Microcoria, Congenital

A number sign (#) is used with this entry because of evidence that congenital microcoria is caused by contiguous gene deletion at chromosome 13q32.

Description

Inherited congenital microcoria, also referred to as congenital miosis, is characterized by bilateral small pupils (diameter less than 2 mm) that result from an underdevelopment of the dilator pupillae muscle of the iris (Holth and Berner, 1923; Simpson and Parsons, 1989). Iris transillumination defects are a constant feature. The pupil dilates poorly or not at all in response to topically administered mydriatic drugs. The disorder is transmitted as an autosomal dominant trait with complete penetrance and is associated with goniodysgenesis and glaucoma (Tawara and Inomata, 1983; Mazzeo et al., 1986; Toulemont et al., 1995).

Clinical Features

Ardouin et al. (1964) described a family in which 25 persons had small pupils due apparently to hypoplasia of the dilator muscle of the iris. Myopia was present in all.

Tawara et al. (2005) restudied 6 affected members of a 3-generation Japanese family with congenital microcoria and goniodysgenetic glaucoma, originally reported by Tawara and Inomata (1983). Two brothers, who were followed for over 2 decades beginning at the ages of 8 and 10 years, had bilateral congenital microcoria. On examination, their irides had a featureless surface with poorly developed collarettes and crypts, and gonioscopy showed high insertion of the iris root into the scleral spur as well as a ciliary body band that was barely seen or invisible. Fundi were poorly visualized due to the patients' small pupils. Both patients developed high intraocular pressures associated with blurred vision and underwent trabeculectomies in their twenties and thirties. Histopathologic examination of iridocorneal angle tissue specimens showed thickened juxtacanalicular connective tissue (JCT) in the trabecular meshwork, with accumulations of extracellular matrix. On electron microscopy, the thickened JCT consisted of many layers of trabecular cells embedded in a basement membrane-like extracellular matrix of fibrous and amorphous material. The brothers' 32-year-old female cousin, followed since age 7 years, also exhibited bilateral congenital microcoria and goniodysgenesis, but had normal intraocular pressures and visual fields. There were no changes in the appearance of the irides, pupils, or iridocorneal angles in any of the 3 patients during follow-up. The brothers' father and the cousin's mother also had microcoria and goniodysgenetic glaucoma, and their deceased grandfather had been diagnosed with microcoria.

Ramirez-Miranda et al. (2011) reported a 3-generation Mexican Mestizo family with congenital microcoria. The proband was a 62-year-old woman who had blurred vision and nyctalopia since childhood and whose vision had gradually been deteriorating over the past 5 years. Examination showed bilateral pupillary diameters of less than 2 mm, with a hyperpigmented peripupillary area, transillumination defects of the peripheral iris, and no response to mydriatic drugs. She also had bilateral dense nuclear cataracts. Intraocular pressure was normal, but fundus could not be evaluated due to the small pupil. Her affected 41-year-old son and 9-year-old grandson had the same iris configuration with normal intraocular pressures, but no cataracts. Ultrabiomicroscopic examination in all 3 affected individuals showed a pupillary diameter of 1.8 mm and thinning of the iris (830 microns), with no angle findings. The proband underwent cataract surgery, at which time the pupillary margin was biopsied; histopathologic analysis confirmed that the iris was thinner as well richer in cells and ground substance, and that it had an incompletely developed dilator muscle. However, the innervation, vasculature, and cellular relationships were normal; in addition, there were no basement membrane alterations of the excised anterior lens capsule, confirming that the developmental anomaly was limited to the iris.

Mapping

Rouillac et al. (1998) described a linkage analysis in the French family reported by Ardouin et al. (1964), adding observations on another branch of the family. They found linkage between the disorder and markers located on 13q31-q32 (maximum lod = 9.79 at theta = 0.0). Haplotype analysis narrowed the linked region to an interval less than 8 cM between markers D13S1239 proximally and D13S1280 distally.

Molecular Genetics

Using comparative genomic hybridization (CGH), Fares-Taie et al. (2015) analyzed DNA from an affected member of the French family with microcoria originally reported by Ardouin et al. (1964) and identified a heterozygous deletion on chromosome 13 that extended from 95,227,374 to 95,277,864 (GRCh37). The centromeric and telomeric breakpoints were located within intron 11 and intron 8 of the tail-to-tail genes TGDS (616146) and GPR180 (607787), respectively. Array CGH confirmed the presence of heterozygous deletions at 13q32.1 in 5 other microcoria families, including those originally reported by Tawara et al. (2005) and Ramirez-Miranda et al. (2011). The deletions, which ranged in size from approximately 35 to 80 kb and invariably encompassed the TGDS and GPR180 genes, were not found in the Database of Genomic Variants or in a cohort of 96 individuals with other diseases analyzed by array CGH. Fares-Taie et al. (2015) noted that unlike TGDS, which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. In their in-house exome database, Fares-Taie et al. (2015) identified a GPR180 nonsense mutation (Q115X) that segregated with goniodysgenesis in a family with Leber congenital amaurosis (LCA; see 204000); however, none of the 5 individuals with both iridocorneal angle dysgenesis and the Q115X substitution had abnormal pupillary responses or iris transillumination. Fares-Taie et al. (2015) also examined heterozygous and homozygous Gpr180-null mouse eyes, and found that they were indistinguishable from adult age-matched controls. In addition, they screened the GPR180 gene in 21 individuals exhibiting goniodysgenesis, including 10 with Axenfeld-Rieger or Peters anomaly and 11 with congenital or juvenile glaucoma, all of whom were negative for mutations in known genes associated with those conditions, but found no GPR180 disease-causing variants. Fares-Taie et al. (2015) suggested that GPR180 ablation, alone or in combination with the loss of elements that regulate the expression of neighboring genes by position effect, may be the cause of microcoria.

Exclusion Studies

In 2 brothers from a 3-generation Japanese family with congenital microcoria and goniodysgenetic glaucoma, originally reported by Tawara and Inomata (1983), Tawara et al. (2005) did not detect any mutations in the CYP1B1 (601771) or MYOC (601652) genes.