Anterior Segment Dysgenesis 1

A number sign (#) is used with this entry because of evidence that anterior segment dysgenesis-1 (ASGD1) is caused by heterozygous mutation in the PITX3 gene (602669) on chromosome 10q24.

Description

Anterior segment dysgeneses (ASGD or ASMD) are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (summary by Cheong et al., 2016).

Anterior segment dysgenesis is sometimes divided into subtypes including aniridia (see 106210), Axenfeld and Rieger anomalies, iridogoniodysgenesis, Peters anomaly, and posterior embryotoxon (Gould and John, 2002).

Some patients with ASGD1 have been reported with the Peters anomaly subtype.

In its simplist form, Peters anomaly involves a central corneal opacity, but it may also involve adherent iris strands. Some patients have keratolenticular content or cataract. The underlying defects in this form of congenital corneal opacity reside in the posterior stroma, Descemet membrane, and corneal endothelium. The disorder results from abnormal migration or function of neural crest cells and may include abnormalities of other anterior segment structures, such as the lens and iris (summary by Withers et al., 1999).

Clinical Features

Hittner et al. (1981) identified a kindred of German descent in which autosomal dominant anterior segment mesenchymal dysgenesis with variable expression affected members of at least 8 generations. Clinical findings ranged from an anterior Schwalbe line with mild cataract to severe corneal opacification with moderate cataract, while visual acuity varied from 20/20 to hand motion only. The proband had corneal transplant and cataract extraction of one eye at age 6 weeks. Microscopic studies of the cornea showed basal epithelial cell protrusions into a thickened Bowman layer, 'activated' keratocytes throughout the entire stroma, no Descemet layer or endothelial cells, and an aggregation of keratocytes posteriorly. The lens showed focal aggregations of vesicles in cortical fibers with extensive epithelial atrophy.

Hittner et al. (1982) examined 15 affected and 13 unaffected members from 4 generations of the kindred with ASMD originally identified by Hittner et al. (1981). All affected individuals had cortical cataracts, some of which were minute and had no visual significance, and 3 patients had optic nerve abnormalities. Corneal opacities with or without iris adhesions were seen in 10 patients; the iris adhesions were associated with both central and peripheral corneal opacities, indicating anterior segment dysgenesis. Affected patients had no skull, limb, umbilical, or genitourinary anomalies, and there was no mental retardation.

Mollica et al. (1985) studied a Sicilian family in which many persons had cataract with microcornea and myopia. Although cataracts started early, they were apparently not congenital. The axial length of the globe was normal. Myopia was thought by the authors to distinguish this disorder from the cataract-microcornea syndromes reported by Friedmann and Wright (1952) and by Polomeno and Cummings (1979). It is possible that these 3 families all had the same disorder. Indeed, Salmon et al. (1988) were of that opinion and documented the syndrome in a 7-generation family. Microcornea and cataract were present in 18 members, and an additional 6 had sclerocornea or Peters anomaly. Most persons with microcornea had a corneal diameter of less than 11 mm in both meridians, with moderately steep corneal curvatures. The inherited cataracts progressed to form a total cataract after visual maturity had been achieved. In the 4 affected children who had not undergone cataract extraction, the common abnormality was a posterior polar lens opacity.

Withers et al. (1999) studied a large Australian kindred segregating anterior segment abnormalities, including cataracts and Peters anomaly, in an autosomal dominant fashion. There were 15 affected individuals in 8 sibships over 4 generations; 13 of the affected members were female, and there was no instance of male-to-male transmission. Corneal clouding was present in 4 individuals; in 1, bilateral clouding was so severe that it precluded examination of the interior of the eye. Bilateral cataracts had been removed in 10 patients at ages ranging from 8 to 38 years. Three individuals examined at the ages of 2 months, 4 years, and 18 months, respectively, had no cataract; reexamination at ages 4 years, 7 years, and 5 years, respectively, showed cataract in one or both lenses of all 3. There was no indication of mental retardation, renal disease, or other clinical signs suggestive of Peters-plus syndrome (see 261540) or WAGR syndrome (194072); similarly, there was no consistent finding of raised intraocular pressures, corectopia, dental hypoplasia, umbilical abnormalities, or other features consistent with Rieger syndrome (see 180500).

Mapping

By linkage analysis in the 6-generation family with ASMD previously reported by Hittner et al. (1982), Semina et al. (1998) found linkage of the disorder to chromosome 10q24-q25 with a lod score of 4.8 (theta = 0.0) with the marker D10S192 in the region of the PITX3 locus.

Exclusion Studies

In a large Australian kindred segregating anterior segment abnormalities, including cataracts and Peters anomaly, in an autosomal dominant fashion, Withers et al. (1999) excluded linkage to the PAX6 gene (607108) on chromosome 11p13.

Inheritance

The transmission pattern of ASMD in the families reported by Hittner et al. (1981) and Withers et al. (1999) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of the kindred with ASMD reported by Hittner et al. (1982), Semina et al. (1998) identified heterozygosity for a 17-bp insertion in the PITX3 gene (602669.0001). The mutation was not found in unaffected members of the family or in 300 ethnically matched control chromosomes.

In affected members of a large Australian kindred segregating anterior segment abnormalities, including Peters anomaly with corneal clouding, iridolenticular corneal adhesions, displaced Schwalbe line, and cataract, previously reported by Withers et al. (1999), Summers et al. (2008) identified heterozygosity for the 17-bp duplication in the PITX3 gene (602669.0001). Noting that there was no difference in the size of the duplication between severely affected and more mildly affected individuals, the authors suggested the existence of modifier loci.

History

Ferrell et al. (1982) found linkage of ASMD and blood group MN (111300), with a lod score of 3.48. Such a linkage would place the ASMD locus on 4q; MN is located on 4q28-q31. Semina et al. (1998) found that the linkage of ASMD to blood group MN reported by Ferrell et al. (1982) was incorrect. Semina et al. (1998) stated that this linkage appears to have been an artifact resulting from low marker heterozygosity and the absence of any available flanking markers for confirmation.