Iris coloboma and a microdeletion of chromosome 22: del(22)(q11.22)

A 22q11 microdeletion is described in a girl with ocular coloboma associated with velo-cardiofacial syndrome (VCFS).

Microdeletion syndromes are a heterogeneous group of disorders caused by deletion of specific regions of chromosomal DNA that are not visible using standard chromosome analysis.¹ Microscopic chromosome deletions are being recognised increasingly as a cause of congenital abnormality and clinical genetic syndromes. Laboratory confirmation of these conditions requires specialist molecular testing that must be requested on the basis of clinical suspicion. Del(22)(q11.22) microdeletion is among the most common of the microdeletion syndromes and is characterised by cardiac malformations (particularly outflow tract), craniofacial features, cleft palate, thymic hypoplasia, and hypoparathyroidism. The severity of the condition can be very variable and is now recognised as the basis of several independently described syndromes: DiGeorge syndrome (DGS), conotruncal face anomaly syndrome, and velo-cardiofacial syndrome (Shprintzen syndrome).² The “velo” in VCFS refers to the palatal abnormalities such as cleft palate that are sometimes present. The characteristic facial appearance of del(22)(q11.22) is a prominent nose, broad nasal root, narrow palpebral fissures, and retrognathia.³ Recognised ocular features include retinal vascular tortuosity, small optic nerves, and narrow palpebral fissures.⁴ An iris coloboma has been described in one case of VCFS⁵ and coloboma was listed as a rare feature in a series of cases of DGS.²

Case report

As part of a population based study of children with congenital anophthalmos, clinical microphthalmos, or iris coloboma (with or without fundus coloboma), we identified a teenage girl with bilateral iris coloboma, right fundus coloboma, left cataract, and clinical microphthalmos (Fig 1). On further examination she was found to have upslanting palpebral fissures, prominent nose, small mouth, dental crowding, unilateral deafness, arachnodactyly, second and third toe syndactyly (Fig 2), a ventriculoseptal defect (VSD) requiring surgical correction, and developmental delay. Both parents had no eye abnormality. A clinical diagnosis of VCFS was made and microsatellite analysis of this girl’s DNA along with that of her parents confirmed a de novo deletion of the paternal 22q11.22 region. Two microsatellite markers (D22S944 and D22S264) within the common three megabase deletion interval demonstrated non-transmission of the paternal allele. In view of this unexpected diagnosis we analysed a further 21 study cases with structural eye malformations (mainly iris coloboma) where DNA was available from both parents. No additional del(22)(q11.22) cases were identified.

Figure 1.

Bilateral iris coloboma with clinical microphthalmos in a girl with velo-cardiofacial syndrome. Note the upslanting and narrow palpebral fissures, wide nasal root and bridge, with prominent nose, and small mouth.

Figure 2.

Second and third toe syndactyly in a girl with velo-cardiofacial syndrome and del(22)(q11.22).

Comment

Here we report a girl with ocular coloboma and VCFS with a molecularly defined deletion of 22q11.22. Iris coloboma occurring in VCFS has been described once, but with no confirmation of a microdeletion.⁵

The cat-eye syndrome (CES), a disorder with a variable pattern of multiple congenital anomalies of which iris coloboma and anal atresia are the best known, is characterised cytogenetically by an extra bisatellited marker chromosome.⁶ This chromosome represents an inverted duplication of part of chromosome 22 (inv dup(22)). The CES critical region overlaps with the proximal area of chromosome 22q deleted in VCFS or DGS. Clearly, this region of chromosome 22 is significant in the aetiology of some ocular colobomas.

Ophthalmologists should be aware of these syndromes and the importance of recognising that eye anomalies such as iris coloboma might be the presenting feature of a systemic developmental disorder. Microdeletion syndromes should be considered even in the presence of a normal macroscopic chromosome report.