• 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 Castori, Yasemin Gunes, Guylene Bertrand, Pierre Bougnères, Eric Clauser, and Caroline Silve.
• Institut National de la Santé et de la Recherche Médicale Unité 986 et Centre de Reference des Maladies Rares du Phosphate et du Calcium, Hôpital de Bicêtre, 94276 Le Kremlin Bicêtre Cedex, France.
• J. Clin. Endocrinol. Metab. 2012 Dec 1;97(12):E2328-38.

ContextAcrodysostosis 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.ObjectiveOur objective was to identify the phenotypic features that distinguish the two genotypes causing acrodysostosis.Patients And MethodsSixteen unrelated patients with acrodysostosis underwent a candidate-gene approach and were investigated for phenotypic features.ResultsAll 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.ConclusionsAll 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.

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