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Acromesomelic dysplasia Hunter-Thompson type (MONDO:0008717) is an autosomal recessive skeletal dysplasia characterized by severe acromesomelic shortening of the limbs with normal axial skeleton and proportionate short stature ([HP:0004322]). While hypomorphic mutations in BMPR1B can cause du Pan dysplasia, the majority of Hunter-Thompson cases arise from biallelic loss-of-function variants in GDF5, a key ligand in BMP signaling (PMID:26105076).
Genetic evidence for GDF5 involvement is limited: few unrelated probands have been reported with confirmed GDF5 null alleles and exclusive segregation for this subtype has not been described. Mode of inheritance is autosomal recessive. A representative loss-of-function variant is c.39C>G (p.Tyr13Ter), which truncates the mature GDF5 protein and abolishes signaling. No additional affected relatives have been reported in GDF5-only families.
Functional studies across BMP/TGF-β assays demonstrate that GDF5 missense and nonsense mutations disrupt disulfide-linked dimer formation and receptor binding, leading to functional haploinsufficiency that recapitulates limb-shortening phenotypes in cellular models.
Integration of genetic and experimental data supports a Limited clinical validity for GDF5 in Hunter-Thompson acromesomelic dysplasia. Additional familial segregation and functional rescue studies are needed to strengthen this association. Key take-home: Biallelic GDF5 loss-of-function variants cause Hunter-Thompson acromesomelic dysplasia, informing diagnosis and carrier screening.
Gene–Disease AssociationLimitedFew reported probands with biallelic GDF5 loss-of-function; no exclusive segregation data Genetic EvidenceLimitedSingle cohort mention of GDF5 null alleles without familial segregation Functional EvidenceModerateIn vitro assays show impaired dimerization and reduced BMP signaling |