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. (Hittner (1981) preferred the designation 'anterior segment mesenchymal dysgenesis,' arguing ... 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. (Hittner (1981) preferred the designation 'anterior segment mesenchymal dysgenesis,' arguing that 'anterior segment' can refer only to the eye, making 'ocular' redundant and that 'mesenchymal' conveys important additional information on the nature of the disorder.) 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 pointed to the family of Green and Johnson (1986) as another example. Salmon et al. (1988) 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. The authors noted that the term 'Peters anomaly' covers a heterogeneous group of congenital anomalies that can be found in a number of developmental conditions. In its simplest form, Peters anomaly (604229) involves a central corneal opacity; in other cases, there may be adherent iris strands, and with a third variant of Peters anomaly, patients also have keratolenticular contact 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. In the Australian family, 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 1 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 (180500). Doucette et al. (2011) studied a 4-generation family from Newfoundland, originally reported by Green and Johnson (1986), in which 11 cases of mild to severe forms of anterior segment dysgenesis segregated as an autosomal dominant trait across 6 sibships. The proband was noted to have bilateral dense corneal opacities at birth; examination under anesthesia revealed corneal opacification of the right eye temporally and hazy cornea nasally, with fine adhesions from the collarette of the iris to the cornea obscuring the angle. The left cornea was more densely opaque with a large central adhesion from the cornea to the lens and peripheral adhesions from the iris to the cornea. Both globes were of normal size, but he had bilateral microcornea. At 6 months of age, the proband underwent left corneal transplant; examination of the corneal tissue showed absent Descemet membrane, partial absence of Bowman membrane, and thinning of the central cornea, consistent with Peters anomaly. Reexamination of the proband at 30 years of age showed a phthisical left eye due to postoperative complications; there was no other facial dysmorphism, and no extraocular features were seen. The proband's father had small posterior subcapsular and central nuclear cataracts noted at 7 years of age; examination at 27 years of age revealed bilateral microcornea, with scleralization and vascularization of the cornea. Gonioscopy showed fine iris processes extending over the trabecular network. He underwent cataract extractions at ages 39 and 40 years because of decreasing visual acuity. Three paternal aunts had lens opacities documented in childhood and underwent cataract extractions in their second or third decades; all 3 had microcornea and mild to moderate scleralization of the cornea with varying degrees of vascularization. In addition, 3 paternal cousins underwent cataract extractions at ages 16 to 40 years; the cataracts were originally described as anterior polar, anterior cortical, nuclear, and posterior subcapsular. There was no evidence that either of the deceased paternal grandparents had any form of anterior segment dysgenesis: both were reported to have normal-sized corneas, and lens opacities that developed and resulted in cataract extraction in the eighth decade of life were attributed to the aging process. Doucette et al. (2011) suggested that one might have had a subclinical phenotype or that gonadal mosaicism might have been present.
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 ... - Mutation in PITX3 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. - Mutation in FOXE3 In a mother and daughter with a prominent anterior Schwalbe line (posterior embryotoxon) and cataract, Semina et al. (2001) identified heterozygosity for a single-nucleotide insertion in the FOXE3 gene (601094.0001). The mutation was not found in 180 control chromosomes. In a large 4-generation Newfoundland family segregating an autosomal dominant form of variable anterior segment dysgenesis, previously reported by Green and Johnson (1986), Doucette et al. (2011) analyzed 9 functional candidate genes and identified a heterozygous non-stop mutation in the FOXE3 gene (X320L; 601094.0003) that segregated with disease in the family and was not found in 141 ethnically matched controls.