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

Author:

Elli Francesca Marta1,Linglart Agnès23,Garin Intza4,de Sanctis Luisa5,Bordogna Paolo1,Grybek Virginie23,Pereda Arrate46,Giachero Federica5,Verrua Elisa1,Hanna Patrick23,Mantovani Giovanna1,Perez de Nanclares Guiomar4

Affiliation:

1. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (F.M.E., E.V., P.B., G.M.), Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Milan, Italy;

2. APHP (A.L., V.G., P.H.), Reference Center for Rare Disorders of the Mineral Metabolism and Plateforme d’expertise Paris Sud Maladies Rares, Le Kremlin Bicêtre, France;

3. INSERM U1169 (A.L., V.G., P.H.), Hôpital Bicêtre, Le Kremlin Bicêtre, et Université Paris-Saclay, France;

4. Molecular (Epi)Genetics Laboratory (I.G., A.P., G.P.d.N.), BioAraba National Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Spain;

5. Department of Public Health and Pediatrics (L.d.S., F.G.), University of Turin, Regina Margherita Children’s Hospital, Health and Science City, Turin, Italy;

6. Department of Biochemistry and Molecular Biology (A.P.), University of Basque Country, Leioa, Spain

Abstract

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.

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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