A

Tatnkwlslmtcimmo

C

AvcnT

rtc(etbwilm

FHHRoaJCS1d

6

The Phenotypic Spectrum of Baraitser-Winter Syndrome: A New Case and Review

of Literature

nuradha Ganesh, MD,a Adila Al-Kindi, FRCP,b Rajeev Jain, MD,c and Sandy Raeburn, MDd

afprdhcaiuent

prrshmaoUrpnmb

D

IdtrBfpncWs

pr

he syndrome of iris coloboma, ptosis, hypertelorism,nd mental retardation (Online Mendelian Inheri-ance in Man - OMIM # 243310; http://www.ncbi.lm.nih.gov/entrez/dispomim.cgi?id�243310), alsonown as the Baraitser-Winter syndrome, originallyas described in a brother and sister and in an unre-

ated girl in 1988.1 Six additional individuals with aimilar phenotype have been reported in the worlditerature.2-6 Microphthalmos, microcornea, and brain

alformations were added to the phenotypic spec-rum of this syndrome in 1995 (Table 1).5 We report ahild who presented with the aforementioned find-ngs. Eye examination revealed bilateral microphthal-

os and typical iris, optic nerve, and choroidal colobo-as. Magnetic resonance imaging of the brain dem-

nstrated pachygyria and cortical atrophy.

ASE REPORT

2-year-old female child was referred for evaluation ofisual impairment, congenital eye anomalies, and psy-homotor delay. She was the firstborn child of healthy,onconsanguineous parents, and was delivered at term.here was no significant perinatal or family history.Growth and mental development were delayed and

anged from the 9- to 10-month level (she had just beguno stand with support and utter a few words). Her headircumference was 44 cm (3rd centile), height was 87 cm50th centile), and weight was 11 kg (10th centile). Thexamination showed dysmorphic features that includedrigonocephaly, persistent metopic ridge, hypertelorism,ilateral ptosis, prominent epicanthal folds, short noseith a broad bridge and a splayed and upturned tip, prom-

nent cheeks, long and hypoplastic philtrum, thin vermil-ion border of the upper lip, high arched palate, mild

icrognathia, and a low posterior hairline (Figure 1).

rom the Department of Ophthalmology,a Neonatal Division, Department of Childealth,b Department of Radiology,c Clinical Genetics Unit,d Sultan Qaboos Universityospital, Muscat, Omaneprint requests: Adila Al-Kindi, FRCP, Institute of Medical Genetics, University Hospitalf Wales, Heath Park, CF 14 4XW, UK (e-mail: kindya@squ.edu.om,dila.alkindy@cardiffandvale.wales.nhs.uk).AAPOS 2005;9:604-606.opyright © 2005 by the American Association for Pediatric Ophthalmology andtrabismus.091-8531/2005/$35.00 � 0

hoi:10.1016/j.jaapos.2005.05.001

04 December 2005

On ocular examination, she fixated and followed objectst 1.5 m with her right eye (OD) but showed no fixation orollowing with her left eye (OS). A left esotropia of 30rism diopters by Krimsky testing was present. The ocularotations were full. The corneas were clear and cornealiameters were 9 � 9.5 mm OD and 7 � 7 mm OSorizontally and vertically respectively. A typical irisoloboma in the inferonasal location was present bilater-lly. Remnants of the tunica vasculosa lentis were observedn both eyes (OS[mt]OD). The lens was clear and intraoc-lar pressure was normal at 12 mm Hg bilaterally. Fundusxamination showed a choroidal coloboma in the infero-asal quadrant, involving the optic nerve and extending tohe ora serrata in both eyes.

Ocular axial lengths measured by A-scan ultrasonogra-hy were 16 mm OD and 13 mm OS. Computed tomog-aphy scan and MRI of the orbits disclosed bilateral infe-onasal choroidal colobomas. MRI of the brain demon-trated widespread, bilateral, pachygyria and bandeterotopia (Figure 2). Hypoplasia and paucity of whiteatter with extensive white matter necrosis in the parietal

nd occipital regions was observed. Mild dilation of theccipital horns of the lateral ventricles was also noted.ltrasound evaluation of the abdomen and echocardiog-

aphy were unremarkable. Chromosome analysis of theeripheral lymphocytes by conventional G-banding wasormal. A diagnosis of Baraitser-Winter syndrome wasade after studying the London Dysmorphology Data-

ase.7

ISCUSSION

n this report we have presented a child with iris, choroi-al, and optic nerve coloboma; ptosis; hypertelorism; men-al retardation; and brain malformations. This phenotypeesembles the previous descriptions of patients with thearaitser-Winter syndrome.1-6 The peculiar craniofacial

eatures (trigonocephaly, hypertelorism, bilateral ptosis,rominent epicanthal folds, broad nasal bridge with shortose and upturned tip, and thin upper lip) are highlyharacteristic and crucial to the diagnosis of the Baraitser-

inter syndrome; our patient’s facial appearance is con-istent with this description.

We have compared the ocular manifestations of ouratient with the ocular findings in the 9 cases previouslyeported. Apart from manifesting the characteristic ptosis,

ypertelorism and typical iris as well as choroidal

Journal of AAPOS

ctp

bicehcp

oCR(atcd

dBaanB

T

PHESMMIICcN

Fwll

Fssthm

Journal of AAPOSVolume 9 Number 6 December 2005 Ganesh et al 605

oloboma, our patient presented with bilateral microph-halmos (left [mt] right), left microcornea, and left esotro-ia.

Multiple cerebral hemispheric malformations haveeen described in the Baraitser-Winter syndrome. Thesenclude lissencephaly, pachygyria, agyria, polymicrogyria,ortical heterotopias, hypoplasia of the anterior pits, agen-sis of the corpus callosum, ventricular dilation, lobaroloprosencephaly, and porencephaly.3,5 Microcephaly isommon. Most patients are mentally handicapped withsychomotor retardation.

There is considerable overlap between the phenotypef patients with the Baraitser-Winter syndrome and theHARGE (Coloboma, Heart Anomaly, Choanal atresia,etardation, Genital and Ear anomalies) association

OMIM # 214800). Both manifest with uveal colobomasnd retardation of growth and mental development. Struc-ural anomalies of the brain have been reported in bothonditions.8 Some patients with Baraitser-Winter syn-

able 1 Comparison of ocular findings in 10 patients with Baraitser Wint

Ayme et al2

Baraitser-Winter1

Case 1 Case 2 Case 3

tosis NR � � �ypertelorism � � � �picanthal folds � � � �trabismus NR NR NR NRicrophthalmos NR NR NR NRicrocornea NR NR NR NR

ris coloboma NR � � �ris heterochromia NR NR NR NRhoroidaloloboma

NR NR NR NR

R, not reported.

IG 1. Photograph of face showing hypertelorism, ptosis, short noseith a broad bridge and a splayed upturned tip, prominent cheeks,

ong hypoplastic philtrum with a thin vermillion border of the upperip, iris coloboma OD, and microcornea OS.

rome have been described to have a congenital heart d

efect, genital and ear anomalies.5 However, patients witharaitser-Winter syndrome have a typical facial appear-nce that is not characteristically noted in the CHARGEssociation. Another distinction from the CHARGE phe-otype is the absence of choanal atresia in the former.araitser-Winter syndrome shares with Noonan syn-

rome

tta3

Ramer et al4,5

Verloes6 Present reportCase 1 Case 2 Case 3

� � � � �� � � � �� � � � �NR NR NR NR �NR NR � NR �NR NR � NR �� � � � �NR NR NR � �NR � � NR �

IG 2. Coronal T2-weighted 3-mm section through the frontal lobeshowing bilateral, diffuse thickening of the cortex, with few andhallow sulci. Note paucity of underlying white matter. The periven-ricular white matter shows cystic changes (arrows). A thin layer ofyperintense white matter is interposed between 2 layers of grayatter, indicating band heterotopia (arrowheads).

er synd

Pallo

���NRNRNR�NR�

rome (OMIM # 163950) mental and growth retardation,

hlNeaspoobhnco

icgbcp

tpaItttms

saiwqo

wdepB

Mnia

1

1

Journal of AAPOSVolume 9 Number 6 December 2005606 Ganesh et al

ypertelorism, ptosis, short neck, and low posterior hair-ine. However, colobomas have not been described in

oonan syndrome and the dysmorphic features are differ-nt. Further, patients with Noonan syndrome have char-cteristic cardiac anomalies.9 A third condition which re-embles the Baraitser-Winter syndrome is frontonasal dys-lasia (median cleft syndrome), which is characterized bycular hypertelorism and a broad nasal root. Althoughcular colobomas and midline defects in the brain haveeen described in this condition,10 eye findings other thanypertelorism are uncommon and intelligence is usuallyormal. Facial features include anomalies of the nasal tip,left lip and palate, and extension of the frontal hairlinento the forehead to form a pronounced widow’s peak.

Various theories have been postulated as to the inher-tance pattern of the Baraitser-Winter syndrome. Its oc-urrence is largely sporadic, but familial occurrence sug-ests the possibility that Baraitser-Winter syndrome coulde inherited as a recessive trait.1 Pericentric inversion ofhromosome 2: inv(2)(p12q14) has been described in 2atients.3

PAX (paired box) genes belong to a multigene familyhat encode transcription factors that are primarily ex-ressed in embryonic tissue. They control the differenti-tion of primordial cells and are involved in organogenesis.t has been postulated that the pattern of malformations inhe Baraitser-Winter syndrome may result from migra-ional misdirection during embryogeneis because of a mu-ation in the PAX-8 gene.5 PAX-8 maps to human chro-osome 2q12-14,11 a site coincident with the chromo-

omal anomaly identified in previous studies.2,3

Patients with Baraitser-Winter syndrome have visuallyignificant ocular abnormalities (colobomas, strabismus,mblyopia, refractive errors) in addition to the character-stic external ocular features. A baseline ophthalmicork-up to delineate the ocular anomalies, with subse-uent follow-up examinations depending on the findings

n initial examination is therefore mandatory in children

ith this condition. Further, a patient with iris or choroi-al coloboma should undergo a comprehensive pediatricvaluation. In the presence of characteristic facial dysmor-hism and structural brain malformations, a diagnosis ofaraitser-Winter syndrome may be entertained.

We gratefully acknowledge Dr. A.M. Uday Kumar, College ofedicine, Sultan Qaboos University, Muscat, Oman, for the cytoge-

etic study, and Dr. John Tolmie, Duncan-Guthrie Institute of Med-cal Genetics, Yorkhill Hospital, Glasgow, for reviewing the manuscriptnd photographs, and providing suggestions for further improvement.

References1. Baraitser M, Winter RM. Iris coloboma, ptosis, hypertelorism, and

mental retardation: a new syndrome. J Med Genet 1988;25:41-3.2. Ayme S, Mattei MG, Mattei JF, Giraud F. Abnormal childhood

phenotypes associated with the same balanced chromosome rear-rangements as in the parents. Hum Genet 1979;48:7-12.

3. Pallotta R. Iris coloboma, ptosis, hypertelorism, and mental retarda-tion: a new syndrome possibly localized on chromosome 2. J MedGenet 1991;28:342-4.

4. Ramer JC, Mascari MJ, Manders E, Ladda RL. Syndrome identifi-cation #149: trigonocephaly, pachygyria, retinal coloboma, and car-diac defect: a distinct syndrome. Dysmorph Clin Genet 1992;6:15-20.

5. Ramer JC, Lin AE, Dobyns WB, Winter R, Ayme S, Pallotta R,Ladda RL. Previously undescribed syndrome: shallow orbits, ptosis,coloboma, trigonocephaly, gyral malformations, and mental andgrowth retardation. Am J Med Genet 1995;57:403-9.

6. Verloes A. Iris coloboma, ptosis, hypertelorism, and mental retarda-tion: Baraitser- Winter syndrome or Noonan syndrome? J MedGenet 1993;30:425-6.

7. London Dysmorphology and Neurogenetics Database, Windowsversion 1.0.3.Oxford: Oxford University Press.

8. Lin AE, Siebert JR, Graham Jr. Central nervous system malforma-tions in the CHARGE association. Am J Med Genet 1990;37:304-10.

9. Allanson JE, Hall JG, Hughes HE, Preus M, Witt RD. Noonansyndrome: the changing phenotype. Am J Med Genet 1985;21:507-14.

0. Temple IK, Brunner B, Jones J, Burn J, Baraitser M. Midline facialdefects with ocular colobomata. Am J Med Genet 1990;37:23-7.

1. Stapleton P, Weith A, Urbanek P, Kozmik Z, Busslinger M. Chro-mosomal localization of seven PAX genes and cloning of a novel

family member, PAX-9. Nature Genet 1993;3:292-8.