LAUSR

Microphthalmia/anophthalmia (M/A) is considered a severe congenital malformation and is the cause of sight impairment worldwide, affecting 3%–12% of children. M/A, as a spectrum, can occur unilaterally or bilaterally, isolated or associated with systemic abnormalities (1,2). The etiology of M/A includes not only genetic abnormalities but also environmental factors. Between 30% to 40% cases of M/A are related to specific genes, and more than 30 genes are implicated. In 10%–15% of patients, the cause of M/A is secondary to chromosomal rearrangements (2). We describe a case with syndromic microphthalmia and a microdeletion encompassing OTX2 identified by array comparative genomic hybridization (aCGH). The affected child was an 11-month-old girl. She had unilateral microphthalmia, severe developmental delay with microcephaly, moderate bilateral sensorineural hearing loss and facial dysmorphism. Ophthalmologic examination revealed bilateral microcornea, stromal iris atrophy and bilateral optic nerve hypoplasia. Evoked visual potentials showed the absence of visual response. TORCH testing was normal, but brain magnetic resonance imaging (MRI) showed left microphthalmia, bilateral optic nerve hypoplasia with the absence of chiasm, corpus callosum hypoplasia and polymicrogyria. The pituitary gland was normal (Figure 1). aCGH analysis showed a 7.16 Mb deletion at 14q22.2-q23.2 (ArrGRCh37 14q22.2-q23.2 55147074_62309258x1). The deleted region involved 81 genes, including OTX2 (Figure 2). The deletion was confirmed by standard karyotype 46,XX,del(14)(q22q23) with a resolution of 450 to 550 bands (Figure 3). Also in this region it is included sine oculis homeobox homolog 6 gene (SIX6) (OMIM: 606326) that has been related with M/A and optic nerve development (3). Both parents had normal karyotypes. Standard karyotype has been a useful test for the detection of chromosomal anomalies in patients with syndromic microphthalmia; the rate of detection is 7%–15% (2). Currently, aCGH provides a much higher resolution and has the advantage of providing the specific genomic points where genetic alterations occur, which makes it possible to establish an exact genotype– phenotype correlation (4). Analysis with aCGH allows the identification of cryptic chromosomal abnormalities in 10%–15% of patients with syndromic M/A and a normal karyotype (2,5). Heterozygous mutations in the orthodenticle drosophila homolog 2 gene (OTX2) (OMIM: 600037) account for 0.7%– 10% of patients withM/A, and the gene is considered the second most frequently involved gene in M/A’s etiology (2,6). Most pathogenic variants in OTX2 are pathogenic truncating and missense variants. However, gene deletions also occur and have been reported in 30%–40% of patients (7). We found that, since 1991, 17 patients have been diagnosed with syndromic M/ A associated with a chromosomal deletion involving the OTX2 gene. Some of these are shown in Table 1. The size of the deletion varied from 1.2 Mb to 8.9 Mb, and there is no clear genotype– phenotype correlation between the clinical severity and the size of the deletion or the surrounding genes involved. OTX2-encoded protein acts as a transcription factor and plays a role in brain, craniofacial and sensory organ development. The phenotype of patients with microdeletions encompassing OTX2 includes M/A spectrum, brain malformations, deafness, anomalies of the extremities, cardiac malformations and urogenital abnormalities (OMIM: 610125) (2,8). The brain malformations described are hypoplasia or the absence of optic nerves and optic chiasm, pituitary abnormalities, ventricular dilatation, partial corpus callosum agenesis and reduced hemispheric white matter (8). Other features observed less frequently are hippocampal abnormal gyration, cerebellar hypoplasia and Chiari malformation (8,9). As far as we know, this is the first patient with perisylvian polymicrogyria; this cerebral dysgenesis is characterized by excessive cortical folds and shallow grooves. Perisylvian polymicrogyria manifests with epilepsy, variable developmental delay with language and food learning difficulties (19). This brain condition explains the neurologic status of the patient. Otherwise, in similar cases with deletion in 14q22q23 it has been postulated that not only OTX2 but also SIX6 are both involved in the ocular and optic nerve development. However, at thismoment it is difficult to establish the exactmechanism (3). In the present case, the 14q22q23 deletion was documented by aCGH and karyotype analyses. There is a correlation between the deleted region and the phenotype of the patient. This case demonstrates the usefulness of cytogenetic and cytogenomic analyses in patients with syndromic M/A.