Corneal Dystrophy, Posterior Amorphous

A number sign (#) is used with this entry because posterior amorphous corneal dystrophy (PACD) is a chromosome 12q21.33 contiguous gene deletion syndrome.

Clinical Features

Carpel et al. (1977) observed a posterior corneal dystrophy characterized by irregular sheetlike areas of opacification with involvement of the Descemet membrane and, in some instances, alterations of the normal endothelial mosaic. There was no evidence of stromal edema, but a uniform thinning was present. The disorder was present in persons in 3 generations, with male-to-male transmission.

Dunn et al. (1984) reported 8 members of a family spanning 5 generations with posterior amorphous corneal dystrophy. Family members manifested this rare abnormality in both its centroperipheral and peripheral forms. Additional features found in these patients included hyperopia, flattened corneal topography, anterior iris surface and stromal abnormalities, fine iris processes extending to the Schwalbe line for 350 degrees, and extension of the opacity to the limbus. The presence of this dystrophy in a 6-month-old family member further suggested the possibility that it was a congenital abnormality.

Weiss et al. (2008) noted that the possible congenital onset, lack of progression, and association with iris abnormalities raised the question of whether this may in fact be a mesodermal dysgenesis rather than a corneal dystrophy.

Johnson et al. (1990) examined an affected 5-year-old boy from a 5-generation family segregating autosomal dominant posterior amorphous corneal dystrophy. He first presented at age 4 years, at which time he had uncorrected visual acuity of counting fingers on the right and 20/400 on the left. He had marked hyperopic astigmatism, right esotropia, and diffuse deep stromal and endothelial haze of both corneas. Reexamination the following year showed a visual acuity of 20/160 in the right eye and 20/50 in the left. Slit-lamp examination showed diffuse deep stromal opacification of both corneas, which were uniformly thin. Penetrating keratoplasty was performed on the right eye and light microscopy of the corneal button showed no evidence of edema, inflammation, or vascularization, and the Descemet membrane appeared normal, but there were several areas where the adjacent stromal lamellae were fractured and disrupted. Electron microscopy revealed varying degrees of disorganization in the stromal lamellae just anterior to the Descemet membrane, ranging from individual collagen fibers running perpendicular to the major axis of fiber orientation within a given lamella, to complete disorganization of the stromal pattern with a swirling appearance to the collagen fibers. The authors stated that it was unclear why this patient's vision was so poor.

Aldave et al. (2010) described a large 6-generation family with PACD in which 20 individuals exhibited posterior corneal stromal lamellar opacification that appeared either at or just anterior to the Descemet membrane. Corneal opacification was bilateral, symmetric, and nonprogressive; it was incomplete in all affected individuals, with areas of corneal lucency interspersed between the regions of swirling posterior lamellar corneal opacification. Affected individuals also demonstrated diffuse corneal thinning and significant corneal flattening, and most showed bilateral superior corneal scleralization. Iris abnormalities, including corectopia and iris coloboma, were observed in some patients. Light microscopy of a corneal specimen from a 60-year-old patient showed irregularity of the posterior stromal lamellae; electron microscopy showed amorphous extracellular material between the stromal lamellae in the anterior cornea as well as cystic membrane-bound structures in the corneal endothelial cells that were suggestive of dilated mitochondria.

Kim et al. (2014) reported a large family (family 2) in which 7 individuals over 2 generations had PACD. Four of those affected had posterior lamellar opacification involving the central and peripheral cornea, and 3 had only peripheral involvement. In the 6 patients who were measured, there was central corneal thinning, and all 6 also showed significant corneal flattening.

Odent et al. (2017) described a 1-year-old boy of African descent who at 4 weeks of age was noted to have small eyes with microcornea, bilateral flat and hazy corneas with an indistinct border between the cornea and sclera, and shallow anterior chambers. Lenses were clear, intraocular pressure was normal, and funduscopy was unremarkable. Biomicroscopy at age 7 months showed a flat cornea with stromal haziness and a diameter of 9 mm. The anterior chamber was very shallow, the limbus was poorly delineated, and he was hypermetropic (+4.5D). Reexamination at 1 year of age showed a decrease in the stromal haze and sharper delineation of the posterior sheetlike opacity, and there was an increase in his hypermetropia to +7.5D bilaterally. Other features in the boy included left intraventricular hemorrhage at 5 days of life with midline shift and ventricular enlargement, for which he underwent placement of ventriculoperitoneal shunts due to progressive hydrocephalus.

Inheritance

Male-to-male transmission in the family reported by Carpel et al. (1977) indicates autosomal dominant inheritance.

Mapping

In a large 6-generation family with PACD, Aldave et al. (2010) performed microsatellite-based genomewide linkage analysis and obtained a single-point lod score of 3.42 (theta = 0) at marker D12S351 on chromosome 12q21.33; the largest multipoint lod score was 3.82 at D12S351. Multipoint scores in this region identified an 11-cM support interval between D12S1708 and D12S346. Fine mapping generated a maximum single-point lod score of 3.53 (theta = 0) at D12S1716, and the largest multipoint lod score was 5.62 at D12S322, with a 3.5-Mb (3.5-cM) linkage support interval between D12S1812 and D12S95, encompassing roughly the entire chromosome band 12q21.33. Haplotype analysis showed heterozygosity for a conserved haplotype segregating through the pedigree in almost all affected individuals; however, the conserved haplotype was also detected in 4 unaffected individuals, consistent with reduced penetrance.

Cytogenetics

In affected members of the large 6-generation family with PACD (family 1) previously studied by Aldave et al. (2010), in whom whole-exome sequencing did not reveal any variants that segregated with disease, Kim et al. (2014) performed copy number analysis and identified a heterozygous 701-kb deletion at chromosome 12q21.33, involving the 4 small leucine-rich proteoglycan (SLRP) genes EPYC (601657), KERA (603288), LUM (600616), and DCN (125255), as well as the CCER1 gene and a nonprotein coding gene, LINC00615. In affected members of a second family with PACD (family 2), Kim et al. (2014) identified heterozygosity for a 1.318-Mb deletion in the 12q21.33 region that segregated with disease; although the deletion was nearly twice as large as that identified in family 1, only the same 6 genes were involved. In a third family with PACD (family 3), previously reported by Johnson et al. (1990), Kim et al. (2014) identified the identical 701-kb deletion that had been detected in family 1. Segregation was confirmed by qPCR in all 3 families, and kinship analyses showed no relatedness between any of the families. Analysis of corneal expression of the 6 deleted genes showed that LUM and KERA had significantly higher expression than DCN, whereas EPYC and CCER1 were not detected in the cornea. In addition, Kim et al. (2014) noted that loss-of-function mouse models involving the Lum and Kera genes showed phenotypic features consistent with those observed in the PACD families.

In a 1-year-old boy of African descent with PACD, Odent et al. (2017) performed microarray-CGH and identified heterozygosity for a de novo 1,671-kb deletion at 12q21.33 that encompassed 11 genes, including DCN, KERA, LUM, EPYC, CCER1, LINC00615, C12ORF79, BTG1 (109580), RPL21P106, CLLU1OS (616989), and CLLU1 (616988). The authors noted that they could not exclude an association between the deletion and the intraventricular hemorrhage that occurred on day 5 of life in this patient.

Molecular Genetics

Exclusion Studies

In a large 6-generation family with PACD mapping to chromosome 12q21.33, Aldave et al. (2010) screened 4 functional candidate genes, KERA, LUM, DCN, and EPYC, but did not find any variants that segregated with disease.