ECE2016 Oral Communications Bone & Calcium Homeostasis (5 abstracts)
The prevalence of GNAS deficiency-related diseases in a large cohort of patients characterized by the EuroPHP network
Francesca Marta Elli 1 , Agnes Linglart 2, , Intza Garin 4 , Luisa de Sanctis 5 , Paolo Bordogna 1 , Virginie Grybek 2, , Arrate Pereda 4 , Federica Giachero 5 , Elisa Verrua 1 , Giovanna Mantovani 1 & Guiomar Perez de Nanclares 4
1Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Milano, Italy; 2APHP, Reference center for rare disorders of the mineral metabolism and Plateforme d’expertise Paris Sud Maladies Rares, Le Kremlin Bicêtre, France; 3INSERM U1169, Hôpital Bicêtre, Le Kremlin Bicêtre, et Université Paris-Saclay, Paris, France; 4Molecular (Epi)Genetics Laboratory, BioAraba National Health Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Spain; 5Department of Public Health and Pediatrics, University of Turin, Regina Margherita Children’s Hospital, Health and Science City, Torino, Italy.
The clinical condition resulting from end-organ resistance to parathormone (rPTH), caused by (epi)genetic alterations of GNAS, was termed as Pseudohypoparathyroidism (PHP). The high phenotype heterogeneity, the existence of additional clinical features such as resistance to other hormones (TSH/GHRH/gonadotropins) and Albright’s hereditary osteodystrophy (AHO), led to the distinction of specific PHP subtypes.
The purpose of the present work is to provide data about PHP-associated molecular defects prevalence. We collected in a specifically designed questionnaire the data from all the patients (pts) characterized by 3 laboratories members of the EuroPHP network, i.e. 407 pts.
Isolated rPTH (126/407, 31%) was caused only by epigenetic defects, as 70% of pts had a loss of imprinting (LoI) affecting all GNAS DMRs and 30% a loss of methylation (LoM) restricted to the A/B DMR. Multihormone resistance with no AHO signs (61/407, 15%) was essentially due to epigenetic defects, 64% to broad LoI and 26% to LoM A/B, although a 10% of pts had a point mutation.
In pts with rPTH and AHO (40/407, 10%), the percentage of point mutation grown up to 28% and methylation defects reduced (59% broad LoI and 13% LoM at A/B). In pts with multihormone resistance and AHO (155/407, 38%), we found all types of molecular defects; in particular, most pts were affected by GNAS point mutations (81%), while the remaining cases were due to either large deletions involving GNAS (6%), or broad LoI (10%) or isolated LoM at A/B (3%). Finally, isolated AHO (18/407, 4%) and POH (7/407, 2%) were caused by point mutations only.
To conclude, this work allowed us, for the first time, to quantify the prevalence of different (epi)genetic lesions in PHP pts. As outcome, we plan to derive objective criteria to guide a cost-efficient strategy of genetic testing and to examine the implications for management and prognosis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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