# A novel GNAS mutation in pseudohypoparathyroidism type 1a with articular flexion deformity: A case report

## TL;DR

A rare case of a Chinese boy with a new GNAS gene mutation causing a combined disorder of pseudohypoparathyroidism and progressive osseous heteroplasia is reported, highlighting the importance of genetic testing.

## Contribution

A novel GNAS mutation is identified in a patient with a rare overlap syndrome of PHP 1a and POH.

## Key findings

- A heterozygous GNAS mutation (c.432+2T>C) was found in a boy and his mother, confirming maternal inheritance.
- The patient exhibited features of both PHP 1a and POH, indicating a rare overlap syndrome.
- Genetic testing and treatment improved symptoms, emphasizing its diagnostic and therapeutic value.

## Abstract

Pseudohypoparathyroidism (PHP) type 1a (PHP 1a) is a rare hereditary disorder characterized by target organ resistance to hormonal signaling and the Albright hereditary osteodystrophy (AHO) phenotype, which features round facial features, short fingers, subcutaneous calcifications, short stature, obesity, and intellectual disability. Progressive osseous heteroplasia (POH) is another rare disorder characterized by heterotopic ossification (HO) that progressively affects skin, subcutaneous tissues, and deep skeletal muscle. PHP 1a is inherited maternally due to a GNAS mutation, while pure POH is inherited paternally. This case study presented a Chinese boy with congenital hypothyroidism, tonic-clonic seizures, hypoparathyroidism, AHO, POH, and joint fixation deformity. Sequencing analysis of GNAS-Gsα revealed a heterozygous C.432+2T>C(P.?) variant (NM_000516.7) affecting the canonical splice donor site of intron 5 in the boy and his mother, indicating maternal inheritance of a GNAS mutation. The patient was diagnosed with POH overlap syndrome (POH/PHP 1a). Following calcium and calcitriol supplementation, he experienced a reduction in seizures, and surgery was performed to correct the joint fixation deformity caused by HO. This case report provided valuable insights into the genotype-phenotype correlations of POH overlap syndrome and underscored the significance of genetic testing in diagnosing rare diseases.