Pseudohypoparathyroidism type 1 A (PHP-1A) is a rare genetic disorder characterized by hypocalcemia, hyperphosfatemia, multi hormones resistance (PTH, TSH, Calcitonin, GH) associated with Albright hereditary osteodystrophy (AHO) features. The disease is caused by GNAS haploinsufficiency due to inherited inactivating mutation of GNAS-gene that codes for the stimulatory alfa subunit of G protein. A positive genotype-phenotype correlation was recently hypothesized. The purpose of this work is to describe a new family affected by PHP-1A. The proband, a 18 years old man, came for the first time to our attention in 2017 for hypocalcemia diagnosed after a tetanic crisis. Physical examination showed the typical features of AHO: round face, stocky habitus with short stature, brachydactyly and ectopic-severe ossification in the back and in the legs. Laboratory tests showed low levels of calcium, high levels of phosphate and high levels of PTH, TSH and calcitonin despite therapy with calcium carbonate, calcitriol and levothyroxine. Computed tomography showed diffuse calcifications rosary-like in the cortex and scalp. Bone radiography showed diffuse soft tissue and costal cartilage calcifications and marked brachydactyly and brachimetacarpy. Family history was remarkable for hypocalcemic crisis associated with neurocognitive impairment and cerebral calcification in the brother. The genetic analysis of the GNAS gene showed a novel large deletion (encompassing exons 17), in the proband, in the brother and in the mother. The daily dose of calcitriol, calcium carbonate and L-thyroxine was increased with good control of hypocalcemia thereafter. At the latest evaluation, serum calcium and TSH levels were normal with a reduction of PTH levels. In conclusion, we have identified an additional PHP-1A family with severe phenotype that supports the hypothesis of a positive genotype-phenotype correlation.
18 - 21 May 2019
European Society of Endocrinology