Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism

Abstract

The cyclic adenosine monophosphate (cAMP) intracellular signaling pathway mediates the physiological effects of several hormones and neurotransmitters, acting by the activation of G-protein coupled receptors (GPCRs) and several downstream intracellular effectors, including the heterotrimeric stimulatory G-protein (Gs), the cAMP-dependent protein kinase A (PKA), and cAMP-specific phosphodiesterases (PDEs). Defective G-protein-mediated signaling has been associated with an increasing number of disorders, including Albright hereditary osteodistrophy (AHO) and pseudohypoparathyroidism (PHP), a heterogeneous group of rare genetic metabolic disorders resulting from molecular defects at the GNAS locus. Moreover, mutations in PRKAR1A and PDE4D genes have been recently detected in patients with acrodysostosis (ACRDYS), showing a skeletal and endocrinological phenotype partially overlapping with AHO/PHP. Despite the high detection rate of molecular defects by currently available molecular approaches, about 30% of AHO/PHP patients still lack a molecular diagnosis, hence the need to screen patients negative for GNAS epi/genetic defects also for chromosomal regions and genes associated with diseases that undergo differential diagnosis with PHP. According to the growing knowledge on Gsa-cAMP signaling-linked disorders, we investigated our series of patients (n ¼ 81) with a clinical diagnosis of PHP/AHO but negative for GNAS anomalies for the presence of novel genetic variants at PRKAR1A and PDE4D genes. Our work allowed the detection of 8 novel missense variants affecting genes so far associated with ACRDYS in 9 patients. Our data further confirm the molecular and clinical overlap among these disorders. We present the data collected from a large series of patients and a brief review of the literature in order to compare our findings with already published data; to look for PRKAR1A/PDE4D mutation spectrum, recurrent mutations, and mutation hot spots; and to identify specific clinical features associated with ACRDYS surveillance during follow-up.

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…Unlike fibrodysplasia ossificans progressiva (FOP), where injury, viral infections and immunizations can lead to ossifications, no formal evidence exists to suggest that the same events lead to ectopic bone formation in GNAS-based conditions. Ectopic ossifications are found in 100%, 80-100%, 30-60% and very uncommonly in patients with POH, PPHP or AHO, PHP1A and PHP1B, respectively, and have never been reported in patients with acrodysostosis 13,61,[75][76][77][78] .…”

“…On radiographs, epiphyses display a cone shape, bone age is advanced and abnormalities might be present at birth or soon thereafter. In some cases, the chondrodysplasia is indistinct from that of AHO [11][12][13]15,61 .…”

“…Other symptoms might also be present in patients with acrodysostosis, such as cognitive impairment 15,62 , being born SGA and resistance to PTH and/or other hormones that signal through G s α 6,13,15,63,64 .…”

“…Patients with PDE4D mutations usually display normal levels of PTH, except in the context of calcifediol deficiency 5,[13][14][15]20,62,63 .…”

“…Acrodysostosis is uncommon; the prevalence of the disease is unknown, and clinical, biochemical and radiological features overlap with those of PHP1A and PPHP 6,[11][12][13][14][15] .…”