Microspherophakia And/or Megalocornea, With Ectopia Lentis And With Or Without Secondary Glaucoma

A number sign (#) is used with this entry because of evidence that microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma, can be caused by homozygous mutation in the LTBP2 gene (602091) on chromosome 14q24.

Description

Microspherophakia (MSP) is a rare disease characterized by smaller and more spherical lenses than normal bilaterally, an increased anteroposterior thickness of the lens, and highly myopic eyes. Lens dislocation or subluxation may occur, leading to defective accommodation (summary by Ben Yahia et al., 2009).

Microspherophakia may occur in association with ectopia lentis and glaucoma, Marfan syndrome (MFS; 154700), and Weill-Marchesani syndrome (WMS; 277600).

Clinical Features

Ben Yahia et al. (2009) studied a sister and brother with isolated microspherophakia from a consanguineous Tunisian family. They had no cardiovascular, musculoskeletal, or metabolic disease, and there was no family history of Marfan syndrome, Weill-Marchesani syndrome, or metabolic disease. Their parents and 4 other sibs were unaffected.

Kumar et al. (2010) studied 2 consanguineous Indian families in which there were 3 brothers and a sister and brother, respectively, with microspherophakia. The 3 brothers all had unilateral lens dislocation into the vitreous cavity. The 23-year-old female presented with blurred vision and was found to have bilateral microspherophakia and secondary glaucoma, as did her 15-year-old brother. None of the 5 affected individuals had enlarged cornea, buphthalmos, abnormal angle structures, or increased axial length, excluding a diagnosis of primary congenital glaucoma in both families. None of the patients from either family had any systemic involvement.

Desir et al. (2010) described 3 sibs, born of first-cousin Moroccan parents, who had bilateral microspherophakia and megalocornea. The proband presented at 18 months of age with impaired vision and was found to have microspherophakia with bilateral lens dislocation, megalocornea, flat irides, and iridodonesis. Eye pressures were normal, and he had axial myopia. He underwent bilateral lensectomy at 2 years of age; 4 to 5 years later he had bilateral retinal detachment, and ocular hypertension developed. A sister was examined at 10 months of age due to megalocornea; she also had microspherophakia, iridodonesis, and axial myopia, with very deep anterior chambers, miotic oval pupils without well-defined borders, and normal eye pressures. She had complete posterior lens dislocation at 6 years of age, and ocular hypertension was noted at 8 years of age. Another sister presented at 18 months of age with axial myopia, megalocornea, microspherophakia without lens dislocation, iridodonesis, iris anomalies including anterior synechiae and iris mamillations, deep anterior chambers, and normal eye pressures. At 5 years of age, she had intermittent anterior dislocation of the left lens, causing acute glaucoma crises, and she underwent emergent extraction of the lens; left retinal detachment developed a few weeks later. Progressive posterior luxation of the right lens and bilateral ocular hypertension were observed. Reexamination of the proband at 14 years of age revealed an increased arm span of 204 cm with a height of 184 cm, and a decreased upper-to-lower body ratio. His hands were normal with no arachnodactyly, and the Walker and Steinberg signs were not present; Marfan syndrome (154700) was considered, but direct analysis of the FBN1 gene (134797) revealed no mutation. His affected sisters had normal upper-to-lower body ratios. Desir et al. (2010) also reported a second family of Macedonian Gypsy descent with 1 affected girl and 1 healthy boy. The girl presented at 2 years of age with megalocornea, and examination showed patchy iris atrophy and a very flat anterior chamber, with anterosuperior dislocation of microspherophakic lenses. Fundi and eye pressures were normal at that time, and her eye pressures were still normal at 3 years of age. All affected children from both families had unremarkable skin, teeth, and gums, and their hearts, valves, and aortic roots were normal by ultrasonography.

Khan et al. (2011) reported 8 affected individuals from 3 consanguineous families with congenital megalocornea and secondary glaucoma due to spherophakia and/or ectopia lentis. The authors noted that 1 patient from each family had spontaneous complete crystalline lens dislocation into the anterior chamber with acute glaucoma during early childhood, an unusual ophthalmic presentation that had previously been most strongly associated with homocystinuria (see 236200); however, homocystinuria screening in these patients was negative. In addition, 2 of the older patients had tall stature and a high-arched palate, but none of the other affected individuals had dysmorphic features, dysmorphic body habitus, or nonocular congenital anomalies.

Inheritance

Small round lens as an isolated abnormality appears to be a recessive. Fleischer (1916), Gil (1928), and Franceschetti (1930) reported affected sibs, and Fleischer (1916) and Franceschetti (1930) reported parental consanguinity.

Ben Yahia et al. (2009) stated that, from 1901 to 2009, 30 sporadic cases of microspherophakia had been reported.

Mapping

In a consanguineous Indian family in which 3 brothers had microspherophakia, Kumar et al. (2010) performed a whole-genome scan and identified a 31.52-cM (22.76-Mb) region of homozygosity between D14S588 and D14S1050 on chromosome 14q24-q32.12. A maximum multipoint lod score of 2.91 was obtained between markers D14S1020 and D14S606. The region contained 110 reference genes. Haplotype analysis in another consanguineous Indian family with microspherophakia did not identify a region of homozygosity, suggesting genetic heterogeneity.

In a consanguineous Moroccan family in which 3 sibs had megalocornea, microspherophakia, ectopia lentis, and secondary glaucoma, Desir et al. (2010) performed homozygosity mapping and identified a region of homozygosity on chromosome 14q23.3-q24.3 that segregated with disease. A maximum multipoint lod score of 2.87 was calculated at D14S1002.

In 4 affected individuals from 2 consanguineous families with megalocornea, lens dislocation, and secondary glaucoma, Khan et al. (2011) detected a common run of homozygosity in a region of 14q containing the LTPB2 gene (602091).

Exclusion Studies

By linkage analysis in the consanguineous Tunisian family segregating isolated microspherophakia, Ben Yahia et al. (2009) found that the 2 affected sibs were heterozygous for all tested markers overlapping the ADAMTS10 gene (608990), and although the sibs shared the same haplotype around the FBN1 gene (134797), no homozygosity by descent was observed, making linkage to FBN1 unlikely under the hypothesis of autosomal recessive inheritance. Ben Yahia et al. (2009) concluded that WMS, which can be caused by mutation in the FBN1 or the ADAMTS10 gene, and isolated microspherophakia are not allelic disorders.

Molecular Genetics

In 3 affected brothers from a consanguineous Indian family segregating microspherophakia mapping to chromosome 14q24-q32.12, Kumar et al. (2010) identified homozygosity for a frameshift mutation in the LTBP2 gene (602091.0005).