Weill–Marchesani Syndrome

Overview

Weill–Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by a distinctive combination of short stature, brachydactyly (short fingers), joint stiffness, and eye abnormalities such as microspherophakia (small, spherical lens), ectopia lentis (dislocated lens), and severe myopia. It was first described by Georges Weill in 1932 and further detailed by Oswald Marchesani in 1939. The syndrome primarily affects the musculoskeletal and ocular systems but can also involve cardiovascular abnormalities in some cases. WMS is genetically heterogeneous, with both autosomal recessive and autosomal dominant forms reported. Early diagnosis and appropriate management can help prevent complications and preserve vision and mobility.

Causes

Weill–Marchesani syndrome can be caused by mutations in several different genes, reflecting its genetic heterogeneity. The main genes associated with the syndrome include:

• ADAMTS10: Mutations in this gene cause the autosomal recessive form of WMS. ADAMTS10 plays a role in the formation of the extracellular matrix, crucial for connective tissue integrity.

• FBN1: Mutations in this gene, which is also associated with Marfan syndrome, can cause an autosomal dominant form of WMS. FBN1 encodes fibrillin-1, a protein important for connective tissue elasticity.

• ADAMTS17 and LTBP2: Less commonly, mutations in these genes have also been linked to phenotypes similar to WMS.

The condition may be inherited in either an autosomal recessive or autosomal dominant manner depending on the specific genetic mutation involved. In the recessive form, both copies of the gene must be mutated for symptoms to appear, whereas in the dominant form, one mutated copy is sufficient to cause the disorder.

Symptoms

Weill–Marchesani syndrome presents with a variety of physical and ocular manifestations. Symptoms can vary but typically include:

Musculoskeletal Features

• Short stature: Adult height is significantly below average.

• Brachydactyly: Short and stubby fingers and toes, often noticeable in early childhood.

• Joint stiffness: Limited range of motion, especially in the fingers and larger joints.

Ocular Features

• Microspherophakia: Abnormally small and spherical lenses that can cause high myopia and increase the risk of lens dislocation.

• Ectopia lentis: Dislocation of the lens, which can lead to blurry vision or visual distortion.

• Severe myopia: Nearsightedness due to lens shape and position.

• Glaucoma: Increased intraocular pressure is common and may lead to vision loss if untreated.

Cardiovascular and Other Features

• Heart defects: Occasionally, individuals may have mitral valve prolapse or other structural heart issues.

• Developmental delays: Rare, but reported in some cases, particularly in the recessive form.

Diagnosis

Diagnosis of Weill–Marchesani syndrome is based on a combination of clinical evaluation, family history, and genetic testing. Diagnostic steps include:

• Physical examination: Assessment of short stature, joint stiffness, and digital abnormalities.

• Ophthalmologic evaluation: Slit-lamp examination, ultrasound biomicroscopy, and intraocular pressure measurement to identify microspherophakia, ectopia lentis, and glaucoma.

• Radiographic imaging: X-rays can confirm brachydactyly and other skeletal features.

• Genetic testing: Confirms mutations in ADAMTS10, FBN1, or other associated genes, and helps differentiate between the recessive and dominant forms.

• Cardiac evaluation: Echocardiogram and EKG may be done to assess for structural heart problems.

Treatment

There is no cure for Weill–Marchesani syndrome, and treatment is aimed at managing symptoms and preventing complications. A multidisciplinary approach involving ophthalmologists, geneticists, orthopedic specialists, and cardiologists is often required. Management strategies include:

Ocular Treatment

• Corrective lenses: For high myopia and vision correction.

• Monitoring for glaucoma: Regular intraocular pressure checks and medical or surgical treatment if necessary.

• Lens dislocation management: Surgical intervention may be needed in cases of severe ectopia lentis.

Musculoskeletal Management

• Physical therapy: To improve joint flexibility and function.

• Orthopedic consultation: May be necessary for severe joint issues or significant stature concerns.

Cardiovascular Management

• Regular cardiac monitoring: Especially in patients with known or suspected heart defects.

• Medication or surgical intervention: For significant valvular abnormalities, if present.

Genetic Counseling

• Essential for affected families to understand the inheritance pattern, recurrence risk, and reproductive options.

Prognosis

The prognosis for individuals with Weill–Marchesani syndrome varies depending on the severity of ocular and cardiovascular complications. With proper medical care, including regular eye exams and treatment of glaucoma or lens dislocation, many patients retain functional vision. Joint stiffness and short stature typically persist but can be managed through supportive therapies. Life expectancy is generally normal, especially in patients without significant cardiac involvement. Early diagnosis, multidisciplinary care, and vigilant monitoring can significantly improve quality of life for individuals with WMS.