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  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
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ECTOPIA LENTIS 2, ISOLATED, AUTOSOMAL RECESSIVE; ECTOL2

ECTOPIA LENTIS 2, ISOLATED, AUTOSOMAL RECESSIVE; ECTOL2

Ectopia lentis is defined as an abnormal stretching of the zonular fibers that leads to lens dislocation, resulting in acute or chronic visual impairment (Greene...

Ectopia lentis is defined as an abnormal stretching of the zonular fibers that leads to lens dislocation, resulting in acute or chronic visual impairment (Greene et al., 2010).

An autosomal dominant form of isolated ectopia lentis (ECTOL1; 129600) is caused by mutation in the FBN1 gene (134797).

Ectopia lentis is a hallmark of several well-known syndromes, e.g., Marfan syndrome (154700), Weill-Marchesani syndrome (see 277600), and homocystinuria (236200).

▼ Clinical Features
Al-Salem (1990) described 2 large consanguineous Arab families of Iraqi and Jordanian origin, respectively, with bilateral isolated ectopia lentis. The condition was generally discovered at school age (5 to 6 years). All patients in both families had normal clear corneas and deep anterior chambers with tremulous irides. There were no areas of iris atrophy, pupillary abnormalities, or iris transillumination in any of the 18 patients examined or their relatives. The subluxated lenses showed variation in their direction from 1 patient to another, but temporal displacement was the most common direction encountered. Refraction showed myopic astigmatism; all patients had normal intraocular pressures and axial lengths. Systemic examination revealed no arachnodactyly, joint hyperextensibility, scoliosis, or cardiac anomalies, and span-to-height measurements were normal in all patients.

Greene et al. (2010) reported 2 Turkish brothers, born of consanguineous parents, who had isolated ectopia lentis. The proband presented at 3.8 years of age with bilateral inferonasal ectopia lentis and reduced visual acuity; endocapsular lensectomies resulted in bilateral visual acuity of 20/25. His 2-year-old brother, who had classic phenylketonuria discovered upon routine newborn screening, presented at age 11 months with bilateral ectopia lentis. Slit-lamp examination in the younger brother revealed posterior synechiae between the lens and the iris, which were believed to be the result of lens dislocation, as there were no signs of or history of uveitis. The parents had normal eye examinations, and physical examination in both boys and their parents ruled out dysmorphic features or musculoskeletal anomalies such as arachnodactyly, scoliosis, or hyperextensibility. In addition, homocystinuria was excluded in the 2 boys.

▼ Inheritance
McKusick (1955) described a consanguineous family in which 4 of 9 sibs were affected with primordial dwarfism and 4 with ectopia lentis, both of which appeared to be inherited as independent autosomal recessive traits.

Ruiz et al. (1986) reported 3 sibs with an apparently autosomal recessive form of isolated ectopia lentis.

Ahram et al. (2009) confirmed autosomal recessive inheritance of isolated ectopia lentis in a family originally reported by Al-Salem (1990).

▼ Mapping
In a large consanguineous Arab family of Jordanian origin with isolated ectopia lentis, originally reported by Al-Salem (1990), Ahram et al. (2009) performed genomewide linkage analysis and obtained a maximum multipoint lod score of 4.4 for marker D1S534 in the pericentromeric region on chromosome 1p13.2-q21.1. Fine mapping defined a 35-Mb critical region between markers D1S1675 and D1S498.

▼ Molecular Genetics
In a large consanguineous Arab family of Jordanian origin with isolated ectopia lentis, originally reported by Al-Salem (1990), Ahram et al. (2009) identified homozygosity for a nonsense mutation in the ADAMTSL4 gene (610113.0001) that segregated with the phenotype and was not found in 380 ethnically matched control chromosomes.

In 2 Turkish brothers with isolated ectopia lentis who were negative for mutation in the FBN1 gene (134797), Greene et al. (2010) identified homozygosity for a splice site mutation in the ADAMTSL4 gene (610113.0002) that was present in heterozygosity in their unaffected parents.

In 6 unrelated patients with FBN1-negative ectopia lentis, including 1 who had ectopia lentis et pupillae (225200), Aragon-Martin et al. (2010) identified homozygous or compound heterozygous mutations in the ADAMTSL4 gene (see, e.g., 610113.0003-610113.0005), including a 20-bp deletion (610113.0003) reported by Christensen et al. (2010) as a founder mutation in Norwegian families with ectopia lentis et pupillae. In 4 families where DNA was available, the unaffected parents were shown to be heterozygous for the mutations.

In 8 patients from 7 German families with isolated ectopia lentis, Neuhann et al. (2011) identified homozygosity for the same 20-bp deletion in the ADAMTSL4 gene (610113.0003). The mutation was found in heterozygosity in unaffected parents and sibs, as well as in 2 of 360 controls. A 4-SNP haplotype was consistently associated with the mutation, suggestive of a founder mutation.

▼ Genotype/Phenotype Correlations
Chandra et al. (2012) studied 16 patients with isolated ectopia lentis and identified homozygous or compound heterozygous mutations in ADAMTSL4 in 8 patients (see, e.g., 610113.0003) and heterozygous mutations in the FBN1 gene in 4 patients. No mutations were identified in the remaining 4 patients. The median age of diagnosis of ectopia lentis was 35 years in patients with FBN1 mutations versus 2 years in patients with ADAMTSL4 mutations (p less than 0.01). Mean axial length was 22.74 mm in FBN1 patients compared to 27.54 mm in ADAMTSL4 patients (p less than 0.01). Other ophthalmic features, including corneal thickness and power, foveal thickness, visual acuity, and direction of lens displacement, were similar for both groups. Chandra et al. (2012) concluded that ADAMTSL4 mutations appear to cause earlier manifestation of ectopia lentis and are associated with increased axial length compared to mutations in FBN1.

Tags: 1q21.2