Microphthalmia, Isolated 1

Description

Microphthalmia designates a heterogeneous group of ocular malformations with a more or less evident reduction in the size of the eyeball. Additional features include high hypermetropia and a short axial length. The size of the anterior chamber and the cornea may also be reduced, whereas the lens is normal or thicker than usual for age (summary by Fuchs et al., 2005).

Genetic Heterogeneity of Isolated Microphthalmia

MCOP1 has been mapped to chromosome 14q32. MCOP2 (610093) is caused by mutation in the CHX10 gene (142993) on chromosome 14q24. MCOP3 (611038) is caused by mutation in the RAX gene (601881) on chromosome 18q21.3. MCOP4 (613094) is caused by mutation in the GDF6 gene (601147) on chromosome 8q22.1. MCOP5 (611040) is caused by mutation in the MFRP gene (606227) on chromosome 11q23. MCOP6 (613517) is caused by mutation in the PRSS56 gene (613858) on chromosome 2q37.1. MCOP7 (613704) is caused by mutation in the GDF3 gene (606522) on chromosome 12p13.1. MCOP8 (615113) is caused by mutation in the ALDH1A3 gene (600463) on chromosome 15q26.

Nomenclature

The term 'anophthalmia' has been misused in the medical literature. True or primary anophthalmia is rarely compatible with life; in such cases, the primary optic vesicle has stopped developing and the abnormal development involves major defects in the brain as well (Francois, 1961). The diagnosis can only be made histologically (Reddy et al., 2003; Morini et al., 2005; Smartt et al., 2005), but this is rarely done. In most published cases, the term 'anophthalmia' is used as a synonym for the more appropriate terms 'extreme microphthalmia' or 'clinical anophthalmia.'

Clinical Features

Cecchetto (1920) reported a pedigree in which 2 brothers, each married to a first cousin, had a child with bilateral clinical anophthalmia. The common grandparents were also first cousins. Hesselberg (1951) reported affected children from first-cousin parents. Sorsby (1934) discovered early reports of affected sibs with normal parents. Ashley (1947) reported an affected Japanese brother and sister.

Warburg (1993) gave a comprehensive phenotypic and etiologic classification of microphthalmos and ocular coloboma. She included the description of a consanguineous Arab family showing that the phenotype in autosomal recessive microphthalmos may include congenital cystic eye, anophthalmos, microphthalmos, or coloboma. Some affected family members were mentally retarded, while others were mentally healthy.

Gill and Harris (1959) reported a family in which the proband and her great-aunt had microphthalmos. Wolff (1930) described a family of 10 children whose parents were first cousins and among whom 3 males and 2 females had microphthalmos, high-grade hyperopia (up to +20d), and glaucoma. Holst (1952) observed 6 cases in 2 related sibships. Oliveira da Silva and Santana de Sousa (1981) used the term 'clinical anophthalmia' for this condition, to signify that clinically the eye appears to be absent, whereas in fact it is only very small. They described an instructive inbred kindred with 4 affected individuals in 3 separate sibships.

Bessant et al. (1999) reported the phenotypic findings in affected individuals in a Pakistani family in which microphthalmia showed linkage to 14q32 (Bessant et al., 1998). All affected individuals had bilateral microphthalmia associated with anterior segment abnormalities, and the best visual acuity achieved was 'perception of light.' Corneal changes included partial or complete congenital sclerocornea (see 181700 and 269400), and the later development of corneal vascularization and anterior staphyloma. Intraocular pressure was greatly elevated in many cases. Sclerocornea has been observed in association with microphthalmia as part of the MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome (309801).

Mapping

In a consanguineous 5-generation Pakistani family in which 6 living members were affected by isolated congenital microphthalmia, Bessant et al. (1998) used whole-genome linkage analysis to map the gene to 14q32. Linkage analysis gave a maximum 2-point lod score of 3.55 for the marker D14S65. Surrounding this marker was a region of homozygosity of 7.3 cM, between markers D14S987 and D14S267, within which the disease gene was predicted to lie. The genes for several eye-specific transcription factors are located on 14q and in the syntenic region of mouse chromosome 12.

Animal Model

Breitman et al. (1987) created microphthalmia in transgenic mice by targeting expression of the diphtheria toxin gene. They used the mouse gamma-2-crystallin promoter fused to a gene encoding a site of toxic gene product to target expression of the diphtheria toxin gene to the mouse eye lens. As little as one molecule per cell of the toxin is estimated to be cytotoxic. The process was referred to as genetic ablation. Subsequent generations of mice showed microphthalmia without evidence of other abnormalities. Palmiter et al. (1987) independently described a similar method to effect the ablation of cells within the exocrine pancreas. Used for the microinjection was a construct in which the elastase I (130120) promoter/enhancer was fused to a gene for diphtheria toxin A polypeptide.

The recessive mouse mutation 'or(J),' which causes microphthalmia, progressive destruction of the retina, and absence of the optic nerve, is caused by mutation in the Chx10 gene; see 142993.