GDF5 – Angel-shaped Phalango-Epiphyseal Dysplasia

GDF5-related Angel-shaped Phalango-Epiphyseal Dysplasia (ASPED) is an autosomal dominant skeletal dysplasia characterized by an "angel-shaped" middle phalanx, brachydactyly, dental abnormalities, hip dysplasia, and delayed skeletal maturation. A Mexican patient presenting with brachydactyly type C features and the distinctive ASPED radiographic sign was found to carry a novel heterozygous GDF5 mutation, confirming that ASPED and brachydactyly type C share a common mutational spectrum in GDF5 (PMID:22828468).

Functional studies of GDF5 mutations associated with brachydactyly type C have demonstrated that heterozygous frameshift and missense variants in the active domain disrupt disulfide-linked dimer formation, leading to functional haploinsufficiency (PMID:12357473). No additional affected relatives were reported, and segregation analysis remains to be performed. Based on a single proband and limited family data, the gene–disease relationship is classified as Limited. Further case series and segregation data are needed to strengthen the clinical validity of GDF5 in ASPED.

Key Take-home: GDF5 haploinsufficiency underlies both brachydactyly C and Angel-shaped Phalango-Epiphyseal Dysplasia, with diagnostic relevance in patients displaying the characteristic “angel-shaped” phalanx.

References

• European journal of medical genetics • 2012 • A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum. PMID:22828468
• American journal of medical genetics • 2002 • The mutational spectrum of brachydactyly type C. PMID:12357473

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