FBN1 – Stiff Skin Syndrome

Heterozygous missense variants in FBN1 have been identified in four individuals from two kindreds presenting with autosomal dominant Stiff Skin Syndrome. In a two-generation Northern Irish family, three affected members exhibited congenital skin induration, hypertrichosis, joint contractures, and variable ophthalmoplegia; sequencing revealed segregation of a c.4710G>C (p.Trp1570Cys) variant in all affected individuals (PMID:26471116). In a second case, a heterozygous c.5243G>A (p.Cys1748Tyr) variant was found in an 8-year-old boy with severe skin tightness and acromicric dysplasia-like features with SSS-like cutaneous presentation (PMID:32406602).

Limited histopathological studies demonstrate dermal mucopolysaccharide deposition, thickened collagen bundles, and excessive collagen aggregation consistent with extracellular matrix microfibril disruption (PMID:32406602). No in vitro or in vivo models specific to SSS have been reported.

Overall, heterozygous FBN1 variants are implicated in an autosomal dominant form of Stiff Skin Syndrome, but evidence is currently limited to small case series and lacks mechanistic modeling. Key take-home: FBN1 sequencing should be considered in patients with early-onset skin induration and joint mobility restriction.

References

• Eye (London, England) • 2016 • The ocular phenotype of stiff-skin syndrome. PMID:26471116
• Molecular genetics & genomic medicine • 2020 • Acromicric dysplasia with stiff skin syndrome-like severe cutaneous presentation in an 8-year-old boy with a missense FBN1 mutation: Case report and literature review. PMID:32406602

Evidence Based Scoring (AI generated)