Weill-Marchesani Syndrome 2

A number sign (#) is used with this entry because Weill-Marchesani syndrome-2 (WMS2) is caused by heterozygous mutation in the FBN1 gene (134797) on chromosome 15q21.

Weill-Marchesani syndrome-2 is allelic to geleophysic dysplasia-2 (614185) and acromicric dysplasia (102370), the skeletal and joint features of which overlap with WMS, as well as Marfan syndrome (154700).

Description

Weill-Marchesani syndrome is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and lens abnormalities (Faivre et al., 2002).

For a general phenotypic description and a discussion of genetic heterogeneity of WMS, see 277600.

Clinical Features

Probert (1953) described a family in which 4 sibs (3 females, 1 male) had spherophakia with brachydactyly, and one of their parents and many relatives had brachymorphism. The inheritance pattern was autosomal dominant. The authors noted the phenotypic similarities to Marfan syndrome.

Gorlin et al. (1974) reported a father and 2 children with WMS. Since the wife was short, this may be an example of backcross mating (homozygote with heterozygote). Jensen et al. (1974) referred to an affected father and daughter, and Young et al. (1986) reported affected mother and son.

Verloes et al. (1992) described an apparently autosomal dominant disorder with features resembling the autosomal recessive form of Weill-Marchesani syndrome (WMS1; 277600). Progressive joint stiffness, glaucoma, and lens dislocation occurred in 3 generations--grandfather, daughter, and grandson. The daughter was 159 cm tall, and the grandfather 169 cm tall. The grandfather had brachydactyly. Verloes et al. (1992) designated the disorder 'glaucoma-lens ectopia-microspherophakia-stiffness-shortness (GEMSS) syndrome' to distinguish it from 'classic' autosomal recessive WMS.

In a literature review of 128 cases of Weill-Marchesani syndrome, including 57 autosomal recessive cases, 50 autosomal dominant cases, and 21 sporadic cases, Faivre et al. (2003) found no significant differences in mode of inheritance for short stature, brachydactyly, thick skin, mild mental retardation (13% of all patients), myopia, or glaucoma. Some differences were found for microspherophakia (94% in AR, 74% in AD), ectopia lentis (64% in AR, 84% in AD), joint limitations (49% in AR, 77% in AD), and cardiac anomalies (39% in AR, 13% in AD). Some heterozygotes for the AR form presented with some mild clinical manifestations of the disease. However, Faivre et al. (2003) concluded that there is general clinical homogeneity despite genetic heterogeneity in WMS.

Mapping

Because ectopia lentis is one of the main manifestations of WMS, Wirtz et al. (1996) proposed fibrillin-1 as a candidate gene for the disorder. They examined 2 affected families, including the one reported by Gorlin et al. (1974). In both families, evidence suggestive of linkage was obtained with markers on chromosome 15q21, with a maximum 2-point lod score of 2.11 for D15S118 at theta = 0. Immunohistochemical examination showed a decrease in fibrillin staining in the dermal-epidermal junctions and in the papillary dermis.

Molecular Genetics

In the affected family reported by Gorlin et al. (1974), Faivre et al. (2003) identified heterozygosity for a 24-bp deletion in the FBN1 gene (134797.0040) which cosegregated with the disease. No mutation in the FBN1 gene was detected in the affected family reported by Wirtz et al. (1996).