Endocrine Abstracts

Pseudohypoparathyroidism (PHP) defines a group of disorders characterized by resistance to PTH. They are classified in type Ia, Ib, Ic and type II according to their clinical and biological characteristics. PHP-Ia is caused by heterozygous mutations in the GNAS1 gene, encoding the alpha subunit of protein Gs. The aim of our study was to describe the diagnostic role of GNAS1 mutation screening in a large group of patients, and to define the intrafamilial transmission pattern and parental imprinting profile.

Fourteen patients were studied. Eleven patients, from 5 unrelated families, had PHP-Ia, associating Albright’s Hereditary Osteodystrophy (AHO), a decreased erythrocyte Gs-alpha protein activity, and other associated hormonal resistances. Two had PHP-Ib, with isolated PTH resistance, normal Gs-alpha activity and absent AHO. One patient had probable PHP-Ic, exhibiting AHO but normal Gs-alpha activity. GNAS1 mutations were identified in all the patients with PHP-Ia. Six different mutations, not previously described, were observed. In 4 families, mutations were transmitted by mothers. In one family, the mutation was de novo. In one family, affected patients had 2 heterozygous GNAS1 mutations, both located on the maternal allele. The 3 studied transmitting mothers had pseudopseudohypoparathyroidism, a condition associating AHO, decreased Gs-alpha activity but normal hormonal profile. We identified the familial GNAS1 mutation in an asymptomatic boy whose father had typical PHP-Ia. Finally, isolated subcutaneous calcifications were identified in 2 related subjects who did not have the familial GNAS1 mutation. We did not identify GNAS1 mutations in PHP-Ib and PHP-Ic subjects.

In conclusion, our study confirms 1) the usefulness of GNAS1 mutation screening in ascertaining PHP-Ia diagnostic, 2) the previously described maternal transmission of PHP-Ia, consistent with paternal imprinting of GNAS1 gene, 3) the need for mutation screening in PHP-Ia related subjects to identify mutation carriers and provide an appropriate genetic counselling.