SAT-805 - Genotype-Phenotype Discordance in Familial Primary Hyperparathyroidism: Parafibromin Loss with CDC73 Germline Mutation in A Young Adult

Introduction: Alterations in the CDC73 gene and loss of parafibromin expression are classically associated with primary hyperparathyroidism and aggressive parathyroid disease. Interpretation may be challenging when patients subsequently develop postoperative hypoparathyroidism, creating a genotype–phenotype discordance. The present case illustrates this scenario and its clinical implications.

Clinical Presentation: A 26-year-old male was evaluated for recurrent nephrolithiasis, flank pain, nausea, vomiting, and hematuria, with a family history of renal lithiasis and prior bilateral urolithiasis surgeries. Laboratory evaluation revealed marked hypercalcemia (total calcium 12.5–12.6 mg/dL, ionized calcium 5.55 mg/dL) with inappropriately elevated PTH (76–82.8 pg/mL) and sufficient 25-hydroxyvitamin D levels, consistent with PHPT. Sestamibi SPECT/CT localized a right inferior parathyroid lesion. Uro-CT demonstrated bilateral renal lithiasis. Parathyroidectomy was performed, and intraoperative pathology revealed a markedly enlarged (1 g) parathyroid gland. Immunohistochemistry showed loss of parafibromin expression, and germline testing confirmed a pathogenic CDC73 mutation. Postoperatively, the patient developed persistent hypoparathyroidism with hypocalcemia and inappropriately normal PTH, requiring chronic calcium and active vitamin D supplementation.

Discussion: This case highlights the importance of recognizing familial PHPT in young patients. Loss of parafibromin serves as a surrogate marker of functional CDC73 inactivation and is associated with an increased risk of recurrence and malignant transformation. Postoperative hypoparathyroidism represents a surgical sequela rather than a disease phenotype and should not obscure the patient’s long-term oncologic risk.

Conclusion: All young patients with nephrolithiasis should undergo biochemical screening for PHPT. When PHPT is diagnosed at a young age, genetic testing is mandatory to identify familial syndromes such as CDC73-related disease, given the increased risk of recurrence, parathyroid carcinoma, and associated manifestations. Lifelong biochemical surveillance is essential.

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