A new autosomal recessive syndrome of ocular colobomas, ichthyosis, brain malformations and endocrine abnormalities in an inbred Emirati family

� 2008 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 146A:813–819 (2008)

New Syndrome

A New Autosomal Recessive Syndrome of OcularColobomas, Ichthyosis, Brain Malformations and

Endocrine Abnormalities in an Inbred Emirati Family

L. Al-Gazali,1* J. Hertecant,2 K. Algawi,3 H. El Teraifi,4 and M. Dattani51Department of Paediatrics, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates

2Department of Paediatrics, Tawam/John-Hopkins Hospital, Al Ain, United Arab Emirates3Department of Ophthalmology, Tawam/John-Hopkins Hospital, Al Ain, United Arab Emirates

4Department of Pathology, Tawam/John-Hopkins Hospital, Al Ain, United Arab Emirates5Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, Institute of Child Health, London, UK

Received 16 April 2007; Accepted 2 September 2007

We report on an inbred Emirati family of Baluchi origin withocular colobomas, ichthyosis, and endocrine abnormalitiesassociated with midline brain malformations and mentalretardation. All affected children had ocular colobomas,developmental delay and midline brain malformations.Hypoplastic pituitary gland was present in all three inves-tigated children. Ichthyosiform dermatitis appeared ininfancy in all surviving children. Other variable featuresinclude congenital heart defects, hypertrichosis and darkskin involving the dorsum of hands and feet associated withmild degree of palmo-plantar keratoderma. Some of thefeatures in this family overlap the CHIME (Coloboma of theeye, Heart defect, Ichthyosiform dermatosis, Mental retarda-

tion, and Ear defect) syndrome. However, several featuresdescribed in CHIME syndrome were not present in thesechildren. These include deafness, seizures, oligodontia, andhair abnormalities. Some of the features in these childrenalso overlap with septo-optic dysplasia (SOD) but opticnerve hypoplasia, mandatory for the diagnosis of SOD, waspresent in one child only. We suggest that these childrenhave a new autosomal recessive syndrome of ocularcolobomas and ichthyosis. � 2008 Wiley-Liss, Inc.

Key words: UAE; ocular colodomas; consanguinity; brainmalformation

How to cite this article: Al-Gazali L, Hertecant J, Algawi K, El Teraifi H, Dattani M. 2008. A new autosomalrecessive syndrome of ocular colobomas, ichthyosis, brainmalformations and endocrine abnormalities in an

inbred Emirati family. Am J Med Genet Part A 146A:813–819.

INTRODUCTION

The CHIME syndrome (OMIM 280000) is a rareneuroectodermal disorder characterized by Colo-boma of the eye, Heart defects, Ichthyosiformdermatosis, Mental retardation, and Ear defect. Sixcases have been reported in the literature [Zunichand Kaye, 1983, 1984; Zunich et al., 1985, 1988;Shashi et al., 1995; Tinschert et al., 1996; Schnur et al.,1997].

Septo-optic dysplasia (SOD) is a variable combi-nation of optic nerve hypoplasia, absence of theseptum pellucidum or midline brain structures andpituitary endocrinopathy. The latter could present atbirth or evolve with time [Wales and Quarrell 1996].Although usually sporadic, autosomal recessiveforms have been described in the literature [Blethenand Weldon 1985; Benner et al., 1990; Wales andQuarrell 1996].

We report on an inbred Emirati family with a newautosomal recessive syndrome with features thatoverlap both CHIME syndrome and SOD.

CLINICAL REPORT

The family is of Baluchi origin and shows multipleconsanguinity (Fig. 1). The first child was a female(IV1), the product of a pregnancy complicated bypre-eclampsia. Prenatal ultrasound showed intra-uterine growth retardation and choroid plexus cyst.Delivery at 35 weeks was normal. Her birth weight

*Correspondence to: L. Al-Gazali, FRCP, Department of Paediatrics,Faculty of Medicine and Health Sciences, UAE University, PO Box 17666,Al Ain, United Arab Emirates. E-mail: [email protected]

DOI 10.1002/ajmg.a.32114

was 1,520 g, length was 42 cm, and head circum-ference was 29 cm. She was noted to have severaldysmorphic features which included asymmetric,thin and long face, hypertelorism, down-slantingpalpebral fissures, arched eyebrows, depressednasal bridge, short upturned nose with smoothphiltrum, and a large mouth with a thin upper lip.The ears were abnormally formed and low set. Therewas reduced subcutaneous tissue with loose over-folded skin. The baby was noted to have abnormaleye movements and detailed ophthalmologicalexamination revealed coloboma of the right pupiland choroid and bilateral atrophy of the optic discs.The baby had feeding problems and slow weightgain. Brain CT scan showed hypodense paren-chyma, minimum dilatation of the frontal horns ofthe ventricles with marked dilatation of the posteriorhorns of the lateral ventricles and increased fluid inthe posterior fossa. Some degree of vermis hypo-plasia could not be ruled out. Bone X-rays showedosteoporosis with increased trabeculation and afracture of the left clavicle. Chromosome analysis

and echocardiography were normal. The babydeveloped repeated chest infection due to aspirationand died in the first 3 months of life.

Patient 2 (IV5), brother of patient 1 was the productof a normal pregnancy. There was a suspicion of fetalheart anomaly on routine ultrasound but detailedultrasound by the cardiologist revealed no heartanomalies except mild biventricular hypertrophy.The delivery was normal. The baby had good Apgarscores andhis birthweightwas 3,155 g.Hewasnotedto have several dysmorphic features. These includedredundant skin over the forehead and neck, down-slanting palpebral fissures, low set ears, depressednasal bridge and a large mouth with thin lips. Theface looked triangular with no fat on the cheeks(Fig. 2). There was contracture of the proximalinterphalangeal joints and ulnar deviation of thefingers. The hands and feet appeared larger thannormal. There was bony prominence on the sacrumwith a dimple. The phallus was small and the lefttestis was undescended. There was generalizedhypertrichosis. Detailed ophthalmological examina-tion at the age of 2 years showed a large coloboma ofthe optic nerve with disc pallor on the left side and asmall and pale optic disc on the right side. Audio-logical assessment showed normal hearing. Echo-cardiography was normal. During infancy he hadfeeding difficulty due to uncoordinated sucking andswallowing leading to repeated aspiration pneumo-nia. Videofluoroscopy swallow study confirmed thathe had marked discoordination of sucking andswallowing and that oral feeding was unsafe. Hewas therefore fed initially by nasogastric tube andlater required gastrostomy. Despite that he hadsevere failure to thrive. Chromosome analysis,

FIG. 1. Pedigree of the family showing multiple consanguinity.

FIG. 2. Patient 2 (IV5). Note triangular face, widely spaced eyes, smooth philtrum, hairy forehead, low set ears, and redundant skin of the neck. [Color figure can beviewed in the online issue, which is available at www.interscience.wiley.com.]

814 AL-GAZALI ET AL.

American Journal of Medical Genetics Part A

telomere screening, very long chain fatty acids, andrenal ultrasound were normal. Carbohydrate defi-cient transferring analysis on Guthrie card showedelevated level with unusual bands interpreted aseither normal genetic variant or indicative ofglycosylation problems. However, repeat analysison a frozen serum sample was reported to be normal(Karolinska Institute, Sweden). MRI brain at the ageof 2 years showed bilateral frontal polymicrogyria, asmall vermis and a very small anterior pituitary glandwith no clear bright spot. The infundibulumappeared hypoplastic and the optic chiasm small.The corpus callosum also appeared hypoplastic, andthe septum pellucidum was absent. Endocrinestudies at the age of 2.62 years revealed a height of86.6 cm (�1.26 SDS), and a weight of 11.3 kg(�1.55 SDS). He had micropenis and the left testiswas not palpable. Endocrine investigations showed apeak cortisol response of 16.8 mg/dl (N> 16.3) inresponse to a low-dose synacthen (500 ng/m2) test,glucagon test showed a peak growth hormone of34 mg/dl (N> 7), IGF1 78 ng/ml (N 20–158, 0 SDS),IGFBP3 1.3 mg/L (NR 0.248–3.716, �2 to �3 SDS),TSH 2 mU/L (NR 0.4–5), FT4 1.2 ng/dl (NR 0.8–1.8),and prolactin 7.8 mg/L (N< 18).

Evaluation at the age of 4.365 years revealed aheight of 94.7 cm (�2.11 SDS) and aweight of 14.3 kg(�1.34 SDS) with a height velocity of 3.2 cm/year.IGF1was 9ng/ml (N 25–188,��3SDS), and IGFBP30.36 mg/L (N 0.578–3.415,��3 SDS). In view of thepoor height velocity and very low IGF1 and IGFBP3,he was commenced on growth hormone treatment.Evaluation 3 months after starting growth hormonetreatment revealed a height of 97.7 cm giving him agrowth velocity of 12 cm/year. The peak cortisol tostandard synacthin test was 17.4 mg/dl (borderlinejN> 20j), IGF1 was 49 ng/ml (N 25–188, �1 SDS),and IGFBP3 was 1.73 mg/L (N 1.578–3.415,�1 to�2SDS). He was walking but had very limited speechand was still gastrostomy dependent. He had dryitchy skin with well-demarcated areas of erythemaand peeling on the trunk, both arms and legs, bothgroins and the base of the penis and scrotum. Therewas some lichenification andhyperkeratosis over thewrists, elbows, knees, and ankles. There was mildhyperkeratosis of the palms and soles. The skin overthe dorsum of the hands and feet was very dark.Repeat ophthalmologic examination confirmed theearlier findings.

Patient 3 (IV13) was a cousin of the previouspatients. He was the product of a normal pregnancyand delivery. There was a suspicion of congenitalheart defect on prenatal ultrasound. His birth weightwas 2,795 g. At birth he was noted to have severaldysmorphic features which included a hairy fore-head and face, downward-slanting palpebral fis-sures, depressed nasal bridge, and large hands withcontracture of the interphalangeal joints (Fig. 3). Theskin over these joints appearedover-creased, and the

feet were long and flat. Ophthalmological examina-tion at the age of 2 years revealed partial coloboma ofthe right iris and complete coloboma of the left iris,bilateral inferior chorio-retinal colobomas with opticnerve head involvement more severe on the left side.The vision was reasonable in the right eye and poorin the left eye. There was a soft systolic murmur andechocardiography showed a small secundum ASD.The baby had difficulty in feeding due to incoordi-nation of sucking and swallowing. He was fed bynasogastric tube. He generally suffered from dryitchy skin and had areas of peeling all over the bodywith some lichenification around the knees, elbowsand wrists (Fig. 4A–D). The skin over the dorsum ofthe hands, feet and knees was thick and dark. Skinbiopsy showed hyperkeratosis and focal paraker-atosis. The granular layer was mainly absent apartfrom focal areas of the upper epidermis. Keratinplugs were present within the epidermis. There wasmoderate infiltration of acute and chronic inflamma-tory cells mainly around blood vessels in the upperdermis. This appearance supported the diagnosis ofichthyosis.

Evaluation at 1.687 years showed a weight of10.75 kg (�0.84 SDS) with a height of 81.9 cm (�0.71SDS), flat occiput, hypertrichosis, downward-slant-ing palpebral fissures, depressed nasal bridge, thinlips, and poor dental hygiene. He had marked visual

FIG. 3. Patient 3 (IV13). Dysmorphic features, camptodactyly, hypertrichosiswith diffuse skin rash with scaling. [Color figure can be viewed in the onlineissue, which is available at www.interscience.wiley.com.]

A NEW AUTOSOMAL RECESSIVE SYNDROME 815


impairment with disconjugate eye movements. Hehad moderate developmental delay and was hypo-tonic. MRI of the brain revealed cerebellar vermishypoplasia, bilateral severe frontal polymicrogyria,delayed mylination and some periventricular graymatter. The corpus callosum and septum pellucidumwere normal. MRI of the pituitary gland revealed asmall anterior pituitary and optic chiasm and normalposterior pituitary and infundibulum. His cortisolconcentration was 2.2 mg/dl (afternoon, NR 3.5–10),prolactin 6.2 mg/L (NR< 18), FT4 1.3 ng/dl (NR 0.8–1.8), TSH1.4mU/L (NR0.4–5), IGF124ng/ml (NR5–135, �2 SDS), IGFBP3 0.77 mg/L (N 1.04–2.515,��3SDS). However, since he was growing at anormal rate at this stage, hewasnot startedongrowthhormone therapy.

Patient 4 (IV11) was the sister of Patient 3, andthe product of a normal pregnancy and delivery.Her birth weight was 2.2 kg. The baby was noted tohave central cyanosis on the first day of life.Echocardiography revealed transposition of thegreat arteries with an intact ventricular septum.This was operated on in the first few months oflife. She was assessed during the first 2 years of lifebecause of reduced vision and delayed develop-ment. Ophthalmological examination revealed asignificant divergent squint of the left eye with leftmicrophthalmia. There was bilateral optic nervehead coloboma. The optic discs were pale but with anormal size.

She had an erythematous itchy rash with scaling allover the body with lichenification and darkening ofthe skin over the elbow, wrist, dorsum of hands,

FIG. 4. Skin in Patient 3. Diffuse scaling (A,B), thick scaly skin on the elbow (C), diffuse scaly rash (D) and hypertrichosis (C,D). [Color figure can be viewed in theonline issue, which is available at www.interscience.wiley.com.]

FIG. 5. Patient 4 (IV11). Note widely spaced eyes, small left eye, smoothphiltrum, and low set ears. [Color figure can be viewed in the online issue,which is available at www.interscience.wiley.com.]



knees, and ankles (Fig. 6A–C). She had mild palmo-planter keratoderma. There was generalized hyper-trichosis. Skin biopsy showed hyperkeratosis andparakeratosis with the formation of occasionalkeratin plugs. There was expansion of the epidermiswith elongation of the rete ridges. The dermis showsperiventricular cuffing by mixed acute and chronicinflammatory cells.

Assessment at the age of 5.068 years revealed aheight of 103.5 cm (�0.9 SDS) and aweight of 13.9 kg(�1.65 SDS). Dysmorphic features included widelyspaced eyes, a small left eye with a small cornea,divergent squint, smooth philtrum, high archedpalate, low set ears, and poor dental hygiene(Fig. 5). She tended to drool and had very poorvisual responses. The earlier ophthalmologic find-ings were confirmed.

MRI of the pituitary gland showed a small anteriorpituitary gland, left microphthalmia and atrophicvisual pathways. The posterior pituitary and theinfundibulum were normal. Endocrine evaluationshowed an IGF1 of 66 ng/ml (NR 25–188) (�1 SD),IGFBP3 1.42 ng/L (NR 1.578–3.415) (�2 SDS),cortisol 4.5 mg/dl (NR 3.5–10), prolactin 3.5 mg/dl(N< 18), FT4 1.2 ng/dl (NR 0.8–1.8), and TSH0.9 mU/L (NR 0.4–5).

DISCUSSION

The CHIME syndrome is a rare neuroectodermaldisorder characterized by ocular colobomas, heartdefect, ichthyosiform dermatosis, mental retarda-tion, and ear defect. Six cases have been reported inthe literature (see Introduction Section). The combi-nation of ocular colobomas and ichthyosiformerythroderma is diagnostic for this syndrome as ithas not been described in any other conditiondelineated up to now (LDDB). The patients in thisreport had ocular colobomas, ichthyosis, and dryskin, congenital heart defects, and developmentaldelay. This combination of abnormalities is verysimilar to those described in CHIME syndrome(Table I).

The spectrum of CHIME syndrome is not fullyestablished as only six cases have been reported inthe literature. Ocular colobomas, ichthyosiformerythroderma and mental retardation seem to beconsistent features while other features are variable.Congenital heart defects was present in four of thesixes cases reported and it ranged from TOF, TGA toPPS and VSD [Shashi et al., 1995; Tinschert et al.,1996]. Of the five cases where neuroimaging wasperformed, three cases showed cerebral atrophy.MRI of the brain which is a more sensitive modalityfor studying CNS structures was not performed in anyof the published cases. In this report MRI of the brainwas performed in three children and showedabnormalities involving midline structures. In twochildren there was a small vermis with frontalpolymicrogyria and a hypoplastic corpus callosumassociated with a hypoplastic anterior pituitary glandand atrophic optic chiasm, while the third child had asmall anterior pituitary gland with atrophic visualpathways. Endocrine studies showed low concen-tration of IGF1 and IGFBP3 in three of the children,suggesting growth hormone deficiency in the threechildren who were investigated. It is possible thatmidline structural brain abnormality is part of thespectrum of CHIME syndrome. However, severalfeatures described in CHIME syndrome were notpresent in the children in this report. These includedeafness, seizures, oligodontia, and hair abnormal-ities. In addition, endocrine abnormalities have notbeen reported in CHIME syndrome. Futhermore,ichthyosis in this syndrome is described as migratorywhere sharply demarcated erythematous and scalyplaques erupt unpredictably and migrate to involveseemingly normal skin over a period of daysto weeks. They resolve spontaneously and theynever become fixed. The scaling and erythematouschanges of the skin in the children in this report alsoresolved spontaneously in some areas, however itwas chronic and fixed in other areas, for exampleover the knees, wrists, elbows, and ankles. Ultra-structural features of the affected skin in CHIMEsyndrome included keratinization with incompletely

FIG. 6. Skin in Patient 4. Dry and scaly (A,B), dark pigmentation with thickening and scaling (B,C). Note overlapping toes (C). [Color figure can be viewed in theonline issue, which is available at www.interscience.wiley.com.]



cornified cells in the lower horny layer, perinuclearedema of granular cells surrounded by a shell ofkeratin filaments and smaller than normal kerato-haylin granules, presenceof inflammatory cells in theepidermis, and disorganization of myelin sheaths incertain but not all deep myelinated nerve fibres[Tinschert et al., 1996]. Most of these changes arenon-specific and can be found in many skindisorders associated with inflammatory infiltration,exocytosis, and exoserosis [Tinschert et al., 1996].Although we were not able to perform electronmicroscopic examination of the skin biobsy inour cases, and the light microscopic examinationshowed non-specific changes, we feel that the skinchanges in the children in this report are differentfrom those seen in CHIME syndrome. Therefore, itseems unlikely that the syndrome in these childrenrepresents a classical form of CHIME syndrome.

We also considered SOD in the differentialdiagnosis (Table I). This is a central midline defectof the brain characterized by optic nerve hypoplasia,various CNS malformations, and endocrinologicaldeficiencies. It is the end result of several differentgenetic abnormalities and in utero injuries. Opticnerve hypoplasia, which is considered mandatoryfor the diagnosis, can be unilateral or bilateral andresult in variable degree of decreased vision. The

CNS malformations include an absent septumpellucidum, aplasia of corpus callosum, cerebellarmalformations, and enlargement of the ventricularsystem [Skarf and Hoyt, 1984; Stanhope et al., 1984;Morishima and Aranoff, 1986]. A point mutation inHESX1 gene which is expressed in the anteriorneurectoderm in a region fated to form the forebrainand Rathke’s pouch (the premordium of the anteriorpituitary gland) was identified in two sibs with thisdisorder as well as some sporadic cases [Dattani et al.,1998; Dattani and Robinson, 2000; Thomas et al.,2001; McNay et al., 2007]. However, a small optic discwhich is mandatory for the diagnosis of SOD, wasobserved in only one patient in this report. Fur-thermore, ocular colobomas which were present inall the children in this report have been describedrarely in association with SOD. Morishima andAranoff [1986] described a male infant with softdysmorphic features, microphallus and underdevel-oped scrotum, optic nerve hypoplasia with acoloboma of the left iris and optic disc. The childdeveloped hypoglycemia and was found to have lowACTH and cortisole level. His CT brain was normal.In addition, there are reports in the literature also ofSOD with other somatic abnormalities [Morishimaand Aranoff, 1986]. Nevertheless, the presence ofichthyosis in all the children in this report and the

TABLE I. Clinical Features of Present Cases Compared to CHIME Syndrome and SOD

1 2 3 4 CHIME SOD

Facial dysmorphic featuresHypertelorism þ þ þ þ 5/6 þBrachycephaly þ þ þ þ 5/6 �Flat, broad nasalroot þ þ þ þ 5/6 þWide mouth þ þ þ þ 3/6 �Abnormal ears þ þ þ þ 5/6 �

SkinIcthyosiform rash ? þ þ þ 6/6 �Thick palm and soles ? þ þ þ 4/6 �Dark pigmentation of knees,

dorsum of hands, and feet? þ þ þ � �

Loose skin at birth þ þ þ ? � �Ocular

Coloboma Bil. pupil andchoroid

Optic nerve (L) Bil.iris choroiretinaland optic disc

Bil. optic disc 6/6 �

Small optic disc � þ (R) � � 0/6 þPale optic disc � þ (R) � þ � �

Other abnormalitiesCardiac anomaly � � ASD TGA 4/6 �CNS anomaly " fluid in post

fossa, ?vermishypoplasia

Absent SP Polymicrogyria Small AP, atrophicvisual pathways

3/6 þ

Dilated lateralventricles

Hypoplastic CC Small vermis Cerebral atrophy

Polymicrogyria,small vermis

Small AP and opticchiasm

Hypoplasia of APMental retardation þ þ þ þ 6/6 þSeizure � � � � 5/6 �Feeding problem þ þ þ þ 3/6 �Renal abnormality � � � � 2/6 �Deafness � � � � þ �Endocrine anomalies ? þ þ þ � þ



absence of optic disc hypoplasia in three out of thefour children in this report make this diagnosisunlikely.

We also considered 3C syndrome (Cranio-cere-bello-cardiac dysplasia) in these children. Thisautosomal recessive syndrome is characterized bythe association of cardiac malformation, cerebellarhypoplasia, and cranial dysmorphism [Ritscher et al.,1987]. Ocular colobomas have been described in thissyndrome [Worle et al., 1994]. Postnatal growthdeficiency is also observed in most patients andsome authors have suggested that growth hormonedeficiency should be considered as a possible causeof the short stature observed in this condition[Wheeler et al., 1999]. However, this diagnosis is alsounlikely since all the children in this report hadichthyosis which is not described in this syndromeand the facial appearance of the children in thisreport is different from that seen in 3C syndrome.

Although someof the features of the children in thisreport might resemble COACH (Cerebellar vermishypoplasia, Oligophrenia, Ataxia, Ocular coloboma,Hepatic fibrosis) syndrome (OMIM 216360), theappearance of the vermis on MRI is not that of molartooth sign (MTS) which is typical for this syndromeand all other Joubert Syndrome Related Disorders[Gleeson et al., 2004].

We suggest that the children in this report have anew autosomal recessive syndrome with featuresoverlapping CHIME syndrome. In view of themultiple consanguinity and large family size itshould be possible to localize the gene and identifythe genetic defect in this family and these studies areunderway.

REFERENCES

Benner JD, Preslan MW, Gratz E, Josly J, Schwartz M, Kelman S.1990. Septo-optic dysplasia in two siblings. Am J Opthal109:632–637.

Blethen SL, Weldon VV. 1985. Hypopituitarism and sepo-opticdysplasia in first cousins. Am J Med Genet 21:123–129.

DattaniMT,Maetines-Barbera J, Thomas PQ, Brickman JM, GuptaR, Martenesson I, Toresson H, Fox M, Wales JKH, HindmarshPC, Krauss S, Beddington RS, Robinson ICAF. 1998. Mutationsin the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 19:125–133.

Gleeson JG, Keeler LC, Parisi MA, Marsh SE, Chance PF, Glass IA,Graham JR Jr, Maria BL, Barkovich AJ, Dobyns WB. 2004.Molar tooth sign of the midbrain-hindbrain junction: Occur-rencec in multiple distinct syndromes. Am J Med Genet Part A125A:125–134.

McNay DEG, Turton JP, Kelberman D, Woods KS, Brauner R,Papadimitriou A, Keller E, Keller A, Hauf N, Krude H, ShaletSM, Dattani MT. 2007. HESX1 mutations are an uncommoncause of septo-optic dysplasia and hypopituitarism. J ClinEndocrinol Metab 92:691–697.

Dattani MT, Robinson IC. 2000. The molecular basis for develop-ment al disorders of the pituitary gland in man. Clin Genet57:337–346.

Morishima A, Aranoff G. 1986. Syndrome of septo-opticdysplasia: The clinical spectrum. Brain Dev 8:233–239.

Ritscher D, Shinzel A, Boltshauser E, Briner J, Arbenz U, Sigg P.1987. Dandy-Walker (like) malformation, atrio-ventricularseptal defect and similar pattern of minor anomalies in 2sisters: A new syndrome? Am J Med Genet 26:481–491.

Schnur RE, Greenbaum BH, Heymann WR, Christensen K, BuckAS, Reid CS. 1997. Acute lymphoblastic leukemia in a childwith CHIME neuroectodermal dysplasia syndrome. Am J MedGenet 72:24–29.

Shashi V, Zunich J, Thaddeus EK, Fryburg JS. 1995. Neuro-ectodermal (CHIME) syndrome: An additional case with longterm follow upof the reported cases. JMed Genet 32:465–469.

Skarf B, Hoyt CS. 1984. Optic nerve hypoplasia in children:Association with anomalies of the endocrine and CNS. ArchOphthalmol 102:62–67.

Stanhope R, Preece MA, Brook CGD. 1984. Hypoplastic opticnerves and pituitary dysfunction: A spectrum of anatomicaland endocrine abnormalities. Arch Dis Child 59:111–114.

Thomas PQ, Dattani MT, Brickman JM, Mcnay D, Warne G,Zacharin M, Cameron F, Hurst J, Woods K, Dunger D,Stanhope R, Forrest S, Robinson ICAF, Beddington RSP. 2001.Heterozygous HESX1 mutations associated with isolatedcongenital pituitary hypoplasia and septo-optic dysplasia.Hum Mol Genet 10:39–45.

Tinschert S, Anton-lamprecht I, Albrecht-Nebe H, Audring H,Zunich M. 1996. Neuroectodermal syndrome: Migrratoryicthyosiform dermatosis, cxolobomas, and other abnormal-ities. Pediatr Dermatol 13:363–371.

Wales JK, Quarrell OWJ. 1996. Evidence for possible Mendelianinheritance of septo-optic dysplasia. Acta Paediatr 85:391–392.

Wheeler PG, Sageghi-Nejad Ab, Elias ER. 1999. The 3C syndrome:Evolution of the phenotype and growth hormone deficiency.Am J Med Genet 87:61–64.

Worle H, Lewin MA, Holder M, Bastanier CK, Kohler B. 1994.Another case of Ritscher-Schinzel syndrome: Cranio-cere-bello-cardiac dysplasia (3C syndrome) with associatedbilateral colobomas. Eur J Pediatr 153:140.

Zunich J, Kaye CI. 1983. New syndrome of congenital ichthyosiswith neurologic abnormalities. Am J Med Genet 15:331–333.

Zunich J, Kaye CI. 1984. Letter to the editor: Additional case reportof new neuroectodermal syndrome. Am J Med Genet 17:707–710.

Zunich J, Burton E, Holbrook K, Kaye CI. 1985. Congenitalmigratory icthyosiform dermatosis with neurologic andophthalmologic abnormalities. Arch Dermatol 121:1149–1156.

Zunich J, Easterly NB, Kaye CI. 1988. Autosomal recessivetransmission of neuroectodermal syndrome. Arch Dermatol124:1188–1189.



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A new autosomal recessive syndrome of ocular colobomas, ichthyosis, brain malformations and endocrine abnormalities in an inbred Emirati family