Endocrine Abstracts

The impairment of the parathyroid hormone (PTH) signaling pathway determines a group of related and highly heterogeneous disorders associated or not with the Albright’s hereditary osteodystrophy (AHO) phenotype, classified as inactivating PTH/PTHrP signaling disorder (iPPSD). iPPSD features are rather difficult to be identified in some casesbecause manifestations are somewhat variable and some AHO characteristics are not specific to a specific disorder. Actually, besides GNASdefects causing pseudohypoparathyroidism (PHP), additional genes of the PTH pathway have been associated to other disorders, that should be considered for establishing a correct diagnosis in patients with no GNAS alterations. The aim of the present work was to discovermolecular alterations in iPPSD patients withno GNAS defects by NGS target sequencing and, afterreview of available clinical data, to identify manifestations useful for an early classification of patients. We investigated by NGS target sequencingof iPPSD associated genes (GNAS, PRKAR1A, PDE4D, PDE3A, PTH1R, PTHLH, HDAC4, HOXD13 and TRPS1) 58 patients referred to our laboratory with a clinical diagnosis of iPPSD, in whom previous genetic testingfailed to identify any GNAS molecular defect. Deleterious variants were filtered and prioritized according toACMG/AMP pathogenicity scoresby the eVai v0.6 tooland potentially causative rare variants were confirmed by Sanger sequencing. By the bioinformatic analysis we discovered 5 novel highly damaging genetic variants, 3 in the PTHLH gene and 2 in the TRPS1 gene, and, after re-evaluation of available clinical data, patients were re-diagnosed as suffering from brachydactyly with short stature (BDE2) and tricho-rhino-phalangeal syndrome (TRPS), respectively. All mutated patients presented both frequent and rare features commonly observed in PHP, BDE2 and TRPS. In particular, TRPS patients were mistakenly identified as PHP because they presented ultrarare signs, PTH resistance in one case and intellectual disability, obesity and subclinical hypothyroidism in the other one, that were already reported in the literature for single cases. In conclusion, our work allowed, by using a NGS gene panel for iPPSD-associated genes, to establish a correct genetic diagnosis, follow-up and genetic counseling in 5 patients misdiagnosed as PHP and to discover novel mutations in PTHLH and TRPS1 genes. No genotype-phenotype correlations were observed and, unfortunately, we did not identify distinctive phenotypic features that could be exclusively associated to a specific syndrome different from PHP and could help in an early classification of patients.