WNT7A – Fuhrmann syndrome

Fuhrmann syndrome is a rare autosomal recessive limb‐malformation disorder characterized by hypoplasia/aplasia of the long bones, ectopic dorsal palms, nail aplasia and joint dysplasia in the hands and feet. Affected individuals present with variable degrees of pelvic dysplasia and bowed radii, with preservation of humeri and elbow joints, distinguishing it from more severe phocomelia phenotypes. Genetic testing for WNT7A should be considered in patients with these characteristic limb findings.

Homozygous missense variants in WNT7A segregate with Fuhrmann syndrome in multiple consanguineous families. The c.325G>A (p.Ala109Thr) and c.874C>T (p.Arg292Cys) variants were identified in two unrelated families with classic Fuhrmann features (PMID:16826533). The c.610G>A (p.Gly204Ser) variant was found in an unrelated patient presenting with Fuhrmann syndrome, broadening the phenotypic spectrum of this allele (PMID:23266637). In total, at least four probands across three unrelated pedigrees and segregation in three additional affected relatives support the gene–disease link.

All pathogenic alleles associated with Fuhrmann syndrome are missense changes within conserved Wnt signature motifs and have not been reported as truncating or splice variants. No recurrent founder variants have been described in nonconsanguineous populations, and carrier frequency data are not available.

Functional assays using retroviral‐mediated expression of human WNT7A in chicken limb‐bud mesenchyme demonstrate that FS‐associated variants impair WNT7A signaling but retain residual activity, consistent with a partial loss‐of‐function mechanism and phenocopying mouse Wnt7a knockout limb defects (PMID:16826533). A recent review classifies Fuhrmann‐associated alleles as hypomorphic relative to complete null mutations in more severe Al‐Awadi/Raas‐Rothschild phenotypes (PMID:23922166).

No conflicting or refuting evidence has been reported. WNT7A variants are not implicated in unrelated disorders such as Müllerian duct anomalies, schizophrenia, or bladder exstrophy, supporting specificity for limb development.

Integration of genetic segregation in multiple families and concordant functional data yields a Moderate–Strong association between WNT7A and Fuhrmann syndrome. Key take‐home: AR WNT7A missense screening enables molecular diagnosis and genetic counseling for Fuhrmann syndrome.

References

• American journal of human genetics • 2006 • Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. PMID:16826533
• American journal of medical genetics. Part A • 2011 • A novel homozygous missense mutation (c.610G>A, p.Gly204Ser) in the WNT7A gene causes tetra-amelia in two Saudi families. PMID:21344627
• Clinical dysmorphology • 2013 • Phenotypic variability of the WNT7A p.Gly204Ser mutation in a Fuhrmann syndrome patient. PMID:23266637
• American journal of medical genetics. Part A • 2013 • Molecular basis of the clinical features of Al-Awadi-Raas-Rothschild and Fuhrmann syndromes. PMID:23922166

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