Ectopia Lentis Et Pupillae

A number sign (#) is used with this entry because of evidence that ectopia lentis et pupillae can be caused by homozygous or compound heterozygous mutation in the ADAMTSL4 gene (610113) on chromosome 1q21.

Autosomal recessive isolated ectopia lentis-2 (ECTO2; 225100) is also caused by mutation in the ADAMTSL4 gene.

Description

Ectopia lentis et pupillae is a congenital hereditary disorder in which there is displacement of the lenses and the pupils, associated with other ocular anomalies, but without systemic manifestations. The condition is usually bilateral, with the lenses and pupils displaced in opposite directions (summary by Cruysberg and Pinckers, 1995). Additional signs include enlarged corneal diameter, increased corneal astigmatism, increased anterior chamber depth, thinning and flattening of the iris with loss of crypts, angle malformation caused by enlarged iris processes, persistent pupillary membrane, loss of zonular fibers, tilted disc, and increased axial length. Secondary manifestations include refractive errors, glaucoma, early cataract development, and retinal detachment. Membrane formation on the posterior aspect of the iris has been observed both in histologic sections and on ultrasound biomicroscopy (summary by Christensen et al., 2010).

Clinical Features

Colley et al. (1991) described 2 pairs of sibs and a fifth unrelated child with this disorder. The parents were nonconsanguineous in all cases. No skeletal, cardiac, or metabolic abnormalities were detected.

Goldberg (1988) described the ophthalmologic features in 16 patients from 8 families. Characteristics in addition to displacement of the lens and pupil included high myopia, retinal detachment, enlarged corneal diameters, and cataract.

Cruysberg and Pinckers (1995) described a kindred in which affected members were observed in 3 generations. In addition to ectopia lentis and ectopia pupillae, the patients had persistent pupillary membrane, iris transillumination, and poor pupillary dilatation. All developed bilateral cataracts before the age of 40 years, and 2 presented with intermittent acute intraocular hypertensive crises.

Christensen et al. (2010) examined 10 affected individuals from 5 Norwegian families segregating autosomal recessive ectopia lentis et pupillae. Dislocation of the lens was seen in all individuals, although there was variability in the extent of dislocation, with minimal displacement in both eyes of 1 patient and 1 eye of another patient. Zonular fibers were missing in the area between the displaced pupil and the edge of the dislocated lens. Prominent displacement of the pupil was seen in 9 eyes of 5 individuals, 7 upward and 2 downward, and in 2 family members, the dislocated pupil was seen primarily in 1 eye. Mild pupillary dislocation was seen in 3 individuals, which was primarily in 1 eye in 2 of them, and in 1 patient, both pupils were centrally positioned. In eyes with prominent displacement of the pupil, the iris surface appeared flat and there were no well-developed crypts or clefts. Transillumination of the iris was seen in 5 patients, and a thin pupillary membrane was seen in 2 patients. Cataract developed relatively early, and all affected individuals over 45 years of age had undergone intracapsular cataract extraction. In contrast to earlier reports, only 2 of the 10 patients had myopia. All patients were of normal stature and none had features of Marfan (154700) or Weill-Marchesani syndromes (277600). Echocardiography was normal in the 2 patients who were studied, and plasma homocysteine levels were normal in the 2 patients tested. No ocular abnormalities were seen in 11 unaffected first-degree relatives who were examined.

Inheritance

The recessive inheritance of combined ectopia lentis and ectopia pupillae has been well established (Siemens, 1920). Whether simple ectopia lentis is a recessive entity separate from this is somewhat doubtful since simple and 'associated' forms are said to occur in the same family (Franceschetti, 1927; Diethelm, 1947).

Walls and Heath (1959) described 3 affected sibs and an affected child of one of these sibs. It seems most likely that this was the familiar recessive disorder, the normal parent of the affected member in the later generation being a heterozygote. To invoke dominant inheritance, one must assume gonadal mosaicism or failure of expression in one of the parents of the affected sibs. These parents, it seems, were not examined.

Cruysberg and Pinckers (1995) described a kindred in which affected members were observed in 3 generations. Although the parents of the first generation, in which there were 5 affected members of a sibship, were consanguineous, Cruysberg and Pinckers (1995) did not observe consanguinity in the next 2 generations. The authors raised the possibility of autosomal dominant inheritance with reduced penetrance. It seems more likely, however, that this was an instance of pseudodominance (McKusick, 1996).

Mapping

Christensen et al. (2010) performed homozygosity mapping in 5 Norwegian families with ectopia lentis et pupillae and identified a 0.67-cM (1.0 Mb) common segment on chromosome 1 in affected individuals, between SNP markers located 148,500,906 bp and 149,507,166 bp from chromosome 1pter (NCBI36). The findings were compatible with a common ancestor approximately 150 generations (4,000 years) earlier.

Molecular Genetics

In 10 affected individuals from 5 Norwegian families with ectopia lentis et pupillae mapping to chromosome 1p, Christensen et al. (2010) sequenced the candidate gene ADAMTSL4 and identified homozygosity for a 20-bp deletion (610113.0003). Obligate heterozygotes had no ocular abnormalities. Screening of 190 local blood donors identified 3 heterozygotes, corresponding to a prevalence for homozygosity of approximately 1:16,000 in this population.

In an 8-year-old Swedish boy with ectopia lentis et pupillae, Aragon-Martin et al. (2010) identified compound heterozygosity for the 20-bp ADAMTSL4 deletion and an 11-bp ADAMTLS4 deletion (610113.0004).

In a Caucasian British patient with ectopia lentis et pupillae, Chandra et al. (2012) identified compound heterozygosity for the 20-bp ADAMTSL4 deletion and a 1-bp insertion in the ADAMTSL4 gene (610113.0007).