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Weill-Marchesani Syndrome (WMS)

Weill-Marchesani Syndrome (WMS)



Overview

Weill-Marchesani syndrome (WMS) is a rare genetic connective tissue disorder characterized by distinctive eye abnormalities (microspherophakia, ectopia lentis), severe myopia, secondary glaucoma, short stature, brachydactyly (short fingers/toes), and joint stiffness. It is inherited via autosomal dominant (often FBN1) or autosomal recessive (ADAMTS10, ADAMTS17, LTBP2) patterns, presenting in childhood.

Symptoms 

Ocular (Eye) Abnormalities:

Microspherophakia: The lens of the eye is unusually small and spherical, present in over 80% of cases.

Ectopia Lentis: The lens is abnormally positioned (dislocated).

Glaucoma: High eye pressure, often leading to severe vision loss or blindness.

Severe Myopia: Extreme nearsightedness.

Cataracts: Clouding of the eye lens.

Skeletal Abnormalities:

Short Stature: Typically, height is below the 1st percentile.

Brachydactyly: Short, stubby fingers and toes.

Stiff Joints: Reduced mobility, particularly in the hands and fingers.

Physical Appearance: Thick skin. Muscle hyperdevelopment (sometimes reported).

Cardiovascular Anomalies: Occurring in about 24% of cases, including pulmonic stenosis, mitral valve prolapse, and septal defects. 

Other Symptoms: Potential for severe breathing issues (laryngeal stenosis) during procedures. Intellect is usually normal.

Causes 

Genetic Mutation Sources:

ADAMTS10 (most common in recessive): Mutations disrupt protein functions essential for ocular, bone, and heart development.

FBN1: Mutations lead to an unstable version of fibrillin-1, a key component of the ciliary zonule, which causes structural issues.

ADAMTS17 & LTBP2: Other, less common genes associated with recessive forms of the syndrome. 

Inheritance Patterns: 

Autosomal Recessive (most frequent): Both parents must be carriers, with a 25% risk for each child to inherit the condition.

Autosomal Dominant: Caused by a single mutated FBN1 gene, often leading to severe ocular issues.

Pathogenesis: The genetic defects cause the ciliary zonule (fibers holding the eye lens) to be weak, leading to increased lens mobility (ectopia lentis) and reduced vision, often resulting in secondary glaucoma

Risk Factors

Family History: A positive family history of the condition is the only established risk factor.

Genetic Inheritance: 

Autosomal Recessive: Commonly linked to ADAMTS10 or ADAMTS17 gene mutations. If both parents are carriers, there is a 25% chance of an affected child in each pregnancy.

Autosomal Dominant: Often linked to FBN1 or LTBP2 mutations. An affected parent has a 50% chance of passing the condition to their child.

Consanguinity: Many cases of autosomal recessive WMS are reported in families with consanguineous unions. 

De Novo Mutations: In cases with no family history, the mutation can occur spontaneously.

Diagnosis

Ocular Examination: Essential to identify microspherophakia, high myopia (often \(> -6.00\) diopters), shallow anterior chamber, and secondary glaucoma.Clinical Features:Ocular: Ectopia lentis (lens dislocation), often leading to pupillary block and acute glaucoma.Skeletal: Short stature, short, stubby fingers/toes (brachydactyly), and joint stiffness.Cardiac: Occasional findings include mitral valve prolapse (MVP) or septal defects.Molecular Genetic Testing: Confirms the diagnosis and determines the inheritance mode (autosomal recessive: ADAMTS10, ADAMTS17, LTBP2; autosomal dominant: FBN1).Imaging: Ultrasound biomicroscopy or Scheimpflug imaging is used to measure the abnormally small and thick lens

Treatment

Early Detection & Monitoring: Regular eye exams (annually) are vital to detect early lens changes and increasing eye pressure.Lens Removal: Early removal of the small, dislocated lens (microspherophakia/ectopia lentis) can prevent secondary glaucoma.Glaucoma Treatment: This includes medications (eye drops), peripheral iridectomy (creating a small hole in the iris to reduce pressure), or, if necessary, trabeculectomy.Avoid Specific Drugs: Avoid using miotics (which constrict the pupil) and mydriatics (which dilate the pupil) as they can cause a severe form of pupillary block glaucoma.Caution with Contact Sports: Due to the instability of the lenses in the eye, patients should be cautious about eye injuries during sports.

Type of Doctor Department : A ophthalmologists, pediatricians, orthopedists , cardiologists

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