PDE4D – Acrodysostosis

Acrodysostosis is a rare autosomal dominant skeletal dysplasia characterized by severe brachydactyly, midfacial hypoplasia, short stature, and varying degrees of intellectual disability. PDE4D encodes a cyclic AMP–specific phosphodiesterase that regulates intracellular cAMP levels and downstream protein kinase A (PKA) signaling.

Initial exome sequencing in ten unrelated acrodysostosis patients identified heterozygous de novo missense variants in PDE4D (c.673C>A (p.Pro225Thr) and c.677T>C (p.Phe226Ser)) in two individuals, alongside additional PDE4D mutations in two more probands (PMID:22464250). Subsequent reports described novel heterozygous missense mutations in multiple sporadic cases and one multigenerational family, including c.569T>C (p.Ser190Phe) segregating in a mother and child (PMID:28515031).

To date, at least 16 de novo heterozygous variants—predominantly missense substitutions—have been reported across more than 12 unrelated probands, with one small deletion (frameshift) noted. No clear founder alleles have emerged, and the spectrum spans upstream regulatory domains to the catalytic core, consistent with a dominant-negative or gain-of-function mechanism.

Segregation in a two-generation pedigree and recurrent de novo occurrences support autosomal dominant inheritance with variable expressivity. One additional affected relative was documented in the familial report, underscoring intra-family phenotypic variability (PMID:28515031).

Functional studies demonstrate that acrodysostosis-associated PDE4D mutants show enhanced activation by PKA and increased basal cAMP hydrolysis in cell models, and recapitulate skeletal abnormalities in zebrafish overexpression and knockdown assays (PMID:24203977; PMID:29016851). Moreover, PDE4D-knockout mice exhibit distal limb shortening, paralleling human brachydactyly (PMID:18702734).

Overall, the genetic and experimental concordance supports a Strong gene–disease association. PDE4D sequencing is clinically actionable for diagnosis and familial counseling in acrodysostosis, and functional data guide considerations for targeted modulation of cAMP signaling.

References

• American Journal of Human Genetics • 2012 • Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis PMID:22464250
• Journal of Clinical Research in Pediatric Endocrinology • 2017 • Phenotypic Variability in a Family with Acrodysostosis Type 2 Caused by a Novel PDE4D Mutation Affecting the Serine Target of Protein Kinase-A Phosphorylation PMID:28515031
• Journal of Medical Genetics • 2014 • Different mutations in PDE4D associated with developmental disorders with mirror phenotypes PMID:24203977
• Human Molecular Genetics • 2017 • Mutations causing acrodysostosis-2 facilitate activation of phosphodiesterase 4D3 PMID:29016851
• European Journal of Neuroscience • 2008 • Enhanced long-term potentiation and impaired learning in phosphodiesterase 4D-knockout (PDE4D) mice PMID:18702734

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