OR24-4 The first Italian series of patients with Progressive Osseous Heteroplasia: screening for GNAS locus genetic and epigenetic defects

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR24-New Mechanisms in Bone Biology: From Cells to Genetics, & Mice to Men
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:00 PM
Room 121 (Moscone Center)
Francesca Marta Elli*1, Annamaria Barbieri2, Paolo Bordogna2, Elena Giardino2, Emanuele Ferrante3, Paolo Beck-Peccoz3, Anna Spada3 and Giovanna Mantovani3
1IRCCS Ca' Granda H Maggiore Policlinico, Milano, Italy, 2IRCCS Cą Granda H Maggiore Policlinico, Milano, Italy, 3IRCCS Cą Granda H Maggiore Policlinico, Milan, Italy
Progressive osseous heteroplasia (POH) is a rare disorder of mesenchymal differentiation associated to paternally inherited inactivating mutations of GNAS gene. Clinically, POH is characterized by heterotopic ossification (HO) of skin and subcutaneous tissues during infancy, that progresses into deep skeletal muscle over childhood. Affected areas may be small or large and involve scattered and variable regions of the body. HO near the joints may lead to stiffness and immobility. Maternal mutations as well as epigentic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright’s hereditary osteodystrophy (AHO). Recently, some reports documented the existence of POH patients showing additional features characteristics of PHP/AHO and proposed POH as part of the spectrum of HO GNAS-associated disorders.

In the current study we investigated 10 unrelated POH patients for GNAS genetic and epigenetic status by Sanger sequencing and MS-MLPA. In a subset of patients we performed parent’s DNA analysis and RNA sequencing in order to establish the parental origin of the mutated allele. In all patients the hallmark was the presence of HO, confirmed by skin biopsy. Endocrinological evaluation included thyroid function test together with serum calcium, phosphate, PTH, 25-OH vitamin D and 24-h urinary calcium measurement. Resistance to TSH was determined only in one patient.

We detected 4 GNAS mutations in 6 of 10 patients, all de novo and predicting truncated proteins. In 3 mutated patients we demonstrated that the mutation occurred on the paternal allele. Moreover, all tested patients resulted having a wild type GNAS imprinting status and no copy number abnormalities affecting STX16 and GNAS loci were found. No evident differences were observed among patients harboring different mutations, as well as between mutated and non-mutated patients.

In conclusion, our results support that POH belongs to a continuum of HO disorders associated with inactivating GNAS mutations and further expand the spectrum of associated genetic defects. Our data strengthen the observation that the same GNAS mutation can present with variable penetrance and that neither the presence/absence nor the mutation type or its location allows to predict a specific phenotype or the severity of the progression. Finally, we investigated the imprinting status of GNAS locus and we observed that, unlike PHP, methylation alterations at GNAS locus are absent or uncommon in POH.

Nothing to Disclose: FME, AB, PB, EG, EF, PB, AS, GM

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Contract grant sponsor: Italian Ministry of Health (GR-2009-1608394).