Phenotypic heterogeneity in AAAS gene mutation

P Barat1, C Goizet2, A Tullio-Pelet3, O Puel1, C Labessan4 and A Barthelemy5

Department of Paediatrics1 and Medical Genetics2, Hopital Pellegrin-Enfants, Bordeaux, France; Unite´ de Recherche sur les HandicapsGenetiques de l’Enfant3, INSERM U-393, Paris, France; Radiology Unit4, Hopital Pellegrin-Enfants, Bordeaux, France; HoˆpitalSaint-Cyr, Villeneuve sur Lot, France

Barat P, Goizet C, Tullio-Pelet A, Puel O, Labessan C, Barthelemy A. Phenotypic heterogeneity inAAAS gene mutation. Acta Pædiatr 2004; 93: 1257–59 Stockholm. ISSN 0803-5253

We report the cases of two sibs of North African origin withAAASgene mutation characterized bythe heterogeneity of their phenotype. While an 8-y-old boy presented with acute adrenal insuffi-ciency and mental retardation, the diagnosis was suggested by the clinical history of his 6-y-oldsister who had symptomatic achalasia and chronic adrenal failure.

Conclusion: Our observations corroborate the phenotypic heterogeneity reported in triple Asyndrome, and underline the possibility of a variable intra-familial expression.

Key words: Endocrinology, genetic, adrenal deficiency, triple A syndrome, Allgrove syndrome

P Barat, Department of Paediatrics, Hoˆpital Pellegrin-Enfants, 33076 Bordeaux Cedex, France(Tel.�33 5 56 79 87 25, fax.�33 5 56 79 56 58, e-mail. baratp@club-internet.fr)

Triple A syndrome (3A syndrome), also known asAllgrove syndrome (AS), is a rare autosomal recessivedisorder characterized by ACTH-resistant adrenal defi-ciency, achalasia of the oesophageal cardia and alacri-mia (1). Autonomic and neurological dysfunctionfrequently complete the clinical spectrum (2–6). Theresponsible gene,AAAS, has recently been identified(5). We present two siblings displaying a heterogeneousphenotype of 3A syndrome in association with ahomozygous mutation in theAAASgene.

Case report 1The index case was an 8-y-old boy issued fromapparently unrelated parents of North Africa origin.His medical history was remarkable for febrile seizuresand mental retardation since the age of 4 y. Hepresented with hypovolaemic shock secondary to severegastroenteritis. Cutaneous and digestive candidiasisoccurred while he was managed in the intensive careunit. Persisting asthenia, hyponatraemia and hyperka-laemia led to a diagnosis of primary adrenal insuffi-ciency (Table 1). Serum calcium level was normal butserum parathyroid hormone (PTH) level was undetect-able. A barium study of the gastro-oesophagus junctionwas normal. The Schirmer test was not performed.Despite the fact that auto-immune antibodies againstadrenal and parathyroid gland were negative, thediagnosis of autoimmune polyendocrinopathy-candi-diasis-ectodermal dystrophy (APECED) syndromewas proposed. Substitution therapy for adrenal failure(hydrocortisone and fludrocortisone) led to metabolicnormalization and improvement of behavioural trou-

bles. He was re-investigated 3 y later in the light of theclinical history of his sister (Case report 2). Both heightand weight were�1.8 standard deviation (SD) for sexand chronological age. Neurological examinationshowed a distally predominant symmetric amyotrophyin lower limbs, symmetric brisk and diffused reflexes, aleft-sided Babinski sign and bilateral foot deformities.Glucocorticoid deficiency was confirmed, PTH leveland calcium level were normal. Asymptomatic achala-sia was revealed on a barium meal. A Schirmer test wasinconclusive because of lack of cooperation, butbilateral keratitis was noted. 3A syndrome was con-firmed by genetic analysis (see Case report 2).

Case report 2This 6-y-old girl is the index case’s sister. Her medicalhistory was remarkable for a single episode of general-ized seizure at 5 y of age and recurrent vomiting for 1 y.Examination showed normal growth (� 0.3 SD for bothheight and weight), hyperpigmentation, teeth dysplasiawith caries, diffusely brisk reflexes without motordeficit, slight body sways upon eye occlusion duringRomberg’s manoeuvre, but no sensory loss regardingtouch, vibration or limb position. Mental developmentwas normal. Endocrine investigations showed primaryadrenal insufficiency without any electrolyte distur-bance (Table 1), and substitutive therapy with hydro-cortisone and fludrocortisone was initiated. A bariummeal followed by oesophago-gastric fibroscopy re-vealed achalasia of the cardia. A Schirmer test demon-strated alacrimia complicated by keratitis. Lumbarosteopenia was shown on dual X-ray absorptiometry

2004 Taylor & Francis. ISSN 0803-5253

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DOI 10.1080/08035250410027706

(bone mineral density�1.8 SD). The sequencing of theAAASgene in the two patients identified a homozygousmutation within intron 14 (IVS14� 1G→A). Bothparents were heterozygous for this mutation.

Discussion3A syndrome or AS was first defined by the presence ofthree cardinal features (achalasia, alacrimia and adrenaldeficiency). Progressively, the clinical spectrum hasbeen enlarged with the description of additionalautonomic and neurological features and of partialforms of the disease (2A syndrome for achalasia andalacrima) (2–6). The neurological presentation is highlyvariable in 3A syndrome with a possible involvement ofboth the peripheral and central nervous system (3–7).The high recurrence of the associated autonomic andneurological features led to the suggested use of theterms 4A and 5A syndrome for denominating thedisease (autonomic anomalies, and amyotrophy andother neurological anomalies were added) (3, 4).

A phenotypic heterogeneity was demonstrated byGrant et al. in a series of 20 affected patients: the onsetof adrenal insufficiency varied from 1.0 to 8.3 y,alacrimia was present since early infancy in 19 cases,achalasia was diagnosed in 15 patients between 2.5 and17.0 y of age, and there was evidence of neurologicalimpairment in 17 patients at a median age of 10.0 y (2).Autonomic disturbances (postural hypotension andanisocoria) were present in 11 patients. Mental retarda-tion was found in 11 of the 17 patients with neurologicaldysfunction.

We present here the cases of two siblings who sharedthe same mutation inAAASbut manifested different

clinical presentations (Table I). The initial sign of theindex case was acute adrenal failure that occurred at 8 y,but mental retardation has been known since the age of4 y and may be, at least partially, secondary to un-detected and untreated chronic adrenal failure. Interest-ingly, an asymptomatic chronic adrenal failure withmineralocorticoid deficiency and without elevation ofplasma renin activity was discovered at the age of 6 y inhis sister. In contrast to her brother, she had normalintellectual development, teeth dysplasia and asympto-matic achalasia, but both had alacrimia and neurologicalsigns. However, the neurological involvement was moresevere in the index case than in his sister. The identi-fication of the two siblings’ phenotypes permitted theinitial misdiagnosis of APECED syndrome in the indexcase to be revised. Genetic analysis confirmed thediagnosis of 3A syndrome with the identification of ahomozygous (IVS14� 1G→A) mutation in theAAASgene. This is the most frequent mutation found inpatients of North Africa origin and results in apremature termination of the predicted protein (5).Tullio-Pellet et al. suggested that this mutation appearedat least 2400 y ago in the North African population andmay have spread to other Mediterranean populations.No phenotype–genotype correlation can be establishedfor this mutation, which has been found both in patientswith autonomous neuropathy or other neurologicalfeatures and in patients with 2A syndrome (5). Mostrecently, Sandrini et al. described eight patients withAS. Five of them, all of Puerto Rican origin, had thesame homozygous mutation, but with a substantialclinical variation between them. Four had alacrima, fourhad achalasia, one presented with neurological defi-ciency and one presented with seizures. Mineralocorti-coid deficiency was found in two AS patients (7).

Our observations corroborate the phenotypic hetero-geneity reported in 3A syndrome and underline thepossibility of variable intra-familial expression. Be-cause of the progressive appearance of signs and of theexistence of partial forms of 3A syndrome, specificattention should be given to the search for signsincluded in the spectrum of the disorder when a childpresents with at least one of the three initial cardinalfeatures. More particularly, we propose that systematicinvestigations should be undertaken during the follow-up of cases withde novoadrenal insufficiency, in orderto early identify the features and to propose appropriatetreatment.

References1. Allgrove J, Clayden GS, Grant DB, Macaulay JC. Familial

glucocorticoid deficiency with achalasia of the cardia and deficienttear production. Lancet 1978; 1: 1284–6

2. Grant DB, Barnes ND, Dumic M, Ginalska-Malinowska M, MillaPJ, Petrykowski W, et al. Neurologic and adrenal dysfunction inthe adrenal insufficiency/alacrima/achalasia (3A) syndrome. ArchDis Child 1993; 68: 779–82

Table 1.Phenotype of the two siblings withAAASgene mutation.

Case 1 2

Sex M FAge (y) 8 6Alacrimia � �Achalasia � (non-symptomatic)� (symptomatic)Primary adrenal insufficiency

ACTH (pmol/l) [2–14]a 306 381Cortisol (nmol/l) [200–700]a �27 39 (38)b

PRA (ng/ml.h) [0.16–2.33]a 0.32 1.77Aldosterone (pmol/l)

[150–500]a127 �70

Na (mmol/l) [136–145]a 130 137K (mmol/l) [3.5–5.3]a 4.2 4.3

Mental retardation � 0Neurological abnormalities � �Lumbar bone mineral density

(SD)NA �1.8

Teeth dysplasia 0 �

NA: not available; PRA: plasma rennin activity; SD: standard devi-ation for sex and chronological age.

a Normal range.b 1 h after ACTH stimulation (250�g syncortin).

1258 Clinical observations ACTA PÆDIATR 93 (2004)

3. Gazarian M, Cowell CT, Bonney M, Grigor WG. The “4A”syndrome: adrenocortical insufficiency associated with achalasia,alacrima, autonomic and other neurological abnormalities. Eur JPediatr 1995; 154: 18–23

4. Goizet C, Catargi B, Tison F, Tullio-Pelet A, Hadj-Rabia S, PujolF, et al. Progressive bulbospinal amyotrophy in Triple A syndromewith AAAS gene mutation. Neurology 2002; 58: 962–5

5. Tulliot-Pelet A, Salomon R, Hadj-Rabia S, Mugnier C, de LaetMH, Chaouachi B, et al. Mutation of a novel WD-repeat proteingene in Allgrove (Triple A) syndrome. Nat Genet 2000; 26: 332–5

6. Houlden H, Smith S, de Carvalho M, Blake J, Mathias C, WoodNW, et al. Clinical and genetic characterization of families withtriple A (Allgrove) syndrome. Brain 2002; 125: 2681–90

7. Sandrini F, Farmakidis C, Kirschner LS, Wu S-M, Tullio-Pellet A,Lyonnet S, et al. Spectrum of mutations of the AAAS gene inAllgrove syndrome: lack of mutations in six kindreds with isolatedresistance to corticotropin. JCEM 2001; 86: 5430–7

Received July 2, 2003; revisions received Oct 11, 2003; acceptedJan. 9, 2004

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Optic nerve glioma and colonic polyposis: report of a new association

SS Sheta1, EA El Toukhy2, HM Khattab3

Departments of Paediatrics1, Ophthalmology2 and Pathology3, Cairo University, Cairo, Egypt

Sheta SS, El Toukhy EA, Khattab HM. Optic nerve glioma and colonic polyposis: report of a newassociation. Acta Pædiatr 2004; 93: 1259–1260. Stockholm. ISSN 0803-5253

Aim: The authors describe the clinical, radiological and histopathological features of an opticnerve glioma associated with colonic polyposis. The association between colonic polyposis andneuroepithelial tumours of the central nervous system has been previously described, but noassociation with optic nerve gliomas has ever been reported.Methods:We report a 14-y-old girlwith colonic polyposis and unilateral proptosis for whom an excisional biopsy of the orbital lesionwas performed.Results:Histopathological evidence of juvenile pilocytic astrocytoma grade 1 wasdetected. Correlation with criteria for Turcot’s syndrome was established.

Conclusion:Optic nerve tumours should be included in the spectrum of central nervous systemlesions associated with colonic polyposis.

Key words: Colonic polyposis, optic nerve glioma, Turcot’s syndrome

Sahar S Sheta, 14-A Dr. El Sobki Street, Dokki, Cairo 12311, Egypt (Fax.�202 3356017, e-mail.sssheta@yahoo.com)

Optic nerve gliomas are the most common primaryoptic nerve tumours, and they usually occur in the firsttwo decades of life (1, 2). Apart from neurofibroma-tosis, there is no known association between optic nervegliomas and systemic disorders (3). Since the opticnerve is essentially a tract of the CNS, optic nervegliomas are essentially brain tumours (4). The associa-tion of primary neuroepithelial tumours, particularlygliomas, with familial intestinal polyposis is welldocumented in the literature and is referred to asTurcot’s syndrome (5–7). We here report on theassociation of an optic nerve glioma with familialintestinal polyposis fulfilling the criteria originallydescribed by Turcot.

Case reportA 14-y-old girl was referred to the paediatric ophthal-mology section with a complaint of right-sided propto-

sis and blurring of vision. The girl has been followed upby one of the authors (Dr Sheta) for 4 y after totalresection of the colon for familial polyposis colisyndrome. On examination, the patient had a vision ofno light perception in the right eye and 20/20 vision inthe left eye. The right eye showed 2 mm of axialproptosis. Ocular motility was free in all directions inboth eyes. Anterior segment exam was normal apartfrom the afferent papillary defect detected in the righteye. Fundus exam showed evidence of optic atrophywith a pale disc in the right eye.

CT scan showed a well-defined oblong intra-conallesion not separable from the right optic nerve andmeasuring 3� 2� 2.1 cm. The lesion showed homo-genous contrast enhancement. The rest of the scan wasnormal apart from the mild forward proptosis of theright eye. An MRI with contrast was done and showedthat the mass was indenting the grossly intact rightglobe anteriorly, while posteriorly it stopped short of theoptic foramen with no evidence of intracranial exten-

ACTA PÆDIATR 93 (2004) Clinical observations 1259