Multiple Endocrine Neoplasia Type 1 Patients Research Articles

Pancreatic Neuroendocrine Neoplasms in Multiple Endocrine Neoplasia Type 1.

Pancreatic neuroendocrine tumors (pNETs) are a rare group of cancers accounting for about 1–2% of all pancreatic neoplasms. About 10% of pNETs arise within endocrine tumor syndromes, such as Multiple Endocrine Neoplasia type 1 (MEN1). pNETs affect 30–80% of MEN1 patients, manifesting prevalently as multiple microadenomas. pNETs in patients with MEN1 are particularly difficult to treat due to differences in their growth potential, their multiplicity, the frequent requirement of extensive surgery, the high rate of post-operative recurrences, and the concomitant development of other tumors. MEN1 syndrome is caused by germinal heterozygote inactivating mutation of the MEN1 gene, encoding the menin tumor suppressor protein. MEN1-related pNETs develop following the complete loss of function of wild-type menin. Menin is a key regulator of endocrine cell plasticity and its loss in these cells is sufficient for tumor initiation. Somatic biallelic loss of wild-type menin in the neuroendocrine pancreas presumably alters the epigenetic control of gene expression, mediated by histone modifications and DNA hypermethylation, as a driver of MEN1-associated pNET tumorigenesis. In this light, epigenetic-based therapies aimed to correct the altered DNA methylation, and/or histone modifications might be a possible therapeutic strategy for MEN1 pNETs, for whom standard treatments fail.

Genomic profiling of multiple tissues in two patients with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome. This hereditary cancer is caused by germline variants in MEN1. Two patients with MEN1 were identified via whole exome sequencing and gene expression profile analysis, conducted for 5,063 patients with various types of cancers. We obtained multiple tumors from each patient; tumors derived from these two MEN1 patients had a loss of the normal MEN1 allele and frequently chromosomal copy number changes. Thus, we investigated whether structural variants were present in the MEN1 patient genomes. Whole-genome sequencing revealed no catastrophic rearrangements, and the tumor samples had very low somatic variants. The two patients had germline variants in MEN1 and some chromosomal copy number changes including on chromosome 11. The only pathogenic variant detected was the MEN1 germline variant, and chromosomal rearrangements led to tumorigenesis in somatic cells. Furthermore, the MEN1 tumor samples displayed a specific signature characterized by T:A>C:G transition. Studies of multiple tumors obtained from single patients are rare in hereditary cancer syndromes, and our results provide insights that the second hit of the tumor suppressor gene MEN1 may be caused by a gross genome rearrangement, not a small insertion and deletion, nor a change in epigenetic regulation.

Clinical Profile and Mutations Associated with Multiple Endocrine Neoplasia-Type1 (MEN1) and Their First-Degree Relatives at Risk of Developing MEN1: A Prospective Study.

Multiple Endocrine Neoplasia type-1 (MEN1) is an autosomal dominant disorder with a combined occurrence of tumours of parathyroid glands, pancreatic islets, and anterior pituitary. About 90% of these patients carry mutations in the MEN1 gene, though the spectrum is not well defined in India. Forty clinically suspected cases of MEN1 were enrolled prospectively over six years; 32 patients (23 index-cases and nine affected relatives) with≥2 classical endocrine tumours of MEN1 were considered definite, and eight were categorised as 'MEN1-like'. Details of their clinical presentation, treatment and mutational analysis including MEN1 gene, 3' and 5' untranslated regions (UTR) of MEN1, CDKN1B, and CaSR genes were collated. Asymptomatic first-degree relatives were also screened. Among the 32 definite MEN1 patients, all had primary hyperparathyroidism, 22 (68.7%) had gastroentero-pancreatic neuroendocrine tumours, and 21 (66%) had pituitary adenoma. Of the 23 definite index-cases, 13 (56.5%) carried mutations in the MEN1 gene. Five of nine affected first-degree relatives (55.5%), and four of 10 asymptomatic relatives (40%) also had MEN1 mutations. Seven of 10 MEN1 mutation-negative definite index-cases harboured p.V109G polymorphism in the CDKN1B gene. All eight MEN1-like cases were negative for mutations and large deletions in MEN1, mutations in 3' and 5' UTR of MEN1, CaSR and CDKN1B genes. The study has helped to clearly document the pattern of mutations among Indian MEN1 patients. However, the absence of MEN1 mutation in ~44% of cases and the presence of p.V109G polymorphism in CDKN1B gene raise the question whether such polymorphisms could independently contribute to pathogenesis.

Breast cancer in multiple endocrine neoplasia type 1 (MEN1).

SummaryA 38-year-old female was identified as carrying a heterozygous pathogenic MEN1 variant (c.1304delG) through predictive genetic testing, following a diagnosis of familial hyperparathyroidism. Routine screening for parathyroid and pituitary disease was negative. However, cross-sectional imaging by CT revealed a 41 mm pancreatic tail mass. Biopsy via endoscopic ultrasound confirmed the lesion to be a well-differentiated (grade 1) pancreatic neuroendocrine tumour (pNET) with MIB1<1%. Biochemically, hyperinsulinaemic hypoglycaemia was confirmed following an overnight fast, which was subsequently managed by diet alone prior to definitive surgery. Pre-operative work-up with octreotide SPECT CT demonstrated avid tracer uptake in the pancreatic lesion and, unexpectedly, a focal area of uptake in the left breast. Further investigation, and subsequent mastectomy, confirmed ductal carcinoma in situ pT2 (23 mm) grade 1, N0 (ER positive; HER2 negative). Following mastectomy, our patient underwent a successful distal pancreatectomy to resect the pNET. Loss of heterozygosity (LOH) at the MEN1 locus was found in both the breast tumour and pNET, thereby in keeping with a 'two-hit' hypothesis of oncogenesis, a suggestive but non-definitive clue for causation. To obtain further support for a causative relationship between MEN1 and breast cancer, we undertook a detailed review of the published literature which overall supports the notion that breast cancer is a MEN1-related malignancy that presents at a younger age and histologically, is typically of ductal subtype. Currently, clinical guidance regarding breast cancer surveillance in MEN1 does not exist and further research is required to establish a clinical and cost-effective surveillance strategy).Learning pointsWe describe a case of pNET and breast cancer diagnosed at a young age of 38 years in a patient who is heterozygous for a pathogenic MEN1 variant. Loss of the wild-type allele was seen in both breast tissue and pNET specimen.Breast cancer may be an under-recognised MEN1-associated malignancy that presents at a younger age than in the general population with a relative risk of 2–3.Further research is required to determine the cost-effectiveness of breast cancer surveillance approach at a younger age in MEN1 patients relative to the general population .

Pancreatoduodenectomy for Neuroendocrine Tumors in Patients with Multiple Endocrine Neoplasia Type 1: An AFCE (Association Francophone de Chirurgie Endocrinienne) and GTE (Groupe d\u2019\xe9tude des Tumeurs Endocrines) Study

AimTo assess postoperative complications and control of hormone secretions following pancreatoduodenectomy (PD) performed on multiple endocrine neoplasia type 1 (MEN1) patients with duodenopancreatic neuroendocrine tumors (DP-NETs).BackgroundThe use of PD to treat MEN1 remains controversial, and evaluating the right place of PD in MEN1 disease makes sense.MethodsThirty-one MEN1 patients from the Groupe d’étude des Tumeurs Endocrines MEN1 cohort who underwent PD for DP-NETs between 1971 and 2013 were included. Early and late postoperative complications, secretory control and overall survival were analyzed.ResultsIndication for surgery was: Zollinger–Ellison syndrome (n = 18; 58%), nonfunctioning tumor (n = 9; 29%), insulinoma (n = 2; 7%), VIPoma (n = 1; 3%) and glucagonoma (n = 1; 3%). Mean follow-up was 141 months (range 0–433). Pancreatic fistulas occurred in 5 patients (16.1%), distant metastases in 6 (mean onset of 43 months; range 13–110 months), postoperative diabetes mellitus in 7 (22%), and pancreatic exocrine insufficiency in 6 (19%). Five-year overall survival was 93.3% [CI 75.8–98.3] and ten-year overall survival was 89.1% [CI 69.6–96.4]. After a mean follow-up of 151 months (range 0–433), the biochemical cure rate for MEN-1 related gastrinomas was 61%.ConclusionIn MEN1 patients, pancreatoduodenectomy can be used to control hormone secretions (gastrin, glucagon, VIP) and to remove large NETs. PD was found to control gastrin secretions in about 60% of cases.

Gastric enterochromaffin-like cell changes in multiple endocrine neoplasia type 1.

Gastric enterochromaffin-like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES. Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014-2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin- and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed. Thirty-eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n=22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206pg/ml vs. 30.5pg/ml, p<.001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p=.302, chromogranin A: p=.464). Enterochromaffin-like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported.

Impact of gastrointestinal symptoms on quality of life in MEN2.

Besides medullary thyroid carcinoma and other endocrinopathies, people with Multiple Endocrine Neoplasia Type 2 (MEN2) are at risk of gastrointestinal (GI) symptoms. To investigate the impact of GI symptoms on the daily lives of patients with MEN2. An online survey was conducted among patients with MEN2 via the Association for Multiple Endocrine Neoplasia Disorders (AMEND). The survey incorporated two validated questionnaires for the assessment of GI symptoms (SAGIS, PAC-QoL). There were 91 respondents, MEN2A (n=57), MEN2B (n=34). People in the MEN2A group reported a high level of GI symptoms, the most prevalent being abdominal pain 85% (n=49), diarrhoea 85% (n=49) and constipation 75% (n=43) with one patient having a SAGIS score>10/12 in the constipation domain. People in the MEN2B group reported constipation in 79% (n=27) with one quarter of these scoring>10/12 in the constipation domain. Other GI symptoms included diarrhoea 62% (n=21), excessive gas and flatulence (79%), epigastric pain (59%) abdominal cramps (76%) and dysphagia (41%). The effect of constipation on quality of life was severe in all MEN2 patients as measured by PAC-QOL and all patients reported dissatisfaction of with their current treatment for constipation. There was a trend towards higher severity of GI symptoms in MEN2B. We report unmet needs of patients with MEN2 syndromes. The GI symptoms, especially constipation, had a severe impact on quality of life in people with MEN2. This suggests that there is room for improvement in the quality of care offered for these patients.

Phenotypes Associated With MEN1 Syndrome: A Focus on Genotype-Phenotype Correlations.

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited tumor syndrome, associated with parathyroid, pituitary, and gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs). MEN1 is usually consequent to different germline and somatic mutations of the MEN1 tumor suppressor gene, although phenocopies have also been reported. This review analyzed main biomedical databases searching for reports on MEN1 gene mutations and focused on aggressive and aberrant clinical manifestations to investigate the potential genotype-phenotype correlation. Despite efforts made by several groups, this link remains elusive to date and evidence that aggressive or aberrant clinical phenotypes may be related to specific mutations has been provided by case reports and small groups of MEN1 patients or families. In such context, a higher risk of aggressive tumor phenotypes has been described in relation to frameshift and non-sense mutations, and predominantly associated with aggressive GEP NETs, particularly pancreatic NETs. In our experience a novel heterozygous missense mutation at c.836C>A in exon 6 was noticed in a MEN1 patient operated for macro-prolactinoma, who progressively developed recurrent parathyroid adenomas, expanding gastrinomas and, long after the first MEN1 manifestation, a neuroendocrine uterine carcinoma. In conclusion, proof of genotype-phenotype correlation is limited but current evidence hints at the need for long-term interdisciplinary surveillance in patients with aggressive phenotypes and genetically confirmed MEN1.

Multiple Endocrine Neoplasia Type 1: The Potential Role of microRNAs in the Management of the Syndrome.

Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited tumor syndrome, characterized by the development of multiple neuroendocrine tumors (NETs) in a single patient. Major manifestations include primary hyperparathyroidism, gastro-entero-pancreatic neuroendocrine tumors, and pituitary adenomas. In addition to these main NETs, various combinations of more than 20 endocrine and non-endocrine tumors have been described in MEN1 patients. Despite advances in diagnostic techniques and treatment options, which are generally similar to those of sporadic tumors, patients with MEN1 have a poor life expectancy, and the need for targeted therapies is strongly felt. MEN1 is caused by germline heterozygous inactivating mutations of the MEN1 gene, which encodes menin, a tumor suppressor protein. The lack of a direct genotype–phenotype correlation does not permit the determination of the exact clinical course of the syndrome. One of the possible causes of this lack of association could be ascribed to epigenetic factors, including microRNAs (miRNAs), single-stranded non-coding small RNAs that negatively regulate post-transcriptional gene expression. Some miRNAs, and their deregulation, have been associated with MEN1 tumorigenesis. Recently, an extracellular class of miRNAs has also been identified (c-miRNAs); variations in their levels showed association with various human diseases, including tumors. The aim of this review is to provide a general overview on the involvement of miRNAs in MEN1 tumor development, to be used as possible targets for novel molecular therapies. The potential role of c-miRNAs as future non-invasive diagnostic and prognostic biomarkers of MEN1 will be discussed as well.

Involvement of the MEN1 Gene in Hormone-Related Cancers: Clues from Molecular Studies, Mouse Models, and Patient Investigations

MEN1 mutation predisposes patients to multiple endocrine neoplasia type 1 (MEN1), a genetic syndrome associated with the predominant co-occurrence of endocrine tumors. Intriguingly, recent evidence has suggested that MEN1 could also be involved in the development of breast and prostate cancers, two major hormone-related cancers. The first clues as to its possible role arose from the identification of the physical and functional interactions between the menin protein, encoded by MEN1, and estrogen receptor α and androgen receptor. In parallel, our team observed that aged heterozygous Men1 mutant mice developed cancerous lesions in mammary glands of female and in the prostate of male mutant mice at low frequencies, in addition to endocrine tumors. Finally, observations made both in MEN1 patients and in sporadic breast and prostate cancers further confirmed the role played by menin in these two cancers. In this review, we present the currently available data concerning the complex and multifaceted involvement of MEN1 in these two types of hormone-dependent cancers.

ARMC5 Alterations in Patients With Sporadic Neuroendocrine Tumors and Multiple Endocrine Neoplasia Type 1 (MEN1).

Adrenal lesions are frequent among patients with sporadic neuroendocrine tumors (spNETs) or multiple endocrine neoplasia type 1 (MEN1). Armadillo repeat-containing 5 (ARMC5)-inactivating variants cause adrenal tumors and possibly other neoplasms. The objective of this work is to investigate a large cohort spNETs or MEN1 patients for changes in the ARMC5 gene. A total of 111 patients, 94 with spNET and 17 with MEN1, were screened for ARMC5 germline alterations. Thirty-six tumors (18 spNETs and 18 MEN1 related) were collected from 20 patients. Blood and tumor DNA samples were genotyped using Sanger sequencing and microsatellite markers for chromosomes. ARMC5 and MEN1 expression were assessed by immunohistochemistry. In 76 of 111 (68.4%) patients, we identified 16 different ARMC5 germline variants, 2 predicted as damaging. There were no differences in the prevalence of ARMC5 variants depending on the presence of MEN1-related adrenal lesions. Loss of heterozygosity (LOH) at chromosome 16p and ARMC5 germline variants were present together in 23 or 34 (67.6%) tumors; in 7 of 23 (30.4%) their presence led to biallelic inactivation of the ARMC5 gene. The latter was more prevalent in MEN1-related tumors than in spNETs (88.9% vs 38.9%; P = .005). LOH at the chromosome 16p (ARMC5) and 11q (MEN1) loci coexisted in 16/18 MEN1-related tumors, which also expressed lower ARMC5 (P = .02) and MEN1 (P = .01) proteins compared to peritumorous tissues. Germline ARMC5 variants are common among spNET and MEN1 patients. ARMC5 haploinsufficiency or biallelic inactivation in spNETs and MEN1-related tumors suggests that ARMC5 may have a role in modifying the phenotype of patients with spNETs and/or MEN1 beyond its known role in macronodular adrenocortical hyperplasia.

Multiple Endocrine Neoplasia Type 1 (MEN1) 5'UTR Deletion, in MEN1 Family, Decreases Menin Expression.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of parathyroid, pancreatic and pituitary tumors, and is due to mutations in the coding region of the MEN1 gene, which encodes menin. We investigated a family with identical twins that had MEN1, with different MEN1 tumors. DNA sequence analysis of the MEN1 coding region had not identified any abnormalities and we hypothesized that deletions and mutations involving the untranslated regions may be involved. Informed consent and venous blood samples were obtained from five family members. Sanger DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses were performed using leukocyte DNA. This revealed a heterozygous 596bp deletion (Δ596bp) between nucleotides -1087 and -492 upstream of the translation start site, located within the MEN1 5' untranslated region (UTR), and includes the core promoter and multiple cis-regulatory regions. To investigate the effects of this 5'UTR deletion on MEN1 promoter activity, we generated luciferase reporter constructs, containing either wild-type 842bp or mutant 246bp MEN1 promoter, and transfected them into human embryonic kidney HEK293 and pancreatic neuroendocrine tumor BON-1 cells. This revealed the Δ596bp mutation to result in significant reductions by 37-fold (p < 0.0001) and 16-fold (p < 0.0001) in luciferase expression in HEK293 and BON-1 cells, respectively, compared to wild-type. The effects of this 5'UTR deletion on MEN1 transcription and translation were assessed using qRT-PCR and Western blot analyses, respectively, of mRNA and protein lysates obtained from Epstein-Barr-virus transformed lymphoblastoid cells derived from affected and unaffected individuals. This demonstrated the Δ596bp mutation to result in significant reductions of 84% (p < 0.05) and 88% (p < 0.05) in MEN1 mRNA and menin protein, respectively, compared to unaffected individuals. Thus, our results report the first germline MEN1 5'UTR mutation and highlight the importance of investigating UTRs in MEN1 patients who do not have coding region mutations. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Patients With MEN1 Are at an Increased Risk for Venous Thromboembolism.

Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder predisposing the development of multiple functional and nonfunctional neuroendocrine tumors (NETs). Only uncommon MEN1-associated functional NETs such as glucagonomas (<1%) and adenocorticotropic hormone-producing tumors (<5%) are known to be associated with hypercoagulability. It is unknown if patients with MEN1 generally have an increased risk of venous thromboembolism (VTE). We queried a prospective natural history study of germline mutation-positive MEN1 patients (n = 286) between 1991 and 2019 for all lifetime events of VTE. The search terms were: DVT, thromb, embol, PE, pulmonary embolism, clot, hematology consult, anticoagulant, coumadin, lovenox, xarelto, warfarin, aspirin, rivaroxaban, and apixaban. Incidence rates were calculated, accounting for age and sex. Comparisons were made to published incidence rates in healthy populations, different types of cancer, and Cushing's syndrome. Thirty-six subjects (median age 45 years, range 16-75) experienced a VTE event, yielding a prevalence rate of 12.9%. The age-sex adjusted incidence rate of VTE is 9.11 per 1000 patient-years, with a sex-adjusted lifetime incidence rate of 2.81 per 1000 patient-years. MEN1-associated lifetime incidence rates are ~2-fold higher than the estimated annual incidence rate in the general population and are comparable to the known risk in the setting of various types of cancer. Approximately 80% of patients who had a VTE were diagnosed with pancreatic NETs, of which 24% were insulinomas. Fourteen patients (42%) experienced perioperative VTE events. MEN1 patients have an increased risk of VTE. Further mechanistic investigation and validation from other MEN1 cohorts are needed to confirm the increased prevalence of VTE in MEN1.

18F-fluorocholine PET/CT in MEN1 Patients with Primary Hyperparathyroidism.

Primary hyperparathyroidism (HPT1) is the most frequent endocrinopathy in multiple endocrine neoplasia type 1 (MEN1). Its surgical management is challenging. We aimed to describe and compare the imaging findings of parathyroid ultrasound (US), sestaMIBI scintigraphy (sestaMIBI), and 18F-fluorocholine (FCH) PET/CT in a series of MEN1 patients with HPT1. Retrospective analysis of a cohort of MEN1 patients with HPT1 assessed by parathyroid US, sestaMIBI scintigraphy and SPECT/CT, and FCH-PET/CT for potential surgery between 2015 and 2019. Twenty-two patients with a confirmed diagnosis of MEN1 who presented with HPT1 and were assessed by the 3 imaging modalities were included. After imaging workups, 11 patients were operated on for the first time, 4 underwent a redo surgery, and 7 did not undergo an operation. The overall patient-based positivity rate of imaging was 91% (20 of 22) for parathyroid US and 96% (21 of 22) for both sestaMIBI and FCH-PET/CT. The 3 imaging modalities demonstrated negative findings in 1/22 patient who did not undergo surgery. Overall, 3 pathologic glands were not detected by any imaging technique. SestaMIBI and FCH-PET/CT both resulted in the same 3 false-positive results in ectopic areas with a significant uptake on two thymic carcinoid tumors and one inflammatory lymph node. FCH-PET/CT provided more surgically relevant data than sestaMIBI in 4/11 patients with initial surgery and in 1/4 patient who underwent redo surgery. Compared to sestaMIBI scintigraphy, FCH-PET/CT provides additional information regarding the number of pathologic parathyroid glands and their localization in MEN1 patients with HPT1.

Pancreatic Neuroendocrine Tumors in Patients with Multiple Endocrine Neoplasia Type 1: Diagnostic Value of Different MRI Sequences

Background: MRI is a useful imaging modality to assess the presence of pancreatic neuroendocrine tumors (PNETs), allowing repeat monitoring examinations in multiple endocrine neoplasia type 1 (MEN-1) patients. Objectives: We aimed to compare the diagnostic accuracy of conventional MRI sequences to identify which sequence better depicts the presence of PNETs in MEN-1 patients. Method: We performed a retrospective analysis of consecutive MEN-1 patients who underwent a conventional MRI protocol to monitor previously proven PNETs. MRI sequences T1-w chemical shift (CS), T2-w HASTE, fat-suppressed (FS) T2-w HASTE, diffusion-weighted imaging (DWI), and pre- and post-contrast FS T1-w sequences were independently analyzed by 2 experienced radiologists using a 3-grade score (no lesion, uncertain lesion, and certain lesion); lesion size and signal intensity were recorded. A Friedman ANOVA and a Wilcoxon pairwise test for the post hoc analysis were used. The sensitivity of each sequence was measured, and the results were analyzed with the χ² test. Results: We included 21 patients with a total of 45 PNETs proven by histology, endoscopic ultrasonography-guided fine-needle aspiration, CT, and nuclear medicine studies. A statistically significant (p < 0.01) difference was observed in the detection performance of each MRI sequence, particularly between DWI (91%) and T2-w FS (85%) sequences in comparison to the others (T1-w CS, T2-w, and pre- and post-contrast FS T1-w, ≤56% for all); no significant (p = 0.5) difference was found between the detection performance of DWI and T2-w FS sequences. No correlation was observed between the qualitative score of each sequence and lesion tumor size. Conclusions: DWI and T2-w FS sequences proved to be the most accurate in the detection of PNETs, thus suggesting a role for an abbreviated MRI protocol without contrast medium administration for monitoring MEN-1 patients.

SUN-128 Impaired Fasting Glucose Is Associated with Insulin Resistance in Patients with Germline Mutations in the Multiple Endocrine Neoplasia Type 1 (MEN1) Gene

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by hyperparathyroidism, pituitary adenomas, and gastro-entero-pancreatic neuroendocrine tumors. Patients with MEN1 mutations have impaired glucose homeostasis, but the role of insulin resistance and beta-cell function is unclear.METHODS: Using a case-control study design, a retrospective analysis of germline mutation-positive MEN 1 patients (n=289) seen at our institution between 1991-2019 was performed. Patients with diabetes and/or insulinoma were excluded. Subjects were age, BMI, sex and race matched 1:1 to unrelated, healthy controls. Fasting glucose, insulin, c-peptide, calcium, PTH, 25-OH vitamin D, cholesterol, LDL, HDL and triglycerides (TG) were compared between two groups. Homeostasis model assessment (HOMA-IR) and HOMA-beta cell function (HOMA-b) were used as surrogate measures of insulin resistance and beta-cell function, respectively. Data is presented as mean ± SD.RESULTS: MEN1 subjects (n=40; age 41±11 years; BMI 29.2±7.2 kg/m2) were matched to healthy controls (age 41±11 years; BMI 29.1±7.5 kg/m2). Only 3 MEN1 patients had no evidence of pancreatic neuroendocrine tumors. Impaired fasting glucose was more prevalent in MEN1 compared with controls (53% vs 10%, p<0.0001). HOMA-IR was positively associated with BMI, but not age, sex, calcium or vitamin D levels in either cohort. HOMA-IR adjusted for age, BMI, and sex was higher in patients with MEN1 compared with controls (4.01 vs. 2.44, adjusted ratio of means 1.54, 95% CI [1.14, 2.07], p=0.005). HOMA-b was not significantly different between the groups (177 vs. 129, adjusted ratio of means 1.17, 95% CI [0.86, 1.58], p=0.23). There were no significant differences in total cholesterol, LDL, HDL, and TG between the groups.CONCLUSION: Lower insulin sensitivity, but not impaired beta cell function may contribute to the higher prevalence of impaired fasting glucose in MEN1 patients compared with controls. Mechanistic studies into the role of menin loss in glucose homeostasis are warranted.

MON-922 Multiple Endocrine Neoplasia Type 1- A Clarion Call for Clarity

A 35-year-old gentleman presented with epigastric pain and bilious emesis. He also endorsed urinary frequency, non-bloody diarrhea and diffuse bone pain. On physical examination he had epigastric tenderness and multiple hyperpigmented skin lesions.An abdominal computed tomography (CT) scan revealed multiple diverticula with peri-colonic fat stranding in the descending and sigmoid colon, concerning for diverticulitis. He was started on a course of metronidazole and ciprofloxacin. A 3.1 cm mass was incidentally noted in the uncinate process of the pancreas. Bilateral adrenal nodules were also appreciated.An endoscopic ultrasound (EUS) guided trans-gastric fine needle aspiration biopsy was performed, revealing a well differentiated pancreatic neuroendocrine tumor (pNET - pT3N1Mx, intermediate risk). Chromogranin A was elevated to 108 ng/ml (reference range <93 ng/ml). Serum and urine metanephrine, V-peptide, gastrin, glucagon and parathyroid hormone related peptide were all normal; indicating a nonfunctioning neuroendocrine tumor. He underwent a pancreaticoduodenectomy. Octreotide scan was unrevealing for residual uptake. Adrenal biopsy revealed adrenal adenomas.Three years later, he presented with severe abdominal pain and a new pancreatic mass was noted on CT. Chromogranin A was elevated to 227 ng/mL. EUS revealed a 0.35 cm mass in the bed of the pancreatic head, encasing the superior mesenteric artery. Pathology was positive for recurrence of the neuroendocrine tumor.He was hypercalcemic to 11.4 mg/dL and parathyroid hormone was elevated to 319 pg/mL. CT neck revealed a 0.1 cm nodule concerning for parathyroid adenoma. He underwent a subtotal parathyroidectomy.Genetic testing confirmed Multiple Endocrine Neoplasia Type 1 (MEN1) with a heterozygous mutation of the menin1 gene.MEN1 is a rare genetic syndrome with affected individuals at increased risk of developing pancreatic, pituitary, parathyroid gland and cutaneous tumors. With a kaleidoscope of presentations, clinicians must maintain a high index of suspicion for MEN1, particularly for cases with nonfunctioning pNETs which present insidiously and are the foremost cause of mortality in MEN1 patients.1Further clarity is needed on MEN1 associated pNET prognostic risk stratification, surveillance and targeted immunochemotherapy.2 Timely and algorithmic screening for MEN 1 syndrome in patients with pancreatic incidentalomas is essential to improving patient outcomes.1.Kamilaris CDC, Stratakis CA. Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis. Front Endocrinol. 2019;10:339. doi:10.3389/fendo.2019.003392.Yates CJ, Newey PJ, Thakker RV. Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1. Lancet Diabetes Endocrinol. 2015;3(11):895-905. doi:10.1016/S2213-8587(15)00043-1

SUN-124 Are Venous Thromboembolic Events Increased in MEN1 Patients?

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder in which patients develop multiple simultaneous hormone-secreting tumors. Most common tumors include: anterior pituitary adenomas (50%), multi-gland parathyroid adenomas (95%), and gastroenteropancreatic neuroendocrine tumors (40-80%). Only rare MEN1 associated glucagonomas (<1%), and ACTH-producing neuroendocrine tumors (<5%) are known to increase risk of hypercoagulability. It is unknown if patients with MEN1 syndrome have increased risk of venous thrombolytic events (VTE), defined as a deep-vein thrombosis and/or pulmonary embolism. Methods: We queried a prospective natural history study of MEN1 patients who tested positive for germline MEN1 mutations (n=287) between 1991-2019 (54 patients on our current protocol were followed before 1991; the earliest was 1971). All lifetime events of VTE were included. Search terms included: DVT, thromb, embol, PE, pulmonary embolism, clot, hematology consult, anticoagulant, coumadin, lovenox, xarelto, warfarin, aspirin, rivaroxaban and apixaban. After initial screening, 10 patients were removed due to insufficient clinical data. Kaplan-Meier analysis was performed to compare age of death between the two cohorts. Results were expressed as mean ± standard deviation. Results: Thirty-four subjects (mean 57.5 years-old, 17 women) were identified with any VTE, yielding a prevalence rate of 13.4%. The incidence of VTE corresponded to 264 events per 100,000 patient-years, which was ~2-fold higher than the estimated annual incidence rate in the general population (104-183/100,000 patient years).1 Kaplan-Meier analysis revealed no significant difference in survival between the two groups (non-VTE cohort mean 81.1 years ± 2.23; VTE cohort mean 77.4 years ± 3.45; p = 0.96). Thirty-two events occurred during the surveillance period at our institution; 9 individuals had more than one VTE. At the time of VTE, 80% had hyperparathyroidism (mean PTH ± SD; 97.56 pg/mL ± 90.76), 21% had hyperprolactinemia (prolactin 25.7μg/L ± 43.41), 62.5% had hypergastrinemia (mean gastrin 1100.9 pg/mL ± 3127.8), and 84.6% had non-functional pancreatic neuroendocrine tumors. One patient was identified to have a Factor V Leiden mutation, 3 patients had lupus anti-coagulant. Eleven patients experienced events within a post-surgical period of 3 months. Conclusions: Hypercoagulability in MEN1 has been previously unidentified. Our cohort data suggests a two-fold increase in the incidence of VTE as compared to the general population, with a high risk occurring within the perioperative period. Further mechanistic investigation and validation from other cohorts are needed to confirm the increased prevalence of VTE in this population. 1Heit, John A., et al. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015 Aug;12(8): 464-474.

SUN-912 The Rare Men of Mississippi Complications in the Diagnosis of Multiple Endocrine Neoplasia Type 1

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal dominant disorder associated with tumors of the parathyroid glands, pituitary gland, and gastroenteropancreatic cells caused by mutations of the MEN1 tumor-suppressor gene. Thescarcity with which this syndrome is encountered makes diagnosis challenging in rural settings. Clinical Case: A 34-year-old male presented to the Emergency Department complaining ofintermittent abdominal pain for the past year, that was associated with nausea, vomiting, and diarrhea. Past medical history was significant for hyperparathyroidism treated with parathyroidectomy, nephrolithiasis, and alcohol-induced chronic pancreatitis. Initial laboratory studies revealed elevated corrected calcium (11.5 mg/dL, n:7.6-10.6 mg/dL) with a subsequent elevated parathyroid hormone level (105, n:14-72 pg/mL). CT scan of the abdomen and pelvis revealed fatty liver changes, nonobstructive nephrolithiasis and pancreatic calcifications. Due to his recurrent symptoms, gastroenterology was consulted for esophagogastroduodenoscopy that revealed erosive esophagitis with multiple duodenal ulcers. The patient was started on a high dose Proton Pump Inhibitor IV and treated supportively. His symptoms improved within a few days. Additional studies were obtained including a gastrin level and H. pylori antigen testing that required sending out to an outside laboratory for analysis. He was discharged with close outpatient follow up scheduled, but then was readmitted two days later with recurrent symptoms. The patient was again treated with supportive care, and was able to provide additional family history revealing parathyroid and ulcer disease in both his father and paternal grandmother, which triggered suspicion for multiple endocrine neoplasia type 1. His gastrin level returned, and was found to be elevated (489 pg/mL, n < 100) with a negative H. pylori antigen, supporting the diagnosis of MEN1. Further diagnostic testing was performed, revealing an elevated serum chromogranin A level (117 ng/mL, n < 15) and abnormalities on MEN1 genetic testing. An Octreotide scan was then performed, showing a single intense area of uptake near the caudate lobe of liver. At this time, he was transferred to a tertiary medical center for further evaluation and management. Conclusion: This case illustrates the significance of suspicion for multiple endocrine neoplasia and the value of a complete history. Additionally, while a serum chromogranin A level can be nonspecific, it can be obtained in an outpatient setting to help differentiate neuroendocrine pathology from other etiologies. Though the symptoms of MEN1 patients can mimic many other disease processes, recognition of symptoms is critical for medical communities to provide swift treatment.

Health-Related Quality of Life in Patients with Multiple Endocrine Neoplasia Type 1

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine tumor syndrome characterized by the triad of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors (pNETs), and pituitary tumors. Patients are confronted with substantial morbidity and are consequently at risk for an impaired quality of life (QOL). Meticulous assessment of QOL and associated factors in a representative population is needed to understand the full spectrum of the burden of the disease. Patients and Methods: A cross-sectional study was performed using the national Dutch MEN1 cohort. Patients with a confirmed MEN1 mutation received the SF-36 Health Related Quality of Life questionnaire and questions regarding sociodemographic and medical history. Results: A total of 227 of 285 (80%) eligible MEN1 patients returned the questionnaires. Health-related QOL scores (HRQOL) in MEN1 patients were significantly lower for the majority of subscales of the SF-36 in comparison with the general Dutch population. The most consistent predictor for HRQOL was employment status, followed by the presence of a pituitary tumor. 16% of patients harboring a pNET and 29% of patients with a pituitary tumor according to the medical records, reported that they were unaware of such a tumor. These subgroups of patients had several significant better QOL scores than patients who were aware of their pNET or pituitary tumors. Conclusion: Patients with MEN1 have an impaired QOL in comparison with the general Dutch population warranting special attention within routine care. For daily practice, physicians should be aware of their patients’ impaired QOL and of the impact of unemployment on QOL.