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Bone and Mineral Metabolism

SAT-737 - Familial Primary Hyperparathyroidism Associated With a GCM2 p.Tyr394Ser Variant: Implications of Multiglandular Disease

Saturday, June 13, 2026
9:30 AM - 4:30 PM CT
Disclosure(s):
Cristina Alonso, MD: No financial relationships to disclose
Maria Mercedes Pineyro, MD: No financial relationships to disclose


Background: Primary hyperparathyroidism (PHPT) has a prevalence of 0.2–1.3%, and approximately 10% of cases are hereditary. Known hereditary forms include MEN1, MEN2A, familial hypocalciuric hypercalcemia, hyperparathyroidism-jaw tumor syndrome, and familial isolated PHPT (FIHP). Germline activating variants in GCM2 (Glial Cell Missing 2), a key transcriptional regulator of parathyroid development and PTH expression located on chromosome 6p24.2, have recently emerged as a novel cause of FIHP, reported in up to 18% of cases. The most frequently germline described variant is c.1181 A>C p.(Tyr394Ser), typically associated with multiglandular and asynchronous disease.
Clinical

Case: A 38-year-old woman was referred for PHPT after recurrent nephrolithiasis requiring multiple urologic interventions. Family history was notable for nephrolithiasis in her mother and brother; her mother had undergone two prior parathyroid surgeries for multiglandular disease. After correction of vitamin D deficiency, persistent hypercalcemia was confirmed (total calcium 10.65-11.21 mg/dL [8.0-10.6]; ionized calcium 1.38 mmol/L, [1.15-1.33]) with inappropriately elevated PTH (167-263 pg/mL, [18.4-80.1]. Neck ultrasound and 99mTc-sestamibi SPECT identified three enlarged glands, suggesting multiglandular disease. A hereditary PHPT panel was negative for classic pathogenic variants but revealed a heterozygous GCM2 c.1181A>C (p.Tyr394Ser) variant of uncertain significance. The patient underwent indocyanine green-guided selective parathyroidectomy with resection of the right superior and right inferior glands; the left inferior gland was identified and clipped. Histopathology showed hypercellular parathyroid tissue with markedly reduced adipose stroma, consistent with parathyroid hyperplasia. Postoperatively, serum calcium normalized; however, PTH remained elevated with persistent hypercalciuria and recurrent nephrolithiasis, consistent with persistent normocalcemic PHPT. Subsequent maternal testing demonstrated the same GCM2 variant, supporting a familial disorder.

Conclusion:
GCM2-related PHPT should be suspected in young patients with familial disease and multiglandular involvement. Expanded genetic testing that includes GCM2, is essential to guide management and may influence surgical decision-making. In this context, focused parathyroidectomy may be insufficient, whereas bilateral neck exploration and subtotal parathyroidectomy may improve long-term cure and reduce reoperations. Family screening is recommended. Further studies are needed to clarify variant penetrance, tumorigenic mechanisms, and potential associations with non-parathyroid neoplasia.

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