Coloboma, Ocular, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that ocular coloboma is caused by heterozygous mutation in the PAX6 gene (607108) on chromosome 11p13. One such patient has been reported.

Description

Coloboma is an ocular birth defect resulting from abnormal development of the eye during embryogenesis. It is defined as a congenital defect in any ocular tissue, typically presenting as absent tissue or a gap, at a site consistent with aberrant closure of the optic fissure. Failure of fusion can lead to coloboma of one or multiple regions of the inferior portion of the eye affecting any part of the globe traversed by the fissure, from the iris to the optic nerve, including the ciliary body, retina, and choroid. Coloboma is also frequently associated with small (microphthalmic) or absent (anophthalmic) eyes as part of an interrelated spectrum of developmental eye anomalies, and can affect either one or both eyes (summary by Kelberman et al., 2014).

Genetic Heterogeneity of Ocular Coloboma

A recessive form of ocular coloboma (216820) is caused by mutation in the SALL2 gene (602219) on chromosome 14q11.

Clinical Features

Barros-Nunez et al. (1995) described a 6-year-old boy in whom bilateral iris coloboma had been observed at birth. Psychomotor development was normal. He showed a typical inferonasal bilateral coloboma of the iris and ciliary body without coloboma of the choroid and retina or optic nerve. Retina, lens, corneal diameters, and visual acuity were normal in both eyes and there were no malformations elsewhere. A male and female first cousin of the proband related through their fathers had iris coloboma and the son of a sister of the father of the proband had unilateral coloboma. The parents in the case of all 3 sibships were normal as were the grandparents. Some unusual molecular mechanism, such as trinucleotide expansion, was suggested, giving the picture of 'delayed mutation' or 'premutation.'

Hornby et al. (2000) correlated visual function with clinical features and biometric findings in the eyes of children with coloboma. Of the 196 eyes with colobomatous malformations, 11 had microphthalmos with cyst (251505), and 185 eyes had coloboma (associated with microcornea in 155 eyes and with normal corneal diameter in 30 eyes). The visual prognosis depended on the phenotype of the more normal eye. Microphthalmos with cyst had the worst prognosis (all worse than 20/400). Microcornea with microphthalmos had a worse prognosis than microcornea without microphthalmos. For microcornea with microphthalmos, 67% saw worse than 20/400. Of the children with microcornea without microphthalmos, 76% saw better than 20/400. Simple coloboma (without microcornea or microphthalmos) had the best visual prognosis: only 7% saw 20/400 or worse. A corneal diameter of less than 6 mm had a poor visual prognosis, whereas a corneal diameter of more than 10 mm had a good prognosis.

Morrison et al. (2000) examined 75 children with iris colobomas. In 13 (17.3%) patients, noticeable iris heterochromia (142500) was present. In patients with unilateral coloboma, the heterochromia was characterized by the darker iris being the one affected with coloboma. In cases of bilateral iris colobomas with clinical microphthalmos and reduced corneal diameter, the variation in iris color was inconsistent. A fundus coloboma was not always present. The authors postulated that the iris coloboma-iris heterochromia association may result from the abnormal closure of the embryonic fissure, resulting in irregular or excessive migration of neural crest cells into the iris stroma. In addition, the high frequency of iris heterochromia-iris coloboma with microphthalmia suggests that an increased density of pigmented cells within the iris stroma may be a contributing factor.

Pigment-dispersion syndrome (600510) and pigmentary glaucoma result from iridozonular friction causing disruption of the iris epithelium and deposition of iris pigment on the anterior segment structures. Tesser (2003) reported a 48-year-old patient with congenital bilateral iris colobomas. Elevated intraocular pressure was present in the eye with a partial iris coloboma and iris transillumination defects but pigment deposition on the ipsilateral corneal endothelium (Krukenberg spindle). The other eye was diagnosed as having mild ocular hypertension, without pigment dispersion or glaucoma, in association with a complete iris coloboma. Tesser (2003) concluded that pigment dispersion was prevented in the eye with the complete iris coloboma.

Iris colobomas occur as part of complex malformation syndromes, e.g., iris coloboma with ptosis, hypertelorism, and mental retardation (243310), craniofacial dysmorphism with ocular coloboma, absent corpus callosum, and aortic dilatation (218340), and Hirschsprung disease, microcephaly, and iris coloboma (235730). Yuksel et al. (1999) described 2 female sibs with an MCA/MR syndrome consisting of pre- and postnatal growth retardation, iris colobomata, spasticity, facial dysmorphism, and dilated cerebral ventricles. Coloboma is a prime feature of the CHARGE association (see 214800).

Gregory-Evans et al. (2004) provided a detailed review of the molecular genetics of ocular coloboma, including a list of inherited disorders and syndromes in which coloboma is a feature.

Inheritance

Pedigrees supporting dominant inheritance have been reported. Eldridge (1967) observed an affected family with a dominant pedigree pattern. Snell (1908) observed 12 cases in 5 generations.

Population Genetics

The estimated prevalence of coloboma is 1 in 10,000 (Stoll et al., 1997).

Kelberman et al. (2014) stated that coloboma is estimated to account for 3 to 11% of blindness in children worldwide. The prevalence varies by population, ranging from 4 to 19 per 100,000 live births across Europe with higher rates reported in populations with a high degree of consanguinity.

Cytogenetics

Arias et al. (1984) studied a patient with de novo deletion of chromosome 2pter-p25.1. ACP1 (171500) and MDH1 (154200) levels were normal, suggesting that these loci are proximal to 2p25.1. The child had bilateral coloboma of the iris.

Molecular Genetics

Azuma et al. (2003) identified a heterozygous mutation in the PAX6 gene (607108.0019) in a 1-year-old boy who had iris anomaly, large coloboma of the optic nerve (120430), retina, and choroid, a remnant of hyaloid vessel proliferation (persistent hyperplastic primary vitreous) bilaterally, and growth and mental retardation.

Associations Pending Confirmation

Asai-Coakwell et al. (2007) characterized a chromosome 8q21.2-q22.1 segmental deletion in a patient with chorioretinal coloboma and found elements of nonallelic homologous recombination and nonhomologous end joining. They demonstrated that the segmental deletion encompasses GDF6 (601147), and that inhibition of gdf6a in zebrafish accurately recapitulated the proband's phenotype. The spectrum of disorders generated by morpholino inhibition of gdf6a and the more severe defects (microphthalmia and anophthalmia) observed at higher doses illustrated the key role of GDF6 in ocular development. In Xenopus, Hanel and Hensey (2006) demonstrated that inhibition of gdf6 resulted in ocular developmental anomalies.

Ye et al. (2010) screened DNA samples from 449 probands with isolated microphthalmia and/or coloboma and 23 probands with skeletal or oculoskeletal phenotypes for mutations in the GDF3 gene and identified a heterozygous missense mutation (L305P; see 606522.0002) in an Asian female with bilateral iris coloboma.