[Genes in the cAMP pathway causing skeletal dysplasia with or without hormonal resistance]

Acrodysostosis refers to a heterogeneous group of rare skeletal dysplasia that share characteristic features including severe brachydactyly, facial dysostosis and nasal hypoplasia. The literature describing acrodysostosis cases has been confusing because some reported patients may have had other phenotypically related diseases presenting Albright Hereditary Osteodystrophy (AHO) such as pseudohypoparathyroidism type 1a (PHP1a) or pseudopseudohypoparathyroidism (PPHP). A question has been whether patients display or not abnormal mineral metabolism associated with resistance to PTH and/or resistance to other hormones that bind G-protein coupled receptors (GPCR) linked to Gsa, as observed in PHP1a. Defects in two genes, PRKAR1A and PDE4D, both important players in the GPCR-Gsa-cAMP-PKA signaling, were recently identified in patients affected with acrodysostosis. This has helped clarify some issues regarding the heterogeneity of acrodysostosis, in particular the presence of hormonal resistance. Two different genetic and phenotypic syndromes are now identified, both with a similar bone dysplasia: acrodysostosis type 1 due to PRKAR1A defects, and acrodysostosis type 2, due to PDE4D defects. The existence of hormone resistance is typical of the acrodysostosis type 1 syndrome. We discuss here the PRKAR1A and PDE4D gene defects and phenotypes identified in acrodysostosis syndromes, in particular in regard to phenotypically related diseases caused by Gsa gene defects in the same signaling pathway.