Oculoauricular Syndrome

A number sign (#) is used with this entry because of evidence that oculoauricular syndrome (OCACS) is caused by homozygous mutation in the HMX1 gene (142992) on chromosome 4p16.

Clinical Features

Franceschetti and Valerio (1945) described a 3-year-old Swiss girl who had bilateral mild microphthalmia with marked corneal opacities similar to corneal sclerosis and increased intraocular pressure on the left, and whose vision was limited to perception of light. She also had bilateral symmetric abnormalities of the external ear, characterized by a primitive appearing intertragic notch and coloboma of the lobule. Her 6-year-old brother also had eye and ear malformations, including bilateral mild microphthalmia with microcornea, inferonasal coloboma of the iris, anteroinferior polar cataract, and microphakia. The fundus was not visible, and he could recognize objects at 30 cm. His ear findings were identical to his sister's; both sibs had normal hearing. Their mother had a bilateral mild symmetric abnormality of the ear lobes. The authors stated that there were no other anomalies in the patients or other family members.

Schorderet et al. (2008) reported a developmental defect affecting the eye and external ear in 3 members of a consanguineous Swiss family, 2 of whom had been described by Franceschetti and Valerio (1945). Their proband, the great-nephew of the previously described sibs, presented at 2 months of age with congenital nystagmus, bilateral microcornea, posterior synechiae, bilateral cataract, colobomatous microphthalmia of the right eye, and anterior segment dysgenesis consisting of incomplete coloboma of the iris, stromal iris cyst of the right eye, and iridocorneal adherences in the left eye. Fundal examination revealed dysplastic macropapillae reminiscent of morning glory syndrome (see 120430), macular hypoplasia, and peripheral inferonasal chorioretinal coloboma. The cataract was rapidly progressive, requiring surgery at 11 months of age. Ophthalmoscopy at 7 years of age revealed the presence of circumferential abnormalities of the retinal pigment epithelium and chorioretinal atrophic lacunae at the equator, and the patient had rod-cone dystrophy on electroretinogram (ERG). His ears showed lobular aplasia, a narrow intertragic notch, and an abnormal bridge connecting the crus of the helix and antihelix, resulting in complete separation between the cymba and the conqua. Audiogram and vestibular function were normal. Reexamination of the great-uncle revealed an inferior chorioretinal coloboma of the right eye and lacunae of the left; the great-aunt's fundus was not visible. Other systemic findings included 3 maxillary dental rows in the great-uncle and spina bifida occulta and moderate dyscrania with flattening of the cranial base and short mandibular rami in the great-aunt.

Gillespie et al. (2015) described 2 male cousins, aged 28 months and 14 years, from a consanguineous Asian family with a complex ocular developmental phenotype and malformed ears. Patient I was unable to open his eyes at birth. At 3 days of age, he was noted to have an inability to fix and follow. He had dense bilateral congenital cataracts requiring lensectomy at age 6 weeks, at which time he was found to have bilateral microcornea with high pachymetry measurements. Short axial lengths were observed, but intraocular pressure was normal. He displayed a manifest horizontal nystagmus with right divergent strabismus. Other developmental abnormalities included colobomatous microphthalmia with inferior iris coloboma, localized sclerocornea in the right eye, and posterior embryotoxon in the left. He also had nasolacrimal duct obstruction. ERGs from both eyes of the patient at age 28 months were symmetrical and well developed in the light-adapted state, but dark adaptation revealed attenuated responses, suggestive of early rod dysfunction. Loss of peripheral vision was also noted at that time. At birth, patient II had bilateral congenital cataracts, with a particularly dense central nuclear component, and significant bilateral microcornea. He also had bilateral microphthalmia that was more severe in the right eye. At age 4 months, he had a lensectomy on the left eye, but the right was inoperable due to the severity of the malformation. Other developmental abnormalities included bilateral inferior iris coloboma, left posterior embryotoxon with anterior synechiae, and sclerocornea of the right eye. His vision began to deteriorate at age 4 years; by age 14 years, his ERG results showed grossly attenuated light- and dark-adapted responses, consistent with a severe generalized retinal dystrophy. Auricular findings in both patients were malformed, low-set pinna with crumpled helix, narrow external acoustic meatus, and deficient lobule. The father of 1 patient had minor external ear abnormalities and marked bilateral posterior embryotoxon.

Mapping

Schorderet et al. (2008) performed homozygosity mapping in a consanguineous Swiss family with an oculoauricular syndrome and identified a unique homozygous region on chromosome 4p16 flanked by D4S2935 and D4S391, obtaining a maximum lod score of 3.37 (theta = 0) at D4S2906. SNP analysis reduced the homozygous interval to a less than 10-Mb region between D4S2935 and D4S419.

By autozygosity mapping in a consanguineous Asian family in which 2 cousins had an oculoauricular syndrome, Gillespie et al. (2015) identified genomic regions identical by descent in the patients on chromosome 17 and chromosome 4; the region on chromosome 4 included the HMX1 gene.

Molecular Genetics

In 3 affected members of a consanguineous Swiss family with an oculoauricular syndrome mapping to chromosome 4p16, Schorderet et al. (2008) identified homozygosity for a 26-bp deletion in the HMX1 gene (142992.0001). The parents of the proband were heterozygous for the deletion, which was not found in more than 250 ethnically matched controls or in more than 500 patients with various eye diseases.

By direct sequencing of the HMX1 gene in 2 male cousins from a consanguineous Asian family with oculoauricular syndrome, Gillespie et al. (2015) identified homozygosity for a missense mutation (Q217P; 142992.0002) at a highly conserved residue. The parents of 1 of the cousins were heterozygous for the mutation, but DNA from the other set of parents was not available.