GDF5 – acromesomelic dysplasia 2B

Acromesomelic dysplasia type 2B (Du Pan syndrome) is an autosomal recessive limb‐patterning disorder characterized by fibular hypoplasia and complex brachydactyly. Affected individuals present with reduced or absent fibulae, shortened middle and distal limb elements, carpotarsal fusions, and deformed phalanges, with axial skeleton spared. Carrier parents are clinically unaffected, consistent with recessive inheritance.

In a consanguineous Pakistani family, all affected individuals were homozygous for a missense variant c.1322T>C (p.Leu441Pro) in GDF5, absent in 44 ethnically matched controls (PMID:12121354). This variant segregated fully with disease in the kindred and predicts a conformational change in the mature domain of GDF5.

A second report described a Polish mother–child pair with Du Pan syndrome harboring three clustered heterozygous CDMP1 (GDF5) mutations on one allele, demonstrating a dominant form through synergistic cis‐acting effects in the active domain (PMID:16222676).

The first prenatal diagnosis of Du Pan syndrome identified a fetus homozygous for c.1322T>C (p.Leu441Pro) following ultrasound findings of bilateral fibular agenesis and ball‐shaped toes mimicking preaxial polydactyly. Parental carrier status was confirmed by sequencing (PMID:37064338).

Functional assays reveal that the p.Leu441Pro substitution abolishes GDF5 binding to BMP type I receptors and prevents Smad1/5 pathway activation, consistent with a loss‐of‐function mechanism in cartilage micromass cultures and BMP receptor interaction studies (PMID:16127465).

Taken together, biallelic and cis‐acting GDF5 variants underlie Du Pan syndrome by impairing ligand–receptor interactions essential for distal limb morphogenesis. These data support a strong gene–disease relationship and underscore the utility of GDF5 sequencing in prenatal and postnatal diagnosis of acromesomelic dysplasia type 2B.

References

• Clinical genetics • 2002 • Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome). PMID:12121354
• American journal of medical genetics. Part A • 2005 • Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene. PMID:16222676
• Molecular syndromology • 2023 • Fibular Agenesis and Ball-Like Toes Mimicking Preaxial Polydactyly: Prenatal Presentation of Du Pan Syndrome. PMID:37064338
• The Journal of clinical investigation • 2005 • Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. PMID:16127465

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