Familial investigation of two cases of pseudohypoparathyroidism

To report the clinical and genetic characteristics of patients diagnosed with pseudohypoparathyroidism (PHP) or inactivating parathyroid hormone (PTH)/PTHrP signaling disorders (iPPSD), and to provide insights for the diagnosis and management of this rare inherited metabolic disorder.

This study focused on two patients diagnosed with PHP or iPPSD, aiming to investigate their clinical and genetic characteristics. Clinical manifestations and biochemical indicators of the two subjects were collected and analyzed. Whole-exome sequencing was employed to detect potential genetic mutations associated with the disorder. Additionally, pedigree analysis was performed to clarify the inheritance pattern of the identified mutation in the families of the two patients.

Both patients presented with recurrent seizures and Albright's hereditary osteodystrophy (AHO) features. Biochemical tests revealed consistent abnormalities in both subjects, including hypocalcemia, hyperphosphatemia, and elevated levels of PTH and thyroid-stimulating hormone (TSH). Whole-exome sequencing successfully isolated a specific four-nucleotide deletion (GACT) within exon 7 of the GNAS gene, confirming the condition as iPPSD2. Pedigree analysis verified that the mutation was maternally inherited in both families; however, the clinical presentation of the mutation varied among relatives in each family.

The symptoms of iPPSD are inconsistent and easily misidentified, which highlights the necessity of early genetic screening and PTH monitoring for patients with AHO-like physical traits or electrolyte imbalances. Precise molecular diagnosis is vital for ensuring effective and timely clinical intervention, as well as for preventing long-term complications associated with this rare metabolic disorder. This study provides valuable clinical and genetic data to enhance the understanding and management of PHP/iPPSD.