ESPE Abstracts (2015) 84 P-2-210

Genetic and Epigenetic Alterations at the GNAS Locus and Clinical Consequences in Pseudohypoparathyroidism: A New Healthcare Pathway

Federica Giacheroa,c, Francesca M Ellib, Marta Bariccoa,c, Patrizia Matarazzoc, Giovanna Mantovanib & Luisa de Sanctisa,c


aDepartment of Public Health and Pediatrics, University of Turin, Turin, Italy; bEndocrinology and Diabetology Unit, University of Milan, Fondazione Ospedale Maggiore Policlinico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; cRegina Margherita Children’s Hospital, Turin, Italy


Background: Genetic and epigenetic alterations at the GNAS locus are responsible for the Gsα protein dysfunctions causing Pseudohypoparathyroidism (PHP), a heterogeneous disease characterized by multiple hormone resistances and AHO signs (short stature, obesity, round face, brachydactyly, subcutaneous ossifications and mental retardation). A clinical overlap among molecular subtypes of the disease (Ia, Ib, Ic and II) makes the current classification inadequate; furthermore a common clinical approach still needs to be defined.

Objective and hypotheses: In the largest Italian case series of (epi)/genetically characterized PHP patients, this work attempts to review and update the clinical data, correlating them to the molecular diagnosis, and to develop a healthcare pathway for patients with AHO/PHP.

Method: The molecular analysis of the GNAS gene and locus identified the causal alteration in 74 subjects (46 genetic and 28 epigenetic mutations). The clinical data at the diagnosis and their evolution during up to 15 years follow-up, were collected using two different cards.

Results: We observed that in all patients the growth impairment increases during the time, while overweight/obesity decreases. Subcutaneous ossifications were detected in patients with gene mutations only, which show also a higher prevalence of brachydactyly. In subjects with epigenetic alterations the disease seems to overt later in life, often with symptomatic hypocalcemia. A temptative healthcare pathway for patients with AHO/PHP has been drawn based on the collected clinical data in our series.

Conclusion: A dedicated healthcare pathway addressing all these aspects in a systematic way would improve the management of the disease, allowing an earlier diagnosis of PHP, which is fundamental to optimize the medical treatment and its timing, (i.e. rGH therapy); however, the different prevalence and features of some AHO signs need to be confirmed by follow-up data, and in the future may lead to a better clinical-oriented molecular analysis.

Funding: This work was supported by the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) on behalf of the dedicated Study Group on Gsα-related diseases.

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