Multiple Endocrine Neoplasia Type 1 Patients Research Articles

Comparison of 68Ga-DOTA-NaI3-Octreotide/tyr3-octreotate positron emission tomography/computed tomography and contrast-enhanced computed tomography in localization of tumors in multiple endocrine neoplasia 1 syndrome.

The optimum imaging modality for the screening of multiple endocrine neoplasia type 1 (MEN1)-associated tumors is not well established. Here, we compare the performance of contrast-enhanced CT (CECT) versus 68Ga DOTA-NOC/TATE PET/CT in MEN1 patients. The retrospective case record study is conducted at a tertiary health-care center. Thirty-four patients, who have undergone both CECT and 68Ga DOTA-NOC/ TATE PET, were included in the analysis. CECT had higher per-lesion sensitivity than 68Ga DOTA-NOC/TATE PET/CT for the detection of parathyroid lesions, (82.6% vs. 24.6%, P < 0.001). 68Ga DOTA-NOC/TATE PET/CT had higher per-lesion sensitivity than CECT for the detection of metastases (85% vs. 47.5%, P < 0.001) and gastrinomas (90% vs. 10%, P = 0.003). When combined use of the two imaging modalities is compared to CECT alone (63.7% vs. 93.1%, P = 0.00012) and 68Ga-DOTA-NOC/TATE PET/CT alone (74.1% vs. 93.1%, P = 0.0057), it provided significantly higher per-lesion sensitivity for the detection of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). 68Ga-DOTA-NOC/ TATE PET was more sensitive for the detection of gastrinomas and metastases than CECT, whereas it was less sensitive for the detection of parathyroid lesions than CECT. The combined use of both the imaging modalities significantly increases the sensitivity for detection of GEP-NETs.

18F-FDOPA PET/CT accurately identifies MEN1-associated pheochromocytoma.

SummaryPheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both 18F-fluorodeoxyglucose (18F-FDG) PET/CT and 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. 18F-FDOPA PET/CT may be beneficial for localization in these patients.Learning points:18F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients.Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions.MEN1 is implicated in the tumorigenesis of PHEO in this patient.

Comparison of 68Ga-Dotatate PET/CT and 18F-FDOPA PET/CT for the diagnosis of pancreatic neuroendocrine tumors in a MEN1 patient

ContextPancreatic neuroendocrine tumors (PNETs) occur in more than 80% of patients with multiple endocrine neoplasia type 1 (MEN1) syndrome, with predominance of small (<1cm) non-functioning tumors, followed by gastrinomas and insulinomas. Due to their small size, the diagnostic performance of conventional MRI and CT imaging is highly variable, with a real risk of false-negatives. Functional imaging on 111In-DTPA-Octreotide SPECT somatostatin receptor scintigraphy (Octreoscan®) is the modality of choice, but shows only 80% sensitivity. Alternatively, 18F-fluorodihydroxyphenylalanine (FDOPA) and, more recently, 68Ga-Dotatate PET/CT imaging are valuable options in case of negative Octreoscan®. Case reportA 55 old-year woman diagnosed with MEN1 syndrome, presented with multiple asymptomatic but progressive PNETs revealed on ultrasound endoscopy. Octreoscan® was negative, as was 18F-FDOPA PET/CT, whereas 68Ga-Dotatate PET/CT detected all PNETs found on endoscopy. ConclusionWe here report the first case of a MEN1 patient who successfully underwent a 68Ga-Dotatate PET/CT for detection and follow-up of PNETs, while both Octreoscan® and 18F-FDOPA PET/CT were negative.

Single gland excision for MEN1-associated primary hyperparathyroidism.

Guidelines advocate subtotal parathyroidectomy (SPTX) or total parathyroidectomy with autotransplantation (TPTX) with bilateral cervical thymectomy for primary hyperparathyroidism (pHPT) associated with multiple endocrine neoplasia type 1 (MEN1). However, both procedures are associated with a significant risk of permanent hypoparathyroidism. The aim of the current study was to compare long-term results of either single gland excision (SGE, 1-2 glands), SPTX and TPTX for the treatment of MEN1-associated pHPT. Data of genetically confirmed MEN1 patients who underwent surgery for pHPT between 1987 and 2017 were retrieved from a prospective database and were retrospectively analysed. Eighty-nine MEN1 patients underwent either TPTX (n=38, 42.7%), SPTX (n=23, 25.8%) or SGE (n=28, 31.5%). The rate of disease persistence after initial surgery was 2.6%, 0% and 14.2% in the TPTX, SPTX and SGE groups, respectively. After median follow-up of 112 (range 7-411) months, the rate of recurrent pHPT was significantly higher in the SGE group (n=19, 21.3%) compared with the TPTX (n=4, 4.4%, P=.001) and the SPTX (n=9, 10.1%, P=.03) groups. Analysis of the recurrence-free time among the surgical groups revealed a significant difference (P=.036). The median time to recurrence was significantly shorter after SGE (101, range 3-301months) than after SPTX (139, range 28-278months, P=.018) and TPTX (204, range 75-396months, P=.049). Twelve (32%) patients who underwent TPTX developed permanent hypoparathyroidism compared with only 4 (17%, P=.06) in the SPTX and 0 in the SGE group (P=.001). Given the high rate of postoperative permanent hypoparathyroidism after TPTX and SPTX, SGE is a valid option for the treatment of MEN1-associated pHPT.

Multiple endocrine neoplasia type 1 in Poland: a two-centre experience.

Multiple endocrine neoplasia type 1 (MEN1) has been causing problems for clinicians since it was first described in 1954 by Wermer. Not only its rarity, but also its variable clinical manifestations and lack of genotype-phenotype correlation make it hard to establish evidence-based guidelines for the management of this syndrome. Nationwide registers and population-based research are the best means to improve knowledge about this rare disease. As yet, there is no example of such research in the Polish population of MEN1 patients. We performed a retrospective analysis of clinical and genetic data of patients diagnosed with MEN1 syndrome and followed-up in two polish referral centres in the years 1994-2018. We analysed 79 patients, of whom the majority were women. The mean age of the patient population was 43 years, mean age at MEN1 diagnosis was 37.95 years, and mean interval from initial symptoms to MEN1 diagnosis was 6.93 years. Primary hyperparathyroidism (PHP), gastroenteropancreatic neuroendocrine tumour (GEP-NET), and pituitary adenoma (PA) developed in 90%, 52%, and 47% of patients, respectively. The dominance of insulinoma with low prevalence of gastrinoma is the most vivid difference, when compared to previously described populations. Moreover, we found 3.5-fold higher risk of developing a pituitary tumour in patients with a frameshift mutation with the STOP codon of the MEN1 gene. The Polish population of patients with MEN1 is different than previously described European and Asian populations, primarily in prevalence of functional NETs. A frameshift mutation with the STOP codon of the MEN1 gene significantly increases the risk of PA. Further studies with a larger cohort of patients are needed to fully describe the Polish population and improve diagnosis and management of the syndrome.

Prognostic factors and survival in MEN1 patients with gastrinomas: Results from the DutchMEN study group (DMSG).

Background and objectivesGastrinomas are the most prevalent functioning neuroendocrine tumors (NET) in multiple endocrine neoplasia type 1 (MEN1). Guidelines suggest medical therapy in most patients, but surgery may be considered in a subgroup. Currently, factors to guide management are necessary. This population‐based cohort study assessed prognostic factors of survival in patients with MEN1‐related gastrinomas.MethodsPatients with MEN1 having gastrinomas were identified in the Dutch MEN1 database from 1990 to 2014 based on fasting serum gastrin (FSG) levels and/or pathology. Predictors of overall survival were assessed using Cox regression.ResultsSixty‐three patients with gastrinoma (16% of the MEN1 population) were identified. Five‐ and 10‐year overall survival rates were 83% and 65%, respectively. Prognostic factors associated with overall survival were initial FSG levels ≥20x upper limit of normal (ULN) (hazard ratio [HR], 6.2 [95% confidence interval, 1.7‐23.0]), pancreatic NET ≥2 cm (HR 4.5; [1.5‐13.1]), synchronous liver metastases (HR 8.9; [2.1‐36.7]), gastroduodenoscopy suspicious for gastric NETs (HR 12.7; [1.4‐115.6]), and multiple concurrent NETs (HR 5.9; [1.2‐27.7]).ConclusionLife expectancy of patients with MEN1 gastrinoma is reduced. FSG levels and pancreatic NETs ≥2 cm are prognostic factors. FSG levels might guide surveillance intensity, step‐up to additional diagnostics, or provide arguments in selecting patients who might benefit from surgery.

Two well-differentiated pancreatic neuroendocrine tumor mouse models

Multiple endocrine neoplasia type 1 (MEN1) is a genetic syndrome in which patients develop neuroendocrine tumors (NETs), including pancreatic neuroendocrine tumors (PanNETs). The prolonged latency of tumor development in MEN1 patients suggests a likelihood that other mutations cooperate with Men1 to induce PanNETs. We propose that Pten loss combined with Men1 loss accelerates tumorigenesis. To test this, we developed two genetically engineered mouse models (GEMMs)—MPR (Men1flox/floxPtenflox/flox RIP-Cre) and MPM (Men1flox/floxPtenflox/flox MIP-Cre) using the Cre-LoxP system with insulin-specific biallelic inactivation of Men1 and Pten. Cre in the MPR mouse model was driven by the transgenic rat insulin 2 promoter while in the MPM mouse model was driven by the knock-in mouse insulin 1 promoter. Both mouse models developed well-differentiated (WD) G1/G2 PanNETs at a much shorter latency than Men1 or Pten single deletion alone and exhibited histopathology of human MEN1-like tumor. The MPR model, additionally, developed pituitary neuroendocrine tumors (PitNETs) in the same mouse at a much shorter latency than Men1 or Pten single deletion alone as well. Our data also demonstrate that Pten plays a role in NE tumorigenesis in pancreas and pituitary. Treatment with the mTOR inhibitor rapamycin delayed the growth of PanNETs in both MPR and MPM mice, as well as the growth of PitNETs, resulting in prolonged survival in MPR mice. Our MPR and MPM mouse models are the first to underscore the cooperative roles of Men1 and Pten in cancer, particularly neuroendocrine cancer. The early onset of WD PanNETs mimicking the human counterpart in MPR and MPM mice at 7 weeks provides an effective platform for evaluating therapeutic opportunities for NETs through targeting the MENIN-mediated and PI3K/AKT/mTOR signaling pathways.

MON-LB055 A Single Center Experience of Multiple Endocrine Neoplasia Type 1 (MEN1) vs Sporadic Insulinoma: What Can We Learn and Where Are We Going?

Background: Further characterization of insulinomas from MEN1 patients versus sporadic cases may help elucidate pathophysiological differences and improve future diagnostic algorithms. Methods A retrospective analysis of all patients with insulinoma were included (MEN1 between 1971-2019; sporadic between 1997-2019). Demographic, clinical, laboratory results including a supervised fast, imaging and intra-arterial calcium stimulation (CaStim) data were retrieved when available. Categorical and continuous variables were compared using Fisher’s exact test and Mann-Whitney U-test, respectively. Results One hundred and thirteen patients were identified with insulinoma (69 women, median 44 years, range 13-78 years); of these, 27 patients had MEN1 (11 women, median 37 years, range 18-64 years). Patients with MEN1-related insulinomas sustained a significantly longer duration of the fast and had larger surgically resected tumors (29.73±15.32 vs 15.4±10.8 hours, p<0.001; and 3.2±1.3 vs 1.6±0.8 cm, p<0.001, respectively). In MEN1 patients, CT and MRI failed to localize a pancreatic neuroendocrine tumor in 3/15 (20%) and 2/11 (18%) of patients. CaStim localized 5/8 (63%) insulinomas in MEN1 patients versus 66/81 (81%) insulinomas in sporadic patients. Conclusion Insulinomas in MEN1 patients are larger and more difficult to localize. The role of insulinoma-specific imaging, including 68Ga-DOTA-exendin-4 PET/CT, may improve localization sensitivity in MEN1 over CaStim. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

MON-320 Lost in the Rugae: High Grade Gastric Neuroendocrine Tumor in an MEN1 Patient with Zollinger-Ellison Syndrome

BACKGROUND: Gastric neuroendocrine tumors (carcinoid) associated with Zollinger Ellison Syndrome (ZES) induced hypergastrinemia in Multiple Endocrine Neoplasia type 1 (MEN1) occur in 15-50% of patients and are generally thought to be benign. Here we present a case of metastatic grade 3 gastric neuroendocrine tumor in MEN1. CASE: A 41-year male with history of MEN1 syndrome manifested by hyperparathyroidism, pancreatic neuroendocrine tumors, and Zollinger-Ellison Syndrome had been followed for 10 years. The patient had undergone yearly surveillance including CT, MRI, upper GI endoscopy (EGD) and 68Ga-DOTATATE, which had identified multiple small foci in the pancreas and duodenum. However, only MRI revealed a T2 hypointense 2.6 cm mildly enhancing mass along the lesser curvature of the stomach that was not visible on CT, MRI, EGD or 68Ga-DOTATATE within the 2 years prior. Gastrin levels remained <500 pg/mL during this time. EGD within 3 months prior to diagnosis demonstrated near complete suppression of acid (on omeprazole 120mg BID) confirmed with an acid output of 0 mEq/hr and no visible masses within the enlarged gastric folds. A follow-up 68Ga-DOTATATE scan identified an intraluminal mass on the medial aspect of the gastric wall (17.55 SUV). On review, the tumor was not able to be visualized on prior scans due to the diffuse ZES-induced hypertrophic gastric mucosa and poorly distended stomach. In addition, 18F-FDG-PET/CT scan demonstrated a faint but discrete photopenic defect associated with known mass in the gastric wall. The patient underwent surgical resection of a 3.5cm mass. Pathology demonstrated strong and diffusely positive synaptophysin and chromogranin A with Ki-67 labelling index (MIB-1) >20% and mitotic count >20 per 10 high powered fields. At the time of diagnosis, this lesion was histologically classified as well to moderately differentiated, high grade neuroendocrine carcinoma (Grade 3), large cell type. Loss of heterozygosity for the MEN1 gene at 11q13 was confirmed in the tumor. Monitoring with serial scans demonstrated right hepatic lobe metastasis by 1-year post-surgery. CONCLUSION: Previous reports of MEN1/ZES gastric carcinoid are associated with high gastrin levels, long disease duration, and are typically grade 1 or 2[i]. Special attention to identification of gastric mucosal nodules with well-controlled ZES is required as these lesions may rarely become malignant. Endnotes i Berna MJ, et al. A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors. JCEM. 2008; 93(5):1582-91.

MON-328 Twenty-Year Follow-Up of a Patient with a Novel MEN1 Gene Mutation

Background: The multiple endocrine neoplasia type 1 (MEN1) syndrome is a rare autosomal dominant inherited tumor syndrome. Mutations in the MEN1 gene are detectable in approximately 70-90% of kindreds with classic MEN1 syndrome (1). We present the case of a patient with a novel MEN1 gene mutation. Clinical Case: A 41 year old Caucasian male with a diagnosis of MEN1 syndrome has been followed up in our clinic for 20 years. At the age of 21, he had two parathyroid glands resection for hypercalcemia which revealed an adenoma of the right superior parathyroid gland. He had one more parathyroid gland resected 6 months later for persistent hypercalcemia. Around that time, he also had appendectomy for suspected appendicitis and the pathology results showed a carcinoid tumor of the appendix. At the age of 33, he underwent total parathyroidectomy, thymectomy, and auto transplantation of half parathyroid gland in the left forearm for recurrent hypercalcemia. At the age of 39, he developed frequent hypoglycemic episodes with symptoms including confusion. Serum glucose levels of 20-30 mg/dL were documented during the episodes. A 72 hours fasting test showed a plasma glucose level of 53 mg/dL, with insulin level of 25.6 mU/L, proinsulin level of 5.2 pmol/L, C-peptide level of 5 ng/mL and low beta- hydroxybutyrate level. In response to 1 mg glucagon intravenous injection, plasma glucose level improved by 83 mg/dL in 30 minutes. He then had selective arterial calcium stimulation test and the results showed the insulin peak rising after stimulation in the splenic artery suggested that the lesion was in the body and tail of the pancreas. He had partial pancreatectomy for insulinoma, however, the pathology results were consistent with vasoactive intestinal polypeptide- producing tumor (VIPoma) rather than insulinoma. The serum tests also supported a diagnosis of VIPoma: the VIP levels were 96.3 pg/mL preoperatively and 65 pg/mL postoperatively. Notably, he had intermittent abdominal pain after food intake and chronic watery diarrhea 5-7 times a day before pancreatectomy, which resolved after the surgery. The patient underwent genetic screening for MEN1 mutations which revealed the presence of a novel germline deletion mutation in exon 8 (1078delC), resulting in frame shifting of its coded menin protein (Arg360fsX13). Conclusion: We describe a novel MEN1 gene mutation (1078delC) in a patient with typical clinical manifestations of MEN1 syndrome including parathyroid adenomas, appendix carcinoid tumor, VIPoma, and insulinoma. The concurrence of pancreatic VIPoma and insulinoma or the existence of a pancreatic neuroendocrine tumor co-producing insulin and VIP in MEN1 patients has not been reported previously. Reference: (1) Agarwal SK. The future: genetics advances in MEN1 therapeutic approaches and management strategies. Endocr Relat Cancer. 2017;24:T119-T134.

MON-335 Phenocopy of Multiple Endocrine Neoplasia Type 1 (MEN1) Due to a Germline Cell Division Cycle 73 (CDC73) Variant

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid tumors, and neuroendocrine tumors (NETs) of the pituitary and pancreas. MEN1 is caused by germline mutations of the tumor suppressor gene MEN1, which are found in >75% of MEN1 patients. The remaining patients may have mutations involving: as yet unidentified genes; or other genes with known involvement in endocrine tumors, e.g. cyclin dependent kinase inhibitor 1B (CDKN1B) which is associated with MEN4. Here, we report a patient who had primary hyperparathyroidism, acromegaly, and a pancreatic NET that showed immuno-staining for glucagon and chromogranin A, which are consistent with MEN1. However, mutational analysis did not identify a MEN1 mutation, and analysis of other genes was undertaken, after informed consent was obtained from the patient. These genes include: CDKN1B; CDKN1A; CDKN2B; CDKN2C;cell cycle division 73 (CDC73), causative for hyperparathyroidism-jaw tumour (HPT-JT) syndrome, an autosomal dominant disorder characterised by occurrence of parathyroid tumors, ossifying fibromas of the jaw, renal tumours and uterine tumors; calcium sensing receptor (CASR), causative for familial hypocalciuric hypercalcemia type 1 (FHH1); and aryl-hydrocarbon receptor-interacting protein (AIP), causative for familial pituitary tumors. This revealed a heterozygous c.1138C>T (p.Leu380Phe) missense mutation of CDC73. This is likely a disease-causing mutation as: 1) the p.Leu380Phe substitution is not present in >120,000 alleles of The Exome Aggregation Consortium (ExAc) database; 2) involves an evolutionary conserved Leu380 residue; and 3) is situated within the parafibromin domain predicted to interact with the polymerase associated factor 1 (PAF1) and RNA polymerase II, (POLR2A) complex. In addition, RNA-Scope analysis, to detect specific CDC73 mRNA transcripts in paraffin embedded sections, of the patient’s pancreatic NET revealed that CDC73 mRNA expression was significantly decreased by >13% (p<0.005) in the tumor cells, compared to normal adjacent islets. Thus, our results suggest the spectrum of tumours associated with CDC73 mutations also includes pancreatic NETs, and demonstrate that CDC73 mutations may result in a phenocopy of MEN1.

Concomitant pancreatic neuroendocrine tumors in hereditary tumor syndromes: who, when and how to operate?

Abstract Pancreatic neuroendocrine tumors (pNETs) might present as part of a complex of hereditary (familial) syndromes caused by germline mutations such as multiple endocrine neoplasia type 1 (MEN1), von Hippel–Lindau syndrome (VHL), tuberous sclerosis, and neurofibromatosis syndromes. Hereditary pNETs are frequently misdiagnosed because their presentation may mimic other more common diseases, resulting in diagnostic delays. Although non-operative (conservative) management could be advocated in select cases in most patients, hereby avoiding surgery without loss of oncological safety, some cases still need operative intervention before malignancy develops. The objective of this review is to address the most recent literature and the evidence it provides for the indications, timing and options of operative treatment for concomitant pNETs in hereditary tumor syndromes. Complete sequencing of the whole gene is recommended for suspected hereditary pNETs. Proven functional pNETs with hereditary tumor syndromes is a good indication for surgical treatment. Conservative management for MEN1 patients with a non-functional pNET of 2 cm or smaller is associated with a low risk of malignant transformation and metastasis development. VHL-related pNETs patients with tumor size &gt;1.5 cm or a missense mutation or any mutation type in exon 3 may benefit from surgical intervention. The parenchyma-sparing surgical strategy should be preferentially performed whenever possible in all hereditary syndromes. The decision to recommend surgery to prevent malignant transformation and tumor spread, which is based on multidisciplinary expertise and the patient's preference, should be balanced with operative mortality and morbidity.

Could the Less-Than Subtotal Parathyroidectomy Be an Option for Treating Young Patients With Multiple Endocrine Neoplasia Type 1-Related Hyperparathyroidism?

Background: The surgical treatment of primary hyperparathyroidism (HPT) in patients with multiple endocrine neoplasia type 1 (MEN1) has evolved due the concern of permanent hypoparathyroidism. As the diagnosis has increased, the extent of operation has decreased. Most MEN1 patients requiring parathyroidectomy are younger than 50 years and they pose a difficult balance to achieve between persistent HPT and life-long hypoparathyroidism. The aim of the present study is to review our experience with a large series of patients with MEN1-related HPT (HPT/MEN1) treated at a single institution in order to find clues to a better treatment decision in these younger cases.Method: Retrospective analysis of consecutive HPT/MEN1 cases treated at a single institution with different operations: total parathyroidectomy and immediate forearm autograft (TPTX-AG), subtotal (STPTX), unintentional less than subtotal (U-LSTPTX) and intentional less than subtotal parathyroidectomy (I-LSTPTX).Results: Considering 84 initial cases operated on since 2011 (TPTX-AG, 39; STPTX, 22, U-LSTPTX, 13, and I-LSTPTX, 10), the rates of hypoparathyroidism were 30.8% (U-LSTPTX), 28.2% (TPTX-AG), 13.6% (STPTX), and 0% (I-LSTPTX). Two-thirds of them (68%; 57/84) were young (<50 years) or asdolescents. MIBI scan was more sensitive to show parathyroid glands and bilateral disease. Considering the concordance of MIBI and ultrasound for the possibility of unilateral clearance, it would be suitable to 22.6% of the cases. Intra-operative parathormone showed a significant decay even after unilateral exploration, but longer follow up is necessary. Overall, there were seven (4%) adolescents in 161 cases treated from 1987 to 2018, three underwent TPTX-AG and four had U-LSTPTX. Five are euparathyroid, one had mild recurrence, and one required a reoperation after 8 years due to the residual gland.Conclusions: Young patients are the most frequent candidates to parathyroidectomy. Less extensive procedures may be planned only if carefully reviewed preoperative imaging studies suggest a localized disease. Patients and their relatives should be fully informed of the risks and benefits during consent process. Future research with larger cohorts and long-term results are necessary to clarify if less than I-LSPTX or unilateral clearance are really adequate in selected groups of patients with HPT/MEN1 presenting lower volume of disease detected by preoperative imaging studies.

Novel Mutations in Serbian MEN1 Patients: Genotype-phenotype Correlation.

SummaryBackgroundMultiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome characterized by the occurrence of primary hyperparathyroidism (PHPT), pituitary adenoma (PA) and pancreatic neuroendocrine tumor (pNET). Whether the underlying mutations in MEN1 gene predict clinical presentation of affected heterozygotes or not, is still a matter of a debate.MethodsClinical and genetic analysis of 90 consecutive MEN1 patients was performed in a retrospective, single – center study.ResultsMEN1 mutation was found in 67 (74.4%) patients belonging to 31 different families. Twenty nine different heteozygous mutations were found, including 6 novel point mutations (W220G, 941delG, 1088del7, 1184insA, 1473del10, 1602del17) and one large deletion of exon 8. Truncating mutations predicted development of pNETs (OR=5.8, 95% CI 1.7 – 19.7%) and PHPT (OR=4.3, 95% CI 1.5 – 12.4%).ConclusionsLarge number of novel mutations among MEN1 patients confirmed previously reported data. PNETs and PHPT were more frequent in patients with truncating mutations.

Adrenocortical carcinoma in patients with MEN1: a kindred report and review of the literature

ObjectiveUp to 40% of multiple endocrine neoplasia type 1 (MEN1) patients may have adrenal cortical tumors. However, adrenocortical carcinoma (ACC) is rare. The clinical manifestations, prevalence, inheritance and prognosis of ACC associated with MEN1 remain unclear. Here we report the clinical manifestations and prevalence of ACC in patients with MEN1.Design and methodsA retrospective analysis of ACC associated with MEN1 patients at a single tertiary care center from December 2001 to June 2017. Genetic analysis of MEN1 and other ACC associated genes, loss of heterozygosity (LOH) of MEN1 locus, immunohistochemistry staining of menin, P53 and β-catenin in ACC tissue were performed.ResultsTwo related patients had ACC associated with MEN1. The father had ENSAT stage IV tumor with excessive production of cortisol; the daughter had nonfunctional ENSAT stage I tumor. Both patients carried novel germline heterozygous mutation (c.400_401insC) of MEN1. The wild-type MEN1 allele was lost in the resected ACC tissue from the daughter with no menin staining. The ACC tissue had nuclear β-catenin staining, with heterozygous CTNNB1 mutation of 357del24 and P53 staining in only 20% cells.ConclusionsACC associated with MEN1 is rare and may occur in familial aggregates.

Intraoperative Decision-Making and Technical Aspects of Parathyroidectomy in Young Patients With MEN1 Related Hyperparathyroidism.

One in 5,000 to 1 in 50,000 births have multiple endocrine neoplasia type 1 (MEN1). MEN1 is a hereditary syndrome clinically defined by the presence of two of the following endocrine tumors in the same patient: parathyroid adenomas, entero-pancreatic endocrine tumors and pituitary tumors. Most commonly, patients with MEN1 manifest primarily with signs and symptoms linked to primary hyperparathyroidism. By age 50, it is estimated that 100% of patients with MEN1 will have been diagnosed with primary hyperparathyroidism. These patients will need to undergo resection of their hyperfunctioning glands, however there is no clear consensus on which procedure to perform and when to perform it in these patients. In this original study we describe and explain the rational of our peri-operative approach and management at MD Anderson Cancer Center of MEN1 patients with hyperparathyroidism. This protocol includes preoperative evaluation, intraoperative decision-making and detailed surgical technique adopted for these patients' care. Additionally we review follow-up and disease management in instances of recurrent primary hyperparathyroidism in patients with MEN1 syndrome.

When Parathyroidectomy Should Be Indicated or Postponed in Adolescents With MEN1-Related Primary Hyperparathyroidism.

Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare inherited endocrine tumor syndrome principally affecting parathyroid glands, neuroendocrine tissues of the gastro-entero-pancreatic and thoracic tracts, and anterior pituitary, caused by germline inactivating mutations of the MEN1 tumor suppressor gene. Primary hyperparathyroidism (PHPT) is usually the first clinical manifestation of the syndrome, normally manifesting during the third decade of life. Cases of affected children and adolescents have been described by the age of 5. Clinical characteristics and therapeutic management of MEN1 in adolescents have been described mainly by case reports. Only two studies on MEN1 patient series under the age of 22 years have recently been published. Given the scarcity of data and the lack of a consistent number of targeted studies, there are currently no specific guidelines available for children and adolescents with MEN1; diagnostic and therapeutic management is, thus, usually the same as for adult patients. Here, we report our experience with 19 adolescent MEN1 patients, developing MEN1-associated PHPT before the age of 20. Fourteen of them, manifesting hypercalcemic PHPT before the age of 20 underwent parathyroidectomy before the age of 25 to control calcemia. Parathyroid surgery restored normal calcemia in all the operated patients. No post-surgical nephrolithiasis has been reported after a mean of 12.0 ± 5.8 years of follow-up. Comparison between pre-surgical and post-surgical values of bone mineral density (BMD) in 2 patients evidenced an improvement of bone mass after parathyroid adenoma ablation. Two patients (14.28%) developed permanent post-surgical hypoparathyroidism.

Results of Duodenopancreatic Reoperations in Multiple Endocrine Neoplasia Type 1.

To evaluate the outcome of duodenopancreatic reoperations in patients with multiple endocrine neoplasia type 1 (MEN1). MEN1 patients who underwent reoperations for duodenopancreatic neuroendocrine neoplasms (dpNENs) were retrieved from a prospective database and retrospectively analyzed. Twelve of 101 MEN1 patients underwent up tothree reoperations, resulting in a total of 18 reoperations for dpNEN recurrence. Patients initially underwent either formal pancreatic resections (n = 7), enucleations (n = 3), or duodenotomy with lymphadenectomy for either NF-pNEN (seven patients), Zollinger-Ellison syndrome (ZES, three patients), organic hyperinsulinism (one patient) or VIPoma (one patient). Six patients had malignant dpNENs with lymph node (n = 5) and/or liver metastases (n = 2). The indication of reoperations was NF-pNEN (five patients), ZES (five patients), organic hyperinsulinism (one patient), and recurrent VIPoma (one patient). Median time to first reoperation was 67.5 (range 6-251) months. Five patients required a second duodenopancreatic reoperation for 60-384months after initial surgery, and one patient underwent a third reoperation after 249months. The rate of complications (Clavien-Dindo≥3) was 28%. Four patients required completion pancreatectomy. Six patients developed pancreoprivic diabetes. After a median follow-up of 18 (6-34) years after initial surgery, ten of 12 patients are alive, one died of metastatic pancreatic VIPoma, and one died of metastatic thymic NEN. Reoperations are frequently necessary for dpNEN in MEN1 patients, but are not associated with an increased perioperative morbidity in specialized centers. Organ-sparing resections should be preferred as initial duodenopancreatic procedures to maintain pancreatic function and avoid completion pancreatectomy.

'Quality in, quality out', a stepwise approach to EBM for rare diseases promoted by MEN1.

Rare diseases pose specific challenges in the field of medical research to provide physicians with evidence-based guidelines derived from studies with sufficient quality. An example of these rare diseases is multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant endocrine tumor syndrome with an estimated occurrence rate of 2–3 per 100,000. For this complex disease, characterized by multiple endocrine tumors, it proves difficult to perform both adequate and feasible studies. The opinion of patients themselves is of utmost importance to identify the gaps in the evidence-based medicine regarding clinical care. In the search for scientific answers to clinical research questions, the aim for best available evidence is obvious. Observational studies within patient cohorts, although prone to bias, seem the most feasible study design regarding the disease prevalence. Knowledge and adaptation to all types of bias is demanded in the strive for answers. Guided by our research on MEN1 patients, we elaborate on strategies to identify sufficient patients, to maximize and maintain patient enrolment and to standardize the data collection process. Preferably, data collection is performed prospectively, however, under certain conditions, data storage in a longitudinal retrospective database with a disease-specific framework is suitable. Considering the global challenges on observational research on rare diseases, we propose a stepwise approach from clinical research questions to scientific answers.

The Importance of an Early and Accurate MEN1 Diagnosis.

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant inherited condition, causing significant morbidity, and a reduction of life expectancy. A timely and accurate diagnosis of MEN1 is paramount to improve disease outcomes. This enables early identification of tumor manifestations allowing timely treatment for reducing morbidity and improving survival. Current management of MEN1 poses two challenges regarding the MEN1 diagnosis: diagnostic delay and the issue of phenocopies. A delay in diagnosis can be caused by a delay in identifying the index case, and by a delay in identifying affected family members of an index case. At present, lag time between diagnosis of MEN1 in index cases and genetic testing of family members was estimated to be 3.5 years. A subsequent delay in diagnosing affected family members was demonstrated to cause potential harm. Non-index cases have been found to develop clinically relevant tumor manifestations during the lag times. Centralized care, monitoring of patients outcomes on a national level and thereby improving awareness of physicians treating MEN1 patients, will contribute to improved care. The second challenge relates to “phenocopies.” Phenocopies refers to the 5–25% of clinically diagnosed patients with MEN1in whom no mutation can be found. Up to now, the clinical diagnosis of MEN1 is defined as the simultaneous presence of at least two of the three characteristic tumors (pituitary, parathyroids, or pancreatic islets). These clinically diagnosed patients undergo intensive follow up. Recent insights, however, challenge the validity of this clinical criterion. The most common mutation-negative MEN1 phenotype is the combination of primary hyperparathyroidism and a pituitary adenoma. This phenotype might also be caused by mutations in the CDKN1B gene, causing the recently described MEN4 syndrome. Moreover, primary hyperparathyroidism and pituitary adenoma are relatively common in the general population. Limiting follow-up in patients with a sporadic co-occurrence of pHPT and PIT could reduce exposure to radiation from imaging, healthcare costs and anxiety.