Weill-Marchesani Syndrome 1

A number sign (#) is used with this entry because Weill-Marchesani syndrome-1 (WMS1) is caused by homozygous or compound heterozygous mutation in the ADAMTS10 gene (608990) on chromosome 19p13.

Description

Weill-Marchesani syndrome is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma, and, occasionally, heart defects (summary by Dagoneau et al., 2004).

Genetic Heterogeneity of Weill-Marchesani Syndrome

A phenotypically similar, autosomal dominant form of WMS (WMS2; 608328) is caused by mutation in the FBN1 gene (134797) on chromosome 15q21. Autosomal recessive WMS3 (614819) is caused by mutation in the LTBP2 gene (602091) on chromosome 14q24. Autosomal recessive WMS4 (613195) is caused by mutation in the ADAMTS17 gene (607511) on chromosome 15q24.

Clinical Features

Weill (1932) and Marchesani (1939) first described the syndrome. Meyer and Holstein (1941) described 4 affected sibs whose parents were related. Features included short stature, spherophakia with glaucoma, and brachydactyly. Rennert (1969) described an affected 9-year-old boy with joint stiffness who had 'difficulty in extending his arms over his head.'

Ferrier et al. (1980) reported an affected 11-year-old girl who also had subvalvular fibromuscular aortic stenosis. Radiologic survey showed a disorder of enchondral growth, particularly evident in the extremities, with short and wide diaphyses, thick cortical bone, and relatively discrete epiphyseal deformities.

Giordano et al. (1997) found a case of WMS showing short stature, progressive joint stiffness, brachydactyly, and ectopia lentis. An unusual feature was the presence of 'primary' osteoporosis in the 28-year-old affected man, who was 130 cm tall.

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.

Kojuri et al. (2007) described cardiac findings in 6 patients, 3 of whom were sibs, with WMS. The most notable ECG abnormality was prolonged QTc (QTc greater than 0.46 sec), which was detected in 3 of 6 patients. The most common echocardiographic abnormality was mitral valve prolapse (MVP), which was detected in 3 patients, 2 of whom also had prolonged QTc. One patient had both MVP and severe congenital valvular aortic stenosis.

Kutz et al. (2008) reported an 86-year-old man with autosomal recessive WMS. He had short stature, short fingers and hands, thick skin, stiff joints, lens dislocation, and severe glaucoma resulting in blindness. Intellect was unaffected.

Mapping

Megarbane et al. (2000) described an inbred Lebanese family in which 3 affected sibs had short stature, brachydactyly, limitation of joint movements, microspherophakia, luxated lenses, glaucoma, and heart malformations. The parents were relatively short but had no other features present in the sibs. Linkage analysis excluded 15q21.1 in the etiology of the syndrome.

Faivre et al. (2002) performed a genomewide search in 2 large affected consanguineous families of Lebanese and Saudi origin consistent with autosomal recessive inheritance. They mapped the disease gene to 19p13.3-p13.2; maximum lod = 5.99 at theta = 0 at locus D19S906.

Molecular Genetics

Dagoneau et al. (2004) described homozygous mutations in the ADAMTS10 gene (608990.0001-608990.0003) in the consanguineous Lebanese and Saudi families studied by Faivre et al. (2002). Dagoneau et al. (2004) stated that more than 100 known genes were found to map to the WMS critical region on 19p13. Of these genes, 5 were regarded as possible candidate genes on the basis of their function. A total of 3 distinct mutations were identified in 2 consanguineous families and in 1 sporadic WMS case, including 1 nonsense mutation and 2 splice mutations. Studies of the normal expression of ADAMTS10 using RT-PCR, Northern blot, and dot-blot analyses showed that ADAMTS10 is expressed in skin, fetal chondrocytes, and fetal and adult heart. Dagoneau et al. (2004) concluded that ADAMTS10 plays a major role in growth and in skin, lens, and heart development in humans.

In an 86-year-old man with autosomal recessive WMS, Kutz et al. (2008) identified compound heterozygosity for mutations in the ADAMTS10 gene (608990.0004-608990.0005).

In affected individuals from 2 consanguineous Saudi Arabian families with Weill-Marchesani syndrome, Morales et al. (2009) identified homozygosity for 2 different missense mutations in the ADAMTS10 gene (608990.0006 and 608990.0007, respectively). The 4 parents were heterozygous for the respective mutations; neither mutation was found in 300 ethnically matched controls. No mutations in ADAMTS10, ADAMTS17 (607511), or FBN1 (134797) were identified in a sporadic case, a 70-year-old man with WMS, suggesting further genetic heterogeneity.

History

McGavic (1959, 1966) reported presumed Weill-Marchesani syndrome in 3 generations, but on reinvestigation McKusick (1972) concluded that this was an instance of autosomal dominant ectopia lentis (129600) in a generally short-statured family.

The sisters reported by Feinberg (1960) did not have WMS. The same sisters were described by Gorlin et al. (1960) as having a possibly new syndrome (see 233500).