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

Late-Breaking Poster Presenter(s)

CA

Cristina Alonso, MD

Chief
Hospital Británico, Montevideo, Uruguay
montevideo, Montevideo, Uruguay

Senior Author/Primary Investigator(s)

CA

Cristina Alonso, MD

Chief
Hospital Británico, Montevideo, Uruguay
montevideo, Montevideo, Uruguay

Co-Author(s)

CA

Cristina Alonso, MD

Chief
Hospital Británico, Montevideo, Uruguay
montevideo, Montevideo, Uruguay
JS

Jorge Santandreu, MD

Associate Professor of Surgery
Hospital Britanico, Montevideo, Uruguay
Montevideo, Montevideo, Uruguay
RG

Rosario Gueiçamburú, MD

Geneticist
Hospital Britanico, Montevideo, Uruguay
Montevideo, Uruguay
XG

Xose González, MD.

Nephrologist
Hospital Britanico, Montevideo, Uruguay
Montevideo, Montevideo, Uruguay
FD

Fermin Domenech, MD.

Urologist
Hospital Britanico
Montevideo, Montevideo, Uruguay
JF

Jorge Facal, MD.

Professor Internal Medicine
Hospital Britanico
Montevideo, Montevideo, Uruguay
MC

Marcelo Chiarella, MD.

Associate Professor Internal Medicine
Hospital Britanico, Montevideo, Uruguay
Montevideo, Montevideo, Uruguay
MP

Maria Pavlove, MD.

Endocrinologist
Hospital Carlos D. Duran, Buenos Aires, Argentina.
Buenos Aires, Buenos Aires, Argentina
Maria Mercedes Pineyro, MD

Endocrinologist
Hospital de Clinicas
Montevideo, URUGUAY

Disclosure(s):

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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