Protein-truncating germline pathogenic variants in the N- and C-terminal exons (2, 9, and 10) of the MEN1 gene may be associated with aggressive pancreatic neuroendocrine tumors. However, the impact of these variants on parathyroid disease is poorly understood. We sought to investigate the effects of genotype and surgical approach on clinical phenotype and postoperative outcomes in patients with multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism.
We identified patients with MEN1 evaluated at our institution from 1985 to 2020 and stratified them by genotype, (truncating variants in exons 2, 9, or 10, or other variants), and index surgical approach, (less-than-subtotal parathyroidectomy [<SPTX], SPTX, or total parathyroidectomy). We analyzed baseline characteristics, persistent/recurrent disease rates, and incidence of postoperative hypoparathyroidism.
Of the 209 patients we identified, primary hyperparathyroidism was diagnosed in 194 (93%) and at a younger median age in those with truncating exon 2, 9, or 10 variants compared with other variants (27 years vs 31 years; P = .006). Median disease-free survival was significantly worse in patients who underwent <SPTX (60 months) than those who underwent <SPTX (152 months; P = .0005) or total parathyroidectomy (210 months; P = .04). Patients with truncating exon 2, 9, or 10 variants who underwent <SPTX had significantly shorter median disease-free survival than those with other variants (30 vs 84 months; P = .007). Prolonged hypoparathyroidism rates after final surgery were highest after total parathyroidectomy (40%), followed by <SPTX (9%) and SPTX (7%).
The MEN1 genotype may affect the age of onset of primary hyperparathyroidism and the time to recurrence after surgery. <SPTX at index operation should be performed with caution, especially in patients with truncating MEN1 variants in exons 2, 9, or 10, as the higher risk of recurrence is not offset by a decreased incidence of permanent hypoparathyroidism compared to upfront SPTX.

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