Multiple Endocrine Neoplasia Type 1 Gene Mutations Research Articles

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.

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.

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.

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

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

In-silico analysis to identify the role of MEN1 missense mutations in breast cancer

Background: The multiple endocrine neoplasia type 1 (MEN1) gene located on chromosome 11q13 encodes menin protein. Previously reported mutations were thought to result in loss of function of menin protein and that they are associated with multiple endocrine neoplasia 1 disorder. However, recently menin has also been characterized as an oncosuppressor protein and it was suggested that mutations in it are associated with various other tumors. Studies indicate that the menin protein stimulates the estrogen receptor (ER) that in turn increases the predisposition for inherited breast cancer. Methods: Here, we used our supervised in-house combinatory in-silico predictor method to investigate the impact of unclassified missense mutations in MEN1 gene found in breast cancer tissue. We also examined the biophysical and biochemical properties to predict the effects of these missense variants on the menin protein stability and interactions. The results are compared with the effects of known pathogenic mutations in menin causing neoplasia. Results: Our analysis indicates that some of the variants found in breast cancer tissue show similar pattern of destabilizing the menin protein and its interactions as the pathogenic variants associated with neoplasia. Taking together with the results of our in-silico consensus predictor, we classify missense mutations in menin protein found in breast cancer tissue into pathogenic and benign, and thus, suggesting as an indicator for early detection of elevated breast cancer risk.

The Genetic Multiplicity- Multiple Endocrine Neoplasia type I

Multiple endocrine neoplasia type 1 (MEN1) is a syndrome emerging from characteristic mutations of MEN1 gene with concurrently enunciated multiple endocrine and tumours and associated non-endocrine neoplasm. Previously designated as Werner’s syndrome, MEN1 syndrome denominates genomic mutation within chromosome 11q13 or a tumour suppressor gene with a distinctive protein product nomenclated as “menin”. MEN1 syndrome demonstrates an autosomal dominant pattern of disease inheritance where genomic mutations delineate a comprehensive (100%) disease penetrance. MEN1 gene was initially identified in 1997 upon chromosome 11q13. Although twelve genetic mutations were primarily identified, currently beyond eighteen hundred genomic mutations are scripted1, 2. MEN1 syndrome is comprised of diverse combination of twenty or more endocrine and non-endocrine tumours exemplifying a classic triad of pituitary, parathyroid and pancreatic neoplasm. Diverse non endocrine tumours enunciated with MEN1 syndrome are denominated with meningioma, ependymoma or angiofibroma1, 2. Endocrine tumours are discerned on account of excessive hormonal secretion engendered from various neoplasm or on account of neoplastic evolution. Approximately 10% instances can occur due to a de-novo genomic variant. Offspring of an individual with MEN1 syndrome quantifies a 50% possibility of inheriting the genomic variant. Cogent prenatal diagnosis can be determined in instances where specific genomic variant of a particular family is known. Physical, psychological and social restrictions are prevalent with MEN1 syndrome. Heterozygotes with MEN1 genetic variant are denominated as carriers and manifest a two- fold possible mortality1, 2.

Molecular Mechanisms of Carcinogenesis Associated with MEN1 Gene Mutation

Despite recent advances in genomics and the discovery of numerous genes involved in carcinogenesis, the mechanisms of malignant transformation of different tissues remain poorly understood in most cases. This review presents the current knowledge on the role of the MEN1 gene and its protein product menin in the development of multiple endocrine neoplasia type 1 (MEN1), or Wermer’s syndrome. Here, we discuss the putative molecular and genetic mechanisms of carcinogenesis associated with the MEN1 gene mutation, as well as available and promising in vivo and in vitro models for studying the molecular basis of the disease. The lack of clear data on the role of the MEN1 gene in tumor initiation and progression in patients with MEN1 syndrome allows us to suggest two models for occurrence of malignant transformation in endocrine tissues.

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.

OR15-3 Extreme Phenotypic Variability of a Novel Mutation of MEN1 Gene in a Family with 14 Carriers across 3 Generations

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease characterized by the development of tumoral lesions usually benign in different glands. The most common tumors involve the parathyroid, pituitary and endocrine pancreas. Over 1300 mutations of MEN1 gene have been identified in approximately 4000 patients. Attempts to identify a correlation between genotype and phenotype have been unsuccessful as symptoms can vary among families and even among relatives that share the same mutation. The aim of this work is to characterize a family with a new mutation of MEN1 gene, through clinical findings, biochemical tests, and morphologic exams. The index case is a 38 years-old man with recurrent renal lithiasis during the last 20-years. In addition to the primary hyperparathyroidism, the patient also presented a pituitary microadenoma with hyperprolactinemia. The coexistence of these two manifestations suggested the diagnosis of MEN1. Genetic tests detected a new heterozygous germinal mutation in the exon 9 of the gene MEN1: c.1321_1323 dup TGG, which is expected to lead to a duplication of the tryptophan (p.Trp 441dup) of the MENIN protein. This variant is not described in the available databases (1000 Genomes e ExAC) nor in the ClinVar (online public archive). The analysis in silico performed with the software Mutation Taster classified this variant as the “pathogenic.” The family history of the patient was collected and a genealogical tree of the family was made. Written informed consent was obtained. The genetic diagnosis proposed to the members of this family identified 14 carriers of the mutation across 3 generations (including the index case), aged between 5 and 71 years old. A screening program to search for alterations in MEN1 positive carriers showed that primary hyperparathyroidism was the most common manifestation involving 6 patients. However, only 50% (2/4) of the subjects above 60 years-old were affected what is in favor of a low penetrance of this mutation. In three adult carriers, the only clinical manifestation was the presence of non-functional pancreatic (3) and lung (1) neuroendocrine tumors; Cushing's disease was the first and so far unique manifestation of the disorder in an 18-year-old girl. Despite sharing the same mutation and being exposed to similar environmental conditions as they all live on the same island, carriers of the mutation in this family presented variable phenotypes. This finding suggests that the nature and effect of the second hit that triggers the tumoral lesion in patients that carry the genomic mutation are mainly unknown. On the other side, this phenotypic variability demands the definition of a screening protocol, to correctly value the clinical manifestations and biochemical tests with implication in the prognosis of these patients.

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.

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing.

Background Loss-of-function germline MEN1 gene mutations account for 75-95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.

Novel Mutations in Serbian MEN1 Patients: Genotype-Phenotype Correlation

Summary Background: Multiple 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. Methods: Clinical and genetic analysis of 90 consecutive MEN1 patients was performed in a retrospective, single – center study. Results: MEN1 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%). Conclusions: Large number of novel mutations among MEN1 patients confirmed previously reported data. PNETs and PHPT were more frequent in patients with truncating mutations.

MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism.

Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real-time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin-negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT.

A pedigree of multiple endocrine neoplasia type 1 with the proband initially presenting adrenal cortical carcinoma

This is a pedigree of multiple endocrine neoplasia type 1(MEN1). The proband pursuit medical assistance because of hypertension and weakness. Adrenal cortical carcinoma with possible Cushing's syndrome was diagnosed after a series of tests. During this process, the proband was found to have hypercalcemia, and he was diagnosed as primary hyperparathyroidism. Adrenal carcinoma plus primary hyperparathyroidism suggested MEN1, which was confirmed by MEN1 gene 400_401insC mutation. Pedigree investigation found six additional patients, including one with high parathyroid hormone level and two without clinical evidence of any MEN1 diseases. The proband died of metastatic malignancy 7 months after diagnosis while the other 3 patients with clinically confirmed MEN1 tumor responded well to surgery, including one with adrenal cortical carcinoma. (Chin J Endocrinol Metab, 2016, 32: 514-519) Key words: Cushing' syndrome; Adrenal cortical carcinoma; Multiple endocrine neoplasia type 1; MEN1 gene mutation

Novel multiple endocrine neoplasia type 1 variations in patients with sporadic primary hyperparathyroidism.

Background and Objectives:Primary hyperparathyroidism (PHPT) can occur either as a sporadic case or in association with syndromes such as multiple endocrine neoplasia. Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal-dominant disease resulting from mutations in MEN1 gene encoding a 621 amino acid long tumor suppressor protein “menin.” We report here the results of MEN1 screening in 31 patients diagnosed with sporadic PHPT.Materials and Methods:Diagnosis of sporadic PHPT was made when blood urea and serum creatinine were normal, serum parathyroid hormone was high, and parathyroid enlargement could be localized on ultrasound and/or parathyroid scan. A total of 31 patients and 50 healthy volunteers were recruited for molecular analysis after taking informed consent.Results:Major symptoms at presentation were bone pain, fatigue, muscle weakness, and renal stones. Molecular genetic analysis revealed the presence of two novel intronic variations, c. 913-79T>A and c. 784-129T>A which by human splicing finder are predicted to cause potential alteration of splicing by either activating an intronic cryptic acceptor site or converting a conserved exonic splicing silencer sequence to an exonic splicing enhancer site. Apart from these, two reported polymorphisms rs144677807 and rs669976 were seen only in patients and none of the controls. Other reported polymorphisms rs2071313 and rs654440 were identified both in controls and patients.Conclusions:This is the first study of MEN1 gene screening in sporadic PHPT in India reporting on the clinical and genetic findings, wherein two novel intronic variations c. 913-79T>A and c. 784-129T>A were identified showing their possible role in disease causation.

Gastrointestinal stromal tumor revealing multiple endocrine neoplasia type 1

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract. The most common primary sites for GISTs are the stomach (60%) and the small intestine (30%). We reported one case of GIST revealing multiple endocrine neoplasia type 1 (MEN1). Case report A 59-year-old female admitted for prolonged fever with cutaneous lesions. The physical exam revealed epigastric pain. The abdominal ultrasonography showed two masses located in the left hypochondrium (intersplenorenal) and epigastric. The abdominal CT scan showed the masses in the splenic hilum and the small gastric curvature. The fine-needle aspiration biopsy concluded to a double location of a stromal tumor. Their immunohistochemical profile was KIT positive. The cuatneous lesions biopsy was inconclusive. The cervico-thoracic CT scan revealed two metastatic pulmonary nodules. Medical treatment using Imatinib (Glivec = 400 mg/d) was indicated. However, one year later the Glivec treatment does not result in complete response. Moreover, during the hospitalization, blood investigations revealed a severe hypercalcemia of 2,96 mmol/l. The diagnosis of primary hyperparathyroidism was confirmed with high level of parathyroid hormone (PTH = 217 pg/mL). The neck ultrasonography showed a parathyroid adenoma. A multiple endocrine neoplasia type 1 was suspected. The MRI concluded to a microadenoma (3 mm). The assessment of MEN1 gene mutation was not documented. Conclusion Our patient represents an undescribed combination of the GIST with MEN 1. Occurrence of GIST could be consistent with the possibility that this neoplasm arose by a mechanism related to the MEN1 gene.

Concurrent Type 2 Diabetes and Multiple Endocrine Neoplasia Type 1 With a Novel MEN1 Gene Mutation

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder that is characterized by the combined occurrence of primary hyperparathyroidism (PHPT), enteropancreatic neuroendocrine tumors and anterior pituitary adenomas. Increased insulin resistance and a higher prevalence of glucose intolerance have been noted in MEN1 families and are associated with increased cardiovascular mortality. Mutations in the MEN1 tumor suppressor gene cause multiple tumors in MEN1 but can also be associated with glycemic dysregulation. A 52-year-old man was admitted for blood glucose control. He had been diagnosed with diabetes 3 years previously. Hypercalcemia was incidentally detected during a blood test. After examination, he was diagnosed with PHPT caused by parathyroid hyperplasia. On genetic analysis, he was found to have a novel mutation in the MEN1 gene (exon 10, c.1590_1606_del; p.Gly532AlafsX20). We report a case of MEN1 with a novel MEN1 gene mutation associated with type 2 diabetes in a patient with no family history of diabetes. This is the first case of MEN1 associated with type 2 diabetes before pancreatic surgery in Korea. J Med Cases. 2014;5(11):596-600 doi: http://dx.doi.org/10.14740/jmc1973w

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations.

To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for. As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals. Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression. There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013-5.76). Among patients who are ≥30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors. Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.