Endocrine Abstracts

JOINT3364

Background: Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterized by target organ resistance to parathyroid hormone (PTH) caused by mutations in the GNAS gene or other upstream targets. This condition often presents with hypocalcemia, hyperphosphatemia, and characteristic skeletal abnormalities. Due to its diverse clinical manifestations, PHP is frequently misdiagnosed, resulting in delayed treatment and increased risk of complications. We present a case of PHP initially misdiagnosed as epilepsy, highlighting the importance of recognizing hypocalcemia as a differential diagnosis in seizure disorders.

Presentation: A 9-year-old girl with a history of congenital hip dislocation and no significant family history was admitted for evaluation of recurrent seizures. No previous records of hypocalcemia were noted. Her first seizure occurred at the age of three and was diagnosed as epilepsy, leading to treatment with sodium valproate. Despite this, she continued to experience 1–2 seizures annually, which escalated to daily seizures three weeks before hospitalization. Upon neurological examination, severe hypocalcemia was identified, and the child was referred to an endocrinologist for further investigation. Physical examination identified features of Albright hereditary osteodystrophy (AHO), including a round face, short stature (-2.0 SD), central obesity (+2.6 SD), brachydactyly, scoliosis, and developmental delay. Initial laboratory results revealed severe hypocalcemia (ionized calcium: 0.65 mmol/L), hyperphosphatemia (2.97 mmol/L), normal magnesium (0.72 mmol/L), vitamin D sufficiency (78.3 ng/ml), and significantly elevated PTH levels (766 pg/ml). Additional biochemical findings included elevated TSH (20.3 mUI/l)with normal FT4 (14 pmol/L), indicating multihormonal resistance. The radiographic evaluation confirmed shortened metacarpal bones, left hip dislocation, hip dysplasia, bilateral femoral flattening, and tibial shortening. Genetic testing via next-generation sequencing identified a heterozygous GNAS variant (c.2T>C; p.Met1?), a previously unreported mutation in GNAS-related disorders. ClinVar and In silico analysis classified this variant as likely pathogenic according to ACMG/AMP guidelines. The child was treated with calcitriol (20 ng/kg/day), oral calcium, and levothyroxine. Following treatment, seizures ceased completely, PTH and TSH levels normalized, and the patient showed a significant height increase of 6.5 cm over nine months (-2.0 SD to -1.5 SD).

Conclusion: This case highlights the diagnostic challenges of PHP, particularly in patients presenting with neurological symptoms such as seizures. We emphasize the importance of serum calcium, phosphate, and PTH evaluation in children with unexplained seizures or AHO-like features. Genetic analysis can provide diagnostic confirmation in ambiguous cases, guiding appropriate management and improving patient outcomes.

Keywords: Pseudohypoparathyroidism, GNAS mutation, hypocalcemia, Albright hereditary osteodystrophy.