ESPE Abstracts

The cause of pseudo-hypoparathyroidism (PHP) is structural mutations or epigenetic modifications of the GNAS gene, which encodes the alpha subunit of the G protein.

The aim: of the study is to compare the genotype of patients with GNAS mutation with their phenotype.

Materials and Methods: 28 patients (16 F and 12 M) diagnosed with PHP were analyzed. Among them, 13 came from six unrelated Polish families and 4 patients from one Italian family.. Genetic analysis of variants in the GNAS gene was performed on genomic DNA samples isolated from peripheral blood. Sequencing of the GNAS gene was performed using NGS technique (HiSeq 1500, Illumina), and the presence of detected variants was confirmed by Sanger sequencing. In one patient, MS-MLPA analysis was additionally performed (ME031 kit, MRC Holland). In silico assessment of the biological and clinical significance of variants was performed using bioinformatics tools Varsome, Franklin, and MutationTaster. Patients' auxological data were compared, including features of Albright's osteodystrophy such as obesity, growth deficiency, brachydactyly, round face, subcutaneous calcifications, and CNS calcifications.

Results: The age of PHP diagnosis ranged from 1 month to 18 years (median 6 years and 1 month). Tests were conducted on 22 patients, with 9 showing de novo mutations and the remaining mutations inherited from the mother. Twenty-one patients were diagnosed with iPPSD 2 (PHP 1A), and one patient was diagnosed with iPPSD3 (PHP1B). The patient with iPPSD3 presented typical features of iPPSD2. Significantly higher levels of phosphates, as well as a higher frequency of Fahr's syndrome, were observed in patients with nonsense mutations. The occurrence of a "round face" was borderline significant: it was not observed in any patient with a missense mutation, while most children with other variants presented a round face. Similarly, the occurrence of a round face was significantly associated with pathogenic variants in exon 12/13 or intron 1/12. as mutation sites. There was no statistically significant correlation between the type of mutation and the occurrence of brachydactyly and subcutaneous calcifications.

Conclusion: 1. The basis for the diagnosis of iPPSD consists of the results of physical examination, laboratory tests, and genetic studies, which confirm the diagnosis, enable predicting inheritance patterns, and complications of treatment 2. A patient diagnosed with iPPSD 3 did not differ phenotypically from patients with iPPSD1. 3. The report is preliminary and requires extended research on a larger group of patients