Anterior Segment Dysgenesis 3

A number sign (#) is used with this entry because of evidence anterior segment dysgenesis-3 (ASGD3) is caused by heterozygous mutation in the FOXC1 gene (601090) on chromosome 6p25.

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 ASGD3 have been reported with the following subtypes: iridogoniodysgenesis, Peters anomaly, Axenfeld anomaly, and Rieger anomaly.

Iridogoniodysgenesis, which is characterized by iris hypoplasia, goniodysgenesis, and juvenile glaucoma, is the result of aberrant migration or terminal induction of the neural crest cells involved in the formation of the anterior segment of the eye (summary by Mears et al., 1996).

Peters anomaly consists of a central corneal leukoma, absence of the posterior corneal stroma and Descemet membrane, and a variable degree of iris and lenticular attachments to the central aspect of the posterior cornea (Peters, 1906).

In Axenfeld anomaly, strands of iris tissue attach to the Schwalbe line; in Rieger anomaly, in addition to the attachment of iris tissue to the Schwalbe line, there is clinically evident iris stromal atrophy with hole or pseudo-hole formation and corectopia (summary by Smith and Traboulsi, 2012).

Clinical Features

Berg (1932) together with Jerndal (1970) reported observations of iridogoniodysgenesis anomaly (IGDA) in 11 generations of a Swedish family, in which 25 of 55 persons examined by an ophthalmologist were found to be affected. All affected members showed dysgenesis of the iris and iridocorneal angle, and every member of the kindred with dysgenesis had developed glaucoma by age 8 years. Elevated intraocular pressure was found in 2 in the neonatal period. The goniodysgenesis had the same appearance as that in infantile congenital glaucoma, which is, however, clearly a distinct disorder in view of its recessive inheritance (see 231300). Berg (1932) postulated a maldevelopment of the iridocorneal angle, which was later confirmed by Jerndal (1972), who reexamined Berg's original pedigree.

Hambresin and Schepens (1946) reported 19 affected individuals from a 6-generation family in which only glaucomatous members had dark chocolate brown irides, with prominent iris vessels and absent surface markings.

Weatherill and Hart (1969) examined 67 members of a 5-generation English family segregating autosomal dominant abnormalities of the anterior segment. Of 30 affected individuals, 24 had developed glaucoma; none had glaucoma without abnormality of the angle. Affected individuals displayed bilateral severe attenuation of the iris stroma, with a clearly visible pigment layer and sphincter pupillae; there were no defects of the pigment epithelium, and the pupil was circular and active. 'Brown' irides appeared to be the color of dark bitter chocolate, and 'blue' irides were a very dark slate gray. The angle defects observed, which were similar in both eyes of an individual, were of 2 types: in one, the angles were grossly abnormal and filled with yellow tissue covered with fine blood vessels, with no normal angle structures apart from the Schwalbe line detected; in the other, the iris was inserted anteriorly into the region of the trabecular meshwork, with many fine iris processes spanning the angle from the iris root to the Schwalbe line but not extending onto the cornea, and with a few abnormal vessels coursing among the iris processes.

Martin and Zorab (1974) described clinical observations from a 25-year follow-up of the 9-generation Scottish family first reported by Zorab (1932), descended from a man who lived at the time of the Battle of Culloden Moor (1745) and was known as 'Ian of the Blackberry Eyes.' The most striking feature of affected members of this family was the dark color of the irides, from which one could tell at a glance whether a particular family member was affected. Furthermore, the iris lacked the usual stromal pattern and had a smooth appearance, with absent crypts. A typical circumferential vessel was seen in the angle by slit-lamp examination. Arising from it were radial vessels coursing toward the pupil on the anterior surface of the iris. The color and vascular changes, present from birth, were found only in affected persons and were never lacking in them. Treatment for glaucoma was usually not necessary until the fourth or fifth decade. Myopia was present in most affected persons.

Pearce et al. (1982, 1983) described a large Canadian family with autosomal dominant iridogoniodysgenesis. Ocular features included marked iris stromal hypoplasia and iridocorneal angle malformations with excess 'woolly' tissue in the angle and anomalous angle vascularity. Nine of 10 affected individuals who were younger than 30 years of age at their initial presentation had elevated intraocular pressures. The remaining affected individual was younger than 1 year of age at the time of examination. Aldinger et al. (2009) analyzed brain imaging of 4 affected members of this pedigree and observed cerebellar vermis hypoplasia in all 4; 1 older individual also showed severe changes in the white matter signal. Aldinger et al. (2009) also studied 2 affected members of the 6-generation family reported by Lehmann et al. (2000) and observed enlarged cisterna magna and mild decrease in cerebellar vermis size.

Nishimura et al. (1998) reported several patients with anterior segment defects, including Axenfeld anomaly, Rieger anomaly, and iris hypoplasia who were found to have mutations in the FOXC1 gene.

Mapping

Mears et al. (1996) reported linkage analysis of 2 pedigrees with IGDA, both originally described by Pearce et al. (1982, 1983), one from the maritime region of Canada, in which linkage to chromosome 4q25 was excluded by Walter et al. (1996), and a second from South Wales. From this analysis, the IGDA locus was mapped to an 8.3-cM region of 6p25 distal to D6S477. The linkage results were consistent with the ocular findings in rare cases of individuals with chromosomal anomalies involving deletion of 6p (Zurcher et al., 1990). The studies of Mears et al. (1996) suggested that there is a major gene involved in eye anterior segment development located on 6p25. Mirzayans et al. (1997) used genome-mismatch scanning to identify the shared chromosomal region in 2 fifth-degree cousins with IGDA from the Canadian family reported by Mears et al. (1996). Markers on the short arm of chromosome 6p were recovered, consistent with the results of conventional linkage analysis conducted in parallel, indicating linkage of IGDA to chromosome 6p25.

Jordan et al. (1997) performed linkage analysis using microsatellite markers in the 9-generation Scottish family with iridogoniodysgenesis originally reported by Zorab (1932) and obtained a peak lod score of 11.63 at a recombination fraction of 0.0 with marker D6S967 mapping to 6p25. Haplotype analysis placed the disease gene in a 6.4-cM interval between the markers D6S1713 and D6S1600. Jordan et al. (1997) described the disorder as a form of open-angle glaucoma in which developmental anomalies of the iris and iridocorneal angle were associated with juvenile-onset glaucoma transmitted as an autosomal dominant trait.

Molecular Genetics

Nishimura et al. (1998) identified 4 different FOXC1 mutations in affected members of 4 unrelated families with various anterior segment defects, including Rieger anomaly (601090.0001 and 601090.0002), Axenfeld anomaly (601090.0003-601090.0004), and iris hypoplasia (601090.0001).

By DNA sequencing of the FOXC1 gene in 5 families and 16 sporadic patients with anterior segment defects, Mears et al. (1998) found 3 mutations, including a 10-bp deletion and a missense mutation (601090.0009), in 2 unrelated individuals with Axenfeld-Rieger anomaly, respectively. Both patients also had glaucoma.

In a 6-generation family segregating autosomal dominant iris hypoplasia with glaucoma mapping to chromosome 6p25, Lehmann et al. (2000) found no mutations in FOXC1 by direct sequencing. Genotyping with microsatellite markers, however, suggested the presence of a chromosomal duplication involving FOXC1 that segregated with the disease phenotype, which was confirmed by FISH in affected individuals (601090.0006).

In a parent and 3 sibs with iris hypoplasia, Nishimura et al. (2001) identified a partial duplications of chromosome 6p25, encompassing the FOXC1 gene (601090.0006), that was not found in the unaffected spouse or sole unaffected offspring. The authors found a different partial duplication of 6p25, also encompassing FOXC1, in a proband with Peters anomaly.

Using genotyping and FISH to investigate the 9-generation Scottish family segregating autosomal dominant iridogoniodysgenesis originally reported by Zorab (1932), Lehmann et al. (2002) demonstrated an interstitial duplication of chromosome 6p25 encompassing the FOXC1 gene (601090.0006). Lehmann et al. (2002) stated that the iris hypoplasia phenotype in the Scottish family was 'identical' to that of the family previously found to have a 6p25 duplication by Lehmann et al. (2000).

In 5 affected members of a 4-generation family segregating autosomal dominant anterior segment defects, Honkanen et al. (2003) identified the F112S mutation (601090.0004) in the FOXC1 gene. All affected individuals had posterior embryotoxon and iris processes; additional ocular findings in 2 patients included iris hypoplasia, corectopia, and glaucoma, and another patient also had Peters anomaly. Extraocular features were present in 4 patients, including 1 patient with hypodontia, flat maxillary processes, and a saddle nose defect, 1 patient with small teeth, 1 patient who had undergone aortic valve replacement, and 1 patient with cardiomegaly and congestive heart failure.

Chanda et al. (2008) analyzed the breakpoint architecture in 10 pedigrees with a diagnosis of glaucoma associated with iris hypoplasia or Axenfeld-Rieger syndrome (RIEG3; 602842) and duplications or deletions at chromosome 6p25, and found that in contrast to most previous examples, the majority of the segmental duplications and deletions utilized coupled homologous and nonhomologous recombination mechanisms. The authors stated that their results extended the mechanisms involved in structural variant formation and provided strong evidence that a spectrum of recombination, DNA repair, and replication underlie chromosome 6p25 rearrangements.

In 2 unrelated patients with iridogoniodysgenesis, Fetterman et al. (2009) identified heterozygosity for a FOXC1 missense mutation in the inhibitory domain (601090.0012) and stated that this was the first missense mutation to be reported outside of the forkhead domain. Noting that the iridogoniodysgenesis phenotype is more commonly associated with FOXC1 duplications than mutations, Fetterman et al. (2009) suggested that FOXC1 duplications and mutations that disrupt the inhibitory domain may lead to disease through similar mechanisms and thus have more similar phenotypes when compared to disease caused by missense mutations with reduced protein function.