A number sign (#) is used with this entry because of evidence that Weill-Marchesani syndrome-4 (WMS4) is caused by homozygous mutation in the ADAMTS17 gene (607511) on chromosome 15q26.

Weill-Marchesani syndrome is a rare connective tissue disorder characterized by microspherophakia, severe myopia, acute and/or chronic glaucoma, and cataract. Other features include brachydactyly and short stature. Patients may also have stiff joints and thickened skin, especially on the hands. Occasionally, cardiac defects or an abnormal heart rhythm is present (summary by Shah et al., 2014).

For a discussion of genetic heterogeneity of Weill-Marchesani syndrome, see WMS1 (277600).

Morales et al. (2009) described 8 individuals, 6 from 2 Saudi Arabian families and 2 sporadic cases, who displayed many of the key features of Weill-Marchesani syndrome, including lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Because none of the patients had brachydactyly or decreased joint flexibility, the authors considered this a 'Weill-Marchesani-like syndrome.'

Khan et al. (2012) reported a Saudi sister and brother, born of first-cousin parents, who had high myopia and spherophakia, with narrow angles in the sister. Both also exhibited short stature. Ocular examination in the sister showed shallow anterior chambers and frequent peripheral anterior iris attachments across the angle, which were considered to represent acquired peripheral anterior synechiae; her brother had moderate anterior chamber depth and showed rare peripheral iris processes on gonioscopy. Neither sib had short hands or feet, joint stiffness, or other nonocular congenital abnormalities.

Shah et al. (2014) studied a 21-year-old woman from a consanguineous Indian family who had bilateral microspherophakia with iridodonesis and phacodonesis, and who also exhibited short stature and brachydactyly. She had light perception only in her right eye, and visual acuity of 20/30 in her left eye. Anterior segment examination showed exotropia of the right eye with a fixed dilated pupil, whereas the left pupil reacted normally. Gonioscopy showed grade 2 angles bilaterally, with peripheral anterior synechiae on the right. Intraocular pressure (IOP) was elevated, and fundus evaluation showed glaucomatous optic atrophy on the right and glaucomatous cupping on the left. At age 23, she underwent trabeculectomy of the left eye, with subsequent control of IOP. She later developed a cataract of the left lens at age 31, for which she underwent surgery, and she underwent laser treatment of a left retinal hole at age 35. Her parents and sibs were unaffected, and she did not have joint stiffness or cardiac abnormalities.

Morales et al. (2009) performed linkage analysis in a consanguineous Saudi Arabian family with a Weill-Marchesani-like syndrome and obtained a maximum lod score of 3.0 on chromosome 15q26.3, in a 2.05-Mb linkage region.

In a consanguineous Saudi family in which a sister and brother had spherophakia and short stature, Khan et al. (2012) performed homozygosity mapping that revealed only 1 region of homozygosity shared by the affected sibs but not by unaffected family members: a 4.9-Mb region on chromosome 15 (chr15:97,531,229-102,397,317) containing 12 genes, of which the most likely candidate was ADAMTS17.

Radner et al. (2013) studied 4 patients from 3 consanguineous Tunisian families with features of Weill-Marchesani syndrome, including short stature, brachydactyly with joint stiffness, microspherophakia, ectopia lentis, and mitral valve defects, who also exhibited collodion membrane at birth that evolved to generalized ichthyosis. All 4 patients shared a 100-kb deletion on chromosome 15q26.3 between SNP markers rs1080492 and rs7179355 that encompassed the first 3 exons of the ADAMTS17 gene, the complete sequence of the noncoding RNA FLJ42289, and exon 13 of the CERS3 gene (615276), including the 3-prime UTR. Haplotype analysis in the 4 patients, who originated from the same geographic region in Tunisia, was consistent with a founder effect. Sequencing of the CERS3 gene in an unrelated Tunisian patient with isolated ichthyosis (ARCI9; 615023) revealed a splice site mutation (615276.0001), suggesting that the skin phenotype in the patients with the Weill-Marchesani syndrome features was due to partial deletion of the CERS3 gene.

Weill-Marchesani syndrome-4 is an autosomal recessive disorder (Morales et al., 2009).

In 4 affected sibs from a consanguineous Saudi Arabian family with features of Weill-Marchesani syndrome, Morales et al. (2009) identified homozygosity for a 1-bp insertion in the ADAMTS17 gene (607511.0001) that fully segregated with the phenotype. Screening of the ADAMTS17 gene patients with a similar phenotype identified a homozygous truncating mutation (607511.0002) in 2 affected sisters from another Saudi Arabian family, and a homozygous splice site mutation in a sporadic case (607511.0003). None of the mutations were detected in 300 ethnically matched controls. A sporadic patient, a 36-year-old woman with similar features, had no mutations in ADAMTS10, ADAMTS17, or FBN1, suggesting genetic heterogeneity.

In a consanguineous Saudi family in which a sister and brother had spherophakia and short stature mapping to chromosome 15, Khan et al. (2012) sequenced the candidate gene ADAMTS17 and identified a 1-bp deletion (607511.0004) that segregated with disease.

In an Indian woman from a consanguineous family with microspherophakia, short stature, and brachydactyly, Shah et al. (2014) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the ADAMTS17 gene (607511.0005) that segregated with disease and was not found in 50 ethnically matched controls or in public variant databases. The proband did not have mutations in other known WMS-associated genes, but did carry homozygous variants in 3 other genes (CAMK1D, 607957; PYROXD2, 617889; SIPA1L3, 616655) that were not found in ethnically matched controls; the authors stated that they could not exclude a contribution by these genes to some aspects of the phenotype. Shah et al. (2014) noted that all reported patients with ADAMTS17 mutations showed consistent features of microspherophakia and short stature, with brachydactyly, joint stiffness, glaucoma, cataract, and cardiac abnormalities being inconsistent findings; they suggested that patients with mutations in WMS-associated genes who exhibit microspherophakia and short stature should be classified as having WMS, rather than a 'WMS-like' syndrome.