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.
The prevalence of GNAS deficiency-related diseases in a large cohort of patients characterized by the EuroPHP network / F.M. Elli, A. Linglart, I. Garin, L. De Sanctis, P. Bordogna, V. Grybek, A. Pereda, F. Giachero, E. Verrua, P. Hanna, G. Mantovani, G.P. De Nanclares. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - 101:10(2016), pp. 3657-3668.
|Titolo:||The prevalence of GNAS deficiency-related diseases in a large cohort of patients characterized by the EuroPHP network|
ELLI, FRANCESCA MARTA (Primo)
MANTOVANI, GIOVANNA (Corresponding)
|Parole Chiave:||endocrinology; diabetes and metabolism; biochemistry; endocrinology; clinical biochemistry; biochemistry (medical)|
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
|Data di pubblicazione:||2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1210/jc.2015-4310|
|Appare nelle tipologie:||01 - Articolo su periodico|