The Impact of Clinical and Genetic Screenings on the Management of the Multiple Endocrine Neoplasia Type 1

Abstract

METHODS:The clinical diagnosis of MEN1 was made in accordance with the Consensus on multiple endocrine neoplasias. Mutation analysis of the entire MEN1 tumor suppressor gene and genetic screening of at-risk family members were performed by direct sequencing. To analyze the implementation of genetic diagnosis, the studied patients were separated into 3 groups: MEN1 index cases (group I), clinically diagnosed MEN1 cases (group II), and genetically diagnosed MEN1 cases (group III). RESULTS: In total, 154 individuals were clinically and genetically studied. We identified 12 different MEN1 mutations. Fifty-two MEN1 cases were identified: 13 in group I, 28 in group II, and 11 in group III. The mean age in group III (27.0 years) was significantly lower than in groups I (39.5 years) and II (42.4 years; P = 0.03 and P = 0.01, respectively). Patients in groups I and II mostly presented 2 or 3 MEN1-related tumors, while 81.8% of those in group III presented 1 or no MEN1-related tumor. Additionally, in group III, 45.4% of cases were asymptomatic, and no metastasis or death was verified. Surveillance for MEN1 mutations allowed the exclusion of 102 noncarriers, including a case of MEN1 phenocopy. CONCLUSION: Our data supports the benefits of clinical and genetic screening for multiple endocrine neoplasia type 1 in the management of this syndrome.

Early-onset, progressive, frequent, extensive, and severe bone mineral and renal complications in multiple endocrine neoplasia type 1–associated primary hyperparathyroidism

“…The mild biochemical disease contrasted with the early-onset, progressive, frequent, extensive, and severe bone demineralization in our HPT/MEN1 subset. The relative excess of symptomatic HPT patients in our sample (81%) also has been reported in other HPT/MEN1 cohorts, (13,15,16,(26)(27)(28) contrasting with the modern SPHPT series (20%). (21)(22)(23)(24)(25) In addition, our data suggest that the asymptomatic stage of MEN1-associated HPT seems to be relatively short because up to 60% of patients younger than 30 years of age were already symptomatic (urolithiasis).…”

“…In all cases, the search for MEN1-related tumors was performed using clinical, biochemical, radiologic, and pathologic procedures, as reported previously. (15,28,29) Urolithiasis was considered a complication of HPT after hypocitraturia, hyperoxaluria, and hyperuricosuria were ruled out. The minimum estimated time of HPT disease was defined as the interval between the age at the first reported renal stone and the BMD analysis; in the asymptomatic cases, it was estimated as the time interval between the age at the HPT diagnosis and the BMD analysis.…”

“…We studied 36 HPT patients (18 males and 18 females) who belonged to 8 unrelated MEN1 families that had been fully characterized both clinically and genetically (15,28,29) (Supplemental Table S1). The following MEN1 disease-causing mutations were identified in the 8 MEN1 families studied: 308del1 (exon 2), I147F (exon 2), 1059del1 (exon 7), L413R (exon 9), 360del4 (exon 2), 375del21 (exon 2), 360del4 (exon 2), and R527X (exon 10), respectively (15,28,29) (Supplemental Fig.…”

“…The following MEN1 disease-causing mutations were identified in the 8 MEN1 families studied: 308del1 (exon 2), I147F (exon 2), 1059del1 (exon 7), L413R (exon 9), 360del4 (exon 2), 375del21 (exon 2), 360del4 (exon 2), and R527X (exon 10), respectively (15,28,29) (Supplemental Fig. S1).…”

“…Also, high frequencies of urolithiasis (>30% to 75%) have been reported systematically in HPT/MEN1, unlike what has been observed in modern SPHPT series (<20%). (1)(2)(3)13,15,(25)(26)(27)(28) Moreover, a progressive decrease in renal function has been reported in patients with SPHPT, although data on the early and late outcomes of urolithiasis-related renal complications in the context of the HPT/MEN1 subset are limited. (1)(2)(3)9,25,27) In the present investigation, we studied 36 patients with uncontrolled primary HPT from 8 unrelated MEN1 families, all of them harboring MEN1 germ-line mutations.…”