Francesca Marta Elli1, Agnès Linglart1, Intza Garin1, Luisa de Sanctis1, Paolo Bordogna1, Virginie Grybek1, Arrate Pereda1, Federica Giachero1, Elisa Verrua1, Patrick Hanna1, Giovanna Mantovani1, Guiomar Perez de Nanclares1. 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; 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; INSERM U1169 (A.L., V.G., P.H.), Hôpital Bicêtre, Le Kremlin Bicêtre, et Université Paris-Saclay, France; Molecular (Epi)Genetics Laboratory (I.G., A.P., G.P.d.N.), BioAraba National Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Spain; 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; 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.
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.
Authors: Kathleen L Curley; Sachini Kahanda; Katia M Perez; Beth A Malow; Ashley H Shoemaker Journal: Horm Res Paediatr Date: 2018-02-16 Impact factor: 2.852
Authors: Katia M Perez; Evon B Lee; Sachini Kahanda; Jessica Duis; Monica Reyes; Harald Jüppner; Ashley H Shoemaker Journal: Am J Med Genet A Date: 2017-11-28 Impact factor: 2.802