Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A in Denmark 1930-2021: A Nationwide Population-Based Retrospective Study

Simple Summary: Multiple endocrine neoplasia 2A (MEN 2A) is a rare hereditary cancer syndrome, in which primary hyperparathyroidism (PHPT) is reported in up to 35% of affected individuals. Recent studies suggest a lower frequency and a milder course of PHPT in MEN 2A, but these studies often lack a strict definition of PHPT and are frequently carried out at smaller research centers. This could result in diverging and incomplete data. Consequently, we aimed to investigate PHPT in a complete nationwide cohort of MEN 2A to suggest a representative frequency and clinical course of PHPT. This may alter the information given to MEN 2A patients by their caretakers on the likelihood of developing PHPT and on the clinical course of PHPT.Studies of primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 2A (MEN 2A) shows divergence in frequency, disease definition, reporting of clinical characteristics and traces of selection bias. This is a nationwide population-based retrospective study of PHPT in MEN 2A, suggesting a representative frequency, with complete reporting and a strict PHPT definition. The Danish MEN 2A cohort 1930-2021 was used. Of 204 MEN 2A cases, 16 had PHPT, resulting in a frequency of 8% (CI, 5-12). Age-related penetrance at 50 years was 8% (CI, 4-15). PHPT was seen in the American Thyroid Association moderate (ATA-MOD) and high (ATA-H) risk groups in 62% and 38% of carriers, respectively. Median age at PHPT diagnosis was 45 years (range, 21-79). A total of 75% were asymptomatic and 25% were symptomatic. Thirteen underwent parathyroid surgery, resulting in a cure of 69%, persistence in 8% and recurrence in 23%. In this first study with a clear PHPT definition and no selection bias, we found a lower frequency of PHPT and age-related penetrance, but a higher age at PHPT diagnosis than often cited. This might be affected by the Danish RET p.Cys611Tyr founder effect. Our study corroborates that PHPT in MEN 2A is often mild, asymptomatic and is associated with both ATA-MOD and ATA-H variants. Likelihood of cure is high, but recurrence is not infrequent and can occur decades after surgery.