Weill-Marchesani syndrome (WMS) is an exceptionally rare genetic disorder that affects connective tissues, primarily manifesting in the eyes and skeletal system. First described by ophthalmologists Weill and Marchesani, this syndrome is characterized by distinctive ocular abnormalities and skeletal anomalies, which can vary widely in severity and presentation.

WMS is primarily caused by mutations in the FBN1 and ADAMTS10 genes, which encode proteins involved in the formation and maintenance of connective tissues, particularly fibrillin-1 and ADAMTS10 enzyme, respectively. These mutations can occur in an autosomal dominant or autosomal recessive manner, influencing how the syndrome is inherited within families.

• Autosomal Dominant Inheritance: In cases where WMS is inherited dominantly, a single copy of the mutated gene from either parent is sufficient to cause the syndrome.
• Autosomal Recessive Inheritance: Recessive forms require both copies of the gene (one from each parent) to be mutated for the syndrome to manifest, typically resulting in more severe symptoms.

1. Ocular Manifestations:
   • Microspherophakia: Characterized by abnormally small and spherical lenses, often leading to refractive errors and vision problems from an early age.
   • Ectopia Lentis: Displacement or dislocation of the lenses within the eye, which can cause astigmatism, blurry vision, and increased risk of secondary complications like glaucoma and retinal detachment.
   • Other Eye Abnormalities: Individuals with WMS may also experience early-onset cataracts, iris anomalies, and occasionally, abnormalities in the optic nerve or cornea.
2. Skeletal Abnormalities:
   • Short Stature: Many individuals with WMS exhibit short stature due to skeletal growth abnormalities, particularly affecting the long bones of the limbs.
   • Joint Stiffness: Joint stiffness, particularly in the fingers and knees, may be present and can contribute to mobility challenges.
3. Other Systemic Involvement:
   • Cardiovascular: While uncommon, there have been reports of individuals with WMS having heart valve abnormalities, which may require monitoring.
   • Respiratory: Rare instances of respiratory complications, such as restrictive lung disease, have been reported but are not typical of the syndrome.

Diagnosing WMS involves a thorough clinical evaluation by a multidisciplinary team, including ophthalmologists, geneticists, and orthopedic specialists. Key diagnostic tools and procedures include:

• Genetic Testing: Identifying mutations in the FBN1 or ADAMTS10 genes through genetic testing can confirm the diagnosis, particularly useful in cases with atypical or overlapping features with other syndromes.
• Ophthalmological Examination: Detailed eye exams to assess lens abnormalities, intraocular pressure, and the presence of any secondary eye complications like glaucoma or cataracts.
• Radiological Imaging: X-rays and other imaging modalities may be used to evaluate skeletal abnormalities, including bone structure and joint alignment.

1. Ophthalmological Management:
   • Regular monitoring of visual acuity and eye health to detect and manage complications early.
   • Surgical interventions, such as lens extraction for significant cataracts or glaucoma management procedures, may be necessary to preserve vision.
2. Orthopedic Care:
   • Managing joint stiffness and skeletal abnormalities through physical therapy and, in some cases, orthopedic surgeries to improve mobility and functional outcomes.
3. Genetic Counseling:
   • Providing families with information about the genetic basis of WMS, inheritance patterns, and options for family planning, and the likelihood of passing on the condition to future generations.

The prognosis for individuals with WMS varies widely based on the severity of symptoms and the effectiveness of early interventions. With comprehensive medical management and regular follow-ups, individuals can experience improved quality of life and minimized risk of severe complications related to ocular and skeletal manifestations.

Ongoing research efforts focus on understanding the underlying genetic mechanisms of WMS, developing targeted therapies, and improving diagnostic techniques. Collaborations between clinicians, researchers, and patient advocacy groups are crucial in advancing knowledge and enhancing care for affected individuals.

Weill-Marchesani syndrome presents a complex array of ocular and skeletal manifestations that require specialized medical management and ongoing support. By raising awareness, promoting research, and enhancing clinical strategies, healthcare professionals can better address the challenges faced by individuals and families affected by this rare genetic condition.

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