Partial trisomy of chromosome 22 resulting from an interstitial duplication of 22q11.2 in a child with typical cat eye syndrome.

Cat eye syndrome (CES) is a rare malformation syndrome with a variable pattern of congenital anomalies. The characteristic features of CES include ocular coloboma, preauricular pits or tags, anal anomalies, and congenital heart and renal malformations. Furthermore, CES may be associated with other craniofacial malformations, skeletal anomalies, and, in some cases, with mental retardation. 2 In almost all cases CES is associated with the cytogenetic finding of a supernumerary marker chromosome consisting of duplicated material of chromosome 22. The marker is usually bisatellite and dicentric (idic(22)(pter→q11.2::q11.2→pter)) and thus results in tetrasomy of the p arm and a part of 22q11.2. 3 Cytogenetically detectable intrachromosomal direct or inverted duplications are rare and can arise with equal frequency by rearrangement between sister chromatids or non-sister chromatids both on the maternal or paternal chromosome. The proximal part of the long arm of chromosome 22 (22q11.2) has been recognised as a hot spot for chromosomal rearrangements and contains both the cat eye and the DiGeorge critical region (for reviews see Kotzot et al and Edelmann et al). Multiple congenital malformations showing overlap with CES can arise from familial translocation t(11;22) in the der(22) syndrome, 8 and, in rare cases, from interstitial duplication of proximal 22q. However, none of these patients described so far with interstitial duplications of 22q showed the full CES phenotype including all major clinical features. We report here a patient with an interstitial inverted duplication of 22q11.2 and typical features of cat eye syndrome including coloboma, preauricular anomalies, heart defect, renal anomalies, and anal atresia. CLINICAL FINDINGS The boy was referred for clinical genetic diagnostics at the age of 3.5 weeks. He was born at term after an uneventful pregnancy; the parents were healthy and unrelated and birth weight was 3650 g, length 54 cm, and head circumference 36.5 cm. Postnatally, he developed a transient cyanosis and was admitted to our neonatal intensive care unit for evaluation of a heart defect and anal atresia. Dysmorphological examination showed characteristic craniofacial features including low set, posteriorily rotated ears, bilateral preauricular pits, hypertelorism, downward slanting palpebral fissures, bilateral ptosis of the eyelids, and bilateral iris colobomata. The nose was short and beaked with a flattened nasal bridge and depressed nasal tip. Further findings were a long philtrum, thin lips, highly arched palate, and micro/retrognathia (fig 1A, B). Organ involvement included a combined heart defect (large secundum atrial septal defect, medium sized pressure reducing muscular perimembranous ventricular septal defect, and tricuspid valve dysplasia with tricuspid regurgitation grade II), kidney anomalies (bilateral dilated renal pelvis), congenital left inguinal hernia, and anal atresia. The cardiac defects did not cause congestive heart failure, thus treatment (preferably interventional device closure) has been postponed until the child reaches a body weight of at least 12 kg. The tricuspid valve function improved spontaneously. The child underwent surgical treatment for the hernia and anal atresia. Detailed ophthalmological examination was performed at the age of 8.5 months and at 13 months, respectively, and disclosed bilateral microphthalmus (left>right) and bilateral anterior and posterior colobomata of the iris and choroid, and subluxated lenses inferiorly. In both eyes the optic nerve head and macula were not visible in the depth of the coloboma (fig 1 C and D). A persistent choroidal artery was found in the left eye. Further findings were intermittent strabismus (esotropia), apparent restriction of eye movements (abduction deficit), and high hyperopia (>13 dp). Owing to bilateral ptosis, severe chin raising was observed. Re-evaluation at the age of 8.5 months and 12 months showed good progress and only moderate developmental delay. Gross impairment of hearing could be excluded. Exact determination of visual acuity was impossible but was considered to be low. Owing to the typical findings of iris coloboma, heart defect, and anal atresia in combination with further malformations in the clinical genetic-dysmorphological analysis, cat eye syndrome was suspected. Key points