Edict Syndrome

A number sign (#) is used with this entry because of evidence that EDICT syndrome is caused by heterozygous mutation in the MIR184 gene (613146) on chromosome 15q25.

Description

EDICT syndrome is an autosomal dominant syndromal anterior segment dysgenesis characterized by endothelial dystrophy, iris hypoplasia, congenital cataract, and thinning of the corneal stroma (Iliff et al., 2012).

Syndromes with overlapping features have been reported, including cornea guttata with anterior polar cataracts (121390) and congenital corneal opacities, cornea guttata, and corectopia (608484).

Clinical Features

Akpek et al. (2002) reported an 81-year-old man with bilateral aphakia, diffuse corneal haze, and corneal thinning associated with guttae. Both pupils were miotic and slightly eccentric with focal areas of iris stromal atrophy. There was a 'beaten-metal' appearance and guttae of the endothelium as well as deep posterior vesicles. Corneal topography revealed bilateral steepening of the corneas, but no apparent cone. There were 8 additional affected family members over the subsequent 2 generations with congenital cataracts and corneal abnormalities, 2 of whom were examined. A 55-year-old daughter had undergone bilateral cataract extractions at 6 years of age. Examination revealed bilateral microcornea (9.5 mm vertically and 10 mm horizontally) as well as symmetric changes of the corneas with uniform steepening and thinning; however, corneal topography did not demonstrate a cone. The pupils were small and mildly eccentric with ectropion pupillae. Specular biomicroscopy revealed normal endothelial cell count, shape, and size. A 16-year-old grandson was diagnosed with bilateral congenital cataracts and myopia at 6 years of age, and with posterior polymorphous dystrophy diagnosed at 7 years of age. Examination showed bilateral thinning of the cornea and mild anterior polar cataracts, and corneal topography revealed rather diffuse steepening of the corneas without a cone. Specular biomicroscopy showed vesicle-like lesions of the endothelium. He also had bilateral small pupils with mild ectropion pupillae. Akpek et al. (2002) concluded that this constellation of autosomal dominantly inherited ocular findings, including corneal endothelial and stromal anomalies with congenital cataracts and iris abnormalities, represented a novel anterior segment disorder.

Hughes et al. (2003) examined 30 members of a large 3-generation Northern Irish family segregating autosomal dominant keratoconus and cataract on 2 occasions at an interval of 5 years. Examination of younger individuals indicated that onset of progressive astigmatism predated onset of lens opacities by 1 to 2 years. Astigmatism manifested around the age of 8 years, and although there was some intrafamilial variation, cones were generally detectable around the age of 9 to 12 years. Individuals who exhibited neither progressive astigmatism nor lens opacities by age 13 years appeared to remain unaffected. Corrective surgery was usually necessary in early adulthood for both keratoconus and cataract.

Dash et al. (2006) restudied the Northern Irish family with autosomal dominant keratoconus and cataract that was originally reported by Hughes et al. (2003). Affected individuals had no abnormalities or signs of anterior segment dysgenesis at birth, with the corneal and lens changes developing after the age of 5 years. Sequential examination of family members indicated that the anterior polar cataract and keratoconus were developmental rather than congenital.

Mapping

In a 3-generation pedigree with an autosomal dominant anterior segment dysgenesis involving corneal steepening and thinning, microcornea, endothelial abnormalities, iris hypoplasia, and congenital anterior polar cataracts, originally reported by Akpek et al. (2002), Jun et al. (2002) performed linkage analysis and obtained a lod score of 2.71 on chromosome 15q22.1-q25.3, between markers D15S993 and D15S202. Jun et al. (2002) proposed the designation 'EDICT' syndrome to represent the clinical findings of endothelial dystrophy, iris hypoplasia, congenital cataract, and corneal stromal thinning.

Hughes et al. (2003) performed genomewide linkage analysis in a large 3-generation Northern Irish family segregating autosomal dominant keratoconus and cataract and found evidence of linkage on chromosome 15, with a maximum 2-point lod score of 3.99 (theta = 0.11) with D15S131. Fine mapping with additional microsatellite markers and recombination analysis defined a 6.5-Mb critical interval flanked by CYP11A (118485) and D15S211, with a maximum 2-point lod score of 8.13 with IREB2 (147582) at chromosome 15q25.1. The authors noted that this is an exceedingly gene-rich region, containing approximately 95 known or predicted genes; 4 positional candidate genes were screened but no causative mutations were found.

In the large 3-generation Northern Irish family segregating autosomal dominant severe keratoconus and early-onset anterior polar cataract, previously studied by Hughes et al. (2003), Dash et al. (2006) refined the linkage region to an approximately 5.5-Mb interval flanked by the MAN2C1 gene (154580) and the D15S211 marker on chromosome 15q. The refined interval excluded 28 candidate genes, and a further 23 candidate genes were excluded by direct sequencing.

Molecular Genetics

In a 3-generation Northern Irish family in which 18 of 38 individuals had an autosomal dominant form of severe anterior keratoconus and early-onset anterior polar cataract, originally reported by Hughes et al. (2003), Hughes et al. (2011) identified a heterozygous mutation in the seed region of the MIR184 gene (57C-T; 613146.0001) that segregated with disease in the family and was not found in 167 unscreened controls.

In 8 affected members of a multigenerational family segregating an autosomal dominant anterior segment dysgenesis (EDICT syndrome) mapping to chromosome 15q22.1-q25.3, originally reported by Akpek et al. (2002), Iliff et al. (2012) analyzed 24 candidate genes and 4 microRNAs residing within the critical interval and identified heterozygosity for the same 57C-T mutation in the seed region of the MIR184 gene as had been found in a family with keratoconus and anterior polar cataract by Hughes et al. (2011). The mutation was not found in 2 unaffected family members, 282 patients with Fuchs corneal dystrophy (see FECD1, 136800), 283 control individuals without corneal dystrophy, or the 1000 Genomes database.

Noting the differences in corneal phenotype between affected members of the 2 families found to carry the same 57C-T mutation in the MIR184 gene (Hughes et al., 2011; Iliff et al., 2012), Iliff et al. (2012) stated that they had performed next-generation sequencing that ruled out any potential coding variant that might modify the phenotype caused by the mutation. In response, Hughes et al. (2012) noted that the 2 families clearly had a very closely related phenotype arising from the same mutation, and suggested that the most useful investigation of genetic modifiers of the corneal-ectasia phenotype would be direct genetic comparison of the 2 affected families.

Nomenclature

Giasin et al. (2012) suggested that the reported corneal phenotype in EDICT syndrome falls within the keratoconus/keratoglobus spectrum. Iliff et al. (2012) responded that the corneal thinning in EDICT is uniform, without the increased central thinning of keratoconus or increased peripheral thinning of keratoglobus, noting that in EDICT patients the corneal steepening is uniform, diffuse, and nonectatic, without a cone or globular contour. In addition, Iliff et al. (2012) stated that there are histopathologic differences between keratoconus/keratoglobus and EDICT, with disruption of the Bowman layer and Descemet membrane in the former and changes resembling Fuchs corneal dystrophy (see FECD1, 136800) and posterior polymorphous corneal dystrophy (see PPCD1, 122000) in the latter.