Familial aggregation of primary hyperparathyroidism and malignancy – nationwide case-control and cohort study

Context Primary hyperparathyroidism presents both in sporadic and hereditary forms, with familial clustering observed in certain genetic syndromes. While emerging research suggests an increased malignancy risk in patients, the extent to which this association extends to their first-degree relatives remains unclear. Understanding familial aggregation of primary hyperparathyroidism and malignancies could reveal underlying genetic risk factors and guide clinical management. Objective To assess familial clustering of primary hyperparathyroidism and malignancies among first-degree relatives of affected patients. Design A nationwide register-based case-control and cohort study including all patients with primary hyperparathyroidism who underwent parathyroidectomy between 2008-2017, with matched controls and their first-degree relatives. Setting Swedish nationwide population-based register study. Participants A total of 6 693 patients born in Sweden after 1932 were matched with 33 393 controls. Main outcome measure Diagnoses of primary hyperparathyroidism and malignancies among first-degree relatives. Results A total of 218 729 first-degree relatives were identified. Relatives of patients had significantly higher odds of primary hyperparathyroidism, particularly if diagnosed at age ≤45 (OR 7.7, 95%CI 5.23–11.34, P<0.001). The risk of malignancy was slightly increased (OR 1.07, 95%CI 1.01–1.13, P=0.017), due to prostate, non-medullary thyroid, and hematologic malignancies. In prospective analysis, no increased risk of malignancy in relatives was observed. Conclusions This study highlights a significant familial aggregation of primary hyperparathyroidism, particularly in early-onset cases. Although a modest overrepresentation of a family history of malignancy was observed, this may reflect multiple comparisons and surveillance bias rather than a true causal link between primary hyperparathyroidism and cancer.