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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. Diagnosis relies on clinical findings, but molecular genetic testing can help confirm the diagnosis. The one gene known to be associated with autosomal recessive WMS is ADAMTS10. (A mutation in FBN1 has been identified in one family with autosomal dominant WMS, but the significance of this finding is still unclear.) Molecular genetic testing for ADAMTS10 is clinically available.
Management. Treatment of manifestations: early detection and removal of an ectopic lens to decrease the possibility of pupillary block and glaucoma; surgical management of glaucoma can include peripheral iridectomy to prevent or relieve pupillary block and trabeculectomy in advanced chronic angle closure glaucoma; medical treatment of glaucoma is difficult because of paradoxical response to miotics and mydriatics. Prevention of secondary complications: Airway management during anesthesia can be difficult because of stiff joints, poorly aligned teeth, and maxillary hypoplasia. Surveillance: periodic ophthalmic examinations for early detection and removal of an ectopic lens. Agents/circumstances to avoid: ophthalmic miotics and mydriatics because they can induce pupillary block.
Genetic counseling. WMS is inherited in an autosomal dominant or autosomal recessive manner. Most individuals diagnosed with autosomal dominant WMS have an affected parent. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with autosomal dominant WMS has a 50% chance of inheriting the mutation. The parents of a child with ADAMTS10-related (autosomal recessive) WMS are obligate heterozygotes and therefore carry one mutant allele. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis is possible for pregnancies at increased risk for ADAMTS10-related WMS if the disease-causing mutations in the family are known.
Diagnostic 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)
Gene. To date, ADAMTS10 is the only gene known to cause WMS [Megarbane et al 2000, Faivre et al 2002, Dagoneau et al 2004].
Faivre, Dollfus et al (2003) reviewed 128 cases from the literature and determined that 57 (45%) were autosomal recessive, 50 (39%) were autosomal dominant, and 21 (16%) were simplex (i.e., a single occurrence in a family).
Other loci. Mutations in FBN1 were found in a large family with autosomal dominant WMS [Faivre, Gorlin et al 2003]; however, the significance of this finding in explaining autosomal dominant WMS is not yet clear.
Clinical testing
ADAMTS10. 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].
| Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|
| Sequence analysis | ADAMTS10 sequence variants | Unknown | Clinical
 |
Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Establishing the diagnosis in a proband relies on clinical findings, but molecular genetic testing can help confirm the diagnosis.
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.
ADAMTS10. No other phenotypes are known to be associated with mutations in this gene.
Weill-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, Dollfus et al 2003]:
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.
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].
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.
Mentition is usually normal.
| Finding | Present in Individuals With: | |
|---|---|---|
| Autosomal Recessive WMS | Autosomal Dominant WMS | |
| Microspherophakia | 94% | 74% |
| Ectopia lentis | 64% | 84% |
| Joint limitations | 49% | 77% |
| Cardiac anomalies | 39% | 13% |
Faivre, Dollfus and colleagues (2003) were unable to distinguish individuals with autosomal recessive WMS from those with autosomal dominant WMS by clinical findings alone.
The penetrance in those with autosomal recessive WMS caused by homozygous ADAMTS10 mutations is thought to be 100%.
The penetrance for autosomal dominant WMS is incomplete and the phenotype shows variable expressivity. The expressivity for autosomal dominant WMS is 91.7% for short stature, 71.4% for brachydactyly, and 45.2%, for abnormal gonioscopic findings, as outlined by Kloepfer and Rosenthal (1955).
Other terms previously used to refer to Weill-Marchesani syndrome:
Spherophakia-brachymorphia syndrome
Mesodermal dysmorphodystrophy, congenital
WMS is described as being very rare. Prevalence has been estimated at 1:100,000 population.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Ectopia 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/mental retardation, 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 mental retardation. 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].
To 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
It 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].
Airway 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].
Periodic ophthalmic examinations for early detection and removal of an ectopic lens can help decrease the possibility of pupillary block and glaucoma.
Use of ophthalmic miotics and mydriatics should be avoided as they can induce pupillary block.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
The 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.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Weill-Marchesani syndrome (WMS) is inherited in an autosomal dominant or autosomal recessive manner.
Faivre, Dollfus and colleagues (2003) reviewed 128 cases from the literature and determined that 57 (45%) were autosomal recessive; 50 (39%) were autosomal dominant; and 21 (16%) were simplex (i.e., a single occurrence in a family) in whom the mode of inheritance could not be determined on clinical findings alone.
Parents of a proband
Most individuals diagnosed with autosomal dominant WMS have an affected parent.
A proband with autosomal dominant WMS may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include ophthalmologic examination for detection of possible microspherophakia and detailed examination by a medical geneticist. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
Note: (1) Although most individuals diagnosed with autosomal dominant WMS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.
Sibs of a proband
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
Offspring of a proband. Each child of an individual with autosomal dominant WMS has a 50% chance of inheriting the mutation.
Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.
Parents of a proband
The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with ADAMTS10-related WMS are obligate heterozygotes (carriers) for a disease-causing mutation in the ADAMTS10 gene.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members is available on a clinical basis once the ADAMTS10 mutations have been identified in the family.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk for ADAMTS10-related WMS is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing alleles in the family must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) has/have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | HGMD |
|---|---|---|---|
| ADAMTS10 | 19p13.3-p13.2 | A disintegrin and metalloproteinase with thrombospondin motifs 10 | ADAMTS10 |
| 277600 | WEILL-MARCHESANI SYNDROME, AUTOSOMAL RECESSIVE |
| 608328 | WEILL-MARCHESANI SYNDROME, AUTOSOMAL DOMINANT |
| 608990 | A DISINTEGRIN-LIKE AND METALLOPROTEINASE WITH THROMBOSPONDIN TYPE 1 MOTIF, 10; ADAMTS10 |
Weill-Marchesani syndrome (WMS) is a disorder of the connective tissue caused by mutations in ADAMTS10. The product of the gene ADAMTS10 belongs to the ADAMTS family of proteins, believed to be anchored to the extracellular matrix.
Normal allelic variants: ADAMTS10 contains 24 coding exons.
Pathologic allelic variants: Faivre and colleagues (2002) reported linkage of WMS to 19 p. Dagoneau and colleagues (2004) reported three distinct nonsense and frameshift mutations in ADAMTS10 in three families with the autosomal recessive form of WMS.
Normal gene product: The ADAMTS10 gene 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 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].
Abnormal gene product: Unknown
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
1 November 2007 (me) Review posted to live Web site
3 August 2007 (et) Original submission
