Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 101, Issue 10, Pages 3657-3668Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2015-4310
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Funding
- European Network
- European Society for Pediatric Endocrinology Research Unit
- Paris-Sud University (projet Attractivite)
- French National Research Agency
- Italian Ministry of Health Grant [GR-2009-1608394]
- Ricerca Corrente Funds
- French Society of Pediatric Endocrinology and Diabetology
- Instituto de Salud Carlos III (Institute of Health Carlos III) of Ministry of Economy and Competitiveness
- European Regional Development Fund Grant [PI13/00467]
- Basque Department of Health Grant [GV2014111017]
- INSERM [U1169]
- I3SNS Program of the Spanish Ministry of Health Grant [CP03/0064 SIVI 1395/09]
- University of Basque Country Grant [48198]
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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.
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