MON-758 - When Hypoparathyroidism Presents Late: A Genetic Diagnosis in Adulthood

Hypoparathyroidism is a rare endocrine disorder characterized by hypocalcemia with inappropriately low or absent parathyroid hormone (PTH), with an estimated prevalence of 23 cases per 100,000. Most cases are postsurgical, while nonsurgical hypoparathyroidism accounts for a smaller proportion including autoimmune, infiltrative, and genetic causes. Advances in molecular diagnostics have identified several genes critical for parathyroid development and function, including GCM2, a transcription factor essential for embryologic parathyroid gland development.
Pathogenic variants in GCM2 represent a rare cause of nonsurgical hypoparathyroidism, often presented in childhood under an autosomal recessive (AR) inheritance. However, partial loss-of-function variants may be associated with delayed or adult-onset disease, contributing to under
recognition in clinical practice.
A 52-year-old female with multiple sclerosis was referred for evaluation of a 15 year longstanding hypocalcemia. She had no history of neck surgery, radiation, or infiltrative disease. Family history was remarkable for autoimmune conditions. Laboratories consistently showed hypocalcemia (corrected calcium 8.2–8.5 mg/dL), low PTH levels (9–14 pg/mL), and normal magnesium, renal function, and fibroblast growth factor-23 (FGF-23) levels. Calcium supplementation was complicated due to an elevated 24-hour urinary calcium excretion. Management included calcitriol and carefully titrated vitamin D, and thiazide diuretics, with target serum calcium levels of 8–8.5 mg/dL. Given her clinical presentation, a genetic evaluation was pursued. An Invitae hypoparathyroidism panel identified a heterozygous likely pathogenic splice-site variant in GCM2 (c.90+2T>G), consistent with carrier status for AR hypoparathyroidism.
This case illustrates the diagnostic challenge of adult-onset nonsurgical hypoparathyroidism in the setting of coexisting autoimmune disease. Although autoimmune mechanisms were initially suspected due to the patient’s history of multiple sclerosis, genetic testing identified a likely pathogenic variant in GCM2, a gene essential for parathyroid development and function. While GCM2-related hypoparathyroidism is classically described in childhood, this case highlights that genetically mediated disease may present later in life and remain unrecognized for years. Identification of a genetic etiology has important clinical implications, shifting management toward lifelong biochemical surveillance, careful calcium and vitamin D titration, and prevention of renal complications. For endocrinologists, this case underscores the value of incorporating genetic evaluation into the workup of unexplained hypoparathyroidism, even in adults with competing autoimmune diagnoses, as precision diagnosis directly informs prognosis, management, and patient counseling.

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