Multiple Endocrine Neoplasia Type 1 Gene Research Articles

Syndromic MEN1 Parathyroid Adenomas Consist of Both Subclonal Nodules and Clonally Independent Tumors

Abstract Background Primary hyperparathyroidism with parathyroid tumors is a characteristic presentation in Multiple Endocrine Neoplasia Type 1 (MEN1), historically referred to as "primary hyperplasia." The question of whether these tumors signify a multi-glandular clonal disorder or hyperplasia remains inconclusive. Loss of Menin protein expression serves as a reliable surrogate marker for biallelic inactivation and indicates a mutation in the MEN1 gene. The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene, associated with MEN4, encodes the p27 protein, whose expression is inadequately explored in the context of syndromic MEN1. Aims The aim was to explore the molecular basis of syndromic MEN1 parathyroid adenomas, identifying hyperplasia, multiple independent clones, and the extent of Menin loss. Additionally, p27 expression was assessed to evaluate its potential in indicating a germline mutation, especially in distinguishing MEN4 as a clinical alternative to MEN1. Methods In this investigation, we examined histomorphology and protein expression of Menin and p27 in parathyroid adenomas from 25 patients in two independent, well-characterized MEN1 cohorts. Loss of heterozygosity (LOH) patterns were evaluated using fluorescence in situ hybridization (FISH) in one MEN1-associated parathyroid adenoma. Furthermore, next-generation sequencing (NGS) was conducted on eleven nodules from four MEN1 patients. Results Morphologically, the majority of MEN1 adenomas displayed multiple distinct nodules, characterized by predominantly lost Menin expression and reduced p27 protein expression. FISH analysis indicated that most nodules exhibited MEN1 loss, with or without centromere 11 loss. NGS demonstrated both subclonal evolution and the existence of clonally unrelated tumors. Conclusion Syndromic MEN1 parathyroid adenomas, therefore, consist of multiple clones with subclones, aligning with the current framework of the novel WHO classification of parathyroid tumors (2022). The observed loss of p27 expression in a significant fraction of MEN1 parathyroids emphasizes the need for caution when inferring MEN4 solely based on p27 expression.

A novel likely pathogenetic variant p.(Cys235Arg) of the MEN1 gene in multiple endocrine neoplasia type 1 with multifocal glucagonomas.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine syndrome caused by pathogenic variants in MEN1 tumor suppressor gene. Diagnosis is commonly based on clinical criteria and confirmed by genetic testing. The objective of the present study was to report on a MEN1 case characterized by multiple pancreatic glucagonomas, with particular concern on the possible predisposing genetic defects. While conducting an extensive review of the most recent scientific evidence on the unusual glucagonoma familial forms, we analyzed the MEN1 gene in a 35-year-old female with MEN1, as well as her son and daughter, using Sanger and next-generation sequencing (NGS) approaches. We additionally explored the functional and structural consequences of the identified variant using in silico analyses. NGS did not show any known pathogenic variant in the tested regions. However, a new non-conservative variant in exon 4 of MEN1 gene was found in heterozygosity in the patient and in her daughter, resulting in an amino acid substitution from hydrophobic cysteine to hydrophilic arginine at c.703T > C, p.(Cys235Arg). This variant is absent from populations databases and was never reported in full papers: its characteristics, together with the high specificity of the patient's clinical phenotype, pointed toward a possible causative role. Our findings confirm the need for careful genetic analysis of patients with MEN1 and establish a likely pathogenic role for the new p.(Cys235Arg) variant, at least in the rare subset of MEN1 associated with glucagonomas.

Syndromic MEN1 parathyroid adenomas consist of both subclonal nodules and clonally independent tumors

Primary hyperparathyroidism with parathyroid tumors is a typical manifestation of Multiple Endocrine Neoplasia Type 1 (MEN1) and is historically termed “primary hyperplasia”. Whether these tumors represent a multi-glandular clonal disease or hyperplasia has not been robustly proven so far. Loss of Menin protein expression is associated with inactivation of both alleles and a good surrogate for a MEN1 gene mutation. The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene is mutated in MEN4 and encodes for protein p27 whose expression is poorly studied in the syndromic MEN1 setting.Here, we analyzed histomorphology and protein expression of Menin and p27 in parathyroid adenomas of 25 patients of two independent, well-characterized MEN1 cohorts. The pattern of loss of heterozygosity (LOH) was assessed by fluorescence in situ hybridization (FISH) in one MEN1-associated parathyroid adenoma. Further, next-generation sequencing (NGS) was performed on eleven nodules of four MEN1 patients.Morphologically, the majority of MEN1 adenomas consisted of multiple distinct nodules, in which Menin expression was mostly lost and p27 protein expression reduced. FISH analysis revealed that most nodules exhibited MEN1 loss, with or without the loss of centromere 11. NGS demonstrated both subclonal evolution and the existence of clonally unrelated tumors.Syndromic MEN1 parathyroid adenomas therefore consist of multiple clones with subclones, which supports the current concept of the novel WHO classification of parathyroid tumors (2022). p27 expression was lost in a large fraction of MEN1 parathyroids and must therefore be used with caution in suggesting MEN4.

O-05 A novel mutation of MEN1 gene in familial Multiple Endocrine Neoplasia Type 1 (MEN1): A report of two cases

Abstract Introduction Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare (1-9/100000) autosomal dominant disease. It is characterized by primary hyperparathyroidism (90%), enteropancreatic tumor (60-70%), non-functional adrenal adenomas (30%) and pituitary tumors (10-20%). Herein, we present two cases in the same family with MEN1 syndrome caused by a novel mutation. Clinical Case 1: 49-year-old male presented to our clinic with fasting hypoglycemia. Fasting serum glucose (FSG) was 51 mg/dl and serum cortisol was 18 ug/dl. During the hypoglycemia in prolonged fasting test, the serum levels of glucose, insulin and C-peptide were 37 mg/dl, 17.3 mu/l, 7.75 ng/ml respectively (Table 1). Abdominal MRI revealed mass lesions in the pancreas (Figure 1). Ultrasonography of the neck and MIBI scintigraphy performed because of the high levels of calcium and parathyroid hormone (PTH), were consistent with parathyroid adenoma (Table 2). Pituitary MRI showed a 12 mm macroadenoma. He underwent parathyroidectomy and distal pancreatectomy simultaneously. The resected specimens revealed a well-differentiated neuroendocrine tumor (NET) of the pancreas and parathyroid adenoma. The patient had no new hypoglycemic episodes after surgery and serum calcium remained within the normal range (Table 2). Central hypothyroidism and hypogonadotropic hypogonadism which was resulted from the pressure of the adenoma was managed medically. Genetic testing revealed a heterozygous mutation in NM_001370251.1:c.949del(HET). First degree relatives of the patient were screened for MEN. Clinical Case 2: The son of case 1, an 18-year-old male, presented with fasting hypoglycemia. He had a BMI of 37 kg/m2 and underwent gastric botox 3 months prior to his presentation. FPG was 52 mg/dl and serum cortisol was 20 ug/dl. Prolonged fasting test confirmed the diagnosis of insulinoma (Table 1). Abdominal MRI showed a pancreatic tail mass 37×22 mm in size. Gallium 68 PET/CT DOTATATE revealed increased uptake in multiple lesions in the pancreas. Ultrasonography and MIBI scintigraphy showed a parathyroid adenoma. A nonfunctional microadenoma was detected in pituitary MRI. The patient underwent distal pancreatectomy. Following pancreatectomy, right superior and left inferior parathyroidectomies were performed. Since his serum calcium levels started to increase in 48 hours after the operation, the patient has had second operation for left superior parathyroidectomy. After the operation, the serum calcium and parathyroid hormone levels were 9.2 mg/dl, 58 pg/ml respectively. Specimens revealed well-differentiated NET and atypical parathyroid adenoma. The patient was found to have the same genetic mutation with his father and during the follow up the serum glucose and calcium levels remained within the normal range (Table 2). Conclusion In the genetic examination the heterozygous mutation NM_001370251.1:c.949del(HET) in exon 7/11 of the MEN1 gene found in our patients represents a novel mutation.Figure 1.MRI showing pancreatic masses Table 1.Laboratory findings Table 2.Prolonged fasting test

The risk of concurrent malignancies in patients with multiple endocrine neoplasia type 1: insights into clinical characteristics of those with multiple endocrine neoplasia type 1.

Summarize and analyze the characteristics of patients with Multiple Endocrine Neoplasia type 1 (MEN-1) who were diagnosed with malignant tumors that do not belong to MEN-1 components. Clinical data from patients with MEN-1 who visited Peking Union Medical College Hospital between April 2012 and April 2022 were collected. We compared the clinical characteristics of patients with malignant tumors outside of their MEN-1 components to those without additional tumors. MEN-1 gene testing was performed on most of these patients using Sanger sequencing, whole-exome sequencing, or MLPA. A total of 221 MEN-1 patients were diagnosed, of which 23 (10.40%) were found to have malignant tumors that did not belong to MEN-1 components, including papillary thyroid carcinoma (PTC) (4.52%), breast cancer (1.81%), urologic neoplasms (1.35%), primary hepatic carcinoma (PCC) (0.09%), meningeal sarcoma (0.05%), glioblastoma (0.05%), cervical cancer (0.05%), and lung carcinoma (0.05%). MEN-1 gene mutations were identified in 11 patients, including missense mutations, frameshift mutations, and splice mutations. The prevalence of each endocrine neoplasm, particularly gastroenteropancreatic neuroendocrine tumor, was higher in MEN-1 patients with other malignant tumors compared to MEN-1 patients without malignant tumors. Our retrospective study revealed a higher incidence of non-MEN-1 component malignant tumors in MEN-1 patients, especially breast cancer, PTC, and urologic neoplasms. These patients also exhibit more severe clinical phenotypes of MEN-1.

Primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1: Impact of genotype and surgical approach on long-term postoperative outcomes

BackgroundProtein-truncating germline pathogenic variants in the N- and C-terminal exons (2, 9, and 10) of the MEN1 gene may be associated with aggressive pancreatic neuroendocrine tumors. However, the impact of these variants on parathyroid disease is poorly understood. We sought to investigate the effects of genotype and surgical approach on clinical phenotype and postoperative outcomes in patients with multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism. MethodsWe identified patients with MEN1 evaluated at our institution from 1985 to 2020 and stratified them by genotype, (truncating variants in exons 2, 9, or 10, or other variants), and index surgical approach, (less-than-subtotal parathyroidectomy [<SPTX], SPTX, or total parathyroidectomy). We analyzed baseline characteristics, persistent/recurrent disease rates, and incidence of postoperative hypoparathyroidism. ResultsOf the 209 patients we identified, primary hyperparathyroidism was diagnosed in 194 (93%) and at a younger median age in those with truncating exon 2, 9, or 10 variants compared with other variants (27 years vs 31 years; P = .006). Median disease-free survival was significantly worse in patients who underwent <SPTX (60 months) than those who underwent <SPTX (152 months; P = .0005) or total parathyroidectomy (210 months; P = .04). Patients with truncating exon 2, 9, or 10 variants who underwent <SPTX had significantly shorter median disease-free survival than those with other variants (30 vs 84 months; P = .007). Prolonged hypoparathyroidism rates after final surgery were highest after total parathyroidectomy (40%), followed by <SPTX (9%) and SPTX (7%). ConclusionThe MEN1 genotype may affect the age of onset of primary hyperparathyroidism and the time to recurrence after surgery. <SPTX at index operation should be performed with caution, especially in patients with truncating MEN1 variants in exons 2, 9, or 10, as the higher risk of recurrence is not offset by a decreased incidence of permanent hypoparathyroidism compared to upfront SPTX.

THU081 Differences In Circulating Microrna Levels In Genetically Confirmed Multiple Endocrine Neoplasia Type 1 And Multiple Endocrine Neoplasia Type 1 Phenocopies As Assessed By Next Generation Sequencing

Abstract Disclosure: D.A. Trukhina: Grant Recipient; Self; Russian Science Foundation (project N 19-15-00398-П). E.O. Mamedova: Grant Recipient; Self; Russian Science Foundation (project N 19-15-00398-П). P.A. Koshkin: Grant Recipient; Self; Russian Science Foundation (project N 19-15-00398-П). A.G. Nikitin: Grant Recipient; Self; Russian Science Foundation (project N 19-15-00398-П). G.A. Melnichenko: Grant Recipient; Self; Russian Science Foundation (project N 19-15-00398-П). Z.E. Belaya: Grant Recipient; Self; Russian Science Foundation (project N 19-15-00398-П). Multiple endocrine neoplasia type 1 (MEN1) is a rare disease caused by mutations in the MEN1 gene encoding the menin protein (gMEN1). This syndrome is characterized by the occurrence of parathyroid tumors, gastroenteropancreatic neuroendocrine tumors (GEP-NETs), pituitary adenomas, as well as other endocrine and non-endocrine tumors. Patients with MEN1 phenotype without MEN1 mutations are considered MEN1 phenocopies (phMEN1). It has not been studied whether the development of MEN1 phenocopies is determined by epigenetic changes, particularly by altered microRNA expression, which can affect menin. Materials &amp; methods Single-center, case-control study: assessment of plasma microRNA expression in patients with gMEN1, phMEN1 and healthy controls. Morning plasma samples were collected from fasting patients and gender-matched controls and stored at –80C. Total RNA isolation was performed using miRNeasy Mini Kit with QIAcube. The libraries were prepared by the QIAseq miRNA Library Kit. Circulating miRNA sequencing was performed on Illumina NextSeq 500. Subsequent data processing was performed using DESeq2 bioinformatics algorithm. Results We enrolled 24 patients with gMEN1 and 12 patients with phMEN1, along with 12 gender-matched controls. The median age of gMEN1 patients was 39 [35; 46]; in phMEN1 — 59 [51;60]; control — 59 [51.5; 62.5]. The gMEN1 group differed in age (p&amp;lt;0,01) compared to phMEN1 and control groups. We divided all assessed microRNAs into 3 groups based on the significance of the results: the first group consisted of samples with the highest level of detected microRNAs (&amp;gt;50 counts), the second group — moderate (10–50), the third group — the lowest (&amp;lt;10).98 microRNAs were differently expressed in groups gMEN1 and phMEN1 (84 upregulated microRNAs, 14 — downregulated). We found increased expression of microRNAs in gMEN1 which interact with menin: hsa-miR-421 (p adj = 0.0004362), hsa-miR-664a-5p (p adj = 0.0037814). We found several microRNAs associated with intestinal and pituitary tumors in gMEN1 and phMEN1 groups: up-regulated hsa-miR-7-5p (p adj = 0.0000084); downregulated hsa-miR-423-5p (p adj &amp;lt; 0.000001) and hsa-miR-432-5p (p adj = 0.0087227). 84 microRNA were differently expressed in groups gMEN1 and control (67 up-regulated microRNAs, 17 — downregulated). When comparing gMEN1 with phMEN1 and control a decrease in hsa-let-7a-5p miRNA was found, which, according to the literature, is downregulated in Men1 gene knockout cell lines. The phMEN1 vs control group showed downregulation of hsa-miR-122-5p (p adj = 0.0080138) and upregulation of hsa-miR-191-5p (p adj = 0.0002144), hsa-miR-486-5p (p adj = 0.0491822) that has been detected in GEP-NETs. Conclusion We found microRNAs which could potentially become biomarkers in the differential diagnosis of gMEN1 and phMEN1. The results need to be validated using a different measurement method with a larger sample size. Presentation: Thursday, June 15, 2023

SAT610 Multiple Endocrine Neoplasia Type 1 - The First Reported Case In An Indigenous Australian

Abstract Disclosure: E. Mignone: None. K. Neal: None. Background: Multiple Endocrine Neoplasia type 1 (MEN1) is a rare and under recognised syndrome. It has not been previously reported in Indigenous Australians for this reason. Clinical Case: A 48-year-old Indigenous Australian female was consulted on by an inpatient endocrine team in March 2020 for persistent hypercalcaemia on a background of a parathyroidectomy in 2011 for primary hyperparathyroidism (PHPTH). She was admitted to a remote Australian hospital for investigation and management of acute on chronic abdominal pain. Relevant medical history included a parathyroidectomy at age 40, multiple PE/DVT, MI, AF, CTEPH, right heart failure, HTLV-1 and recurrent abdominal pain presumed secondary to GORD. Gastroscopy from 2013 revealed chronic gastritis with hundreds of gastric polyps discovered on subsequent gastroscopy in 2015. The young age of PHPTH combined with her chronic gastritis and polyps prompted neuroendocrine tumour (NET) screening, including MEN1. At time of consult in 2020, laboratory studies were consistent with recurrence of PHPTH with a corrected calcium of 2.9 mmol/L (2.15-2.57mmol/L), serum PTH level 31.5 pmol/L (1-7pmol/L), vitamin D level 30 nmol/L, 24-hour urinary calcium variable between low and high. NET markers were markedly elevated with a gastrin level of 14042 ng/L (&amp;lt;100 ng/L), pancreatic polypeptide 2905 pmol/L (&amp;lt;55 pmol/L), urine 5HIAA ratio 8 mmol/L (&amp;lt;4 mmol/L), vasoactive intestinal peptide and glucagon levels normal. Pituitary studies, serum calcitonin, plasma metanephrines and PTH related protein levels were within normal limits. A CT of the abdomen showed thickened gastric folds, and persistent liver and IVC lesions from 2018. A diagnosis of Zollinger Ellison Syndrome (ZES) was made. Eventually, genetic testing was positive for a rare heterozygous variant of c.207dupC in exon 2 of MEN1 gene. A 68-gallium-DOTATATE PET/CT showed multiple avid pancreatic, gastric, nodal and liver lesions with high somatostatin receptor expression, suggestive of a neuroendocrine malignancy. Treatment was based largely on symptom control due to poor overall prognosis from underlying cardiorespiratory comorbidities. Abdominal pain from ZES was managed with a high dose PPI, H2 receptor antagonist and subcutaneous somatostatin analogue were trialled. Hypercalcaemia was treated with IV bisphosphonate therapy. Calcimimetic analogues were considered however patient declined. Genetic counselling was attempted however many cultural and logistical barriers were identified and family declined further testing. Unfortunately, our patient died in 2021 from presumed multifactorial respiratory failure. Conclusion: High index of suspicion is required to diagnose MEN1. This is particularly true within the Indigenous Australian population, with no prior documented cases reported. Presentation: Saturday, June 17, 2023

Ultrasound-guided microwave ablation in the treatment of recurrent primary hyperparathyroidism in a patient with MEN1: a case report.

Multiple endocrine neoplasia type 1 (MEN1) is an inherited endocrine syndrome caused by the mutation in the tumor suppressor gene MEN1. The recurrence rate of primary hyperparathyroidism (PHPT) in patients with MEN1 after parathyroidectomy remains high, and the management of recurrent hyperparathyroidism is still challenging. We reported a 44-year-old woman with MEN1 combined with PHPT who was diagnosed through genetic screening of the patient and her family members. After parathyroidectomy to remove one parathyroid gland, the patient suffered from persistent high levels of serum calcium and parathyroid hormone, which returned to normal at up to 8 months after ultrasound-guided microwave ablation (MWA) for bilateral parathyroid glands, suggesting an acceptable short-term prognosis. Ultrasound-guided MWA for parathyroid nodules may be an effective therapeutic strategy for recurrent PHPT in MEN1 patients.

Expressions of Cushing's syndrome in multiple endocrine neoplasia type 1.

Cushing's syndrome (CS) resulting from endogenous hypercortisolism can be sporadic or can occur in the context of familial disease because of pituitary or extra-pituitary neuroendocrine tumors. Multiple endocrine neoplasia type 1 (MEN1) is unique among familial endocrine tumor syndromes because hypercortisolism in this context can result from pituitary, adrenal, or thymic neuroendocrine tumors and can therefore reflect either ACTH-dependent or ACTH-independent pathophysiologies. The prominent expressions of MEN1 include primary hyperparathyroidism, tumors of the anterior pituitary, gastroenteropancreatic neuroendocrine tumors, and bronchial carcinoid tumors along with several common non-endocrine manifestations such as cutaneous angiofibromas and leiomyomas. Pituitary tumors are present in about 40% of MEN1 patients, and up to 10% of such tumors secrete ACTH that can result in Cushing's disease. Adrenocortical neoplasms occur frequently in MEN1. Although such adrenal tumors are mostly clinically silent, this category can include benign or malignant tumors causing hypercortisolism and CS. Ectopic tumoral ACTH secretion has also been observed in MEN1, almost exclusively originating from thymic neuroendocrine tumors. The range of clinical presentations, etiologies, and diagnostic challenges of CS in MEN1 are reviewed herein with an emphasis on the medical literature since 1997, when the MEN1 gene was identified.

Diagnostic Utility of Menin Immunohistochemistry in Patients With Multiple Endocrine Neoplasia Type 1 Syndrome.

A clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) syndrome is usually confirmed with genetic testing in the germline. It is expected that menin protein expression is lost in MEN1-related tumors. Therefore, we investigated the potential of menin immunohistochemistry in parathyroid adenomas as an additional tool in the recognition and genetic diagnosis of MEN1 syndrome. Local pathology archives were searched for parathyroid tumors from patients with MEN1 syndrome and without MEN1, including sporadic, patients with multiple endocrine neoplasia type 2A and hyperparathyroidism-jaw parathyroid tumors. Menin immunohistochemistry was performed and its use to identify MEN1-related tumors was assessed. Twenty-nine parathyroid tumors from 16 patients with MEN1 and 61 patients with parathyroid tumors from 32 non-MEN1 were evaluated. Immunohistochemical nuclear menin loss in one or more tumors was found in 100% of patients with MEN1 and 9% of patients with non-MEN1. In patients with multiple tumors, menin loss in at least one tumor was seen in 100% of 8 patients with MEN1 and 21% of patients with 14 non-MEN1. Using a cutoff of at least 2 tumors showing menin loss per patient, the positive and negative predictive values for the diagnosis MEN1 were both 100%. The practical and additional value of menin immunohistochemistry in clinical genetic MEN1 diagnosis is further illustrated by menin immunohistochemistry in 2 cases with a germline variant of unknown significance in the MEN1 gene. Menin immunohistochemistry is useful in the recognition of MEN1 syndrome as well as in the clinical genetic analysis of patients with inconclusive MEN1 germline testing.

Abstract #1412022: A Rare Case of Multiple Endocrine Neoplasia Type 1 (MEN1) Presenting with Recurrent Abdominal Pain

MEN1 is a rare genetic disorder characterized by combined occurrence of two or more tumors involving parathyroid, anterior pituitary and the neuroendocrine tissue of gastro-entero-pancreatic organ system. We present a case of a young male with recurrent abdominal pain who was later diagnosed with MEN1 syndrome. 27-year-old male with past medical history of chronic abdominal pain presented for an episode of acute upper abdominal pain which was constant and worsened with any movement or palpation. His family history was significant for father having parathyroid disorder and skin lesions. On examination, he was ill appearing with tachycardia, multiple skin lesions and tenderness in upper abdomen. Labs were significant for leukocytosis and hypercalcemia (corrected level 10.5 mg/dl). Rest of the electrolytes, kidney function, liver enzymes and lipase were normal. Computed tomography (CT) abdomen showed inflammatory changes and thickening along the distal stomach/proximal duodenum with scattered free air, concerning for a perforated ulcer. Indeterminate bilateral adrenal nodules were also noted. Patient underwent emergent exploratory laparotomy and was noted to have small perforation in the anterior proximal portion of the duodenum which was repaired. Post-operatively, work up for persistent hypercalcemia revealed parathyroid hormone levels of 152 pg/ml and 25-hydroxy vitamin D of 13.7 ng/ml. He was diagnosed with primary hyperparathyroidism and upon stabilization, discharged with plan for outpatient follow-up. After few months, he had another admission due to worsening epigastric pain. Repeat CT abdomen showed multiple pancreatic lesions involving head, tail and uncinate process and stable adrenal nodules. Presence of pancreatic lesions, gastric ulcers, hyperparathyroidism, adrenal nodules, and multiple skin lesions raised concern of MEN1. Further evaluation showed elevated gastrin level (633 pg/ml), chromogranin level (2464 ng/mL) and mildly elevated prolactin. Rest of pituitary and adrenal axis hormone levels were normal. MEN1 gene testing was positive. No pituitary lesion was identified on magnetic resonance imaging brain. He underwent subtotal parathyroidectomy and cervical thymectomy. He was continued on twice daily pantoprazole and was discharged home in stable condition. MEN1 tumor types and age of tumor onset can differ significantly, and tumors become evident either by hormonal overproduction or by tumor growth. There are no genotype phenotype correlations, even within the same family. Pharmacological therapies to suppress hypersecretion are often first line and can be successful in up to 50% patients. Surgery is an option for patients with hypersecretion unresponsive to medical therapy, compression of the optic nerves and/or chiasma endangering vision or when there is uncertainty of diagnosis requiring biopsy. MEN1 is linked with higher mortality. Approximately 70% of the MEN1 deaths are due to thymic neuroendocrine tumors (NETs) and duodenopancreatic-NETs. Early diagnosis of tumors with appropriate interventions can significantly improve patient survival.

Whole-exome sequencing as a tool for searching for genetic background modifiers in MEN1 patients with neuroendocrine pancreatic tumours, including insulinomas.

Multiple endocrine neoplasia type 1 (MEN1) is a monogenic disease caused by inactivating variants in the MEN1 gene. Although the reason for its development is well-known, disease phenotypes are unpredictable and differ even among carriers of the same pathogenic driver mutation. Genetic, epigenetic, and environmental factors may play a role in driving the individual phenotype. Those factors, however, still mostly remain unidentified. In our work, we focused on the inherited genetic background in pancreatic neuroendocrine neoplasms (pNENs) in MEN1 patients, and the pancreatic tumour subgroup with insulinoma. Whole exome sequencing was performed in MEN1 patients. The symptoms of interest were pancreatic neuroendocrine tumours in one analysis and insulinoma in the second. The study included families as well as unrelated cases. Genes with variants that are not neutral to the encoded gene product were defined in symptom-positive patients as compared to symptom-negative controls. The interpretation of the results was based on functional annotations and pathways shared between all patients with the given symptom in the course of MEN1. Whole-exome screening of family members and unrelated patients with and without pNENs revealed a number of pathways that are common for all the analysed cases with pNENs. Those included pathways crucial for morphogenesis and development, proper insulin signalling, and structural cellular organization. An additional analysis of insulinoma pNEN patients revealed additional pathways engaged in glucose and lipid homeostasis, and several non-canonical insulin-regulating mechanisms. Our results show the existence of pathways that are identified in a non-literature-predefined manner, which might have a modifying function in MEN1, differentiating the specific clinical outcomes. Those results, although preliminary, provide evidence of the reasonableness of performing large-scale studies addressing the genetic background of MEN1 patients in determining their individual outcomes.

AIP gene germline variants in adult Polish patients with apparently sporadic pituitary macroadenomas.

Up to 5% of all pituitary tumors are hereditary e.g. due to MEN1 or aryl hydrocarbon receptor-interacting protein (AIP) genes mutations. The study was aimed at the assessment of the frequency and characteristics of AIP-mutation related tumors in patients with apparently sporadic pituitary macroadenomas in the Polish population. The study included 131 patients (57 males, 74 females; median age 42 years) diagnosed with pituitary macroadenomas, and with a negative family history of familial isolated pituitary adenoma (FIPA) or multiple endocrine neoplasia type 1 (MEN1) syndromes. Sanger sequencing was used for the assessment of AIP gene variants. The study was approved by the Ethics Board of JUMC. AIP variants were identified in five of the 131 included subjects (3.8%): one diagnosed with Cushing's disease, two with acromegaly, and two with non-secreting adenomas. Patients harboring hereditary AIP gene alterations did not differ from the rest of the study group in median age at diagnosis (41.0 vs. 42.5 years, P=0.8), median largest tumor diameter (25 vs. 24mm, P=0.6), gender distribution (60.0% vs. 56.3% females, P=0.8), secreting tumor frequency (60.0% vs. 67.5%, P=0.7), or acromegaly diagnosis frequency (40.0% vs.37.3%, P=0.9). In our series of apparently sporadic pituitary macroadenomas, AIP gene variant carriers did not differ substantially from patients with negative genetic testing. A risk factor-centred approach to AIP genetic screening may result in missing germline variants. Considering the clinical impact of such genetic variants and their relatively low penetrance, it is, however, doubtful if general genetic screening benefits the whole cohort of pituitary macroadenoma patients and their families.

Approach of Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome-Related Skin Tumors.

Non-endocrine findings in patients with MEN1 (multiple endocrine neoplasia) syndrome also include skin lesions, especially tumor-type lesions. This is a narrative review of the English-language medical literature including original studies concerning MEN1 and dermatological issues (apart from dermatologic features of each endocrine tumor/neuroendocrine neoplasia), identified through a PubMed-based search (based on clinical relevance, with no timeline restriction or concern regarding the level of statistical significance). We identified 27 original studies involving clinical presentation of patients with MEN1 and cutaneous tumors; eight other original studies that also included the genetic background; and four additional original studies were included. The largest cohorts were from studies in Italy (N = 145 individuals), Spain (N = 90), the United States (N = 48 and N = 32), and Japan (N = 28). The age of patients varied from 18 to 76 years, with the majority of individuals in their forties. The most common cutaneous tumors are angiofibromas (AF), collagenomas (CG), and lipomas (L). Other lesions are atypical nevi, basocellular carcinoma, squamous cell carcinoma, acrochordons, papillomatosis confluens et reticularis, gingival papules, and cutaneous T-cell lymphoma of the eyelid. Non-tumor aspects are confetti-like hypopigmentation, café-au-lait macules, and gingival papules. MEN1 gene, respective menin involvement has also been found in melanomas, but the association with MEN1 remains debatable. Typically, cutaneous tumors (AF, CG, and L) are benign and are surgically treated only for cosmetic reasons. Some of them are reported as first presentation. Even though skin lesions are not pathognomonic, recognizing them plays an important role in early identification of MEN1 patients. Whether a subgroup of MEN1 subjects is prone to developing these types of cutaneous lesions and how they influence MEN1 evolution is still an open issue.

LBODP106 Multi-omics Analyses Of MEN1 Missense Mutations Identify Disruption Of Menin-MLL And Menin-JunD Interactions As Critical Requirements For Molecular Pathogenicity

Abstract Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 endocrine tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes. Interestingly, we identified three missense mutations, R52G, E255K and E359K, which predominantly reduce the interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions. Presentation: No date and time listed

ODP328 Longitudinal Multidisciplinary Approach for Cabergoline-Resistant Aggressive Prolactinoma Complicated by Multiple Endocrine Neoplasia Type 1

Abstract Background Cabergoline-resistant prolactinomas comprise approximately 10% of all prolactinomas, and sometimes show aggressive features including invasion or higher proliferation profiles. The treatment for such cabergoline-resistant aggressive prolactinomas is challenging and requires a multidisciplinary approach. Clinical case: A 47-year-old woman was diagnosed with hyperprolactinemia after complaining of menstrual irregularities at 20 years old. No neoplastic lesion was identified in the suprasellar region, and 0.25 mg/week cabergoline was initiated. At 35 years’ old, an adenoma was suspected on the right side of the pituitary gland, though plasma prolactin values were sustained without any clinical symptoms. When the patient was 46 years old, her prolactin levels elevated to 202 ng/ml, and magnetic resonance imaging showed a tumor invaded bilateral cavernous sinuses. Because prolactin levels and tumor size continued to increase despite increasing the cabergoline dose to 1 mg/week, endoscopic transsphenoidal surgery was performed. The tumor nearly total removal, the postoperative prolactin levels decreased to 00, but started to increase again in a short period of time. Pathologic assessment revealed a high Ki-67 index (20%) and diffusely positive prolactin alongside negative expression of other anterior hormones. The tumor remained in the cavernous sinus and postoperative prolactin levels tended to increase over time. Cabergoline was restarted and increased to 7mg/week, although prolactin levels were not suppressed. Magnetic resonance imaging and computed tomography scanning showed no metastasis, and octreotide scintigraphy revealed no abnormal accumulation except for the tumor in the cavernous sinus. Radiation therapy was administered to the remaining tumor, and prolactin levels gradually decreased. Thereafter, hypercalcemia and high intact parathyroid hormone levels were found in the presence of left-inferior parathyroid enlargement, leading to a diagnosis of multiple endocrine neoplasia type 1 (MEN1). The patient had no family history of endocrine disease. MEN1 gene mutation was not detected by direct sequencing. Discussion Functional pituitary adenomas including prolactinomas and growth hormone-producing pituitary adenomas are usually benign with a Ki-67 index of approximately 1%, little mitosis, and slow progression 1) . However, pituitary adenomas in MEN1 patients have a higher rate of drug resistance and histological invasiveness than sporadic adenomas, which results in a higher postoperative recurrence rate and a lower normalization rate of approximately 40% 2) . For this case, close monitoring for tumor growth and metastasis was essential.

Genetic Dissection of Primary Aldosteronism in a Patient With MEN1 and Ipsilateral Adrenocortical Carcinoma and Adenoma.

Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1. A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L-1675 pmol/L; normal range [N]: <165 post saline infusion) and suppressed renin levels (<5 ng/L; N: 5-20). Catecholamines, androgens, 24-hour urinary cortisol, and pituitary panel were normal. A right open adrenalectomy revealed a concomitant 4-cm oncocytic ACC and a 2.3-cm adrenocortical adenoma. Immunohistochemistry showed high expression of aldosterone synthase protein in the adenoma but not in the ACC, supporting excess aldosterone production by the adenoma. After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma. To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients.

147 Synchronous Parathyroidectomy and Extended Thymectomy in Multiple Endocrine Neoplasia Type 1- a Case Report

Abstract In recent decades there has been a significant advancement in the management of neuroendocrine tumours (NETs) associated with multiple endocrine neoplasia type 1 (MEN-1). Hormone excess accounted for 75% of all MEN-1 deaths, however since the introduction of hormone blocking medication, deaths in patients with MEN-1 are now predominantly due to the malignant effects of the tumours. Half of all MEN-1 related deaths are due to tumours that are difficult to diagnose, including thymic NETs. Complete surgical resection is the mainstay of treatment for MEN-1 associated thymic NETs. The case patient was a 49-year-old male who was being investigated for a 3-month history of symptoms consistent with hypercalcaemia. Initially a chest X-ray demonstrated a large anterior mediastinal mass. Further imaging revealed parathyroid lesions and a calcified lesion in the uncinate process of the pancreas. This combination of symptoms and radiological evidence raised the possibility of MEN-1 as the diagnosis. The lesions were biopsy-proven atypical carcinoid NETs and the patient later underwent simultaneous neck dissection for bilateral subtotal parathyroidectomy and a midline sternotomy for total thymectomy of the large mediastinal mass. Further testing revealed the pancreatic mass was another primary tumour and the patient is scheduled for excision of this. In addition, the patient is also being treated with Lanreotide alongside chemotherapy. Mutation of the MEN-1 gene was later confirmed on genetic testing. Due to the increase in mortality from neuroendocrine malignancy, it is becoming ever more important to understand how to manage multiple NETs from a surgical perspective.

Multi-omics analyses of MEN1 missense mutations identify disruption of menin–MLL and menin–JunD interactions as critical requirements for molecular pathogenicity

BackgroundLoss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors.ResultsHere, we applied and in silico screening approach for 253 disease-related MEN1 missense mutations in order to select a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/MLL2 and JunD complexes. Interestingly, we identified three missense mutations, R52G, E255K and E359K, which predominantly reduce the MLL1 and MLL2 interactions when compared with JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites.ConclusionsOur results underline the effects of MEN1 gene mutations in both familial and sporadic tumors of endocrine origin on the interactions of menin with the MLL1 and MLL2 histone H3K4 methyltransferase complexes and with JunD-containing transcription factors. Menin binding pocket mutants R52G, E255K and E359K have differential effects on MLL1/MLL2 and JunD interactions, which translate into differential genomic binding patterns. Our findings encourage future studies addressing the pathophysiological relevance of the separate MLL1/MLL2- and JunD-dependent functions of menin mutants in MEN1 disease model systems.