PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance

Agnès Linglart, Helena Fryssira, Olaf Hiort, Paul Martin Holterhus, Guiomar Perez De Nanclares, Jesús Argente, Claudine Heinrichs, Alma Kuechler, Giovanna Mantovani, Bruno Leheup, Philippe Wicart, Virginie Chassot, Dorothée Schmidt, Óscar Rubio-Cabezas, Annette Richter-Unruh, Sara Berrade, Arrate Pereda, Emese Boros, Maria Teresa Muñoz-Calvo, Marco CastoriYasemin Gunes, Guylene Bertrand, Pierre Bougnères, Eric Clauser, Caroline Silve*

*Corresponding author for this work
82 Citations (Scopus)


Context: Acrodysostosis is a rare skeletal dysplasia that is associated with multiple resistance to G protein-coupled receptor (GPCR) signaling hormones in a subset of patients. Acrodysostosis is genetically heterogeneous because it results from heterozygous mutations in PRKAR1A or PDE4D, two key actors in the GPCR-cAMP-protein kinase A pathway. Objective: Our objective was to identify the phenotypic features that distinguish the two genotypes causing acrodysostosis. Patients and Methods: Sixteen unrelated patients with acrodysostosis underwent a candidategene approach and were investigated for phenotypic features. Results: All patients had heterozygous de novo mutations. Fourteen patients carried a PRKAR1A mutation (PRKAR1A patients), five each a novel PRKAR1A mutation (p.Q285R, p.G289E, p.A328V, p.R335L, or p.Q372X), nine the reported PRKAR1A p.R368X mutation; two patients harbored a mutation in PDE4D (PDE4D patients) (one novel mutation, p.A227S; one reported, p.E590A). All PRKAR1A, but none of the PDE4D mutated patients were resistant to PTH and TSH. Two PRKAR1A patients each with a novel mutation presented a specific pattern of brachydactyly. One PDE4D patient presented with acroskyphodysplasia. Additional phenotypic differences included mental retardation in PDE4D patients. In addition, we report the presence of pigmented skin lesions in PRKAR1A and PDE4D patients, a feature not yet described in the acrodysostosis entity. Conclusions: All PRKAR1A and PDE4D patients present similar bone dysplasia characterizing acrodysostosis. Phenotypic differences, including the presence of resistance to GPCR-cAMP signaling hormones in PRKAR1A but not PDE4D patients, indicate phenotype-genotype correlations and highlight the specific contributions of PRKAR1A and PDE4D in cAMP signaling in different tissues.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Issue number12
Pages (from-to)E2328-E2338
Publication statusPublished - 12.2012

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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