Autosomal dominant iridogoniodysgenesis type 1, 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 ... Autosomal dominant iridogoniodysgenesis type 1, 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). - Genetic Heterogeneity of Iridogoniodysgenesis Another form of iridogoniodysgenesis (IRID2; 137600) can also be caused by mutation in the PITX2 gene (601542) on chromosome 4q25-q26. See 308500 for discussion of an apparently X-linked recessive form of iris hypoplasia and glaucoma. See 609515 for a form of iridogoniodysgenesis associated with skeletal anomalies.
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 ... 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.
In a patient with primary congenital glaucoma who had a balanced translocation between 6p25 and 13q22, Nishimura et al. (1998) cloned the chromosomal breakpoints and identified 2 candidate genes, 1 of which was the FKHL7 (FOXC1) gene. In ... In a patient with primary congenital glaucoma who had a balanced translocation between 6p25 and 13q22, Nishimura et al. (1998) cloned the chromosomal breakpoints and identified 2 candidate genes, 1 of which was the FKHL7 (FOXC1) gene. In a second primary congenital glaucoma patient with partial 6p monosomy, the FOXC1 gene was found to be deleted. 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), and iris hypoplasia (601090.0001). The authors concluded that mutations in FOXC1 cause a spectrum of glaucoma phenotypes. 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 (604229). 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). 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 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.