Weill-Marchesani Syndrome

From EyeWiki


Disease

Weill-Marchesani syndrome, also known as Spherophakia-Brachymorphia syndrome, is an inherited connective tissue disorder characterized by abnormalities of the lens of the eye, secondary glaucoma, short stature, brachycephaly, joint stiffness, and cardiovascular defects.[1]

Weill-Marchesani syndrome may be inherited in Autosomal Dominant and Autosomal Recessive patterns.

Autosomal Recessive Weill-Marchesani syndrome often presents with microspherophakia and cardiac anomalies.[2]

Autosomal Dominant Weill-Marchesani syndrome often presents with ectopia lentis and joint limitations.[2]

Genetics

Weill-Marchesani syndrome can present either as a sporadic mutation or via an autosomal recessive or autosomal dominant inheritance pattern. Four genes have been found to be associated with Weill-Marchesani syndrome. Intra and interfamilial variable expressivity is observed in Weill-Marchesani syndrome.[3]

Autosomal Dominant Weill-Marchesani Syndrome Gene: FBN-1 (WMS 2)

Autosomal Recessive Weill-Marchesani Syndrome Genes: ADAMTS10 (WMS 1), ADAMTS17 (WMS 4), and LTPBP2 (WMS 3)

Autosomal recessive and autosomal dominant inheritance account for roughly 45% and 39% of Weill-Marchesani syndrome cases, respectively, while the remaining cases are sporadic.[2]

Generally, genes associated with Weill-Marchesani syndrome provide instructions for the production of enzymes and extracellular matrix proteins responsible for connective tissue integrity.

Epidemiology

Weill-Marchesani syndrome is a rare disease in the general population. The prevalence is estimated to be 1 case in 100,000 in the population.[3]

Pathophysiology

Decreased visual acuity results from increased refractive power of the hyper-spherical lens. This spherical change results in myopia. Due to impairment in extracellular matrix proteins and enzymes involved with the production of fibrillin, zonular weakness allows for a highly mobile lens which can lead to pupillary block with. anterior dislocation of the lens.[4] Fibrillin, a glycoprotein, is the principal component of the ciliary zonule which exists as a structural scaffold of extensible microfibrils. Fibrillin is also present in many connective tissues including blood vessels, lung, ligaments, and dermis.[5]

Fibrillin is implicated directly by defects in the FBN1 gene. The ADAMTS superfamily of proteins act as zinc metalloproteases that appear to be involved in proteoglycan processing. ADAMTS proteins partner with Fibrillin-1 to fulfill its structural and regulatory role and biogenesis. The exact mechanism is unknown, but clinical presentation resembling Weill-Marchesani syndrome with defective ADAMTS and normal FBN-1 suggests an association between the two sets of genes.[6]

Diagnosis

Genetic Testing: Definitive diagnosis can be made in a proband by identification of biallelic pathogenic variants in ADAMTS10, ADAMTS17, and LTPBP2 or by a heterozygous pathogenic variant in FBN1 by molecular genetic testing if clinical presentation is inconclusive. Genetic testing can be performed via serial single-gene testing in individuals with a high clinical suspicion, or via comprehensive genomic testing when the phenotype is indistinguishable from other connective tissue abnormalities. Exome sequencing is the most commonly used comprehensive genomic testing approach.[3]

Ophthalmoscopic examination and Anterior Segment Optical Coherence Tomography: Identify lens shape and position.[7]

Physical Exam: Identify brachydactyly, short stature, and cardiac abnormalities

Clinical Presentation

Ocular abnormalities are typically recognized in childhood (mean age 7.5 years) with routine eye examinations. Findings may include microspherophakia (small spherical lens), myopia secondary to an abnormally shaped lens, lens dislocation/abnormal positioning, secondary glaucoma, and increased corneal thickness.[8] Individuals may present with severe myopia with narrow anterior chambers but absent myopic retinopathy.[3]

Systemic presenting features may include short stature in all affected individuals, brachydactyly (short fingers or toes), progressive joint stiffness, thickened skin, pseudomuscular build, cardiovascular defects, and mild intellectual disability.

Cardiovascular defects may include a patent ductus arteriosis, pulmonic stenosis, thoracic aortic aneurysm, cervical artery dissection, or prolonged QT interval.[3]

Radiographic findings may include shortened long tubular bones, delayed bone age, and broad proximal phalanges.[3]

Differential diagnosis

  • Ectopia Lentis
  • Homocystinuria
  • Marfan syndrome
  • Geleophysic Dysplasia
  • Acromicric Dysplasia
  • Myhre Syndrome

Management

While there is no cure for Weill-Marchesani syndrome, management is focused on the visual and systemic manifestations.

Early removal of the microspherophakic lens is recommended to improve visual acuity, control intraocular pressure, and to prevent pupillary block and glaucoma. Glaucoma can be managed with peripheral iridectomy and trabeculectomy. Annual ocular examinations of family members of patients with Weill-Marchesani syndrome allow for early diagnosis of Weill-Marchesani syndrome.[9]

Systemic symptoms may be managed with physical therapy for joint issues. Regular cardiac follow up with echocardiogram and electrocardiography are important.

Genetic evaluation is recommended for family members of patients with Weill-Marchesani syndrome to determine genetic risk and carrier status.

Annual ophthalmic examinations as well as regular medical examinations are recommended to assess growth and joint mobility. Periodic examinations are also recommended to screen for cardiac anomalies.

Anesthesia may be difficult in these individuals due to stiff joints and maxillary hypoplasia.[10]

Ophthalmic miotics and mydriatics should be avoided to decrease the risk of pupillary block in these patients. Individuals should be counseled on the risk of ocular complications with contact sports.[3]

Prognosis

Weill-Marchesani syndrome has a good prognosis with early detection.

Conclusion

Weill Marchesani syndrome is a rare genetic condition that involves ocular and systemic abnormalities. It is classified into 4 subtypes according to the affected genes. There is no cure for Weill Marchesani syndrome Management is focused on treating the symptoms currently.

  1. Weill-Marchesani Syndrome. Genetic and Rare Diseases Information Center (GARD). 2017. https://rarediseases.info.nih.gov/diseases/4936/weill-marchesani-syndrome. Accessed March 1 2021.
  2. 2.0 2.1 2.2 Faivre L, Dollfus H, Lyonnet S, et al. Clinical homogeneity and genetic heterogeneity in Weill–Marchesani syndrome. Am J Me Genet A. 2003:123(2), 204-207.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Marzin P, Cormier-Daire V, Tsilou E. Weill-Marchesani Syndrome. 2007 Nov 1 [Updated 2020 Dec 10]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1114/.
  4. Yazgan S, Çelik T, Çelik E. Insufficiency of YAG laser iridotomy to prevent pupillary Block glaucoma in a microspherophakic patient with Weill-Marchesani syndrome. İstanbul Med J. 2018:19, 73-5.
  5. Ashworth JL, Kielty CM, McLeod D. (2000). Fibrillin and the eye. Br J Ophthalmol. 2000:84(11), 1312-1317.
  6. Hubmacher D, Apte SS. Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function. Cell Mol Life Sci. 2011:68(19), 3137-3148.
  7. Guo H, Wu X, Cai K, Qiao Z. Weill-Marchesani syndrome with advanced glaucoma and corneal endothelial dysfunction: a case report and literature review. BMC ophthalmol, 2015:15(1), 1-4.
  8. Roszkowska AM, Aragona, P. Corneal microstructural analysis in Weill-Marchesani syndrome by in vivo confocal microscopy. Open Access J Ophthalmol, 2011(5)48.
  9. Weill-Marchesani Syndrome. National Organization for Rare Disorders (NORD). 2015; https://rarediseases.org/rare-diseases/weill-marchesani-syndrome/. Accessed March 1 2021.
  10. Dal D, Sahin A, Aypar U. Anesthetic management of a patient with Weill-Marchesani syndrome. Acta anaesthesiol Scand. 2003:47(3), 369–370. https://doi.org/10.1034/j.1399-6576.2003.00069.x
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