Clinical Diagnosis

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)

Molecular Genetic Testing

Gene. To date, ADAMTS10 is the only gene in which mutation is known to cause WMS [Megarbane et al 2000, Faivre et al 2002, Dagoneau et al 2004].

Faivre et al [2003a] 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 et al 2003b]; however, the significance of this finding in explaining autosomal dominant WMS is not yet clear.

Clinical testing

• Sequence analysis
  
  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].

Table 1. Summary of Molecular Genetic Testing Used in ADAMTS10-Related Weill-Marchesani Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1	Test Availability
ADAMTS10	Sequence analysis	Sequence variants 2	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.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

ADAMTS10. No other phenotypes are known to be associated with mutations in this gene.

Natural History

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 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.

• 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.

Genotype-Phenotype Correlations

Genotype-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.

Faivre et al [2003a] were unable to distinguish individuals with autosomal recessive WMS from those with autosomal dominant WMS by clinical findings alone.

Penetrance

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 & Rosenthal [1955].

Nomenclature

Other terms previously used to refer to Weill-Marchesani syndrome:

• Spherophakia-brachymorphia syndrome

• Mesodermal dysmorphodystrophy, congenital

Prevalence

WMS is described as being very rare. Prevalence has been estimated at 1:100,000 population.

Evaluations Following Initial Diagnosis

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

Treatment of Manifestations

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].

Prevention of Secondary Complications

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].

Surveillance

Periodic ophthalmic examinations for early detection and removal of an ectopic lens can help decrease the possibility of pupillary block and glaucoma.

Agents/Circumstances to Avoid

Use of ophthalmic miotics and mydriatics should be avoided as they can induce pupillary block.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

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.

Other

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.

Mode of Inheritance

Weill-Marchesani syndrome (WMS) is inherited in an autosomal dominant or autosomal recessive manner.

Faivre et al [2003a] 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.

Risk to Family Members — Autosomal Dominant Inheritance

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.

Risk to Family Members — Autosomal Recessive Inheritance

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 ADAMTS10.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is available on a clinical basis once the ADAMTS10 mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk 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.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

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 to 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 has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Weill-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.

Normal allelic variants. ADAMTS10 contains 24 coding exons.

Pathologic allelic variants. Faivre et al [2002] reported linkage of WMS to 19 p. 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 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

Literature Cited

1. Chang BM, Liebmann JM. et al. Angle closure in younger patients. Trans Am Ophthalmol Soc. 2002;100:201–12. [PMC free article: PMC1358963] [PubMed: 12545694]
2. Dagoneau N, Benoist-Lasselin C, Huber C, Faivre L, Megarbane A, Alswaid A, Dollfus H, Alembik Y, Munnich A, Legeai-Mallet L, Cormier-Daire V. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet. 2004;75:801–6. [PMC free article: PMC1182109] [PubMed: 15368195]
3. Dal D, Sahin A, Aypar U. Anesthetic management of a patient with Weill-Marchesani syndrome. Acta Anaesthesiol Scand. 2003;47:369–70. [PubMed: 12648208]
4. Evereklioglu C, Hepsen IF, Er H. Weill-Marchesani syndrome in three generations. Eye. 1999;13:773–7. [PubMed: 10707143]
5. Faivre L, Dollfus H, Lyonnet S, Alembik Y, Megarbane A, Samples J, Gorlin RJ, Alswaid A, Feingold J, Le Merrer M, Munnich A, Cormier-Daire V. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am J Med Genet A. 2003a;123:204–7. [PubMed: 14598350]
6. Faivre L, Gorlin RJ, Wirtz MK, Godfrey M, Dagoneau N, Samples JR, Le Merrer M, Collod-Beroud G, Boileau C, Munnich A, Cormier-Daire V. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet. 2003b;40:34–6. [PMC free article: PMC1735272] [PubMed: 12525539]
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8. Fuchs J, Rosenberg T. Congenital ectopia lentis. A Danish national survey. Acta Ophthalmol Scand. 1998;76:20–6. [PubMed: 9541430]
9. Harasymowycz P, Wilson R. Surgical treatment of advanced chronic angle closure glaucoma in Weill-Marchesani syndrome. J Pediatr Ophthalmol Strabismus. 2004;41:295–9. [PubMed: 15478742]
10. Jones GC. ADAMTS proteinases: potential therapeutic targets? Curr Pharm Biotechnol. 2006;7:25–31. [PubMed: 16472131]
11. Karabiyik L. Airway management of a patient with Weill-Marchesani syndrome. J Clin Anesth. 2003;15:214–6. [PubMed: 12770659]
12. Kloepfer HW, Rosenthal JW. Possible genetic carriers in the spherophakia-brachymorphia syndrome. Am J Hum Genet. 1955;7(4):398–425. [PMC free article: PMC1716673] [PubMed: 13275462]
13. Megarbane A, Mustapha M, Bleik J, Waked N, Delague V, Loiselet J. Exclusion of chromosome 15q21.1 in autosomal-recessive Weill-Marchesani syndrome in an inbred Lebanese family. Clin Genet. 2000;58:473–8. [PubMed: 11149617]
14. Razeghinejad MR, Safavian H. Central corneal thickness in patients with Weill-Marchesani syndrome. Am J Ophthalmol. 2006;142:507–8. [PubMed: 16935606]
15. Riad W, Abouammoh M, Fathy M. Anesthetic characteristics and airway evaluation of patients with Weill-Marchesani syndrome. Middle East J Anesthesiol. 2006;18:725–31. [PubMed: 16749567]
16. Ritch R, Chang BM, Liebmann JM. Angle closure in younger patients. Ophthalmology. 2003;110:1880–9. [PubMed: 14522758]
17. Verloes A, Hermia JP, Galand A, Koulischer L, Dodinval P. Glaucoma-lens ectopia-microspherophakia-stiffness-shortness (GEMSS) syndrome: a dominant disease with manifestations of Weill-Marchesani syndromes. Am J Med Genet. 1992;44:48–51. [PubMed: 1519650]

Suggested Reading

1. Burakgazi AZ, Ozbek Z, Rapuano CJ, Rhee DJ. Long-term complications of iris-claw phakic intraocular lens implantation in Weill-Marchesani syndrome. Cornea. 2006;25:361–3. [PubMed: 16633042]
2. Chu BS. Weill-Marchesani syndrome and secondary glaucoma associated with ectopia lentis. Clin Exp Optom. 2006;89:95–9. [PubMed: 16494613]
3. Collod-Beroud G, Le Bourdelles S, Ades L, Ala-Kokko L, Booms P, Boxer M, Child A, Comeglio P, De Paepe A, Hyland JC, Holman K, Kaitila I, Loeys B, Matyas G, Nuytinck L, Peltonen L, Rantamaki T, Robinson P, Steinmann B, Junien C, Beroud C, Boileau C. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 2003;22:199–208. [PubMed: 12938084]
4. Jethani J, Mishra A, Shetty S, Vijayalakshmi P. Weill-Marchesani syndrome associated with retinitis pigmentosa. Indian J Ophthalmol. 2007;55:142–3. [PubMed: 17322607]
5. Madugula A, Chandrasekaran R, Rakesh G. Homatropine and psychosis in Weill-Marchesani syndrome. J Am Acad Child Adolesc Psychiatry. 2006;45:769–70. [PubMed: 16832313]
6. Saricaoglu MS, Sengun A, Karakurt A, Colluoglu Z. Autosomal dominant Weill-Marchesani syndrome and glaucoma management. Saudi Med J. 2005;26:1468–9. [PubMed: 16155673]
7. Wentzloff JN, Kaldawy RM. et al. Weill-Marchesani syndrome. J Pediatr Ophthalmol Strabismus. 2006;43:192. [PubMed: 16761646]

Revision History

• 1 November 2007 (me) Review posted to live Web site

• 3 August 2007 (et) Original submission