DiagnosisClinical DiagnosisDiagnostic criteria for Weill-Marchesani syndrome (WMS) have not been formally established. The clinical diagnosis of WMS is considered when the following are observed:Eye anomalies including microspherophakia and ectopia lentis Short stature Brachydactyly Joint stiffness Heart defects (occasional) A WMS-like syndrome has been described in individuals who manifest the above features with the exception of brachydactyly and joint stiffness. [Morales et al 2009]. Molecular Genetic TestingGenesMutations in ADAMTS10 are known to cause autosomal recessive WMS [Megarbane et al 2000, Faivre et al 2002, Dagoneau et al 2004]. A mutation in FBN1 was found in a large family with autosomal dominant WMS [Faivre et al 2003b] and recently a direct interaction between the ADAMTS10 and FBN1 protein products was demonstrated [Kutz et al 2011] (see Molecular Genetics). A mutation in LTBP2 was recently identified in one family with autosomal recessive WMS [Haji-Seyed-Javadi et al 2012]. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Weill-Marchesani SyndromeView in own windowGene SymbolProportion of Weill-Marchesani Syndrome Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityADAMTS10Mutations identified in the vast majority of patientsSequence analysisSequence variants ^{1, 2ClinicalDeletion / duplication analysis 3Unknown; none reported 4, 5FBN1Mutation identified in one familySequence analysisSequence variants 1ClinicalDeletion / duplication analysis 3In-frame exonic / multiexonic deletions 5LTBP2Mutation identified in one familySequence analysisSequence variants 1Clinical1. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.2. Analysis of the entire coding region identified homozygous mutations in two large consanguineous families and one simplex case (i.e., a single occurrence in a family) [Dagoneau et al 2004].3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.4. No deletions or duplications involving ADAMTS10 have been reported to cause ADAMTS10-related Weill-Marchesani syndrome.5. De Backer et al [2007]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. The diagnosis is primarily established by clinical findings, but molecular genetic testing can help to confirm the diagnosis. In those suspected of having autosomal recessive WMSSequence analysis of ADAMTS10 can be pursued first.If sequence analysis of ADAMTS10 does not identify two disease-causing mutations, sequence analysis of LTBP2 can be considered.In those suspected of having autosomal dominant WMSSequence analysis of FBN1 can be pursued first.If no disease-causing mutation is identified, deletion/duplication analysis of FBN1 should be considered. In simplex cases for which a mode of inheritance is not knownConsider sequence analysis of ADAMTS10 first, followed by sequence analysis of LTBPS if two disease-causing mutations in ADAMTS10 are not identified.If no disease-causing mutations in either ADAMTS10 or LTBPS are identified, sequence analysis followed by deletion/duplication analysis of FBN1 can be considered.Carrier testing for relatives at risk for autosomal recessive WMS requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for autosomal recessive WMS and are not at risk of developing the disorder.Prenatal diagnosis for pregnancies at risk for autosomal recessive WMS requires prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) DisordersADAMTS10. No other phenotypes are known to be associated with mutations in this gene. LTBP2. Mutations in LTBP2 are also associated with the following phenotypes:Congenital glaucomaMicrospherophakia and/or megalocornea with ectopia lentis with or without secondary glaucoma (MSPKA) [Desir et al 2010, Khan et al 2011]Isolated microspherophakia [Ben Yahia et al 2009, Kumar et al 2010]FBN1. Mutations in FBN1 are also associated with the following phenotypes:Geleophysic dysplasiaAcromicric dysplasia [Le Goff et al 2011] Marfan syndromeIsolated ectopia lentisMASS (mitral valve, aorta, skeleton, skin) syndromeThoracic aortic aneurysms and aortic dissections}

Natural HistoryWeill-Marchesani syndrome (WMS) is a connective tissue disorder that usually presents in childhood with short stature and/or ocular problems. The autosomal recessive and autosomal dominant forms of WMS share clinical manifestations in the following systems [Faivre et al 2003a].Eyes. The mean age of recognition of an ocular problem is 7.5 years. Microspherophakia (small spherical lens) is the most important manifestation of WMS. Microspherophakia results in lenticular myopia (i.e., myopia primarily resulting from abnormal shape of the lens), ectopia lentis (abnormal position of the lens), and glaucoma (elevation of the intraocular pressure). Lenticular myopia is usually the first ophthalmologic finding. Ectopia lentis usually results in downward displacement of the lens. Glaucoma is the most serious complication because it can lead to blindness. In most cases glaucoma results from pupillary block resulting from forward movement of the lens or by dislocation of the lens into the anterior chamber. Increased central corneal thickness has been recognized as a pathologic feature of WMS that may lead to overestimation of intraocular pressure by applanation tonometers [Razeghinejad & Safavian 2006].Loss of vision occurs earlier in WMS and is more severe than in other lens dislocation syndromes. In some cases, lens dislocation and pupillary block appear after blunt trauma to the eye weakens the zonular fibers.Presenile vitreous liquefaction has been described in a large family with autosomal dominant WMS [Evereklioglu et al 1999].Retinal vascular tortuosity in the absence of congenital heart disease has been described in one affected individual [Gallagher et al 2011].Retinitis pigmentosa has been reported in an affected female age 14 years [Jethani et al 2007].Growth. Proportionate short stature is an essential part of the syndrome. An adult male with WMS is expected to achieve a height of 142-169 cm while an adult female is expected to achieve a height of 130-157 cm. Digits and joints. Digits are short (brachydactyly) and joints are stiff. Heart abnormalities are occasionally seen and include patent ductus arteriosus and pulmonary stenosis. Mentation is usually normal.

Genotype-Phenotype CorrelationsGenotype-phenotype correlations are limited. Faivre et al [2003a] reviewed 128 cases from the literature (57 autosomal recessive, 50 autosomal dominant, and 21 simplex [i.e., a single occurrence in a family]) and concluded that the three groups showed no significant differences in myopia, glaucoma, cataract, short stature, brachydactyly, thick skin, muscular build, or intellectual disability. Findings for which differences were found are shown in Table 2.Table 2. Phenotypic Differences in Weill-Marchesani Syndrome by Mode of InheritanceView in own windowFindingPresent in Individuals with:Autosomal Recessive WMSAutosomal Dominant WMSMicrospherophakia94%74%Ectopia lentis64%84%Joint limitations49%77%Cardiac anomalies39%13%Faivre et al [2003a]Faivre et al [2003a] were unable to distinguish individuals with autosomal recessive WMS from those with autosomal dominant WMS by clinical findings alone.

Differential DiagnosisEctopia lentis can also occur in the following conditions [Fuchs & Rosenberg 1998]. All, however, are clinically distinct from Weill-Marchesani syndrome (WMS):Marfan syndrome is a disorder of connective tissue with a high degree of clinical variability. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Myopia and ectopia lentis are the most common ocular features. Skeletal system involvement is characterized by bone overgrowth and joint laxity. The extremities are disproportionately long for trunk size (dolichostenomelia). Overgrowth of the ribs can result in pectus excavatum or pectus carinatum. Scoliosis is common and can be mild or severe and progressive. Cardiovascular manifestations include dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. FBN1 is the only gene known to be associated with Marfan syndrome and therefore Marfan syndrome is allelic to autosomal dominant WMS. Inheritance is autosomal dominant. Homocystinuria is a metabolic disorder caused by cystathionine β-synthase deficiency; it is characterized by developmental delay/intellectual disability, ectopia lentis (usually inferior), severe myopia, skeletal abnormalities, and thromboembolism. Individuals are often tall and slender with an asthenic habitus ("marfanoid"). Other features that may occur include seizures, psychiatric problems, and extrapyramidal signs including dystonia, hypopigmentation, pancreatitis, malar flush, and livedo reticularis. The cardinal biochemical features of homocystinuria are markedly increased concentrations of plasma homocystine, total homocysteine, and methionine; increased concentration of urine homocystine; and reduced cystathionineβ-synthase (CBS) enzyme activity. CBS is the only gene known to be associated with homocystinuria caused by cystathionine β-synthase deficiency. Inheritance is autosomal recessive. Sulfite oxidase deficiency is a rare disorder of lens luxation with severe neurologic symptoms: untreatable seizures, opisthotonus, attenuated growth of the brain, and intellectual disability. It results from an isolated deficiency in the enzyme sulfite oxidase, which is responsible for the oxidation of sulfite to sulfate or as molybdenum cofactor deficiency. Inheritance is autosomal recessive. Hyperlysinemia is a rare metabolic disorder found to be caused by mutation in the gene encoding alpha-aminoadipic semialdehyde synthase. Inheritance is autosomal recessive. Simple dominant ectopia lentis. Mutations in FBN1 have been identified in some families. Inheritance is autosomal dominant. Ectopia lentis and pupilae. In this condition the lens and the pupil are usually displaced in opposite directions. Inheritance is autosomal recessive. Glaucoma-lens ectopia-microspherophakia-stiffness-shortness (GEMSS) syndrome has features resembling WMS. Inheritance is autosomal dominant [Verloes et al 1992]. Mutations in ADAMTS17 have been described in one family with WMS-like symptoms [Morales et al 2009]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Autosomal dominant WMSAutosomal recessive WMS

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Weill-Marchesani syndrome (WMS), the following evaluations should be performed:Complete ophthalmologic examination Evaluation by a medical geneticist Cardiac echocardiogram Treatment of ManifestationsIt is not possible to generalize the management of the ocular complications of WMS.The medical treatment of glaucoma is difficult because of paradoxical response to miotics and mydriatics. A peripheral iridectomy should be performed to prevent or relieve pupillary block [Chang et al 2002, Ritch et al 2003]. Lens extraction and/or trabeculectomy may be necessary in some persons with advanced chronic angle closure glaucoma [Harasymowycz & Wilson 2004]. Individuals with WMS were recently reported to have increased central corneal thickness, which needs to be considered in the diagnosis and follow-up of glaucoma because increased central corneal thickness may lead to overestimation of intraocular pressure by applanation tonometers [Razeghinejad & Safavian 2006]. Prevention of Secondary ComplicationsAirway management during anesthesia can be difficult in persons with WMS because of stiff joints, poorly aligned teeth, and maxillary hypoplasia [Dal et al 2003, Karabiyik 2003, Riad et al 2006].SurveillancePeriodic ophthalmic examinations for early detection and removal of an ectopic lens can help decrease the possibility of pupillary block and glaucoma.Agents/Circumstances to AvoidUse of ophthalmic miotics and mydriatics should be avoided as they can induce pupillary block.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationThe protein product of ADAMTS10 could be a potential therapeutic target for the treatment of autosomal recessive WMS [Jones 2006].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Weill-Marchesani Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFBN115q21​.1Fibrillin-1FBN1 @ LOVDFBN1ADAMTS1019p13​.2A disintegrin and metalloproteinase with thrombospondin motifs 10ADAMTS10 @ LOVDADAMTS10LTBP214q24​.3Latent-transforming growth factor beta-binding protein 2LTBP2 homepage - Mendelian genesLTBP2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Weill-Marchesani Syndrome (View All in OMIM) View in own window 134797FIBRILLIN 1; FBN1 277600WEILL-MARCHESANI SYNDROME 1; WMS1 602091LATENT TRANSFORMING GROWTH FACTOR-BETA-BINDING PROTEIN 2; LTBP2 608328WEILL-MARCHESANI SYNDROME 2; WMS2 608990A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 10; ADAMTS10 614819WEILL-MARCHESANI SYNDROME 3; WMS3Molecular Genetic PathogenesisWeill-Marchesani syndrome (WMS) is a disorder of the connective tissue caused by mutations in ADAMTS10. The protein product of ADAMTS10 belongs to the ADAMTS family of proteins, believed to be anchored to the extracellular matrix. The disorder may also be caused by mutations in FBN1 and recently a direct interaction between the protein products encoded by ADAMTS10 and FBN1 has been demonstrated; the ADAMTS10 protein promotes FBN1 deposition in extracellular matrix of cultured fibroblasts [Kutz et al 2011]. ADAMTS10 Normal allelic variants. ADAMTS10 contains 24 coding exons. Pathologic allelic variants. Dagoneau et al [2004] reported three distinct nonsense and frameshift mutations in ADAMTS10 in three families with the autosomal recessive form of WMS. Normal gene product. ADAMTS10 encodes a protein that belongs to a family of metalloproteases, ADAMTS (a disintegrin-like and metalloprotease with thrombospondin motifs). ADAMTS-10 differs from other members of the ADAMTS family by the presence of its five TS domains and a unique C-terminal PLAC (protease and lacunin) domain and is closely related to ADAMTS6. Studies of the normal expression of ADAMTS10 showed that it is expressed in skin, fetal chondrocytes, and fetal and adult heart [Dagoneau et al 2004]. Abnormal gene product. Unknown FBN1Normal allelic variants. FBN1 is a large gene comprising 65 exons.Pathologic allelic variants. Heterozygosity for a 24-bp deletion in FBN1 has been identified by Faivre et al [2003b] in one family with autosomal dominant Weill-Marchesani syndrome. Normal gene product. FBN1 encodes a member of the fibrillin family. The encoded protein is a large, 350-kd extracellular matrix glycoprotein that serves as a structural component of 10- to 12-nm calcium-binding microfibrils. These microfibrils provide force bearing structural support in elastic and non-elastic connective tissue throughout the body.Abnormal gene product. UnknownLTBP2Normal allelic variants. LTBP2 comprises 35 exons.Pathologic allelic variants. Haji-Seyed-Javadi et al [2012] identified homozygosity for a missense mutation in LTBP2 in a large consanguineous family with Well Marchesani syndrome.Normal gene product. The protein encoded by LTBP2 belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. The 1,821-amino acid protein consists of 20 epidermal growth factor (EGF)-like domains, four transforming growth factor-beta binding protein (TB)-like modules (each containing eight cysteine residues), and an N-terminal signal peptide.Abnormal gene product. Unknown