Weill-Marchesani syndrome
Weill-Marchesani syndrome (WMS) is a rare genetic disorder characterized by distinctive physical and ocular features. First identified in the early 20th century, WMS is classified as a connective tissue disorder, affecting the body's support structures. Common symptoms include short stature, brachydactyly (short fingers), joint stiffness, and various eye abnormalities such as microspherophakia (small lens), severe myopia (nearsightedness), ectopia of the lens, and glaucoma. The syndrome can arise from both autosomal dominant and recessive genetic inheritance, with mutations identified in the ADAMTS10 and FBN1 genes.
Individuals with WMS face a higher prevalence of ocular complications, which can lead to serious conditions like glaucoma, potentially resulting in blindness if not properly managed. While there is no cure for WMS, treatment focuses on addressing specific symptoms, and patients are advised to consult a range of specialists for comprehensive care. Despite the challenges posed by the condition, many individuals with WMS lead healthy lives and have normal intelligence. Genetic counseling may provide valuable insights for affected families, especially in cases of consanguinity, where the risk of autosomal recessive conditions is elevated.
Weill-Marchesani syndrome
ALSO KNOWN AS: WMS; WM syndrome; spherophakia-brachymorphia syndrome; congenital mesodermal dysmorphology
DEFINITION Weill-Marchesani syndrome (WMS) is a genetic disorder first reported by George Weill in 1932 and subsequentially delineated by Oswald Marchesan in 1939. WMS is classified as a disorder of connective tissue, which binds together, supports, and strengthens muscles, joints, organs, and skin. Short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lens, severe myopia, and glaucoma are all characteristic of WMS. Both autosomal recessive and dominant modes of inheritance have been described. Although not all causes are known, mutations in both ADAMTS10 and FBN1genes have been found.
Risk Factors
The offspring of consanguineous relationships are at a higher risk for autosomal recessive conditions. Many people reported with autosomal recessive WMS were members of consanguineous families. The majority of individuals with the autosomal dominant form have a family history. If no family history is found, it is likely a result of a de novo (sporadic) mutation. There are no other reported factors associated with an increased risk for having a child with WMS. The has been estimated at 1 in 100,000 people.
Etiology and Genetics
The of WMS syndrome depends on the mode of inheritance. WMS is inherited in both an autosomal dominant (AD) and autosomal recessive (AR) manner. AD refers to a type of condition that can be inherited by a single parent. A person who is (one working gene and one nonworking gene) is affected with the condition. The recurrence risk for the offspring of individuals who are affected is 50 percent. AR refers to a type of condition that has to be inherited by both parents. In an AR condition, a person who is heterozygous is referred to as a carrier and is unaffected. When two carriers of the same nonworking gene have children, they have a 25 percent chance of having a child who is (with two nonworking genes) and thus affected with the condition. The AR mode of inheritance seems to be more frequent then the AD form.
Homozygous mutations within the ADAMTS10 gene located on chromosome locus 19p13.3-p13.2 are responsible for the AR form. The ADAMTS10 gene codes for a protein product belonging to the ADAMTS family of proteins, which are involved in the extracellular matrix. The protein is expressed in the skin, fetal chondrocytes (a cartilage cell), and in the fetal and adult heart. Mutations in the ADAMTS10 gene are associated with impairment of support, adhesion, movement, and regulation of cells.
Heterozygous mutations within the FBN1gene located on chromosome locus 15q21.1 have been found in a large Lebanese family where mode of inheritance is AD. The significance of this finding remains unclear in the etiology of WMS. FBN1 codes for the protein fibrillin-1, involved in making fibers that help strengthen and allow for flexibility of the connective tissues. Mutations lead to a nonfunctional protein product, leaving the connective tissue compromised.
Symptoms
Despite the genetically heterogeneous nature of WMS, there is clinical homogeneity between all forms. The major features of WMS involve ocular (eye) problems including microspherophakia (small lens) in 84 percent, ectopia (abnormal placement) of the lens in 73 percent, severe myopia (nearsightedness) in 94 percent, glaucoma in 80 percent, and cataracts in 23 percent. Usually myopia is the first finding, while glaucoma is the most serious and may lead to blindness. Other features include brachydactyly (short fingers) in 98 percent, joint stiffness in 62 percent, and short stature in 98 percent with an average adult height of 130 to 157 centimeters (cm) for females and 142 to 169 cm for males. Cardiac anomalies are seen in 24 percent of patients, including pulmonary stenosis, mitral valve insufficiency, aortic valve stenosis, ductus ateriosus, and ventricular septal defects. Intelligence is usually normal.
Screening and Diagnosis
The diagnosis of WMS is made clinically; however, no diagnostic criteria have been proposed. Molecular genetic testing may be available to confirm the diagnosis, clarify risks for family members, and allow for prenatal diagnosis. Currently testing is offered clinically for ADAMTS10. The detection rate is unknown, however, and many people with a clinical diagnosis have no mutation found. Carrier and require prior identification of the disease-causing mutation. Population screening for WMS is not available.
Treatment and Therapy
There is no cure for WMS. Treatment depends on manifestations as appropriate. Often the most significant complication is the optical manifestations of this condition and cardiac abnormalities when seen. For optimal care, patients should see a variety of specialists, including a clinical geneticist, genetic counselor, ophthalmologist, physical therapist, and cardiologist.
Prevention and Outcomes
Prenatal or preimplantation genetic diagnosis is available if the cause is known. Benefits are gained from early detection and treatment of ocular manifestations. The use of ophthalmic miotics and mydriatics should be avoided, as they can induce pupillary block. Although mild intellectual deficits have been reported, most individuals have normal intelligence and live long and productive lives.
Bibliography
Dagoneau, N., et al. “ADAMTS10 Mutations in Autosomal Recessive Weill-Marchesani Syndrome.” American Journal of Human Genetics 75.5 (2005): 801–6. Print.
Faivre, L., et al. “Clinical Homogeneity and Genetic Heterogeneity in Weill-Marchesani Syndrome.” American Journal of Medical Genetics Part C 123 (2003): 204–7. Print.
Huang, Junting. "Abnormal Lens Thickening in a Child with Weill-Marchesani Syndrome 4: A Three-Year Follow-Up Case Report." Frontiers in Medicine, vol. 9, 8 Jan. 2023, doi.org/10.3389/fmed.2022.1021489. Accessed 10 Sept. 2024.
"Weill-Marchesani Syndrome." Gene Reviews. NCBI, 14 Feb. 2013. Web. 2 Sept. 2014.
"Weill-Marchesani Syndrome." Genetics Home Reference. Nat'l. Lib. of Medecine, Oct. 2008. Web. 2 Sept. 2014.