Macrophthalmia, Colobomatous, With Microcornea

A number sign (#) is used with this entry because of evidence that colobomatous macrophthalmia with microcornea (MACOM) is a contiguous gene deletion syndrome resulting from an approximately 22-kb heterozygous deletion on chromosome 2p22.2, involving the CRIM1 (606189) and FEZ2 (604826) genes.

Clinical Features

Bateman and Maumenee (1984) described a family with colobomatous macrophthalmia with microcornea. The affected members, otherwise normal, were 1 woman and her monozygotic twin sister with 2 sons. The twins had bilateral microcornea, coloboma starting from the iris and extending to the optic nerve, axial enlargement, posterior staphyloma, and high myopia. The sons of the proposita's sister presented an incomplete and unilateral pattern of these defects, suggesting variability in the expression of the syndrome. Pallotta et al. (1998) described a second family in which the syndrome was transmitted through 4 generations with no male-to-male transmission.

Toker et al. (2003) described a Turkish family with 13 affected individuals in 3 generations. All affected members of the family had bilateral involvement with typical inferonasal iris coloboma, chorioretinal coloboma, microcornea, and varying degrees of axial enlargement associated with myopia. Additional findings included flatter corneal curvatures and shallower anterior chambers. Iridocorneal angle abnormalities associated with elevation of intraocular pressure were detected in 3 patients. The pedigree confirmed the autosomal dominant pattern of inheritance with male-to-male transmission in 2 instances and with complete penetrance.

Mapping

Elcioglu et al. (2007) performed genotyping and linkage analysis in the 3-generation Turkish family with colobomatous macrophthalmia and microcornea reported by Toker et al. (2003) and obtained a maximum lod score of 3.61 (theta = 0) at marker D2S1788. Recombination events positioned the locus, which they called MACOM, on chromosome 2p23-p16 in a 22-Mb interval between D2S2263 and D2S1352; mutation analysis of 3 candidate genes, SIX2 (604994), SIX3 (603714), and CYP1B1 (601771), did not reveal any causative mutations.

Cytogenetics

By whole-exome sequencing and CNV analysis in the 3-generation Turkish family with MACOM mapping to chromosome 2p23-p16, originally reported by Toker et al. (2003), Beleggia et al. (2015) identified an approximately 22-kb heterozygous deletion on chromosome 2 that segregated fully with disease. The deletion encompassed exons 14 through 17 of the CRIM1 gene (606189) as well as most of the 3-prime UTR of the FEZ2 gene (604826). Analysis of polymorphisms in CRIM1 and FEZ2 showed significant reduction of the mutant allele of CRIM1, consistent with early degradation, whereas there was no significant reduction in the amount of the FEZ2 mutant allele. In mice homozygous for loss of Crim1 in the head surface ectoderm and ocular mesenchyme, the authors observed morphologic changes overlapping the developmental eye anomalies present in patients with MACOM syndrome, including microcornea, a shallow anterior chamber, and a narrower eye without diminished axial diameter. Beleggia et al. (2015) concluded that CRIM1 is the causative gene for MACOM syndrome. No causative mutation or deletion/duplication involving CRIM1 was identified in the index patient from the family with MACOM described by Bateman and Maumenee (1984), suggesting further genetic heterogeneity of MACOM syndrome.