The Prevalence of GNAS Deficiency-Related Diseases in a Large Cohort of Patients Characterized by the EuroPHP Network

J Clin Endocrinol Metab. 2016 Oct;101(10):3657-3668. doi: 10.1210/jc.2015-4310. Epub 2016 Jul 18.


Context: The term pseudohypoparathyroidism (PHP) was coined to describe the clinical condition resulting from end-organ resistance to parathormone (rPTH), caused by genetic and/or epigenetic alterations within or upstream of GNAS. Although knowledge about PHP is growing, there are few data on the prevalence of underlying molecular defects.

Objective: The purpose of our study was to ascertain the relative prevalence of PHP-associated molecular defects.

Design: With a specially designed questionnaire, we collected data from all patients (n = 407) clinically and molecularly characterized to date by expert referral centers in France, Italy, and Spain.

Results: Isolated rPTH (126/407, 31%) was caused only by epigenetic defects, 70% of patients showing loss of imprinting affecting all four GNAS differentially methylated regions and 30% loss of methylation restricted to the GNAS A/B:TSS-DMR. Multihormone resistance with no Albright's hereditary osteodystrophy (AHO) signs (61/407, 15%) was essentially due to epigenetic defects, although 10% of patients had point mutations. In patients with rPTH and AHO (40/407, 10%), the rate of point mutations was higher (28%) and methylation defects lower (about 70%). In patients with multihormone resistance and AHO (155/407, 38%), all types of molecular defects appeared with different frequencies. Finally, isolated AHO (18/407, 4%) and progressive osseous heteroplasia (7/407, 2%) were exclusively caused by point mutations.

Conclusion: With European data, we have established the prevalence of various genetic and epigenetic lesions in PHP-affected patients. Using these findings, we will develop objective criteria to guide cost-effective strategies for genetic testing and explore the implications for management and prognosis.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Chromogranins
  • Epigenesis, Genetic
  • Female
  • France / epidemiology
  • GTP-Binding Protein alpha Subunits, Gs / deficiency*
  • Humans
  • Italy / epidemiology
  • Male
  • Mutation
  • Parathyroid Hormone*
  • Prevalence
  • Pseudohypoparathyroidism / epidemiology
  • Pseudohypoparathyroidism / genetics*
  • Spain / epidemiology
  • Young Adult


  • Chromogranins
  • Parathyroid Hormone
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs