MEN1 Gene Mutation Research Articles

8207 Insights From a Case of Insulinoma and Possible Genetic Variants in a Young Woman With Recurrent Hypoglycemia

Abstract Disclosure: M.A. Brandao: None. A. Bharara: None. V.I. Moncada Castro: None. T.C. Tsai: None. Y. Wu: None. S. Marquez Flores: None. K. Divari: None. Introduction: Insulinomas are neuroendocrine neoplasms causing hyperinsulinemic hypoglycemia. They are rare, with a prevalence of 1-4 people per million of the general population. Key features are symptoms of hypoglycemia, low plasma glucose, and symptom relief by correcting hypoglycemia. Here, we report a patient with recurrent hypoglycemia who was found to have insulinoma. Several variants of uncertain significance (VUS) were detected in this patient. This gives us some insights into a broader perspective. Clinical case: A 28-year-old healthy female was found unresponsive by her partner. Blood glucose (BG) was 40 mg/dL when paramedics arrived. She received dextrose and rapidly recovered. She was briefly hospitalized and received glucose infusion with improvement. Subsequently, the patient developed episodes of blurry vision and weakness. She had been eating more frequently to prevent symptoms. Her weight was stable at 65.77 kg. She had not been on any medications. She continued to experience hypoglycemic episodes with BG dropping to 30 mg/dL, so she sought evaluation from an endocrinologist. Laboratory work-up showed Proinsulin of 530.6 pmol/L, C-peptide 5 ng/ml, TSH 1.01 mciu/ml, Beta-hydroxybutyrate (BHOB) 0.7 mg/dL, hemoglobin A1c 4.7%, calcium 8.9 mg/dL, albumin 4.1. Abdominal computed tomography (CT) scan showed an 11 mm nodule anterior to the pancreatic tail. No discrete calcification was noted. Magnetic resonance imaging (MRI) of the abdomen redemonstrated the 10 x 6mm, slightly exophytic lesion in the pancreatic tail. Therefore, she underwent laparoscopic enucleation with pathology showing a 1.7cm well-differentiated grade 2 neuroendocrine tumor, with positive margins. Given its indolent nature, further surgical resection was not recommended. Germline testing showed several VUS: the AXIN2 gene (c.1822C>G), GPC3 gene (c.565G>T), NF2 gene (c.296A>G), RECQL4 gene (c.2791C>G). However, no pathogenic variants were identified. Surveillance MRI of the abdomen six months after the surgery has shown no evidence of recurrent disease. The patient has remained euglycemic and symptoms have not recurred. Conclusion: Insulinomas are typically sporadic but may occur due to an activating T372R mutation in the Yin Yang. It may also occur in the setting of multiple endocrine neoplasia type 1 (MEN-1) syndrome caused by MEN1 gene mutations. Although no pathogenic variant mutations associated with insulinoma were found, several VUS that have not yet been described as related to insulinoma were detected in this patient. Routine genetic testing in newly diagnosed patients is not always recommended. Therefore, further efforts are required to understand genetic mutations and epigenetic modifiers associated with insulinoma. Validation of identified VUS and additional genetic testing in young patients with insulinoma are crucial. Presentation: 6/2/2024

Clinical characterization of a cohort of patients with multiple endocrine neoplasia syndrome type 1 (MEN1): role of the MEN1 gene mutation on the phenotypic expression of the syndrome

Clinical characterization of a cohort of patients with multiple endocrine neoplasia syndrome type 1 (MEN1): role of the MEN1 gene mutation on the phenotypic expression of the syndrome

Plasma miRNA expression in patients with genetically confirmed multiple endocrine neoplasia type 1 syndrome and its phenocopies

MEN-1 is a rare autosomal dominant disease caused by mutations in MEN1 gene encoding the menin protein. This syndrome is characterized by the occurrence of parathyroid tumors, gastroenteropancreatic neuroendocrine tumors, pituitary adenomas, as well as other endocrine and non-endocrine tumors. If a patient with the MEN-1 phenotype carry no mutations in the MEN1 gene, the condition considers a phenocopy of syndrome (phMEN1). The possible cause of this changes could be changes in epigenetic regulation, particularly in microRNA expression that might affect menin signaling pathways. to identify differently expressed circulating miRNAs in plasma in patients with genetically confirmed MEN-1 syndrome, its phenocopies and healthy controls. single-center, case-control study was conducted. We assessed plasma microRNA expression in patients with genetically confirmed MEN-1 (gMEN1), phMEN1 and healthy controls. Morning plasma samples were collected from fasting patients and stored at -80°C. Total RNA isolation was performed using miRNeasy Mini Kit with QIAcube. Thelibraries were prepared by the QIAseq miRNA Library Kit following the manufacturer. Circulating miRNA sequencing was done on Illumina NextSeq 500 (Illumina). Subsequent data processing was performed using the DESeq2 bioinformatics algorithm. we enrolled 21 consecutive patients with gMEN1 and 11 patients with phMEN1, along with 12 gender matched controls. Median age of gMEN1 was 38,0 [34,0; 41,0]; in phMEN1 - 59,0 [51,0; 60,0]; control - 59,5 [51,5; 62,5]. The gMEN1 group differed in age (p<0.01) but not gender (р=0.739) or BMI (р=0.116) compared to phMEN1 and controls group, the last two groups did not differ by these parameters (p>0.05). 25 microRNA were differently expressed in groups gMEN1 and phMEN1 (21 upregulated microRNAs, 4 - downregulated). Comparison of samples from the phMEN-1 group and relatively healthy controls revealed 10 differently expressed microRNAs: 5 - upregulated; 5 - downregulated. In the gMEN-1 and control groups, 26 differently expressed microRNAs were found: 24 - upregulated; 2 - downregulated. The miRNAs most differing in expression among the groups were selected for further validation by RT-qPCR (in the groups of gMEN1 vs phMEN1 - miR-3613-5p, miR-335-5p, miR-32-5p, miR-425-3p, miR-25-5p, miR-576-5p, miR-215-5p, miR-30a-3p, miR-141-3p, miR-760, miR-501-3p; gMEN1 vs control - miR-1976, miR-144-5p miR-532-3p, miR-375; as well as in phMEN1 vs control - miR-944, miR-191-5p, miR-98-5p). In a pilot study, we detected microRNAs that may be expressed differently between patients with gMEN-1 and phMEN-1. The results need to be validated using different measurement method with larger sample size.

Predicting the presence of MEN1 gene mutation based on the clinical phenotype of patients with primary hyperparathyroidism

Timely referral of patients for genetic testing to rule out MEN1-associated primary PHPT is important factor in determining treatment strategy and prognosis. In the context of the limited availability of genetic testing, the search for clinical markers indicative of MEN1 gene mutations remains an extremely relevant task. To determine the diagnostic value of clinical features of primary PHPT in young patients for predicting the presence of MEN1 gene mutations. A single-center, prospective study was conducted at the Endocrinology Research Centre, involving 273 patients with PHPT in the period 2015-2022. Based on the results of genetic and laboratory tests, patients were divided into three groups: those with MEN1 gene mutations (MEN+ group, n=71), those without MEN1 gene mutations - isolated sporadic PHPT (MEN- group, n=158), and patients with PHPT and associated endocrine gland disorders - MEN-1 syndrome phenocopies (PHEN group, n=32). Subgroups of patients younger than 40 years of age were also identified. Comparative analysis was performed among the independent groups and subgroups, and logistic regression analysis was used to develop a mathematical model for predicting the probability of the presence of MEN1 gene mutation. Patients in the MEN+ and MEN- groups were comparable by gender and age at manifestation, as well as calcium-phosphorus metabolism parameters and PHPT complications. In the PHEN group, PHPT manifested at older age compared to the other groups (p<0.001 for all), with lower total calcium levels and a trend toward lower iPTH concentrations. The MEN+ group had a significantly higher frequency of multiglandular parathyroid (PG) involvement, PHPT recurrence, and positive family history compared to the MEN- and PHEN groups. Histologically, adenomas predominated in the PHEN and MEN- groups (92% and 94%, respectively), whereas hyperplasia of PGs were more common in the MEN+ group (49%). None of the PHEN patients had all three «classic» components of the MEN-1 syndrome, and the clinical course of PHPT was similar to that of the MEN- group. These differences were also observed in the subgroups of patients younger than 40 years, which formed the basis for the development of a mathematical model. The logistic regression equation for predicting the probability of the presence of the MEN1 gene mutation included eight predictors, with a diagnostic sensitivity of 96% and specificity of 98%. Based on the analysis performed, eight hereditary predictors of PHPT within the MEN-1 syndrome were identified. A mathematical model was developed to predict the presence of the MEN1 gene mutation in patients, which demonstrated high classification performance on the training dataset. Further refinement of the model will help improve the quality of medical care for patients with PHPT.

THU506 A Not-So-Simple Case Of Hyperparathyroidism

Abstract Disclosure: P.J. Bhatt: None. S. Rabiei: None. V. Kantorovich: None. Multiple endocrine neoplasia 1 (MEN-1) is a rare autosomal dominant disorder caused by an inactivating mutation of the MEN-1 tumor suppressor gene and is associated with tumors of the parathyroid (95%), endocrine pancreas (40-70%) and anterior pituitary (30-40%). Primary hyperparathyroidism is the most frequent and earliest expression of MEN1 syndrome with a typical onset at age 20-25 in inherited cases, reaching 100% penetrance after age 50. Current guidelines recommend genetic testing in all individuals with primary hyperparathyroidism diagnosed at a young age, with multiglandular disease, or with family history of primary hyperparathyroidism. A 58 year old female with a history of L. breast cancer, pulmonary embolisms, DM2, and recurrent nephrolithiasis was diagnosed with primary hyperparathyroidism at age 36 and had a parathyroidectomy with 3.5 gland removal and later a total thyroidectomy. She continued to be symptomatic and was found to have an ectopic parathyroid gland in her chest requiring parathyroid gland reimplantation 18 years later. After 3 years, she was admitted for a CHF exacerbation and a pancreatic tail lesion was incidentally discovered. There was no mention of pancreatic lesions prior to this reading. Family history was pertinent for a father with nephrolithiasis. Her daughter had recurrent nephrolithiasis, hyperparathyroidism and was found to have a MEN 1 variant of uncertain significance, prompting the patient to seek genetic counseling. 22 years after her initial diagnosis of hyperparathyroidism, she tested positive for a likely pathologic heterozygous variant mutation of the MEN1 gene called 1747C>T. At endocrinology follow-up, she was asymptomatic. Labs showed elevated Chromogranin A at 1,799 ng/ dL [<311] and gastrin 174pg/mL [</=100]. FSH, LH, prolactin, free alpha subunit, cortisol, and IGF-1 were normal. Further imaging confirmed a DOTATATE-avid 1.1cm nodular lesion in the pancreatic tail, concerning for a neuroendocrine tumor. MEN1 gene mutation is associated with MEN1 syndrome, familial isolated hyperparathyroidism and has an autosomal dominant predisposition to thyroid cancer and paraganglioma-pheochromocytoma syndrome. The 1747C>T sequence change creates a premature translational stop signal in the MEN1 gene and disrupts the NLS2 domain of the MEN1 protein, which is important for DNA binding and repression of cell proliferation. Upon diagnosis of multiglandular hyperparathyroidism, the patient should have been sent for genetic testing and instead, became an example of a multisystem failure to identify and provide necessary testing and treatment. Until her variant diagnosis, her pancreatic tumor was not identified as such. The main cause of mortality in MEN-1 patients is malignant spread of neuroendocrine tumors, hence early detection and prompt treatment are of the utmost importance to preserve quality of life and improve survival. Presentation: Thursday, June 15, 2023

Cutaneous lesions and other non-endocrine manifestations of Multiple Endocrine Neoplasia type 1 syndrome.

Multiple Endocrine Neoplasia type 1 is a rare genetic syndrome mainly caused by mutations of MEN1 gene and characterized by a combination of several endocrine and non-endocrine manifestations. The objective of this study was to describe cutaneous lesions and other non-endocrine manifestations of MEN1 in a cohort of patients with familial (F) and sporadic (S) MEN1, compare the prevalence of these manifestations between the two cohorts, and investigate the correlation with MEN1 mutation status. We collected phenotypic and genotypic data of 185 patients with F-MEN1 and S-MEN1 followed from 1997 to 2022. The associations between F-MEN1 and S-MEN1 or MEN1 mutation-positive and mutation-negative patients and non-endocrine manifestations were determined using chi-square or Fisher's exact tests or multivariate exact logistic regression analyses. The prevalence of angiofibromas was significantly higher in F-MEN1 than in S-MEN1 in both the whole (p < 0.001) and index case (p = 0.003) cohorts. The prevalence of lipomas was also significantly higher in F-MEN1 than in S-MEN1 (p = 0.009) and in MEN1 mutation-positive than in MEN1 mutation-negative (p = 0.01) index cases. In the whole cohort, the prevalence of lipomas was significantly higher in MEN1 mutation-positive compared to MEN1 mutation-negative patients (OR = 2.7, p = 0.02) and in F-MEN1 than in S-MEN1 (p = 0.03), only after adjustment for age. No significant differences were observed for the other non-endocrine manifestations between the two cohorts. Hibernoma and collagenoma were each present in one patient (0.5%) and meningioma and neuroblastoma in 2.7% and 0.5%, respectively. Gastric leiomyoma was present in 1.1% of the patients and uterine leiomyoma in 14% of women. Thyroid cancer, breast cancer, lung cancer, basal cell carcinoma, melanoma, and colorectal cancer were present in 4.9%, 2.7%, 1.6%, 1.6%, 2.2%, and 0.5% of the whole series, respectively. We found a significantly higher prevalence of angiofibromas and lipomas in F-MEN1 compared with S-MEN1 and in MEN1 mutation-positive compared to MEN1 mutation-negative patients. In patients with one major endocrine manifestation of MEN1 , the presence of cutaneous lesions might suggest the diagnosis of MEN1 and a possible indication for genetic screening.

Phenotypic presentation of MEN1 (NM_130799.2):c.758delC (p.Ser253CysfsTer28) rs1592648765 pathogenic mutation of MEN-1 gene: a case report

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

RF25 | PMON147 Plasma MicroRNA Expression in Phenocopy of Multiple Endocrine Neoplasia Type 1 Compared to Patients with Acromegaly and Primary Hyperparathyroidism: Potential Biomarkers of Multiple Endocrine Tumor Growth

Abstract Introduction Changes in the expression of microRNA facilitate in the formation of various tumors. MEN1 is a rare disease caused by mutations in MEN1 gene encoding the menin protein and characterize by the occurrence of parathyroid, pituitary, gastroenteropancreatic and other tumors. If a patient with the MEN1 phenotype carry no mutations in the MEN1 gene, the condition considers a phenocopy of syndrome (phMEN1). We hypothesize that the pathogenic link among the above sporadic tumors might be represented by molecular pathways involving the MEN1 gene and epigenetic regulations — particularly microRNAs. Materials &amp; methods Single-center, case-control study: assessment of plasma microRNA expression in patients with phMEN1, acromegaly (AM), primary hyperparathyroidism (PHPT) and healthy controls. Morning plasma samples were collected from fasting patients and age- and sex-matched controls and stored at –80°C. Total RNA isolation: miRNeasy Mini Kit with QIAcube. The libraries were prepared by the QIAseq miRNA Library Kit following the manufacturer. Circulating miRNA sequencing was done on Illumina NextSeq 500 (Illumina). Subsequent data processing was performed using the DESeq2 bioinformatics algorithm. Results We enrolled 36 consecutive patients (12 patients in each group) with phMEN1, AM, PHPT, along with 12 age and gender matched controls. Median age of phMEN1 group — 59 [52; 60.5]; AM — 59 [52; 63]; PHPT — 60.5 [54; 62.5]; control — 59 [51.5; 62.5]. The groups did not differ in age (p=0.88) and gender – in all groups were 11 women and 1 man (p=1.00). We divided all assessed microRNAs into 3 groups based on the significance of the results; the first group consisted of samples with the highest levels of detected microRNAs (&amp;gt;50), the second group — moderate (10–50), the third group — the lowest (&amp;lt;10). The microRNA expression pattern was almost the same between AM and phMEN1 groups (15 microRNAs upregulated, 10 — downregulated), we found slightly decreased hsa-miR-4301 (padj=0.038); it is interesting that phMEN group when compared to PHPT and control groups showed decline in hsa-miR-4301 too. PHPT and control groups had also quite similar expression profile (4 microRNAs upregulated, 19 — downregulated). 607 microRNA were differently expressed in groups phMEN1 and PHPT (473 upregulated microRNAs, 134 — downregulated). We found increased expression of some microRNAs that interferes with menin: hsa-miR-24-1-5p (padj=0.0008), hsa-miR-24-3p (padj=0.034), hsa-miR-26a-5p (padj=0.0005), hsa-miR-421 (padj=0.018), hsa-miR-762 (padj=0.027). In addition, we found decreased microRNAs with oncogene potential: miR-3182 (padj=0.007), hsa-miR-875-5p (padj&amp;lt;0.001), hsa-miR-6749-5p (padj&amp;lt;0.001). 173 microRNA differed in phMEN1 and control groups (11 microRNAs upregulated, 162 — downregulated). We detected several decreased microRNAs in phMEN1 that participate in tumor genesis: hsa-miR-625-3p (padj&amp;lt;0.005), hsa-miR-3168 (padj=0,028), hsa-miR-302b-3p (padj&amp;lt;0.001). Conclusion We found microRNAs, which could potentially become biomarkers in phMEN1 diagnosis. The results need to be validated using different measurement method with larger sample size. Likewise further assessment of plasma microRNA expression in genetically confirmed MEN1 patients is needed. Presentation: Monday, June 13, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Novel pathogenetic mutation of MEN1 gene causing hyperparathyroidism, pancreatic glucagonoma, adrenal adenoma, and collagenomas

Novel pathogenetic mutation of MEN1 gene causing hyperparathyroidism, pancreatic glucagonoma, adrenal adenoma, and collagenomas

Bronchial Carcinoids: From Molecular Background to Treatment Approach.

Simple SummaryBronchial carcinoids (BCs) are uncommon and usually slow growing neuroendocrine epithelial malignancies that represent less than 2% of all lung cancers. Differences in the extent of molecular alterations between neuroendocrine carcinomas and BCs may underline the differences in the aggressiveness of these lesions. Moreover, although atypical BCs and typical BCs have similar set of mutations, some differential molecular and genetic alterations have been described between these two entities. A better understanding of the genetic and molecular background of BCs would allow a better selection of medical treatments in these patients. Regarding treatment, most BCs can be cured by surgery; however, inoperable tumors are mostly insensitive to chemotherapy and radiotherapy. In advanced BCs, the only drug that has a positive phase III clinical trial in BCs is everolimus. Somatostatin analogues constitute the gold standard for symptomatic relief. Peptide receptor radionuclide therapy has been associated with longer progression free. The efficacy of other treatments such as antiangiogenic agents and immunotherapy is still not established.A better understanding of the genetic and molecular background of bronchial carcinoids (BCs) would allow a better estimation of the risk of disease progression and the personalization of treatment in cases of advanced disease. Molecular studies confirmed that lungs neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are different entities; thus, no progression of NET to NEC is expected. In BCs, MEN1 gene mutations and deletions and decreased gene expression have been associated with a poor prognosis. ATRX mutation has also been linked to a shorter disease-specific survival. In terms of therapeutic targets, PI3K/AKT/mTOR pathway mutations have been described in 13% of typical carcinoids (TCs) and 39% of atypical carcinoids (ACs), representing a targetable mutation with kinase inhibitors. Regarding treatment, surgical resection is usually curative in localized BCs and adjuvant treatment is not routinely recommended. Multiple options for systemic therapy exist for patients with advanced BCs, although limited by a heterogeneity in the scientific evidence behind their use recommendation. These options include somatostatin analogues, everolimus, peptide receptor radionuclide therapy, chemotherapy, radiotherapy, antiangiogenic agents, and immunotherapy. In this article, we provide a comprehensive review about the molecular and genetic background of BCs, and about the treatment of local and metastatic disease, as well as the main paraneoplastic syndromes that have been associated with this tumor.

The Effect of Gene Mutations on Metastasis and Overall Survival in Metastatic and Nonmetastatic Colon Cancers.

Objective:It is known that many genes are associated with colon cancer. We aimed to investigate the effect of gene mutations on metastasis and overall survival in metastatic and non metastatic colon cancers. Methods:A total of 50 patients with metastatic (n=25) and non metastatic (n=25) diagnosed with colon cancer between 2010 and 2018 were included in the study. APC, MUTYH, RAD50, MEN1, ATM, PALB2, NSH2, BRCA1, BRCA2, MLH1, BRIP1, TP53, PTEN, BARD1, MSH6, PMS2, NBN, and FAM175A gene mutations were evaluated using the next generation sequencing method. The effect of gene mutations on metastasis and overall survival were evaluated. Results:The mean age of patients with colon cancer without distant metastasis was 48.64±14.72 years and for patients with distance metases was 56.68±11.65. The mean survival time of colon cancer patients with distant organ metastasis after the metastasis date was 104.36±58.59 weeks. The presence of APC, MUTYH, and TP53 genetic mutations was observed with a higher rate in metastatic colon cancer (p<0.05). Conclusion:We showed that APC, MUTYH, and TP53 mutations are associated with distant organ metastasis.

Multiple endocrine neoplasia type 1 with a frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas:\xa0case report

BackgroundMultiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by pituitary neoplasia, primary hyperparathyroidism and pancreatic endocrine tumor. Here we show a case of MEN1 with a germline frameshift mutation in its gene accompanied by a giant cervical lipoma and multiple fatty deposits in the pancreas.Case presentationA 28-year-old man noticed the decreased visual acuity of both eyes and visited our institution. Since he was diagnosed as visual disturbance and brain computer tomography (CT) showed a mass in the pituitary fossa, he was hospitalized in our institution. Endoscopic trans-sphenoidal hypophysectomy and total parathyroidectomy with auto-transplantation were performed, and a giant cervical lipoma was resected. Furthermore, in genetic search, we found a germline frameshift mutation in MEN1 gene leading to the appearance of a new stop codon.ConclusionsWe should bear in mind that giant skin lipoma and multiple abnormal fatty deposits in the pancreas could be complicated with MEN1.

Diagnosis and Molecular Profiles of Large Cell Neuroendocrine Carcinoma With Potential Targets for Therapy

Large cell neuroendocrine carcinoma (LCNEC) together with small cell carcinoma (SCLC) and typical and atypical carcinoids form the group of pulmonary neuroendocrine tumors. LCNEC and SCLC are high-grade carcinomas. Although both can be found outside the thoracic cavity, they are most common in the lung. LCNEC differs from SCLC by morphologic pattern, and by cytological features such as nuclear size, nucleoli, chromatin pattern, but also by genetic differences. Originally thought to represent a single entity, it became evident, that three subgroups of LCNEC can be identified at the molecular level: a SCLC-like type with loss of retinoblastoma 1 gene (RB1) and TP53 mutations; a non-small cell lung carcinoma (NSCLC)-like type with wildtype RB1, TP53 mutation, and activating mutations of the phosphoinositol-3 kinase (PI3K-CA), or loss of PTEN; and a carcinoid-like type with MEN1 gene mutation. These subtypes can be identified by immunohistochemical staining for RB1, p53, and molecular analysis for PI3K and MEN1 mutations. These subtypes might also respond differently to chemotherapy. Immuno-oncologic treatment has also been applied to LCNEC, however, in addition to the evaluation of tumor cells the stroma evaluation seems to be important. Based on personal experiences with these tumors and available references this review will try to encompass our present knowledge in this rare entity and provoke new studies for better treatment of this carcinoma.

Multifocal pancreatic PPoma in the setting of MEN1: Case report and review of literature.

Introduction and importanceFunctioning pancreatic neuroendocrine tumors (pNETs) that express pancreatic polypeptide—PPomas—do not yet have a pathognomonic clinical syndrome associated with them due to their overall rarity and diverse symptoms. Moreover, in patients with MEN1, the often multifocal nature of pNETs presents a unique clinical issue.Case presentationWe report a case of a 22-year-old man with a known MEN1 gene mutation who was suffering from severe diarrhea (7–8 bowel movements per day) and was found to have only elevated PP levels on biochemical work-up. Ga68-DOTATATE PET/CT showed multifocal tumors in the body and tail of the pancreas that were not evident on contrast-enhanced CT. The patient underwent a successful laparoscopic radical antegrade modular pancreatosplenectomy (RAMP) and recovered well post-operatively with complete resolution of his diarrhea. Immunohistochemistry showed multiple pure PPomas.Clinical discussionThis case highlights the unique propensity for multifocal disease in patients with MEN1 mutations and the utility of functional imaging by somatostatin analogs, i.e., Ga68-DOTATATE PET/CT, in order to perform oncologic laparoscopic pancreatic resections.ConclusionPPomas in the setting of MEN1 mutations are a unique clinical entity due to their diverse associated clinical syndromes and propensity for multifocal disease.

Differences in Menin Expression in Pituitary Adenomas in Multiple Endocrine Neoplasia Type 1, Its Phenocopies and Sporadic Acromegaly

Introduction: Multiple endocrine neoplasia type 1 syndrome (MEN 1) is caused by mutations in MEN1 gene, encoding menin protein. A combination of pituitary adenomas (PA) and primary hyperparathyroidism (PHPT) in patients without MEN1 mutations is defined as MEN 1 phenocopy. The aim of the study is to find if there are any differences in menin expression in PA of patients with genetically confirmed MEN 1, MEN 1 phenocopies and sporadic acromegaly.Materials and Methods: Formalin-fixed paraffin-embedded PA tissues were obtained from 9 genetically confirmed MEN 1 patients (group 1), 12 patients with MEN 1 phenocopies (a combination of PA and PHPT) (group 2) and 14 patients with sporadic acromegaly (group 3). The integrity of the tissues was tested by immunohistochemistry (IHC) using antibodies against the nuclear protein Pit-1. MEN1 mutations were confirmed or excluded by Sanger sequencing or by NGS (NextSeq550, Illumina, USA). Expression of menin was assessed using IHC (Anti-Menin antibody — ChIP Grade, Abcam, UK).Results: The distribution of PA by the type of secretion in group 1 was: 3 — ACTH-secreting, 2 — PRL-secreting, 2 — GH+PRL, 1 — TSH+PRL, 1 — ACTH+PRL, 1 — silent gonadotroph adenoma. All 12 PA from group 2 were GH-secreting. All 14 PA in group 3 were GH-secreting without mixed secretion. The median age at the moment of transsphenoidal surgery in group 1 was 35 years [27; 47], in group 2 — 59 years [56; 65], in group 3 — 56 years [53; 62]. There were 2 men and 7 women in group 1; 2 men and 10 women in group 2; 4 men and 10 women in group 3. In group 1 patients did not receive somatostation analogues (SSA), 7 patients received cabergoline. In group 2 seven patients received SSA, in group 3 — 4 patients received SSA, 2 patients received cabergoline. The results of menin staining were (negative staining/positive cytoplasmic staining/positive nuclear staining): group 1 — 4/4/0; group 2 — 0/11/1; group 3 — 1/7/6. Phenocopy group showed significantly more cytoplasmic expression of menin than in MEN 1 group (p<0.008). MEN 1 group also differed from sporadic acromegaly group by nuclear expression of menin (p<0.015). No statistical significance between sporadic and phenocopy groups was found (p=0.07). Although there were no differences among these groups, the group 2 showed weak nuclear expression only in one case, while in group 3 the menin staining was present both in the nucleus and cytoplasm in equal proportions.Conclusion: Menin expression is generally preserved in PA in MEN 1 phenocopies and sporadic acromegaly, though with different pattern of nuclear and cytoplasmic expression, while its expression varies in PA in MEN 1. These findings suggest that pathogenesis of PA in MEN 1 phenocopies and sporadic acromegaly may have similarities. The mechanisms of co-occurrence of PA and PHPT in MEN 1 phenocopies are poorly understood and epigenetic modifications downstream menin interacting pathways could play a role.

Сучасні погляди на генетичну детермінованість СТГ-секретуючих аденом гіпофіза (огляд літератури та власні дослідження)

Актуальність. В роботі наведений огляд сучасних даних літератури щодо генетичної складової в етіології та патогенезі гормонально активної аденоми гіпофіза, що секретує соматотропний гормон (СТГ) і клінічними проявами якої є синдром акромегалії та/або гігантизму— синдром множинної ендокринної неоплазії 1, синдром Мак-К’юна— Олбрайта, комплекс Карні, акрогігантизм (Х-зчеплений), сімейні ізольовані аденоми гіпофіза (FIPA). Матеріали та методи. Для виявлення мутацій в гені AIP та з метою верифікації FIPA були обстежені 26 хворих української популяції (19 жінок та 7 чоловіків), в яких акромегалія була діагностована в підлітковому або молодому віці, і проведений генетичний аналіз. Для визначення генетичної детермінованості щодо розвитку СТГ-секретуючої аденоми гіпофіза та диференціальної діагностики синдромів FIPA та MEN1 методом секвенування (MLPA— Ligation-dependent Probe Amplification) було проведене дослідження генів (MLPA, P244-C1) за участю екзонів 1–6 MEN1, (MLPA, P017-D1) AIP. Результати. Серед обстежених тільки у двох осіб були визначені мутації гена AIP. В одного хворого генетичний скринінг на мутацію гена MEN1 був негативним, і жодних клінічних симптомів, що свідчать про синдром Мак-К’юна— Олбрайта, не було виявлено. Варіант гетерозиготного місенсу c.714C&gt;G (p.Cys238Trp) виявлений у гені AIP. Цей аналіз гена AIP сумісний з генетичною схильністю до аденом гіпофіза. У нащадків даного пацієнта 50% шансів успадкувати цей варіант. У іншої хворої з діагнозом «синдром множинної ендокринної неоплазії типу1 (синдром Вермера): інсулінома, аденоми прищитоподібних залоз (2), первинний гіперпаратиреоз» встановлений варіант гетерозиготного місенсу c.134A&gt;G (p.Glu45Gly), що був виявлений у гені MEN1. Варіант c.l34A&gt;G (p.Glu45Gly), клас 4, ймовірно, є патогенним. Поширеність цього варіанта в загальній популяції невідома, тому він є дуже рідкісним. Висновки. Проведення генетичного аналізу є доцільним у хворих дитячого та молодого віку або в осіб, у яких СТГ-секретуюча макро-/гігантська аденома гіпофіза була діагностована в молодому віці (до 35 років), незалежно від сімейної обтяженості щодо аденом гіпофіза. У хворих з обтяженою спадковістю генетичний аналіз доцільно проводити у будь-якому разі для виявлення FIPA та прогнозування подальшого перебігу захворювання та ефективності лікування аналогами соматостатину.

A rare case of multiple endocrine neoplasia type 1 initially presenting as an asymptomatic, huge mediastinal mass: case report

BackgroundMultiple endocrine neoplasia type 1 (MEN1) is a rare inherited syndrome that concurrently involves various endocrine glands. We report a rare case of MEN1 in a 43-year-old man whose first manifestation was an asymptomatic mediastinal mass.Case presentationA 13-cm-sized mediastinal mass was diagnosed as an atypical thymic carcinoid by computed tomography and percutaneous needle biopsy. In addition, hypercalcemia from a left inferior parathyroid hyperplasia, and a non-functioning gastric neuroendocrine tumor seen on esophagogastroduodenoscopy were found. Therefore, the patient was clinically diagnosed with MEN1 syndrome, and underwent surgical resection of thymic carcinoid tumor after pre-operative concurrent chemoradiation therapy to decrease tumor size and volume. Parathyroid lesion and gastric neuroendocrine tumor were also removed. Finally, a MEN1 gene mutation was observed in the patient and his 7-year-old son.ConclusionDespite its rare occurrence, thymic carcinoid tumor should be considered as a MEN1-associated tumor and necessitates screening of other endocrine glands. Thymic carcinoid tumor carries a poor prognosis in patients with MEN1, and thus it needs to be carefully monitored even after radical excision.

IS THAT THE R171Q AMINO ACID VARIANT IN EXON 3 OF THE MEN1 GENE IS RELATED TO AGE, TO PLAY A MUTATING ROLE?

Background/aim: Several studies demonstrated that the R171Q amino acid variant in exon 3 of MEN1 gene is a polymorphism, and in some new studies it is probably a mutation. We found in our study of twelve cases, two young cases have this variant and developed multiple endocrine neoplasia type1. Materials and methods: twelve MEN1 young patients (7 female, 5 male) aged between 20 and 40 years old, were included in our study. After investigating each patient, biochemical and molecular researches is done. We sequenced exon 3 of the MEN1 gene of patients and some members of their families. Results: Ten patients have MEN1 syndrome and they have no mutation in MEN1 gene. Two patients from separated families have a c.512G&gt;A heterozygote variant. Phenotypically the two cases have hyperparathyroidism in young age. One of them developed others tumors later. Conclusion: The R171Q variant is a mutation in some cases; causes hyperparathyroidism and will develop further MEN1 lesions later, and it is just a polymorphism in other cases. We believe that when this polymorphism combines with young age in severe depression, it will lead to MEN1 syndrome, which will make this polymorphism considered a genetic mutation

A novel mutation of the MEN1 gene in a patient with multiple endocrine neoplasia type 1 and recurrent fibromyxoid sarcoma \u2013 a case report

BackgroundMultiple endocrine neoplasia type 1 (MEN1) syndrome is usually accompanied by endocrine tumors, but non-endocrine tumors can occur as well. However, the coexistence of MEN1 syndrome and malignant tumor such as low-grade fibromyxoid sarcoma has not been described in the literature. Moreover, the MEN1 gene mutations have not been identified in patients with fibromyxoid sarcoma, so far.Case presentationWe present a patient with a long-year endocrine follow-up due to multiple endocrine tumors. During his lifespan, he has been surgically treated for pancreatic gastrinoma, parathyroid hyperplasia, atypical pulmonary carcinoid, various benign mesenchymal, and several skin tumors (basocellular tumor, lipomas, and fibromas) which raised a high clinical suspicion of MEN1 syndrome but the patient refused genetic testing. Recently, he developed a novel malignant tumor – recurrent low-grade fibromyxoid sarcoma of the trunk and extremities with multiple subsequent operations. The patient eventually accepted the genetic testing which proved him to be a carrier of a novel mutation in the MEN1 gene.ConclusionsUnlike some other syndromes where a genetic mutation can predict clinical course, there is no genotype-phenotype correlation in MEN1 syndrome. Therefore, these patients require lifelong and multidisciplinary surveillance, not only for typical endocrine and benign non-endocrine tumors but also for diverse and even more malignant forms. The atypical clinical presentation should pose suspicion about new gene mutation and serve as a warning in the further follow-up.

Rare Somatic MEN1 Gene Pathogenic Variant in a Patient Affected by Atypical Parathyroid Adenoma.

Objective Atypical parathyroid adenoma is a rare neoplasm, showing atypical histological features intermediate between classic benign adenoma and the rarest parathyroid carcinoma, whose the clinical behaviour and outcome is not yet understood or predictable. Up to date only two cases of atypical adenoma were found associated to a MEN1 syndrome, and only one was proved to carry a pathogenic variant of the MEN1 gene. Design We report the clinical, histologic, and molecular findings of a 44-year-old woman, presenting with a histologically proved atypical parathyroid adenoma with an apparent aggressive behaviour. Methods and Results CDC73 gene was screened at germline and somatic levels with no results. Whole exome sequencing performed on DNA extracted from blood leukocytes and tumour tissue revealed a somatic MEN1 gene heterozygous variant, c.912+1G > A, of the splicing donor site of exon 6. On immunohistochemistry, downregulation of the menin protein expression in the neoplastic cells was also observed. Conclusions We report the second case of a rare association of a somatic MEN1 gene mutation in a patient with atypical parathyroid adenoma. We suggest that MEN1 gene could be an underestimate genetic determinant of these rare histological entities, and we highlight the utility of a complete genetic screening protocol, by the use of next-generation sequencing technology in such undetermined clinical cases with no frank clinical presentation.