Acrodysostosis syndromes

Abstract

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.

Figure 1

Photographs and X rays of the face and hand of a 12-year-old patient affected with ADOHR resulting from the R368X mutation in PRKAR1A. (a) Side and (b) front photographs of the face. Note the facial dysostosis and severe maxilla-nasal hypoplasia. Photograph (c) and radiograph (d) of the left hand. Note the shortening of all metacarpals and phalanges, and the bulky and stocky aspect of all the affected bones. Standard X-rays show the short and broad metacarpals and phalanges, the cone-shaped epiphyses and advanced carpal and tarsal maturation.

Figure 2

Schematic representation of PRKAR1A indicating the functionally important domains. The numbers indicate the amino-acid residues at the domain boundaries (NP_002725). The exons coding for the domains are also indicated. The activatory mutations identified in ADOHR patients (bold) and in cell lines are indicated above the diagram. Inhibitory point mutations identified in patients with the Carney complex are indicated below the diagram. DD, dimerization domain; N-li, N-linker; IS, inhibitory site; C-li, C linker; CBA and CBB, cAMP-binding domain A and B.

Figure 3

Schematic representation of long isoforms of PDE4D indicating the functionally important domains. The numbers indicate the amino-acid residues at the domain boundaries (NP_001098101). The exons coding for the domains are also indicated. The catalytic domain is shared by all isoforms, the upstream conserved region 1 (ucr1) is shared by all long isoforms, and the upstream conserved region 2 (ucr2) is shared by all isoforms except for the super-short isoform. The missense mutations identified in patients with ADOP4 are shown above the diagram. UCR, upstream conserved region; LR, linker region; Cat, catalytic domain.