Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study

Abstract

Objective Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases. Design and methods An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017. Results Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4–1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis. Conclusions Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.

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

“…Four carried the RET p.Cys611Tyr variant and were 2–3 years old at the last follow-up and therefore below the recommended age for PHPT screening in the ATA-MOD group, starting at age 16 years [ 47 ]. Combined with the fact that the hitherto youngest p.Cys611Tyr carrier reported with PHPT was 40 years at diagnosis, one might methodologically justify including the four cases in our overall cohort as not having PHPT [ 48 ]. This would not change the PHPT frequency but reduce the number of missings to 4%.…”

Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance

“…Inherited MTC syndromes include multiple endocrine neoplasia type 2 (MEN2A and MEN2B) and familial MTC (FMTC) [8,9]. MTC is associated with pheocromocytoma (PCC) and parathyroid hyperplasia/primary hyperparathyroidism (PHPT) in MEN2A, [10,11], and with PCC, marfanoid habitus and ganglioneuromatosis of the gut and oral mucosa in MEN2B [12]; conversely, FMTC is characterized by multiple cases of MTC in the family, with no other clinical manifestations [13].…”

Multiple Endocrine Neoplasia 2A Detected by Peptic Ulcer Perforation with Hypercalcemia

“…3) Recent an international multicenter study reported that the prevalence of PHPT as first manifestation of MEN 2A was only 0.9% (10 cases out of 1085 MEN 2A). 4) In this case, we diagnosed PHPT firstly because of incidental finding of hypercalcemia and then we could confirm medullary thyroid carcinoma during localization study of PHPT. Coexisting thyroid tumor is easily found because parathyroid and thyroid are in adjacent location.…”