyme activity was demonstrated by mutagenesis and transient expression study. Mapping of the mutation onto a three-dimensional

model of human MCM constructed by homology with the Propionibacterium shermanii enzyme shows that it lies in a highly conserved secondary structure motif and might suggest impaired folding and/or poor stability compatible with the mut degrees phenotype. Finally, a 1% N219Y carrier frequency was observed in a French anonymous control population. Thus, N219Y is the first frequent mut mutation to be reported in the Caucasian population. [References: 17] AMIEL J., ATTIE-BITACH T., MARIANOWSKI R., CORMIER-DAIRE V., ABADIE V., BONNET D., GONZALES M., CHEMOUNY S., BRUNELLE F., MUNNICH A., MANACH Y., LYONNET S. Temporal bone anomaly proposed as a major criteria for diagnosis of charge syndrome. Amer. J. Med. Genet., 99 (2), 124-127, 2001 (Services cités : Fédération de Pédiatrie, Génétique Médicale Pédiatrique, Oto-Rhino-Laryngologie) The acronym CHARGE defines a non-random clustering of congenital malformations of unknown origin. Classical diagnostic criteria include: 1) one major feature namely coloboma/microphthalmia or choanal atresia, and 2) four of the six features designated in the CHARGE acronym. Interestingly, all CHARGE patients hitherto reported had partial or complete semicircular canal hypoplasia on temporal bone CTscan. We report on semicircular canal agenesis/hypoplasia in three patients with three to four features of the CHARGE syndrome and neither coloboma nor choanal atresia and we propose to include temporal bone malformations as a major criteria for diagnosis of CHARGE syndrome, (C) 2001 Wiley-Liss, Inc. [References: 12] ANJOT M.N., RAQBI F., ABADIE V., DESGUERRE I. Radiological case of the month - Aicardi-Goutieres syndrome. Archives Pédiatrie, 8 (9), 987-989, 2001 (Services cités : Département de Pédiatrie) BASTARD J.P., ROBERT J.J., JARDEL C., BRUCKERT E., GRIMALDI A., HAINQUE B. Is quantitative insulin sensitivity check index, a fair insulin sensitivity index in humans? Diabetes Metab., 27 (1), 69-70, 2001 (Services cités : Fédération de Pédiatrie) BAUJAT G., FAURE T., ZAOUCHE A., VIARME F.F., COULY G., ABADIE V. Oroesophageal motor disorders in pierre robin syndrome. J. Pediat. Gastroenterol. Nutr., 32 (3), 297-302, 2001 (Services cités : Département de Pédiatrie, Gastroentérologie Pédiatrique, Stomatologie & Chirurgie Maxillo-Faciale) Background: Feeding disorders are one of the main clinical features in PRS, which combines a posterior U-shaped cleft palate, retrognathia, and glossoptosis. The aim of this study was to evaluate the oral and esophageal motor function of children with PRS without additional neurologic symptoms. Methods: All children hospitalized with Pierre Robin syndrome either isolated (n = 27) or associated with Stickler syndrome (n = 8) were included. Clinical evaluation of their oroesophageal disorders and systematic esophageal manometry were performed. Results: Feeding disorders were always present, but type of disorder varied from one child to another. Esophageal disorders were frequent and seemed to be resistant to classic gastroesophageal reflux treatment. Eighty-six percent of the children required nasogastric tube feeding for a mean

duration of 8.6 months. Esophageal manometric abnormalities were noted in 50% of the children: lower esophageal sphincter hypertonia, failure of lower esophageal sphincter relaxation at deglutition, and esophageal dyskinesia. These clinical and manometric disorders showed a trend to spontaneous regression after 12 months. Conclusion: In the current Pierre Robin syndrome series, clinical and manometric anomalies of oroesophageal motility were always present. The authors identified an unusual manometric pattern that has also been described in situations of neurovegetative instability. It could reflect dysregulation of the control of the central pattern generators of swallowing in the brain stem. [References: 36] BERRIOT-VAROQUEAUX N., DANNOURA A.H., MOREAU A., VERTHIER N., SASSOLAS A., CADIOT G., LACHAUX A., MUNCK A., SCHMITZ J., AGGERBECK L.P., SAMSON-BOUMA M.E. Apolipoprotein b48 glycosylation in abetalipoproteinemia and anderson's disease. Gastroenterology, 121 (5), 1101-1108, 2001 (Services cités : Département de Pédiatrie) Background & Aims: Abetalipoproteinemia and Anderson's disease are hereditary lipid malabsorption syndromes. In abetalipoproteinemia, lipoprotein assembly is defective because of mutations in the microsomal triglyceride transfer protein. Here, we evaluated the intracellular transport of apolipoprotein B48 to localize the defect in Anderson's disease. Methods: Asparagine-linked oligosaccharide processing of apolipoprotein B48 in normal and affected individuals was determined by the endoglycosidase H and IF sensitivities of the protein after metabolic labeling of intestinal explants in organ culture. Cell ultrastructure was evaluated with electron microscopy. Results: In Anderson's disease as in normal individuals, there was a time-dependent transformation of high mannose endoglycosidase H-sensitive oligosaccharides, of endoplasmic reticulum origin, to complex endoglycosidase H-resistant oligosaccharides, added in the Golgi network. In contrast, despite the translocation of apolipoprotein B48 into the endoplasmic reticulum in patients with abetalipoproteinemia and in biopsies treated with Brefeldin A, which blocks anterograde transport between the endoplasmic reticulum and the Golgi network, there was no transformation of endoglycosidase H-sensitive oligosaccharides. Conclusions: In abetalipoproteinemia and Anderson's disease, apolipoprotein B48 is completely translocated into the endoplasmic reticulum, but only in Anderson's disease is the protein transported to the Golgi apparatus. This suggests that Anderson's disease is caused by a post-Golgi cargo-specific secretion defect. [References: 36] BROWN N.F., MULLUR R.S., SUBRAMANIAN I., ESSER V., BENNETT M.J., SAUDUBRAY J.M., FEIGENBAUM A.S., KOBARI J.A., MACLEOD P.M., MCGARRY J.D., COHEN J.C. Molecular characterization of l-cpt i deficiency in six patients: insights into function of the native enzyme. J. Lipid Res., 42 (7), 1134-1142, 2001 (Services cités : Département de Pédiatrie) Carnitine palmitoyltransferase I (CPT I) catalyzes the formation of acylcarnitine, the first step in the oxidation of long-chain fatty acids in mitochondria, The enzyme exists as liver (L-CPT I) and muscle (M-CPT I) isoforms that are encoded by separate genes. Genetic deficiency of L-CPT I, which has been reported in 16 patients from 13 families, is characterized by episodes of hypoketotic hypoglycemia beginning in early childhood and is usually associated with fasting or illness. To date, only two mutations associated with L-CPT I deficiency have been reported. In

the present study we have identified and characterized the mutations underlying L-CPT I deficiency in six patients: five with classic symptoms of L-CPT I deficiency and one with symptoms that have not previously been associated with this disorder (muscle cramps and pain), Transfection of the mutant L-CPT I cDNAs in COS cells resulted in L-CPT I mRNA levels that were comparable to those expressed from the wild-type construct. Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability. The patient with atypical symptoms had similar to 20% of normal L-CPT I activity and was homozygous for a mutation (c.1436C -->T) that substituted leucine for proline at codon 479. Assays performed with his cultured skin fibroblasts indicated that this mutation confers partial resistance to the inhibitory effects of malonyl-CoA.jlr The demonstration of L-CPT I deficiency in this patient suggests that the spectrum of clinical sequelae associated with loss or alteration of L-CPT I function may be broader than was previously recognized. [References: 43] CHIGOT V., de LONLAY P., NASSOGNE M.C., LABORDE K., DELAGNE V., FOURNET J.C., NIHOUL-FEKETE C., SAUDUBRAY J.M., BRUNELLE F. Pancreatic arterial calcium stimulation in the diagnosis and localisation of persistent hyperinsulinemic hypoglycaemia of infancy. Pediat. Radiol., 31 (9), 650-655, 2001 (Services cités : Anatomo-Pathologie, Département de Pédiatrie, Radiologie Pédiatrique, Explorations Fonctionnelles, Chirurgie Pédiatrique, Métabolisme-Neurologie Génétique Pédiatrique) Background. Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is often resistant to medical therapy. Surgery is therefore necessary. It is due to focal adenomatous islet-cell hyperplasia treatable by partial pancreatectomy, or diffuse beta-cell hyperfunction, which requires near-total pancreatectomy. Pancreatic venous sampling (PVS) is the reference technique for the preoperative diagnosis and localization of focal forms of PHHI in the pancreas. However, hypoglycaemia is necessary to analyse the results and PVS is technically challenging. Pancreatic arterial calcium stimulation (PACS) is technically easier and does not require hypoglycaemia. Aim. To study the accuracy in the diagnosis and localization of PHHI. Materials and methods. PACS was performed in 12 patients and correlated with histology. Results. The accuracy of PACS is poor in diffuse lesions since only two of six cases were correctly identified by this test. Five of six focal lesions were correctly recognized and located. Conclusions. PACS is less accurate than PVS in PHHI. Currently, it should be performed only when PVS fails. [References: 25] CHRETIENNOT-BARA C., GUET A., BALZAMO E., NOSEDA G., TORCHET M.F., ROTHSHILD C., BLAKIME C., SCHMIT J.P. Spinal hematoma in the hemophiliac child: diagnostic problems. Archives Pédiatrie, 8 (8), 828-833, 2001 (Services cités : Centre d'Hémobiologie François JOSSO, Radiologie Pédiatrique, Département de Pédiatrie) Spinal epidural hematoma is an uncommon complication in hemophilia. Case reports.-The cases of an extensive epidural hematoma in two boys with severe hemophilia are reported. Conclusion.-Acute onset of severe neck pain or backache leads to the diagnosis of epidural hematoma in children with hemophilia, even in the absence of neurologic symptoms. Early diagnosis is important and relies on magnetic resonance imaging. Replacement therapy is mandatory and

must be prescribed before neuroradiologic imaging. Generally, children have a good neurologic outcome. (C) 2001 Editions scientifiques et medicales Elsevier SAS. [References: 11] COLOMB V. Home artificial nutrition in children. Archives Pédiatrie, 8 (1), 79-85, 2001 (Services cités : Fédération de Pédiatrie, Gastroentérologie Pédiatrique) Home enteral and parenteral nutritions are logical alternatives to long-term hospitalization when a long-term nutritional support is required. They are effective and safe methods, compatible with a good quality of life. Major cost savings have been demonstrated as a result of home nutrition rather than hospitalization. Nevertheless, one must not underestimate the importance of the families' teaching and the medical follow-up to prevent somatic and psychological complications. The quality of home nutrition programmes depends on the organization of the nutrition support teams based on close collaboration between the various involved professionals. (C) 2001 Editions scientifiques et medicales Elsevier SAS. [References: 12] DE LEERSNYDER H., de BLOIS M.C., VEKEMANS M., SIDI D., VILLAIN E., KINDERMANS C., MUNNICH A. Beta(1)-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, smith-magenis syndrome. J. Med. Genet., 38 (9), 586-590, 2001 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique, U393, Histo-Embryologie & Cytogénétique) Smith-Magenis syndrome (SMS) is a clinically recognisable contiguous gene syndrome ascribed to interstitial deletions of chromosome 17p11.2. Patients have a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Serum melatonin levels and day-night behaviour were studied in nine SMS children (aged 4 to 17 years) given acebutolol, a selective beta (1)-adrenergic antagonist (10 mg/kg early in the morning). Cardiac examination, serum melatonin, motor activity recordings, and sleep diaries were monitored before and after drug administration. The present study shows that a single morning dose of acebutolol suppressed the inappropriate secretion of melatonin in SMS. A significant improvement of inappropriate behaviour with increased concentration, delayed sleep onset, increased hours of sleep, and delayed waking were also noted. These results suggest that beta (1)-adrenergic antagonists help to manage hyperactivity, enhance cognitive performance, and reduce sleep disorders in SMS. [References: 30] DE LONLAY P., BENELLI C., FOUQUE F., GANGULY A., ARAL B., DIONISI-VICI C., TOUATI G., HEINRICHS C., RABIER D., KAMOUN P., ROBERT J.J., STANLEY C., SAUDUBRAY J.M. Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. Pediat. Res., 50 (3), 353-357, 2001 (Services cités : Biochimie Médicale, Fédération de Pédiatrie, U530, Génétique Médicale Pédiatrique) Hyperinsulinism and hyperammonemia syndrome has been reported as a cause of moderately severe hyperinsulinism with diffuse involvement of the pancreas. The disorder is caused by gain of function mutations in the GLUD1 gene. resulting in a decreased inhibitory effect of guanosine triphosphate on the glutamate dehydrogenase (GDH) enzyme. Twelve unrelated patients (six

males, six females) with hyperinsulinism and hyperammonemia syndrome have been investigated. The phenotypes were clinically heterogeneous, with neonatal and infancy-onset hypoglycemia and variable responsiveness to medical (diazoxide) and dietary (leucine-restricted diet) treatment. Hyperammonemia (90-200 mu mol/L, normal < 50 mu mol/L) was constant and not influenced by oral protein, by protein- and leucine-restricted diet, or by sodium benzoate or N-carbamylglutamate administration. The patients had mean basal GDH activity (18.3 +/- 0.9 nmol/min/mg protein) not different from controls (17.9 +/- 1.8 nmol/min/mg protein) in cultured lymphoblasts. The sensitivity of GDH activity to inhibition by guanosine triphosphate was reduced in all patient lymphoblast cultures (IC50, or concentrations required for 50% inhibition of GDH activity. ranging from 140 to 580 nM, compared with control IC50 value of 83 +/- 1.0 nmol/L). The allosteric effect of ADP was within the normal range. The activating effect of leucine on GDH activity varied among the patients, with a significant decrease of sensitivity that was correlated with the negative clinical response to a leucine-restricted diet in plasma glucose levels in four patients. Molecular studies were per-formed in 11 patients. Heterozygous mutations were localized in the antenna region (four patients in exon 11, two patients in exon 12) as well as in the guanosine triphosphate binding site (two patients in exon 6, two patients in exon 7) of the GLUD1 gene. No mutation has been found in one patient after sequencing the exons 5-13 of the gene. [References: 22] DE LONLAY P., SETA N., BARROT S., CHABROL B., DROUIN V., GABRIEL B.M., JOURNEL H., KRETZ M., LAURENT J., LE MERRER M., LEROY A., PEDESPAN D., SARDA P., VILLENEUVE N., SCHMITZ J., VAN SCHAFTINGEN E., MATTHIJS G., JAEKEN J., KORNER C., MUNNICH A., SAUDUBRAY J.M., CORMIER-DAIRE V. A broad spectrum of clinical presentations in congenital disorders of glycosylation i: a series of 26 cases. J. Med. Genet., 38 (1), 14-19, 2001 (Services cités : Génétique Médicale Pédiatrique, Métabolisme-Neurologie Génétique Pédiatrique, Département de Pédiatrie) INTRODUCTION: Congenital disorders of glycosylation (CDG), or carbohydrate deficient glycoprotein syndromes, form a new group of multisystem disorders characterised by defective glycoprotein biosynthesis, ascribed to various biochemical mechanisms. METHODS: We report the clinical, biological, and molecular analysis of 26 CDG I patients, including 20 CDG Ia, two CDG Ib, one CDG Ic, and three CDG Ix, detected by western blotting and isoelectric focusing of serum transferrin. RESULTS: Based on the clinical features, CDG Ia could be split into two subtypes: a neurological form with psychomotor retardation, strabismus, cerebellar hypoplasia, and retinitis pigmentosa (n=11), and a multivisceral form with neurological and extraneurological manifestations including liver, cardiac, renal, or gastrointestinal involvement (n=9). Interestingly, dysmorphic features, inverted nipples, cerebellar hypoplasia, and abnormal subcutaneous fat distribution were not consistently observed in CDG Ia. By contrast, the two CDG Ib patients had severe liver disease, enteropathy, and hyperinsulinaemic hypoglycaemia but no neurological involvement. Finally, the CDG Ic patient and one of the CDG Ix patients had psychomotor retardation and seizures. The other CDG Ix patients had severe proximal tubulopathy, bilateral cataract, and white matter abnormalities (one patient), or multiorgan failure and multiple birth defects (one patient). CONCLUSIONS: Owing to the remarkable clinical variability of CDG, this novel disease probably remains largely underdiagnosed. The successful treatment of CDG Ib patients with oral mannose emphasises the paramount importance of early diagnosis of PMI deficiency.

DE LONLAY P., VALNOT I., BARRIENTOS A., GORBATYUK M., TZAGOLOFF A., TAANMAN J.W., BENAYOUN E., CHRETIEN D., KADHOM N., LOMBES A., de BAULNY H.O., NIAUDET P., MUNNICH M., RUSTIN P., ROTIG A. A mutant mitochondrial respiratory chain assembly protein causes complex iii deficiency in patients with tubulopathy, encephalopathy and liver failure. Nat. Genet., 29 (1), 57-60, 2001 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique, U393, Néphrologie Pédiatrique) Complex III (CIII; ubiquinol cytochrome c reductase of the mitochondrial respiratory chain) catalyzes electron transfer from succinate and nicotinamide adenine dinucleotide-linked dehydrogenases to cytochrome c. CIII is made up of 11 subunits, of which all but one (cytochrome b) are encoded by nuclear DNA. CIII deficiencies are rare and manifest heterogeneous clinical presentations(1,2). Although pathogenic mutations in the gene encoding mitochondrial cytochrome b have been described(3-7), mutations in the nuclear-DNA-encoded subunits have not been reported. Involvement of various genes has been indicated in assembly of yeast CIII (refs. 8-11). So far only one such gene, BCS1L, has been identified in human(12). BCS1L represents, therefore, an obvious candidate gene in CIII deficiency. Here,we report BCS1L mutations in six patients, from four unrelated families and presenting neonatal proximal tubulopathy, hepatic involvement and encephalopathy. Complementation study in yeast confirmed the deleterious effect of these mutations. Mutation of BCS1L would seem to be a frequent cause of CIII deficiency, as one-third of our patients have BCS1L mutations. [References: 25] DE LONLAY-DEBENEY P., FOURNET J.C., TOUATI G., ROBERT J.J., JUNIEN C., SAUDUBRAY J.M. Hyperinsulinism. Archives Pédiatrie, 8 (Suppl 2), 298S-300S, 2001 (Services cités : Département de Pédiatrie) DE MONTALEMBERT M., DAVIES S.C. Is hydroxyurea leukemogenic in children with sickle cell disease ? Blood, 98 (9), 2878-2879, 2001 (Services cités : Département de Pédiatrie) DUCROCQ R., BENKERROU M., BRAHIMI L., BELLOY M., BRIARD M.L., VILMER E., ELION J. Neonatal screening for sickle cell disease: evaluation of a five-year experience in the northern part of the paris area. Archives Pédiatrie, 8 (5), 474-480, 2001 (Services cités : Département de Pédiatrie) We report a five-year experience of targeted neonatal screening for sickle cell disease in the northern part of the Paris area as well as the follow-up procedure of screened patients. Population. - This geographic area in France is characterized by a high frequency of populations at risk for sickle cell disease. Results, - Among 115,480 tested newborns, 250 patients were diagnosed (frequency: 1/462). The quality of the screening was attested by the high frequency (5.34%) of newborn carriers for a hemoglobin abnormality (n = 6168). We developed an

optimized strategy which avoids the majority of pit-falls (false positive and false negative responses), except for S/HPFH. More than 95% of sickle cell disease was followed, the majority by medical sickle cell disease experts from hospitals. Only two deaths were recorded during this time period. Conclusion. - We demonstrate the efficiency of targeting the proposed methodological strategy and the follow-up of affected newborns, a major argument demonstrating the importance of newborn screening. (C) 2001 Editions scientifiques et medicales Elsevier SAS. [References: 18] FOURNET J.C., MAYAUD C., de LONLAY P., GROSS-MORAND M.S., VERKARRE V., CASTANET M., DEVILLERS M., RAHIER J., BRUNELLE F., ROBERT J.J., NIHOUL-FEKETE C., SAUDUBRAY J.M., JUNIEN C. Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism - association with a reduction to hamozygosity of a mutation in abcc8 or kcnj11. Amer. J. Pathol., 158 (6), 2177-2184, 2001 (Services cités : Anatomo-Pathologie, Département de Pédiatrie, U383, Chirurgie Pédiatrique, Radiologie Pédiatrique) Congenital hyperinsulinism (CHI), previously named persistent hyperinsulinemic hypoglycemia of infancy, is characterized by profound hypoglycemia because of excessive insulin secretion. CHI presents as two different morphological forms: a diffuse form with functional abnormality of islets throughout the pancreas and a focal form with focal islet cell adenomatous hyperplasia, which can be cured by partial pancreatectomy. Recently, we have shown that focal adenomatous hyperplasia involves the specific loss of the maternal 11p15 region and a constitutional mutation of a paternally inherited allele of the gene encoding the regulating subunit of the K-ATP(+) channel, the sulfonylurea receptor (ABCC8 or SUR1), In the present study on a large series of 31 patients, describing both morphological features and molecular data, we report that 61% of cases (19 out of 31) tarried a paternally inherited mutation not only in the ABCC8 gene as previously described but also in the second gene encoding the K-ATP(+) channel, the inward rectifying potassium channel (KCNJ11 or KIR6.2), in 15 cases and 4 cases, respectively. Moreover our results are consistent with the presence of a duplicated paternal 11p15 allele probably because of mitotic recombination of reduplication of the paternal chromosome after somatic loss of the maternal chromosome. In agreement with the loss of the maternal chromosome, the level of expression of a maternally expressed tumor suppressor gene, H19, was greatly reduced com pared to the level of expression of the paternally expressed growth promoter gene, IGF2, The expression of IGF2 was on average only moderately increased. Thus, focal forms of CHI can be considered to be a recessive somatic disease, associating an imbalance in the expression of imprinted genes in the 11p15.5 region to a somatic reduction to homozygosity of an ABCC8- or KCNJ11-recessive mutation, The former is responsible for the abnormal growth rate, as in embryonic tumors, whereas the latter leads to unregulated secretion of insulin. [References: 52] HOLDER-ESPINASSE M., ABADIE V., CORMIER-DAIRE V., BEYLER C., MANACH Y., MUNNICH A., LYONNET S., COULY G., AMIEL J. Pierre Robin sequence: a series of 117 consecutive cases. J. Pediat., 139 (4), 588-590, 2001 (Services cités : Département de Pédiatrie, Génétique Médicale Pédiatrique, Stomatologie & Chirurgie Maxillo-Faciale, Oto-Rhino-Laryngologie) A series of 117 cases of Pierre Robin Sequence are classified as isolated (48%), syndromic (35%), and with associated anomalies (17%); the latter group had a poor long-term prognosis. In

isolated Pierre Robin Sequence, familial cases and a high incidence of twins were noted. Among syndromic Pierre Robin Sequence, 4 syndromes represent more than 50% of the diagnoses. [References: 15] KIEFFER-RENAUX V., BULTEAU C., GRILL J., LEVY-PIEBOIS C., COUANET D., PIERRE-KAHN A., HARTMANN O., KALIFA C. Visual agnosia after treatment of a posterior fossa ependymoma in a 16-month-old girl. J. Child Neurol., 16 (9), 698-704, 2001 (Services cités : Département de Pédiatrie, Neurochirurgie Pédiatrique) We present the clinical observation of a 16-month-old girl treated for a posterior fossa ependymoma who experienced severe and delayed visual dysfunction. She was initially treated by surgery and conventional chemotherapy. When she relapsed at age 3 years, the salvage treatment combined high-dose chemotherapy, second surgery, and local irradiation. At age 4 years, disturbed gait and dysarthric speech appeared rapidly, and she became unable to recognize objects and people. Computed tomography revealed bilateral calcifications in the cerebellum and temporal and occipital lobes but no relapse. The neuropsychologic evaluations revealed signs of visual agnosia and marked intellectual impairment. The role of the different treatment modalities in the pathogenesis of this unusual syndrome is discussed. [References: 44] LACAILLE F., SOKAL E. Living-related liver transplantation. J. Pediat. Gastroenterol. Nutr., 33 (4), 431-438, 2001 (Services cités : Département de Pédiatrie) MACMULLEN C., FANG J., HSU B.Y.L., KELLY A., de LONLAY-DEBENEY P., SAUDUBRAY J.M., GANGULY A., SMITH T.J., STANLEY C.A. Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J. Clin. Endocrinol. Metabol., 86 (4), 1782-1787, 2001 (Services cités : Département de Pédiatrie) The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism in which affected children have recurrent symptomatic hypoglycemia together with asymptomatic, persistent elevations of plasma ammonium levels. We have shown that the disorder is caused by dominant mutations of the mitochondrial enzyme, glutamate dehydrogenase (GDH), that impair sensitivity to the allosteric inhibitor, GTP. In 65 HI/HA probands screened for GDH mutations, we identified 19 (29%) who had mutations in a new domain, encoded by exons 6 and 7. Six new mutations were found: Ser(217)Cys, Arg(221)Cys, Arg(265)Thr, Tyr(266)Cys, Arg(269)Cys and Arg(269)His. In all five mutations tested, lymphoblast GDH showed reduced sensitivity to allosteric inhibition by GTP (IC50, 60-250 vs. 20-50 nmol/L in normal subjects), consistent with a gain of enzyme function. Studies of ATP allosteric effects on GDH showed a triphasic response with a decrease in high affinity inhibition of enzyme activity in HI/HA lymphoblasts. All of the residues altered by exons 6 and 7 HI/HA mutations lie in the GTP-binding domain of the enzyme. These data confirm the importance of allosteric regulation of GDH as a control site for amino acid-stimulated insulin secretion and indicate that the GTP-binding site is essential for regulation of GDH activity by both GTP and ATP. [References: 30] MAHE E., TORCHET M.F., CHRETIENNOT C., BUFFET P., BODEMER C.

Chronic papular onchodermatitis. Archives Pédiatrie, 8 (6), 604-607, 2001 (Services cités : Dermatologie, Département de Pédiatrie, Infectiologie) 'River blindness' is the main problem of onchocerciasis. Despite a high prevalence of onchocerciasis in endemic countries, cases of imported cutaneous or ocular onchocerciasis in France are rare. Case report, - We report the case of a chronic papular onchodermatitis with voluminous lymphadenopathy in a Cameroonian child, resolving with a treatment of ivermectin. Conclusion, - The main symptom of cutaneous onchocerciasis is pruritus, which symptom may alert physicians when dealing with patients who come from endemic countries for onchocerciasis, Cutaneous aspects may vary depending on length of exposure to antigens and immune responses by the host against microfilariae. Nowadays, onchocerciasis is treated with a single dose of ivermectin, which is sufficient for eye and cutaneous symptoms. However, this therapy is efficient only against microfilariae, and treaments have to be repeated many times to avoid relapses linked to persistence of adult worms. (C) 2001 Editions scientifiques et medicales Elsevier SAS. [References: 8] MENNI F., de LONLAY P., SEVIN C., TOUATI G., PEIGNE C., BARBIER V., NIHOUL-FEKETE C., SAUDUBRAY J.M., ROBERT J.J. Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics, 107 (3), 476-479, 2001 (Services cités : Chirurgie Pédiatrique, Fédération de Pédiatrie, Métabolisme-Neurologie Génétique Pédiatrique) Objective. To evaluate the neurologic outcomes of neonates and infants suffering from persistent hyperinsulinemic hypoglycemia of infancy (PHHI). Methods. The neurologic development of 90 PHHI patients was studied retrospectively. Sixty-three patients were treated surgically and 27 were treated medically. Fifty-four patients were neonates, of whom 8 were treated medically and 46 were operated on (19 for a focal adenomatous hyperplasia and 27 for diffuse hyperinsulinism). Thirty-six patients had infancy-onset hyperinsulinism, of whom 19 were treated medically and 17 underwent pancreatectomy (10 patients for a focal adenomatous hyperplasia and 7 for diffuse hyperinsulinism). Results. Severe psychomotor retardation was found in 7 patients, 6 with neonatal-onset PHHI. Intermediate psychomotor disability existed in 12 patients; epilepsy existed in 16. Neonatal-onset was the main risk factor for severe retardation or epilepsy. Medically treated patients were less severely affected than those treated by surgery, and there was no difference between the diffuse and focal forms of hyperinsulinism. Conclusion. Neonatal hyperinsulinemic hypoglycemia is still a severe disease with an important risk to rapidly develop severe mental retardation and epilepsy. [References: 23] MITANCHEZ D., RABIER D., MOKHTARI M., DURRMEYER X., MENGET A., LARSSON A., SAUDUBRAY J.M. 5-oxoprolinuria: a cause of neonatal metabolic acidosis. Acta Paediatr., 90 (7), 827-828, 2001 (Services cités : Département de Pédiatrie, Métabolisme-Neurologie Génétique Pédiatrique) RAQBI F., ZERAH M., BODEMER C., LENOIR G. Dermoid cysts revealed by meningitis with medullary compression. Archives Pédiatrie, 8 (5), 499-503, 2001 (Services cités : Département de Pédiatrie, Neurochirurgie Pédiatrique, Dermatologie)

The spinal dermal sinus tracts in the lumbosacral region are not usually recognized, especially when they are not associated with other cutaneous lesions. In these sites, the sinus tracts communicate with the dura in 90% of cases, leading to an important risk of meningitis. Case reports. - Two infants (9 and 12 months old) were hospitalized for meningitis. The hospitalization was preceded two weeks earlier by stubborn constipation, which revealed a neural compression. The physical and MRI examination showed a lumbosacral sinus in contact with a dermoid or an epidermoid tumor. These cysts were infected with anaerobic organisms. Despite surgery and antibiotic therapy, one child remained paraplegic. Conclusion. - Dermal sinuses above the intergluteal crease should be surgically excised at the time of diagnosis in all patients, regardless of the patient's age or neurologic findings. (C) 2001 Editions scientifiques et medicales Elsevier SAS. [References: 13] SERMET-GAUDELUS I., LESNE-HULIN A., LENOIR G., SINGLAS E., BERCHE P., HENNEQUIN C. Sputum itraconazole concentrations in cystic fibrosis patients. Antimicrob. Agents Chemother., 45 (6), 1937-1938, 2001 (Services cités : Département de Pédiatrie, Laboratoire de Microbiologie) Itraconazole diffusion in sputum was studied in 11 cystic fibrosis patients,vith allergic bronchopulmonary aspergillosis. There was a high interindividual variability in sputum itraconazole concentration and sputum/ serum drug concentration ratio. Three children had sputum drug concentrations before oral administration that were lower than the itraconazole MIC at which 90% of Aspergillus fumigatus strains were inhibited, although their serum drug concentrations were within the therapeutic range. [References: 14] SERMET-GAUDELUS I., HUBERT D., TURCK D. Le concept d'antibiotherapie inhalee dans la mucoviscidose. A propos d'une forme galenique adaptee de la tobramycine. Archives Pédiatrie, 8 884s-893s, 2001 (Services cités : Département de Pédiatrie) SERMET-GAUDELUS I., GARABEDIAN M., DECHAUX M., LENOIR G., REY J., TIEDER M. Hereditary hypophosphatemic rickets with hypercalciuria: report of a new kindred. Nephron, 88 (1), 83-86, 2001 (Services cités : Département de Pédiatrie, Explorations Fonctionnelles) We report a new kindred of hereditary hypophosphatemic rickets with hypercalciuria, The symptomatic child and several relatives had increased renal phosphate clearance leading to hypophosphatemia, hyperabsorptive hypercalciuria, low PTH and increased 1,25-(OH)(2)D serum level. However, association with vitamin D deficiency and normal urinary excretion of cyclic AMP might suggest another tubular defect in phosphate transport. Copyright (C) 2001 S. Karger AG, Basel. [References: 11] ZIPPER E., VILA G., DABBAS M., BERTRAND C., MOUREN-SIMEONI M.C., ROBERT J.J., RICOUR C. Childhood and adolescent obesity, mental disorders and familial psychopathology. Presse Medicale, 30 (30), 1489-1495, 2001 (Services cités : Fédération de Pédiatrie, Gastroentérologie Pédiatrique, Pédo-Psychiatrie)

Objective The purpose of this study was to evaluate the type and frequency of psychopathological disorders observed in obese children and adolescents. We also looked for a correlation between psychic disorders in the obese children, the degree of obesity and paternal psychopathology. Patients and methods The study group included 84 obese children and adolescents aged 5 to 16 to years (mean age 10.9 +/- 2.8 years). ere were 55 girls and 29 boys. The z-score expressing deviation from the ideal body mass index (IMC) varied from +2 to +10.6 (mean +5.4 + 1.9). Psychopathological disorders observed in these obese patents were compared in children and adolescents with insulin-dependent diabetes mellitus. The standard diagnostic interview (K-SADS PL) and self-administered questionnaires (Sielberger STAIC-Trait for anxiety and CDI for depression in children or CBCL or GHQ for their parents) were also used to evaluate psychic disorders. Results More than half of the obese children (47 out of 84) had a DSM-IV diagnosis, often involving anxiety (n = 28). The rate of internalized and externalized psychopathological disorders (measured by STAIC-Trait and CBCL) was higher in the obese children than in the diabetics, The children's psychopathological disorders were more marked if their parents were perturbed, particularly when their mother had an internalised disorder. No correlation was found between the degree obesity and psychopathological disorders in the obese children and adolescents. Conclusion Our findings show the frequency of mental disorders in obese children and point out the importance of parental psychopathology. This underlines the usefulness of a pedopsychiatric approach implicating the entire family for therapeutic management of these patients. [References: 29] 2000 ABADIE V., BONNET D., LYONNET S., COULY G. Dysfunction of the brain stem and congenital heart defects. Archives Pédiatrie, 7 Suppl 2 145s-149s, 2000 (Services cités : Stomatologie & Chirurgie Maxillo-Faciale, Génétique Médicale Pédiatrique, Département de Pédiatrie) ABADIE V., WIENER VACHER S., MORISSEAU DURAND M.P., POREE C., AMIEL J., AMANOU L., PEIGNE C., LYONNET S., MANAC'H Y. Vestibular anomalies in charge syndrome: investigations on and consequences for postural development. Eur. J. Pediat., 159 (8), 569-574, 2000 (Services cités : Radiologie Pédiatrique, Oto-Rhino-Laryngologie, Génétique Médicale Pédiatrique, Département de Pédiatrie) Recently, vestibular anomalies have been described as a frequent feature in children with coloboma-heart-atresia-retarded-genital-ear (CHARGE) syndrome. They are likely to play an important role in the psychomotor retardation affecting these children. In order to test this hypothesis, we prospectively performed complete vestibular investigations in a series of 17 CHARGE syndrome patients including inner ear CT scan and functional vestibular evaluation of both canal and otolith functions. These results were correlated with the postural anomalies observed during the children's development and showed that vestibular dysfunction is a constant feature in CHARGE syndrome and has very good sensitivity for confirming the diagnosis. Anomalies of semicircular canals were frequently found (94%), easily detectable on CT scan and associated with no response on canal function evaluation. They were considered as partly responsible for the retardation of postural stages. Vestibular functional tests were consistently abnormal but allowed detection of residual otolith function in most patients (94%). All children

of this series had an atypical pattern of postural behaviour that we consider to be related to their vestibular anomalies. Residual otolith function seems to have a positive influence for postural development. Conclusion Vestibular investigations are valuable for diagnosis, developmental assessment, and adaptation of specific rehabilitation programmes in CHARGE syndrome patients. [References: 19] ABADIE V., CHAMPAGNAT J., FORTIN G. Branchiomotor activities in mouse embryo. Neuroreport, 11 (1), 141-145, 2000 (Services cités : Département de Pédiatrie) Using a novel isolated hindbrain in vitro preparation, we demonstrate that, in the mouse, branchiomotor activities from trigeminal, facial, glossopharyngeal and vagal nerves start during segmentation, a crucial and conserved period of hindbrain embryogenesis. At embryonic day (E) 10.5, branchiomotor nerves are independently active in bursts, become coactive at a low frequency (about 0.5 min(-1) at E12.5, before high frequency (about 15 min(-1)) fetal breathing starts at E14.5. Comparison with observations in chick reveals a transient episodic rhythmic pattern highly similar in mouse at E13.5 and chick at E7. This pattern is proposed as a marker identifying a phylotypic stage during the development of hindbrain neuronal networks in vertebrates. NeuroReport 11:141-145 (C) 2000 Lippincott Williams & Wilkins. [References: 18] CASTELNAU P., LE MERRER M., DIATLOFF ZITO C., MARQUIS E., TETE M.J., ROBERT J.J. Wolcott-rallison syndrome: a case with endocrine and exocrine pancreatic deficiency and pancreatic hypotrophy. Eur. J. Pediat., 159 (8), 631-633, 2000 (Services cités : U393, U383, Fédération de Pédiatrie) Clinical analysis and genetic investigations of new Eases of Wolcott-Rallison syndrome are needed to evaluate the role of the gene(s) directly or indirectly implicated in pancreas development and in the aetiology of the syndrome. [References: 8] CHRETIENNOT C., ANDREU J., SIMON I., AMIEL J., ZERAH M. Radiological quiz of the month - klippel-feil syndrome. Archives Pédiatrie, 7 (9), 982-984, 2000 (Services cités : Radiologie Pédiatrique, Génétique Médicale Pédiatrique, Neurochirurgie Pédiatrique, Département de Pédiatrie) DE LONLAY DEBENEY P., ROBERT J.J., SAUDUBRAY J.M. Molecular basis of hyperinsulinisms. Ann. Endocrinol., 61 (2), 139, 2000 (Services cités : Département de Pédiatrie) DE LONLAY P., NASSOGNE M.C., VAN GENNIP A.H., VAN CRUCHTEN A.C., de VILLEMEUR T.B., CRETZ M., STOLL C., LAUNAY J.M., STEENBERGER-SPANTE G.C.V., VAN DEN HEUVEL L.P.W., WEVERS R.A., SAUDUBRAY J.M., ABELING N.G.G.M. Tyrosine hydroxylase deficiency unresponsive to l-dopa treatment with unusual clinical and biochemical presentation.

J. Inherit. Metab. Dis., 23 (8), 819-825, 2000 (Services cités : Métabolisme-Neurologie Génétique Pédiatrique, Département de Pédiatrie) Tyrosine hydroxylase (TH) deficiency is generally considered as a cause of the autosomal recessive form of dopa-responsive dystonia, also known as Segawa disease. Clinical hallmarks comprise parkinsonian and other extrapyramidal symptoms. Biochemically the defect leads to the defective synthesis of catecholamines, in particular dopamine. The diagnosis relies on a characteristic pattern of biogenic amine metabolites exclusively in the CSF and can be confirmed by establishing a mutation in the TH gene. Here we present a patient meeting all diagnostic criteria, including a new homozygous mutation (926T >C) with confirmed parental heterozygosity, extrapyramidal symptoms, but atypical other symptoms with periodic neurological episodes observed every 4 days and unresponsive to dopa treatment. The CSF biochemical abnormalities were severe. Uncharacteristically, a strongly abnormal urinary catecholamine metabolite pattern was also consistently observed. The atypical presentation of this patient shows that the clinical and metabolic phenotype of TH deficiency is more variable than formerly thought, and that the condition should no longer be considered as a treatable disorder per se. [References: 13] DE LONLAY P., CORMIER DAIRE V., VUILLAUMIER BARROT S., CUER M., DURAND G., MUNNICH A., SAUDUBRAY J.M., SETA N. "Carbohydrate-deficient glycoprotein" syndrome. Archives Pédiatrie, 7 (2), 173-184, 2000 (Services cités : Biochimie Générale, Département de Pédiatrie) Carbohydrate-deficient glycoprotein syndrome (CDGS) is a newly delineated group of inherited multisystemic disorders associated with abnormal glycosylation of a number of serum glycoproteins. Several types have been described on the basis of clinical presentation and biochemical changes of the glycosylation of serum transferrin and attributed to different enzymatic defects, their clinical presentations are fully different and a clinical heterogeneity is observed within a same type of CDGS. Patients with CDGS type la usually present with neurologic (hypotonia, strabismus and cerebellar hypoplasia) and cutaneous (inverted nipples, abnormal distribution of adipose tissue) abnormalities, together with multivisceral involvement (digestive, hepatic, cardiac, renal). However, neurologic and cutaneous symptoms may be absent, so that CDGS must be looked for in case of unexplained organ failure such as isolated liver insufficiency; cardiomyopathy: pericarditis, tubulopathy, nephrotic syndrome, vascular accident or retinitis pigmentosa. Patients with CDGS type Ib present with liver disease, enteropathy and hypoglycemia without neurologic involvement. These patients are successfully treated with oral mannose administration, emphasizing the importance of making the diagnosis. Patients with CDGS type Ic present with mild psychomotor retardation and seizures. Patients with CDGS type II have psychomotor retardation associated with severe gastrointestinal disorder dysmorphic features and abnormal electroretinogram. Other types (III, IV) are less clearly defined and the clinical presentation includes convulsive encephalopathy. Biological abnormalities such as mild hepatic cytolysis, hematologic and hormonal abnormalities are consistently observed in CDGS type I, as well as renal hyperechogeneity, leading one to look for this syndrome when they are associated. Until now, only four enzymatic deficiencies have been identified (types la, Ib, Ic, II). (C) 2000 Editions scientifiques et medicales Elsevier SAS. [References: 66] DE MONTALEMBERT M. Transfusion in patients with hemoglobinopathies.

Transfus. Clin. Biol., 7 (6), 553-55+, 2000 (Services cités : Département de Pédiatrie) A-Thalassemia involves a production deficiency concerning the synthesis of alpha -globin chains, and beta- thalassemia involves the beta -globin chains. Only a few patients in France are affected by the major form of thalassemia (certain types of homozygotic beta -thalassemia). Also, the systematic screening of 'at-risk' couples and prenatal diagnosis has helped to considerably reduce the incidence of new cases. The decision to perform regular blood transfusions is made when Hb levels fall below values that are compatible with normal activity. Hb levels above 10 g/dL permit normal educational, recreational and professional activity. This level is generally maintained via a 15 mL/kg erythrocyte concentrate supplement every three weeks, or 20 mL/kg every four weeks. However the appearance of antierythrocytic autoantibodies is possible, and this may also result in an increase in blood transfusion requirements, In intermediate thalassemia patients, residual Hb levels are maintained at between 7 and 10 g/dL, and transfusion of erythrocyte concentrates is only made in the case of aggravation of chronic anemia or when there are signs of intolerance to chronic anemia. In France, there is relatively large population of patients with sickle cell disease. Blood transfusion is a major element in the treatment of these patients. Simple transfusion is performed in cases of a lack of iron or folates, increased hemolysis, splenic nic sequestration or parvovirus 19 infection. The target hematocrit should mostly remain at the patient's baseline value. Exchange transfusions are not performed oil a regular basis, but only in cases of stroke or of her severe vaso-occlusive events, or when a patient has to be prepared for surgery. A minority of subjects are involved in chronic blood transfusion, which is used mostly to prevent cerebrovascular accidents but also in cases of cardiac, renal, or respiratory insufficiency. There is an increased prevalence of antierythrocytic alloimmunization in sickle cell patients, most probably because of the discrepancies in red cell antigens between mainly Caucasian blood donors and Afro-Caribbean recipients. (C) 2000 Editions scientifiques et medicales Elsevier SAS. [References: 10] FAIVRE L., PRIEUR A.M., LE MERRER M., HAYEM F., PENET C., WOO P., HOFER M., DAGONEAU N., SERMET I., MUNNICH A., CORMIER-DAIRE V. Clinical variability and genetic homogeneity of the camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Amer. J. Med. Genet., 95 (3), 233-236, 2000 (Services cités : Histo-Embryologie & Cytogénétique, Génétique Médicale Pédiatrique, Département de Pédiatrie) The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is an autosomal recessive condition characterized by the association of congenital or early onset camptodactyly and noninflammatory arthropathy with synovial hyperplasia. Progressive coxa vara deformity and/or noninflammatory pericardial or pleural effusions have been observed in some patients. Recently, the disease gene has been assigned to human chromosome region 1q25-q31, and truncating mutations have been identified in the megakaryocyte stimulating factor gene. Studying 12 patients from 8 unrelated families, we emphasized hip and spine involvement, particularly in the course of the disease as shown in a 58-year-old patient. Despite clinical variability, linkage studies support genetic homogeneity of the disease. FAIVRE L., CORMIER-DAIRE V., CHRETIEN D., VON KLEIST-RETZOW J.C., AMIEL J., DOMMERGUES M., SAUDUBRAY J.M., DUMEZ Y., ROTIG A., RUSTIN P., MUNNICH A.

Determination of enzyme activities for prenatal diagnosis of respiratory chain deficiency. Prenatal Diag., 20 (9), 732-737, 2000 (Services cités : U393, Génétique Médicale Pédiatrique, Département de Pédiatrie) Genetic counselling and prenatal diagnosis are major issues of mitochondrial respiratory chain deficiency, especially as these conditions are largely untreatable. In the absence of known mitochondrial or nuclear gene mutations, measurement of respiratory chain enzyme activities represents the only possibility to prevent recurrence of the disease in affected families. We carried out enzymatic prenatal diagnosis in 21 pregnancies from 10 unrelated couples using uncultured choriocytes and/or amniocytes. Twelve babies were born and are healthy, seven pregnancies were discontinued early on because of an enzyme deficiency detected prenatally. In two cases, a fetus which appeared normal after early and/or late prenatal diagnosis, turned out to be affected. We conclude that a deficient enzyme activity is indicative of recurrence, but a normal result at 10 weeks of gestation does not give conclusive evidence as to the outcome of the pregnancy. We therefore suggest the following procedure: (1) a choriocentesis or an amniocentesis in early pregnancy when the proband expresses the disease in cultured skin fibroblasts; (2) a second amniocentesis at 28 weeks' gestation should be offered to avoid false negative results due to a possible late expression of the disease, in combination with: (3) a careful and repeated ultrasound survey for detection of growth failure in the third trimester; (4) prenatal diagnosis should not be performed in case of late onset clinical symptoms in the proband; and (5) parents should be aware of the possibility of false negative results. Prenatal diagnosis should not be proposed for a complex I deficiency as this enzyme activity cannot be accurately measured in fetal cells. Copyright (C) 2000 John Wiley & Sons, Ltd. [References: 23] FEUILLET-FIEUX M.N., SERMET I., EDELMAN A., TOROSSI T., FERREC M., GUILLOT M., LENOIR G., BONNEFONT J.P., THUILLIER L. Identification of a novel mutation, 1087delT, in exon 7 of the CFTR gene in a patient with cystic fibrosis. Hum. Mutat., 16 (1), 95, 2000 (Services cités : U467, Département de Pédiatrie, Biochimie Médicale) FOURNET J.C., MAYAUD C., de LONLAYA P., VERKARRE V., RAHIER J., BRUNELLE F., ROBERT J.J., NIHOUL FEKETE C., SAUDUBRAY J.M., JUNIEN C. Loss of imprinted genes and paternal sur1 mutations lead to focal form of congenital hyperinsulinism. Hormone Res., 53 (Suppl 1), 2-6, 2000 (Services cités : U383, Radiologie Pédiatrique, Département de Pédiatrie, Anatomo-Pathologie) Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a heterogeneous disorder characterized by profound hypoglycaemia due to inappropriate hypersecretion of insulin. An important diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI), because the management differs significantly. The intriguing similarity between islet cell hyperplasia and tumourigenesis prompted us to investigate whether the imprinted genes in the 11p15 region are involved. Results showed that diffuse forms are caused by constitutional homozygous or compound heterozygous mutations of the SUR1 gene. In contrast, focal forms are caused by loss of the maternally inherited 11p15 region, resulting in both loss of the maternally expressed tumour suppressor genes accounting for hyperplasia and somatic reduction to hemizygosity or homozygosity of the paternally inherited SUR1, limited to the lesion. Thus, this somatic disorder,

which leads both to P-cell proliferation and to hyperinsulinism, can be considered the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation. Copyright (C) 2000 S. Karger AG, Basel. [References: 33] GIURGEA I., RAQBI F., NIHOUL-FEKETE C., COULY G., ABADIE V. Congenital microgastria with pierre robin sequence sequence and partial trismus. Clin. Dysmorphol., 9 (4), 307-308, 2000 (Services cités : Chirurgie Pédiatrique, Département de Pédiatrie, Stomatologie & Chirurgie Maxillo-Faciale) A female with congenital microgastria, Pierre Robin sequence and partial trismus is described. This is a previously undescribed association and the etiology of the association is discussed. Clin Dysmorphol 9: 307-308 (C) 2000 Lippincott Williams & Wilkins. [References: 6] HAYEM F. Fpapa syndrome. Archives Pédiatrie, 7 (8), 898, 2000 (Services cités : Département de Pédiatrie) LACAILLE F. Lamivudine treatment for children with interferon refractory chronic hepatitis B. Hepatology, 32 (5), 1180, 2000 (Services cités : Département de Pédiatrie) LESPRIT E., ESCUDIER E., ROGER G., PRULIERE V., LENOIR G., REINERT P., COSTE A. Characterization of inflammatory reaction in upper airways of cystic fibrosis patients. Histol. Histopathol., 15 (2), 395-402, 2000 (Services cités : Fédération de Pédiatrie) Inflammatory cell populations have not been yet precisely evaluated in cystic fibrosis (CF) airways. We intended to characterize morphological modifications, inflammatory cell infiltration and cell proliferation in nasal tissues obtained from 15 CF patients and from 6 non-CF patients with nasal polyposis. Morphological analysis showed an intense inflammatory infiltration in CF and non-CF tissues with only few modifications in the epithelium from CF tissues. Inflammatory cell populations characterized by specific immunolabeling were quantified, showing a predominance of macrophages and T- and B-lymphocytes and only moderate numbers of neutrophils in CF tissues; in non-CF polyps, lymphocytes and eosinophils were abundant. Proliferating cell percentages quantified after proliferating cell nuclear antigen immunolabeling were 5.3+/-4.1% (mean +/- SD) in CF polyps and 3.1+/-1.2% in non-CF polyps in epithelium but were very low in lamina propria. Intense inflammation in nasal tissues from CF patients is therefore dominated by macrophages and lymphocytes rather than by neutrophils. While morphology is preserved, proliferation is high in epithelium from CF polyps. These findings should be regarded in the future for a better understanding of inflammation in CF airway disease. [References: 25] LUCOTTE G., BATHELIER C., MERCIER G., GERARD N., LENOIR G., SEMONIN O., FONTAINE K.

Localization of the gene for fibrodysplasia ossificans progressiva (fop) to chromosome 17q21-22. Genet. Counsel., 11 (4), 329-334, 2000 (Services cités : Département de Pédiatrie) Fibrodysplasia ossificans progressiva (FOP) is a very rare disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of muscles. To identify the chromosomal localization of the FOP gene, we conducted a genomewide linkage analysis using seven affected families. The FOP phenotype is linked to markers located in the 17q21-22 region (LOD score of 3.41 at the recombination fraction theta = 0). Crossover events localize the putative FOP gene within a 12cM interval, bordered proximally by D17S809 and distally by D17S1838. Noggin (NOG) gene, located in 17q22, is an excellent candidate gene for FOP. [References: 20] SALIBA Z., BAH G., MARTIN D., ABADIE V., AZAR Z., FRAISSE A., SIDI D., KACHANER J., BONNET D. Pseudo inherited left heart obstructive defects revealing a maternal phenylketonuria. Arch. Mal. Coeur Vaisseaux, 93 (5), 649-652, 2000 (Services cités : Fédération de Pédiatrie, Cardiologie Pédiatrique) If an adequate diet is not given to mothers with phenylketonuria, their offsprings often exhibit intra-uterine growth retardation with associated microcephaly and various malformations. Here, we report two families in whom we observed recurrent left heart malformations associated with microcephaly masquerading as a mendelian condition and revealing a maternal phenylketonuria. These observations suggest that when confronted to recurrent heart malformations with extra-cardiac defects that are not due either to an inherited chromosomal anomaly or to a well characterized mendelian disease, a maternal teratogen should be identified and more particularly maternal hyperphenylalaninemia if an intra-uterine growth retardation or a microcephaly is part of the syndrome. [References: 10] SERMET GAUDELUS I., ABADIE V., STAMBOULI F., HENNEQUIN C., LENOIR G., GENDREL D. Haemophagocytic syndrome in plasmodium falciparum malaria. Acta Paediatr., 89 (3), 368-369, 2000 (Services cités : Département de Pédiatrie) SERMET GAUDELUS I., POISSON SALOMON A.S., COLOMB V., BRUSSET M.C., MOSSER F., BERRIER F., RICOUR C. Simple pediatric nutritional risk score to identify children at risk of malnutrition. Amer. J. Clin. Nutr., 72 (1), 64-70, 2000 (Services cités : Département de Pédiatrie) Background: Although hospitalized children are at risk of malnutrition, routine screening of nutritional status has been hindered by lack of a validated nutritional assessment tool. Objective: Our aim was to develop a simple pediatric nutritional risk score that could be used at hospital admission to identify patients at risk of acute malnutrition during hospitalization. Design: Nutritional risk was assessed prospectively in 296 children. Anthropometric measurements, food intake, ability to eat and retain food, medical condition, and symptoms interfering with feeding (pain, dyspnea, and depression) were evaluated within 48 h of admission. Pathology was classified as mild (grade 1), moderate (grade 2), or severe (grade 3). The risk of weight loss was investigated with stepwise logistic regression. Results: Weight loss during hospitalization

occurred in 65% of the children and was >2% of admission weight in 45% of patients. Multivariate analysis indicated that food intake <50%, pain, and grade 2 and 3 pathologic conditions (P = 0.0001 for all) were associated with weight losses of >2%. The nutritional risk score ranged from 0 to 5 and was calculated by adding the values for the significant risk factors as follows: 1 for food intake <50%. I for pain, 1 for grade 2 pathologic condition, and 3 for grade 3 pathologic condition. A score of 1 or 2 indicated moderate risk and a score greater than or equal to 3 indicated high risk of malnutrition. Conclusions: This simple score is suitable for routine use to identify patients at risk of malnutrition during hospitalization. Implementation may prevent hospital-acquired malnutrition. [References: 34] SERMET GAUDELUS I., HULIN A., FERRONI A., SILLY C., GAILLARD J.L., BERCHE P., LENOIR G. Pharmacologic particularities of antibiotics in cystic fibrosis. Archives Pédiatrie, 7 (5), 519-528, 2000 (Services cités : Pharmacie, Laboratoire de Microbiologie, Fédération de Pédiatrie) Antibiotherapy is one of the main treatment in cystic fibrosis. Antibiotic administration schedules are different from normal patients because of pharmacokinetic and pharmacodynamic particularities. In moderate disease, the digestive resorption of antibiotics is delayed and their half-life is reduced due to an increase in total clearance. In severe disease, the volume of distribution of antibiotics is increased due to the higher proportion of lean mass in these malnourished patients. Other particularities limit the action of antibiotics such as thick sputum, which limits drug penetration; the property of Pseudomonas aeruginosa to be surrounded by a biofilm; alteration of local antibacterial defense; and inhibition of antibiotics by local factors, Systematic prescription of a bitherapy beta-lactam-aminoglycosid and obtaining high antibiotic concentration in situ might limit this antagonism. In spite of particular therapeutic schedules such as single daily dose for aminoglycosid and continuous infusion for beta-lactams, the intervals between administrations must be narrowed for time-dependent antibiotics and the total daily dose increased by 20 to 30% for concentration-dependent antibiotics. (C) 2000 Editions scientifiques et medicales Elsevier SAS. [References: 62] SERMET GAUDELUS I., BONNEFONT J.P., NGUYEN-KHOA A.T., LENOIR G. Normal sweat test does not exclude the diagnosis of cystic fibrosis. Archives Pédiatrie, 7 (6), 594-596, 2000 (Services cités : U467, Génétique Médicale Pédiatrique, Département de Pédiatrie) SERMET GAUDELUS I., FERRONI A., GAILLARD J.L., SILLY C., CHRETIENNOT C., LENOIR G., BERCHE P. Antibiotic therapy in cystic fibrosis. Archives Pédiatrie, 7 (6), 645-656, 2000 (Services cités : Département de Pédiatrie) Antibiotherapy is one of the main treatments of cystic fibrosis, contributing to a better nutritional and respiratory status and a prolonged survival. The choice of antibiotics depends on quantitative and qualitative analysis of sputum, bacteria resistance phenotypes and severity of infection. Haemophilus influenzae infection can be treated orally with the association of amoxicillin-clavulanic acid or a cephalosporin. Staphylococcus aureus generally remains sensitive to usual antibiotics, in case of a methicillin-resistant strain, an oral bitherapy or a parenteral cure can be proposed. Treatment of Pseudomonas aeruginosa is different in case of first colonization or

chronic infection: in first colonization, parenteral antibiotherapy (beta-lactams-aminoglycosids) followed by inhaled antibiotherapy may eradicate the bacteria; in chronic infections, exacerbations require parenteral bi-antibiotherapy (beta-lactams or quinolons and aminoglycosids) for 15 to 21 days, inhaled antibiotics between the cures being useful to decrease the number of exacerbation. A careful monitoring of antibiotherapy is necessary because of possible induction of bacterial resistance, nephrotoxicity and ototoxicity of aminosids and allergy to beta-lactams. (C) 2000 Editions scientifiques ef medicales Elsevier SAS. [References: 102] 1999 ABADIE V., CHAMPAGNAT J., FORTIN G., COULY G. Sucking-swallowing-breathing control and stem development genes. Archives Pédiatrie, 6 (10), 1043-1047, 1999 (Services cités : Département de Pédiatrie, Stomatologie & Chirurgie Maxillo-Faciale) BODEMER C., ROTIG A., RUSTIN P., CORMIER V., NIAUDET P., SAUDUBRAY J.M., RABIER D., MUNNICH A., de PROST Y. Hair and skin disorders as signs of mitochondrial disease. Pediatrics, 103 (2), 428-433, 1999 (Services cités : Département de Pédiatrie) Objective. To compare and explore the skin manifestations of mitochondrial disorders in 14 children with puzzling and unexpected cutaneous presentations. BRESSON J.L., JEAY S., GAGNERAULT M.C., KAYSER C., BERESSI N., WU Z., KINET S., DARDENNE M., POSTEL-VINAY M.C. Growth hormone (GH) and prolactin receptors in human peripheral blood mononuclear cells: relation with age and GH-binding protein. Endocrinology, 140 (7), 3203-3209, 1999 (Services cités : U344, UMR 8603, Département de Pédiatrie) GH receptors (GHRs) and PRL receptors (PRLRs) were studied in human peripheral blood mononuclear cells (PBMC) using flow cytometry, biotinylated anti-GH receptor monoclonal antibody 10B8, and biotinylated human PRL. Variations of GHR and PRLR expression and the relationship of plasma GHBP and GH receptor in PBMC subsets were examined as a function of age and sex. By double immunofluorescence staining, we show that about 30% of total cells express GH receptors, with a low expression in T cells, whereas almost all B cells and monocytes are GH receptor positive. Four age groups were defined among the 64 normal volunteers, aged 12 to 85 yr, who were included in the study. The percentage of PBMC expressing GH receptors is significantly lower in group 2 (20-40 yr) than in group 1 (12-20 yr) and group 4 (>60 yr). In T cells, monocytes and B cells, no significant changes are detected in either the percentage of GH receptor positive cells or in the GH receptor level per cell. The level of PRLRs expressed in PBMC is significantly higher in age group 2 than in age group 4. A negative correlation is observed between plasma GHBP and the percentage of PBMC expressing GH receptors. These results suggest that regulation of GH receptors in lymphocytes and in other target cells could be different. [References: 33] CHRETIENNOT C., MAROUTSI E., NOSEDA G.,B.O.U.H.N.I.K. Radiological quiz of the month - vertebral findings revealing hodgkin's disease. Archives Pédiatrie, 6 (12), 1322-1324, 1999

(Services cités : Radiologie Pédiatrique, Département de Pédiatrie) COLOMB V. Home parenteral nutrition: the pediatric point of view. Nutrition, 15 (2), 172-173, 1999 (Services cités : Fédération de Pédiatrie, Gastroentérologie Pédiatrique) DAMOTTE D., COLOMB V., CANIONI D., MICHEL J.L., JOBERT A., GOULET O., CEZARD J.P., SARNACKI S., REVILLON Y., RICOUR C., AIGRAIN Y., BROUSSE N., PEUCHMAUR M., JAN D. Morphologic features of large bowel biopsies in combined small and large bowel transplantations could predict clinical rejection. Transplant. Proc., 31 (1-2), 593, 1999 (Services cités : Département de Pédiatrie, Anatomo-Pathologie) DE LONLAY P., CUER M., VUILLAUMIER-BARROT S., BEAUNE G., CASTELNAU P., KRETZ M., DURAND G., SAUDUBRAY J.M., SETA N. Hypersulinemic hypoglycemia as a presenting sign in phosphomannose isomerase deficiency: A new manifestation of carbohydrate-deficient glycoprotein syndrome treatable with mannose. J. Pediat., 135 (3), 379-383, 1999 (Services cités : Département de Pédiatrie) We report the case of a patient with carbohydrate-deficient glycoprotein syndrome type Ib who developed normally until 3 months of age, when she was referred to the hospital for evaluation of hypoglycemia that was found to be related to hyperinsulinism. She also had vomiting episodes, hepatomegaly, and intractable diarrhea, which evoked the diagnosis of carbohydrate-deficient glycoprotein syndrome. Oral mannose treatment at a dose of 0.17 g/kg body weight 6 times/d was followed by a clinical improvement and normalization of blood glucose, aminotransferases, and coagulation factor levels. Hyperinsulinemic hypoglycemia should be considered as a leading sign of carbohydrate-deficient glycoprotein syndrome type Ib, especially when it is associated with enteropathy and abnormal liver tests. [References: 19] DE LONLAY-DEBENEY P., POGGI-TRAVERT F., FOURNET J.C., SEMPOUX C., VICI C.D., BRUNELLE F., TOUATI G., RAHIER J., JUNIEN C., NIHOUL-FEKETE C., ROBERT J.J., SAUDUBRAY J.M. Clinical features of 52 neonates with hyperinsulinism. N. Engl. J. Med., 340 (15), 1169-1175, 1999 (Services cités : Département de Pédiatrie) Background Neonatal hyperinsulinemic hypoglycemia is often resistant to medical therapy and is often treated with near-total pancreatectomy. However, the pancreatic lesions may be focal and treatable by partial pancreatic resection. GOULET O., JOBERT-GIRAUD A., MICHEL J.L., JAUBERT F., LORTAT-JACOB S., COLOMB V., CUENOD-JABRI B., JAN D., BROUSSE N., GAILLARD D., NIHOUL-FEKETE C., RICOUR C. Chronic intestinal pseudo-obstruction syndrome in pediatric patients. Eur. J. Pediatr. Surg., 9 (2), 83-89, 1999 (Services cités : Département de Pédiatrie)

The aim of this study was to report the presentation and outcome of 22 consecutive children (13 female) who presented with a syndrome of chronic intestinal pseudo-obstruction with or without urinary tract involvement. We analyse the main clinical and histopathological features and discuss therapeutic management, Ten patients had signs of intestinal obstruction at birth, in which 6 presented antenatally with megacystis on ultrasound. Six children presented with constipation and/or obstruction between 1 and 6 months of age and in 6 other patients diagnosis was made between the ages of 1 and 12 years. There was a family history in 4 patients. Investigations showed diffusely dilated gut on x-ray with slow transit on small bowel follow through. Absent or abnormal motor migrating complex with low amplitude contractions were demonstrated on duodeno-jejunal manometry in 12/13. Megacystis occurred in 15/21 and megaureter in 2/21. Full thickness biopsies (n = 22) revealed involvement of muscle layers in 8, and abnormal myenteric plexus on histochemistry in 13. In 1, the biopsies were inconclusive. Recurrent urinary tract infections occurred in all with structural urinary tract abnormality and most had bacterial overgrowth. Severe recurrent episodes of obstruction which required parenteral nutrition (PN) occurred in all patients. Drugs were unhelpful and decompression ileostomies or colostomies were performed in 20/22. Five children died from sepsis (n = 3) or sudden death. Eleven patients remain partially or totally dependent on PN despite decompression ileostomy in 10/11, Six patients underwent colectomy and ileorectal pull-through, 2 of which remain on long-term PN, while the others are totally orally fed. Despite careful histological study pointing to 2 main forms, myopathy and neuropathy, the etiology of primary intestinal pseudoobstruction syndromes remains unknown, It may present antenatally while most of the time the gut and the urinary tract are diffusely involved. The condition has a high morbidity with a percentage requiring long-term PN. Although the mortality rate is high (23 %), careful treatment of urinary tract infections and bacterial overgrowth, decompression surgery and judicious use of PN allows survival to adult life. [References: 42] GOULET O., JAN D., LACAILLE F., COLOMB V., MICHEL J.L., DAMOTTE D., JOUVET P., BROUSSE N., FAURE C., CEZARD J.P., SARNACKI S., PEUCHMAUR M., HUBERT P., RICOUR C., REVILLON Y. Intestinal transplantation in children: preliminary experience in Paris. J. Parent. Enter. Nutr., 23 (5 Suppl), S121-S125, 1999 (Services cités : Département de Pédiatrie, Anatomo-Pathologie) From November 1994 to November 1998, 20 children (2.5 to 14 years) received a jejunoileal graft alone (SBTx; n = 10) or in combination with the liver (SBLTx; n = 10 and/or the right colon (5 SBTx). Indications were intractable diarrhea of infancy (n = 8), short bowel syndrome (n = 6), extensive Hirschsprung disease (n = 4), and chronic intestinal pseudoobstruction (n = 2). Immunosuppression included tacrolimus, methylprednisolone, and azathioprine. Current follow-up ranges from 6 to 54 months. Five patients died (3 SBTx) within the first 2 months. Acute liver rejection occurred in 5 patients during the first 2 months. Sixteen episodes of intestinal rejection during the first 3 months in 11 patients (8 in 4 SBTx) were successfully treated in all but 3 by increasing tacrolimus dose and/or a 3-day methyprednisolone bolus or required antilymphoglobulins in 3 cases. Surgical complications occurred 8 times after SBLTx and 3 after SBTx. Infectious complications were more frequent in SBLTx recipients. Reversible Epstein-Barr virus-related posttransplant lymphoproliferative disease occurred in 3 recipients. Five presented cytomegalovirus infection. The SB graft was removed in 5 recipients (3 chronic rejection). All patients were started with oral and/or enteral feeding from the 7th postoperative day by using either normal food or protein hydrolysate diet. Currently, 10 of 11 children (8

SBLTx) achieved digestive autonomy after 5 to 30 weeks. All recipients gained weight; however, growth velocity remained reduced during the first 6 months because of the steroid therapy. Overall graft and patient survival is higher after SBLTx. Intestinal transplantation is indicated for patients with permanent intestinal failure. However, because parenteral nutrition is generally well tolerated, even for long periods, each indication for transplantation must be weighed carefully in terms of risk and quality of life. JAN D., MICHEL J.L., GOULET O., SARNACKI S., LACAILLE F., DAMOTTE D., CEZARD J.P., AIGRAIN Y., BROUSSE N., PEUCHMAUR M., RENGEVAL A., COLOMB V., JOUVET P., RICOUR C., REVILLON Y. Up-to-date evolution of small bowel transplantation in children with intestinal failure. J. Pediat. Surg., 34 (5), 841-3; dis, 1999 (Services cités : Anatomo-Pathologie, Département de Pédiatrie) Purpose: The aim of the authors was to report an up-to-date review of their experience with 26 intestinal transplantations in children since 1987. KOLETZKO B., AGGETT P.J., AGOSTONI C., BAERLOCHER K., BRESSON J.L., COOKE R.J., DECSI T., DEUTSCH J., JANDA J., MANZ F., MOYA M., RIGO J., SOCHA J. Pesticides in dietary foods for infants and young children. Report of the Working Group on Pesticides in Baby Foods of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Arch. Dis. Child., 80 (1), 91-92, 1999 (Services cités : Département de Pédiatrie) LACAILLE F., BELGHITI J., SAUVAT F., MICHEL J.L., FARGES O., RENGEVAL A., SARNACKI S., SAYEGH N., JAN D., REVILLON Y. Liver transplantation with a living related donor in children. Gastroentérol. Clin. Biol., 23 (6-7), 710-716, 1999 (Services cités : Département de Pédiatrie, Radiologie Pédiatrique, Anesthésie Pédiatrique, Chirurgie Pédiatrique) Objectifs - Liver transplantation with living related donor has been recently developed to compensate for the insufficient number of liver grafts for children. The major problem is ethical because it implies voluntary mutilation of a healthy person This paper report results in 37 living related donors. LACAILLE F., FOURNET J.C., SAYEGH N., JAUBERT F., REVILLON Y. Inflammatory pseudotumor of the liver: a rare benign tumor mimicking a malignancy. Liver Transplant. Surg., 5 (1), 83-85, 1999 (Services cités : Département de Pédiatrie) We describe a 9-month-old boy in whom a hepatic tumor called angioma was diagnosed on ultrasonography, performed for abdominal pain. He was asymptomatic until 9 months later, when he presented with weight loss, jaundice, and a hard tumor in the left liver lobe. Radiological examination showed a calcified and heterogeneous tumor, amputation of the left portal vein, and dilatation of bile ducts, strongly suggesting malignancy. However, liver biopsy showed the typical findings of inflammatory pseudotumor, which are myofibroblastic cells and perivascular plasmocytes in a dense collagenous stroma. The tumor was surgically removed without local

recurrence with a 2-year follow-up. Inflammatory pseudotumor in childhood is more common in the lung and elsewhere is often mistaken for a slowly growing cancer. This case points out the difficulties in the radiological evaluation of liver tumors in childhood and the importance of the histological differentiation of this lesion from malignancy before laparotomy for adequate indication of the treatment, which includes no medical treatment and surgery as conservative as possible. LACAILLE F., FOURNET J.C., BLANCHE S. Clinical utility of liver biopsy in children with acquired immunodeficiency syndrome. Pediat. Inf. Dis. J., 18 (2), 143-147, 1999 (Services cités : Département de Pédiatrie) Background, Little is known about hepatic histology in children with AIDS, although the liver is frequently involved in the course of HIV infection. The clinical utility of liver biopsy in these patients is not well-defined. We reviewed retrospectively the results of this procedure in a group of infected children better to delineate its indications. LE MASME A. Medical problems of internationally adopted children. Archives Pédiatrie, 6 (5), 569-572, 1999 (Services cités : CUDR, Département de Pédiatrie) Adopted children from foreign countries represent a high risk population for infectious diseases, nutritional problems and neuro-developmental delay. Medical screening including clinical and biological evaluation is recommended after arrival. (C) 1999 Elsevier, Paris. [References: 14] LENOIR G., MONNIER A., MARAIS P. Cystic fibrosis: home antibiotic therapy. Rev. Fr. Allergol. Immunol. Clin., 39 (6), 520-522, 1999 (Services cités : Département de Pédiatrie) ROBERT J.J., TETE M.J., GUEST G., GAGNADOUX M.F., NIAUDET P., BROYER M. Diabetes mellitus in patients with infantile cystinosis after renal transplantation. Pediat. Nephrol., 13 (6), 524-529, 1999 (Services cités : Fédération de Pédiatrie, Néphrologie Pédiatrique) Diabetes mellitus is a frequent long-term complication of infantile nephropathic cystinosis. We studied 44 cystinotic patients, aged 22.1+/-5.4 years, transplanted at a mean age of 11.3+/-2.5 years; 25% were treated with insulin at 20 years of age or 10 years after transplantation, and over half required insulin at latest follow-up. In comparison, diabetes mellitus occurred in only 1% of non-cystinotic transplanted patients. Sequential oral glucose tolerance tests (OGTTs) in these patients showed the progressive deterioration of glucose metabolism All but 2 patients had an abnormal response at latest follow-up. The high doses of corticosteroid given after transplantation or during rejection episodes were responsible for transient insulin dependency. However, the development of impaired glucose tolerance and diabetes mellitus depended mainly on the cystinotic process, which developed slowly with time. The deterioration of glucose tolerance was correlated with a decreased early phase of insulin secretion, estimated from the plasma insulin level at 30 min of the OGTT, while there was no evidence of insulin resistance. The occurrence of diabetes mellitus correlated with a worsening of the vital prognosis. [References: 28]

ROGER G., MORISSEAU-DURAND M.P., VAN DEN ABBEELE T., NICOLLAS R., TRIGLIA J.M., NARCY P., ABADIE V., MANAC'H Y., GARABEDIAN E.N. The CHARGE Association - The role of tracheotomy. Arch. Otolar.- Head Neck Surg., 125 (1), 33-38, 1999 (Services cités : Département de Pédiatrie, Oto-Rhino-Laryngologie) Objectives: To evaluate the need for a tracheotomy and its timing during the evolution of an association of malformations, including coloboma, heart defects, choanal atresia, developmental and growth retardation, genitourinary malformation, and ear anomalies (CHARGE association). SAUDUBRAY J.M., TOUATI G., DELONLAY P., JOUVET P., NARCY C., LAURENT J., RABIER D., KAMOUN P., JAN D., REVILLON Y. Liver transplantation in urea cycle disorders. Eur. J. Pediat., 158 (Suppl 2), S55-S59, 1999 (Services cités : Fédération de Pédiatrie, Biochimie Médicale) We report here our experience in the long-term management of 28 patients with citrullinaemia, 13 patients with carbamoyl phosphate synthase deficiency and 15 patients with argininosuccinic aciduria. In addition, we report a national French survey of 119 patients with ornithine transcarbamylase (OTC) deficiency enzymatically characterized in our laboratory. We also include in this report four personal patients (two with OTC and two with citrullinaemia) who were liver transplanted, and one OTC patient from the National French survey. Although this retrospective series is not really representative of the modern treatment combining low protein diet and arginine, sodium benzoate and sodium phenylbutyrate, it is obvious that the long-term outcome of all urea cycle disorders remains very guarded. We highlight the severity of the neonatal forms of such disorders, and mostly for OTC-deficient males. According to this evidence, our policy is not to treat such severely affected patients in the neonatal period who die anyway spontaneously within 2 to 3 days. At the present time, we only have three patients with neonatal citrullinaemia, aged 1, 6 and 10 years respectively, who are still doing well. One of them has been successfully liver transplanted at 5 years. Another transplanted patient died in the post-surgical phase. We emphasize the unexpected severity of argininosuccinic aciduria in which there is no one patient doing well. This is a rather surprising finding as this disorder is easy to manage and rarely presents with recurrent attacks of hyperammonaemia when it is treated by arginine supplementation. This consideration would suggest to extend the indication of orthotopic liver transplantation in this disorder. Finally, the most difficult indication is in the late onset symptomatic female OTC group. In this last group, despite a significant residual activity due to heterozygote status, even with a variable lyonisation, only seven girls are still mentally and neurologically normal. Interestingly, three of these seven were liver-transplanted before the constitution of irreversible neurological damage. These three girls and their family declare their well-being, their feeling to be cured and enjoy their normal life. [References: 18] SAUDUBRAY J.M., TOUATI G., DELONLAY P., JOUVET P., SCHLENZIG J., NARCY C., LAURENT J., RABIER D., KAMOUN P., JAN D., REVILLON Y. Liver transplantation in propionic acidaemia. Eur. J. Pediat., 158 (Suppl 2), S65-S69, 1999 (Services cités : Fédération de Pédiatrie, Biochimie Médicale) Despite the improvement in dietary therapy during the past 20 years, the overall outcome of severe forms of propionic acidaemia (PA) remains often disappointing. Good results can be obtained at a very high price in terms of medical attention, family burden and high cost. In most

early onset forms of PA, the intake of natural protein must be rigidly restricted to 8-12 g/day for the first 3 years of life, and then slowly increased to 15-20 g/day by the age of 6-8 years. Supplementation with a precursor-free aminoacid mixture to provide 1.5 g/kg protein per day is generally recommended, although remains controversial. From the age of 1 year onward, these children are often severely anorectic and most of the diet must be delivered by nocturnal gastric drip feeding or gastrostomy. Metronidazole is very effective in reducing the excretion of propionate metabolites derived from the gut. L-carnitine (50 to 100 mg/kg) is systematically given to promote propionylcarnitine synthesis and excretion. We report here a retrospective study of 33 patients with PA diagnosed during the last 20 years in our hospital. Of them, 2 have been liver transplanted. In these two patients who presented frequent severe and unexpected metabolic decompensations despite good compliance with the dietary therapy, orthotopic liver transplantation (OLT) was done at 7 and 9 years respectively. One child died 15 months after transplantation due to a severe lymphoproliferative disorder; the other child now aged 13.5 years is doing well. Despite a persistent methylcitrate excretion, she is under normal moderate daily protein intake (40-50 g/day) and still on carnitine supplementation. Interestingly, another patient who filled the criteria for OLT (very frequent and severe decompensations leading to frequent admissions to the intensive care unit despite excellent dietary management) was also placed on the list for OLT. From the time he was registered onward, he experienced no further episodes of metabolic decompensation, there was almost no interruption in his daily intake and he gained height and weight and developed well. He was finally removed from the list and is still doing very well 2 years thereafter. Correction of propionylCoA carboxylase deficiency restricted to hepatic tissues seems to induce a change towards clinical normalisation and a milder biochemical phenotype. Liver transplanted PA patients still require slight protein restriction and carnitine treatment. We consider that at the moment OLT should only be performed in severe forms of PA, mostly characterised by frequent and unexpected episodes of metabolic decompensation despite good dietary therapy. However, a strict appreciation of these criteria is difficult. A more generalised indication for OLT in PA will require more information about the long-term outcome of transplanted patients. We should also await other alternatives like auxiliary partial OLT from living donors or transplantation of isolated allogenic hepatocytes, genetically modified or not. [References: 28] SAUDUBRAY J.M., MARTIN D., de LONLAY P., TOUATI G., POGGI-TRAVERT F., BONNET D., JOUVET P., BOUTRON M., SLAMA A., VIANEY-SABAN C., BONNEFONT J.P., RABIER D., KAMOUN P., BRIVET M. Recognition and management of fatty acid oxidation defects: A series of 107 patients. J. Inherit. Metab. Dis., 22 (4), 488-502, 1999 (Services cités : Biochimie Médicale, Département de Pédiatrie) In recent years tremendous progress has been made with respect to the enzymology of the mitochondrial fatty acid beta-oxidation machinery and defects therein. Firstly, a number of new mitochondrial beta-oxidation enzymes have been identified, including very-long-chain acyl-CoA dehydrogenase (VLCAD) and mitochondrial trifunctional protein (MTP). Secondly, the introduction of tandem MS for the analysis of plasma acylcarnitines has greatly facilitated the identification of patients with a defect in fatty acid oxidation (FAO). These two developments explain why the number of defined FAO disorders has increased dramatically, making FAO disorders the most rapidly growing group of inborn errors of metabolism. In this review we describe the current state of knowledge of the enzymes involved in the mitochondrial oxidation of straight-chain, branched-chain and (poly)unsaturated fatty acyl-CoAs as well as disorders of

fatty acid oxidation. The laboratory diagnosis of these disorders is described, with particular emphasis on the methods used to identify the underlying enzyme defect and the molecular mutations. In addition, a simple flowchart is presented as a guide to the identification of mitochondrial FAO-disorders. Finally, treatment strategies are discussed briefly. [References: 59] SERMET-GAUDELUS I., STAMBOULI F., ABADIE V., GOUTIERES F., LENOIR G., GENDREL D., GAILLARD J.L. Rapid improvement of intracranial tuberculomas after addition of ofloxacin to first-line antituberculosis treatment. Eur. J. Clin. Microbiol. Infect. Dis., 18 (10), 726-728, 1999 (Services cités : Département de Pédiatrie) Reported here is the case of a 9-year-old girl presenting with disseminated tuberculosis, the manifestations of which included mediastinal adenopathy, an osteolytic parietal lesion with a large associated scalp abscess, cerebral empyema, meningoencephalitis, and tuberculomas. No clear improvement was observed after 4 weeks of first-line antituberculosis treatment (10 mg/kg rifampin, 15 mg/kg isoniazid, 30 mg/kg ethambutol, 30 mg/kg pyrazinamide). The isolation of an isoniazid-resistant organism prompted institution of ofloxacin. Introduction of this drug was associated with dramatic improvement. Its good penetration into the central nervous system and its distribution into macrophages suggest that this drug may be of interest for the treatment of intracranial tuberculomas, particularly those due to isoniazid-resistant strains. SERMET-GAUDELUS I., STOVEN V., ANNEREAU J.P., WITKO-SARSAT V., REINERT P., GUYOT M., DESCAMPS-LATSCHA B., LALLEMAND J.Y., LENOIR G. Interest of colchicine for the treatment of cystic fibrosis patients. Preliminary report. Mediat. Inflamm., 8 (1), 13-15, 1999 (Services cités : U507, Département de Pédiatrie) CYSTIC fibrosis (CF) lung disease is characterized by persistent inflammation. Antiinflammatory drugs, such as corticosteroids and ibuprofene, have proved to slow the decline of pulmonary function although their use is limited because of frequent adverse events. We hypothesized that colchicine could be an alternative treatment because of its antiinflammatory properties and upregulatory effect on cystic fibrosis transmembrane regulator (CFTR) closely related proteins. We herein present results obtained in an open study of eight CF children treated with colchicine for at least 6 months. Clinical status was better in all patients and respiratory function tests significantly improved in five. Median duration of antibiotherapy decreased significantly. These preliminary results support our hypothesis of a beneficial effect of colchicine in CF patients and stress the need for a controlled therapeutic trial. [References: 22] SOKAL E.M., SOKOL R., CORMIER V., LACAILLE F., MCKIERNAN P., VAN SPRONSEN F.J., BERNARD O., SAUDUBRAY J.M. Liver transplantation in mitochondrial respiratory chain disorders. Eur. J. Pediat., 158 (Suppl 2), S81-S84, 1999 (Services cités : Département de Pédiatrie) Mitochondrial respiratory chain disease may lead to neonatal or late onset liver failure, requiring liver transplantation. In rare cases, the disease is restricted to the liver and the patient is cured after surgery. More frequently, other organs are simultaneously involved and neuromuscular or other extra-hepatic symptoms may pre-exist, or appear in the post-transplant follow up. Pre-transplant evaluation should aim to rule out neurological disease, which may be difficult to

differentiate from signs accompanying liver insufficiency. Cerebrospinal fluid lactic acid levels, compared to blood lactate, may be suggestive of central nervous system involvement. Of 11 cases with respiratory chain disorders who had liver transplantation in various centres, 4 are alive and well on follow up, and 6 died, three of them having developed neurological disease post orthotopic liver transplantation. All three patients with initial liver and gastro-intestinal disease died early after transplantation, indicating that these may be poor candidates for this procedure. TELLIER B., JOUVET P., HUBERT P., NIAUDET P. Prognostic factors in neonatal acute renal failure. Ann. Pédiatr., 46 (4), 216-222, 1999 (Services cités : Fédération de Pédiatrie) A retrospective study was conducted to evaluate the prognosis of acute renal failure (ARF) in neonates and to identify factors predictive of death or of residual neurological or renal function impairment. Fifty-seven neonates admitted to a polyvalent pediatric intensive care unit between 1990 and 1995 were included based on serum creatinine elevation above 150 mu mol/l within 28 days of birth. Anuria was present in 32 cases and oliguria in 11. Serum sodium was lower than 130 mmol/l in 44 cases and serum potassium higher than 5 mmol/l in 38 cases. Peritoneal dialysis was used in 14 patients and hemo filtration in six. There were 29 in-hospital deaths, and 83% of all deaths were due to prerenal causes of ARF. Among the 28 survivors, six had a developmental delay and three had chronic renal failure defined as serum creatinine levels greater than 50 mu mol/l beyond six months of age corrected for gestational age at birth. In this retrospective study, four factors were associated with a greater risk of death or residual neurological impairment, namely age younger than 24 h at admission, the underlying condition, low or absent urine output, and multiorgan failure syndrome. In most cases, even those treated by renal support techniques, renal function returned to normal. [References: 22] WITKO-SARSAT V., HALBWACHS-MECARELLI L., SCHUSTER A., NUSBAUM P., UEKI I., CANTELOUP S., LENOIR G., DESCAMPS-LATSCHA B., NADEL J.A. Proteinase 3, a potent secretagogue in airways, is present in cystic fibrosis sputum. Amer. J. Respir. Cell Molec. Biol., 20 (4), 729-736, 1999 (Services cités : U507, Fédération de Pédiatrie) We evaluated the roles of proteinase 3 (PR3) and human neutrophil elastase (HNE), two neutrophil serine proteinases in the mechanisms leading to airway inflammation and hypersecretion in cystic fibrosis (CF). Using specific enzyme-linked immunosorbent assay (ELISA), we found higher levels of PR3 than HNE in sputum from CF patients. Using two inhibitors, ICI (Imperial Chemical Industries) 200,355 (which inhibits both HNE and PR3) and secretory leukoproteinase inhibitor (SLPI) (which inhibits only HNE), we showed that PR3 was enzymatically active in sputum, and its activity, as assessed by SLPI-resistant serine proteinase activity, correlated highly with its antigenic concentration measured by ELISA. Interestingly, sputum pellet-associated serine proteinase activity was mostly due to HNE. PR3 purified from neutrophil azurophil granules triggered airway gland secretion, as measured by the release of radiolabeled molecules from cultured bovine tracheal serous cells pulse-labeled with Na235SO4. This secretory activity was inhibited by ICI 200,355. PR3 concentration in CF sputum was highly correlated with taurine concentration, a reliable marker of airway inflammation and respiratory scores (e.g., FEV1%), whereas no significant correlation was observed with HNE. We verified that Pseudomonas aeruginosa proteinases did not interfere with the assessment of PR3 and HNE. Indeed, the PR3/HNE ratio was greatest in patients chronically infected by P. aeruginosa. We

suggest that PR3 may play a role in the hypersecretory process that is characteristic of CF.