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

J Clin Endocrinol Metab. 2012 Dec;97(12):E2328-38. doi: 10.1210/jc.2012-2326. Epub 2012 Oct 5.


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 candidate-gene 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.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics*
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / physiology
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / genetics*
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / physiology
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Diagnostic Techniques, Endocrine
  • Drug Resistance / genetics*
  • Dysostoses / complications*
  • Dysostoses / diagnosis
  • Dysostoses / genetics*
  • Female
  • Hormones* / metabolism
  • Hormones* / pharmacology
  • Humans
  • Intellectual Disability / complications*
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Male
  • Osteochondrodysplasias / complications*
  • Osteochondrodysplasias / diagnosis
  • Osteochondrodysplasias / genetics*
  • Parathyroid Hormone / administration & dosage
  • Parathyroid Hormone / metabolism
  • Parathyroid Hormone / pharmacology
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / physiology
  • Syndrome
  • Thyroid Hormone Resistance Syndrome / complications
  • Thyroid Hormone Resistance Syndrome / diagnosis
  • Thyroid Hormone Resistance Syndrome / genetics
  • Young Adult


  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • Hormones
  • PRKAR1A protein, human
  • Parathyroid Hormone
  • Receptors, G-Protein-Coupled
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4D protein, human

Supplementary concepts

  • Acrodysostosis