Acrodysostosis (
ADO) 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 with
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 Gsα, as observed in PHP1a. The recent identification in patients affected with
acrodysostosis of defects in two genes, PRKAR1A and PDE4D, both important players in the GPCR-Gsα-cAMP-PKA signaling, 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: ADOHR, due to PRKAR1A defects, and ADOP4 (our denomination), due to PDE4D defects. The existence of GPCR-
hormone resistance is typical of the ADOHR syndrome. We review here the PRKAR1A and PDE4D gene defects and phenotypes identified in
acrodysostosis syndromes, and discuss them in view of phenotypically related diseases caused by defects in the same signaling pathway.