Case Of Multiple Endocrine Neoplasia Type 1 Research Articles

SAT180 Comparison Between Sporadic Primary Hyperparathyroidism And Multiple Endocrine Neoplasia Type 1 (MEN1)-Associated Primary Hyperparathyroidism: A Retrospective Analysis Of The Indian PHPT Registry

Abstract Disclosure: S. Bhadada: None. A.M. Chakraborty: None. P. Kumari: None. R. Pal: None. A. Sood: None. D. Dahiya: None. S.D. Rao: None. Introduction: Multiple endocrine neoplasia type 1 (MEN1)-associated tumours are located in parathyroid, pituitary and pancreatoduodenal locations. Though heterogenous, the most consistent presentation of MEN1 is primary hyperparathyroidism (PHPT) seen in almost 100% of cases. Comparisons between sporadic and MEN1 PHPT patients are sparse in the literature. Objective: To retrospectively compare the demography, clinical manifestations, management, and outcome of sporadic PHPT and MEN1-associated PHPT patients. Design and setting: A registry-based (www.indianphptregistry.com) retrospective cohort study from a tertiary care hospital in North India. Methods and patients: The medical records and clinical data of sporadic PHPT patients and MEN1-associated PHPT patients registered in the Indian PHPT registry were analysed. Result: A total of 616 PHPT patients have been registered in the electronic registry, 72 of whom (11.68%) were MEN1-associated PHPT. The mean age of sporadic PHPT patients was 43.4 ± 14.3, whereas MEN1-associated PHPT was 35.8 ± 13.5 years (p<0.05). Among MEN1-associated PHPT cases, 66 (90%) were index cases at the time of presentation, and the rest were detected on family screening. For both sporadic PHPT and MEN1-associated PHPT, the most common presenting symptom was bone pain, followed by renal stone disease. Sporadic PHPT and MEN1 PHPT both had comparable mean calcium (11.9 ± 1.5 vs 11.9 ± 1.6 mg/dl), mean phosphate (2.7 ± 1 vs 2.58 ± 0.7 mg/dl), median PTH (314; IQR 161-984 pg/ml vs 292; IQR 180-818 pg/ml) level at presentation. Median 25-hydroxyvitamin D level was 19.3; IQR 10.4-30.4 ng/dl, and 15; IQR 8.1 – 25.1 ng/dl (p<0.05) for sporadic PHPT and MEN1-associated PHPT respectively. Multiglandular disease was common in MEN1-associated PHPT (40.2%) compared to sporadic cases (3%). Median tumour weight was higher in sporadic cases (2.5; IQR 0.8- 7.3 gm) compared to MEN1 cases (1.9; IQR 1.08 – 4.05 gm). Ultrasound neck and Sesta-MIBI concordance rate among sporadic cases was 57%, whereas MEN1 cases were 70.8%. Median post-surgery decline in PTH and calcium was more in the case of sporadic PHPT in comparison to MEN1-associated PHPT 84.81% vs 46.7% and 23.4% vs 16.59 % respectively (p<0.05). Discussion: MEN1-associated PHPT patients presented at an earlier age than sporadic cases. There was no statistical difference in PTH, calcium or phosphate levels between the two cohorts, but 25-hydroxyvitamin D levels were lower in MEN1-associated PHPT. Localisation was better in the case of the MEN-1 cohort as per as the Sesta-MIBI and USG concordance was concerned. Postoperative fall of PTH and calcium was more in sporadic cases than in MEN1 cases. Presentation: Saturday, June 17, 2023

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

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

SUN-917 Aggressive De Novo MEN1 Variant in a Child with Metastatic Pancreatic Acth and Crh Co-Secreting Neuroendocrine Tumor: Diagnosis and 10-Year Follow Up

Background:In Multiple Endocrine Neoplasia type 1 (MEN1) only about 2% of pituitary adenomas are ACTH-secreting. Cushing Syndrome due to ectopic ACTH or CRH secretion from neuroendocrine tumors (NETs), carcinoid tumors, or pheochromocytomas is very rare, though patients with MEN1 are at increased risk for these three types of tumors, as well as autonomous adrenal secretion of cortisol. The 10-year follow up of a previously-reported case of a child with MEN1 and metastatic pancreatic ACTH/CRH-secreting NET is presented.Clinical Case:A previously-reported (J Clin Endocrinol Metab, 2015) now 21 yo female presented to the National Institutes of Health (NIH) at 11 yo with persistent hypercortisolemia despite transsphenoidal surgery for suspected Cushing Disease. However, the resected tissue revealed pituitary hyperplasia, and she remained hypercortisolemic. A CRH test was consistent with an ectopic source, and abdominal CT, PET scan, and Octreotide scan revealed a mass in the pancreatic tail. The patient underwent partial pancreatectomy at 11 yo with the resected tissue staining positive for ACTH and CRH. However, she remained hypercortisolemic, so bilateral adrenalectomy was performed. At 12 yo metastases were found, so Octreotide therapy was initiated. She continued to have elevated ACTH levels > 1000 pg/mL (5-46).Additionally, a pituitary adenoma was noted at 12 yo, which has since increased in size. The patient also developed mild primary hyperparathyroidism, first noted at 19 yo. Sequencing of MEN1 for the patient and her parents revealed a de novo heterozygous c.1546dupC variant, consistent with sporadic MEN1. The patient also had a chromosome 8p23.2 duplication that was present in unaffected relatives.Conclusion:While 2% of patients with MEN1 may develop Cushing Syndrome due to an ACTH-secreting pituitary adenoma, it is also important to consider ectopic secretion of ACTH/CRH from MEN1-associated NETs, carcinoid tumors, or pheochromocytomas, as well as autonomous adrenal secretion of cortisol. Given the early age and severe presentation of MEN1 features in this patient, the c.1546dupC heterozygous variant of MEN1, which has been previously reported in multiple other cases of MEN1, may represent a higher-risk causative variant of MEN1. Alternatively, expression of this variant may have been affected by the concurrent presence of an otherwise apparently benign chromosomal variant.

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.

Recent Topics Around Multiple Endocrine Neoplasia Type 1.

Multiple endocrine neoplasia type 1 (MEN1) is complex with regard to clinical expressions, management, and molecular pathways. Advances are being made broadly and in focused aspects. Selected topics are presented for their developments since publication of the most recent MEN1 consensus guidelines 6 years ago. Topics were selected for clinical impact or broad interest or both. For each topic, information was obtained from original reports and reviews. The selected topics are as follows: tumor behavior and breast cancer in MEN1; foregut neuroectoderm tumor screening, biomarkers periodically to detect tumor emergence of foregut neuroectoderm tumors, 68Ga dotatate positron emission tomography/computed tomography for pancreatic and duodenal neuroectodermal tumor imaging, and glucagon-like peptide-1 receptor scintigraphy for insulinoma; therapy, the size of pancreatic neuroendocrine tumor (NET) as one criterion for surgery, minimally invasive surgery of pancreatic NETs, and 177Lu dotatate therapy; MEN1 gene, the search for the MEN1/menin pathway and MEN1 or GCM2 mutation in familial isolated hyperparathyroidism, and MEN1 mutation-positive vs mutation-negative cases of MEN1 are different. MEN1 topics are a rich and fast-moving area. Important highlights stand out, and major and rapid advances will continue into the near future.

Is estrogen exposure a protective factor for pancreatic neuroendocrine tumours in female patients with multiple endocrine neoplasia syndrome type 1?

Pancreatic neuroendocrine tumours (PNETs) are the most common cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Women have been shown to have improved survival, which may suggest a possible protective effect of female sex hormones. The aim of this study was to evaluate the relationship between estrogen exposure and PNET tumourigenesis, tumour growth and survival in female MEN1 patients with these tumours. We performed a retrospective chart review of the existing MEN1 database in our institution. Detailed information about female patients' menstrual and reproductive history, and PNET clinicopathologic characteristics was collected. Questionnaires regarding estrogen exposure were used to collect information that was missing in the database. Of 293 confirmed MEN1 cases, 141 women met the inclusion criteria. We used measures of cumulative estrogen exposure time (CEET), parity, live birth pregnancies and bilateral oophorectomy to estimate estrogen exposure. There was no significant association between CEET and time to PNET diagnosis (hazard ratio=0·966, P=0·380). For the correlation between estrogen exposure and PNET type, size, numbers, distant metastasis, lymph node metastasis, lymphovascular invasion, AJCC (American Joint Committee on Cancer) stage and overall survival, only CEET was significantly correlated with PNET size (P=0·043). In female patients with MEN1, estrogen exposure may inhibit PNET growth. A demonstrable protective effect against PNET tumourigenesis, tumour growth and survival of patients with these tumours may require a larger cohort.

Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE for Metastatic Neuroendocrine Tumor Occurring in Association with Multiple Endocrine Neoplasia Type 1 and Cushing's Syndrome.

Neuroendocrine tumor (NET) occurring in association with other endocrine syndromes forms a distinct entity. The aim was to assess the therapy response profile of the routine peptide receptor radionuclide therapy (PRRT) in this relatively uncommon but clinically challenging subgroup of patients. A retrospective analysis was undertaken from the case records from those who were treated with 177Lu-DOTATATE for metastatic NET. In addition to assessing the therapeutic efficacy, emphasis was also given to study lesional sites and scan pattern. A total of 5 cases were found: In this series of five cases, four belonged to multiple endocrine neoplasia type 1 (MEN1) syndrome; in these four MEN1 syndrome patients, the primary site of NET was thymic region (n = 1), duodenum (n = 1), and pancreas (n = 2). The fifth case was of Cushing's syndrome with the primary site of NET in the thymus. A good symptomatic response was observed in all MEN1 syndrome cases (100%) and progression of symptoms in the patient with Cushing's syndrome. The biochemical response (assessed by measurement of tumor marker serum chromogranin A) demonstrated very good partial response (defined by more than 75% reduction of tumor marker) in 2 MEN1 cases and Cushing's syndrome, good partial response (25–75% reduction of tumor marker) in the remaining 2 MEN1 cases. Scan wise (assessed by technetium [99mTc]-hydrazinonicotinamide [HYNIC]-tektrotyd [TOC]/68Ga-DOTA-NOC/TATE positron emission tomography-computed tomography [PET-CT] and fluorodeoxyglucose [FDG] PET-CT) partial response was observed in 3 MEN1 cases, stable disease was noted in one MEN1 case and disease progression was noted in the patient with Cushing's syndrome. The change in FDG uptake was found to be an important sensitive scan parameter in the treatment evaluation of NETs compared to somatostatin receptor-based imaging in the cases with low MiB1 index. In our series, good palliative response to 177Lu-DOTA-octreotate (DOTATATE) PRRT was observed in most NET patients associated with MEN1 syndrome without any major hematological or renal toxicity.

Utility of chromogranin A, pancreatic polypeptide, glucagon and gastrin in the diagnosis and follow-up of pancreatic neuroendocrine tumours in multiple endocrine neoplasia type 1 patients.

Pancreatic neuroendocrine tumours (PNETs) are the major source of disease-specific mortality in multiple endocrine neoplasia type 1 (MEN1) patients. Chromogranin A (CgA), pancreatic polypeptide (PP), glucagon and gastrin have some diagnostic value in sporadic PNETs, but there is very little evidence for their efficacy in diagnosing PNETs in MEN1 patients. We performed a retrospective chart review of the existing MEN1 database in our institution. One hundred and thirteen patients were eligible for diagnostic value analysis of tumour markers. Patients were excluded if measurement of tumour markers was missing, either 3 months prior to PNET diagnosis (PNET patients) or prior to abdominal imaging (non-PNET patients). Clinicopathologic characteristics and of tumour marker measurements were analysed. Of 293 confirmed MEN1 cases, 55 PNETs and 58 non-PNETs met inclusion criteria. The area under the curve (AUC) for CgA, PP, glucagon and gastrin in MEN1 cases was 59·5%, 64·1%, 77·0% and 75·9%, respectively. The AUC for the combination of CgA, PP and gastrin was 59·6%. PP, but not CgA, glucagon or gastrin was significantly associated with both age and PNET functional status (P = 0·0485 and 0·0188, respectively). No markers were significantly associated with sex, PNET size, tumour number, tumour location, American Joint Committee on Cancer (AJCC) stage, presence of lymph node metastasis, lymphovascular invasion or overall survival. CgA values were not significantly lower following PNET resection than pre-operatively (P = 0·554). The value of blood markers for diagnosing PNETs in MEN1 patients is relatively low, even when used in combination.

Bronchopulmonary Neuroendocrine Neoplasms and Their Precursor Lesions in Multiple Endocrine Neoplasia Type 1

Objective: The prevalence and clinical behavior of bronchopulmonary neuroendocrine tumors (bNET) associated with multiple endocrine neoplasia type 1 (MEN1) are not well defined. This study aimed to determine the prevalence, potential precursor lesions and prognosis of bNET in patients with MEN1. Methods: A database of 75 prospectively collected MEN1 cases was retrospectively analyzed for bNET. Patient characteristics, imaging and treatment were evaluated. Resection specimens of operated patients were reassessed by two specialized pathologists. Available CT scans of the whole cohort were reviewed to determine the prevalence of bronchopulmonary nodules. Results: Five of the 75 MEN1 patients (6.6%; 2 male, 3 female) developed histologically confirmed bNET after a median follow-up of 134 months. The median age at diagnosis of bNET was 47 years (range 31-67), and all patients were asymptomatic. Four patients underwent anatomic lung resections with lymphadenectomy; the remaining patient with multiple lesions had only a wedge resection of the largest bNET. Tumor sizes ranged from 7 to 32 mm in diameter, and all bNET were well differentiated. Two patients had lymph node metastases. Two of 4 reevaluated resection specimens revealed multifocal bNET, and 3 specimens showed tumorlets (up to 3) associated with multifocal areas of a neuroendocrine cell hyperplasia within the subsegmental bronchi. One bNET-related death (1.3%) occurred during long-term follow-up. Review of the available CT scans of the patients without proven bNET revealed small bronchopulmonary lesions (≥3 mm) in 16 of 53 cases (30.2%). Conclusions: bNET in MEN1 might be more common than previously recognized. Their natural course seems to be rather benign. Multifocal tumorlets and multifocal neuroendocrine cell hyperplasia might represent their precursor lesions.

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

Multiple endocrine neoplasia type 1 associated with breast cancer: A case report and review of the literature.

Multiple endocrine neoplasia type 1 (MEN1) is a cancer predisposition syndrome that includes a combination of endocrine and non-endocrine tumors. The present study reports a rare case of MEN1 associated with breast cancer with the MEN1 gene mutation. A 45-year-old female was diagnosed with breast cancer subsequent to presenting with a right breast mass. Pre-operative radiological studies indicated right breast cancer with a suspicious metastatic nodule of the lung. Further studies demonstrated bilateral thyroid nodules, a neuroendocrine tumor of the pancreas, paraganglioma, a left adrenal adenoma, gallstones, uterine subserosal myoma and pituitary macroadenoma. Laboratory examinations revealed hypercalcemia, hypophosphatemia and an increased intact parathyroid hormone level. The workup for the suspected MEN syndrome revealed an increased basal plasma level of insulin-like growth factor-1, prolactin and calcitonin, and an increased 24-h urinary free cortisol level. The patient underwent surgical removal of the breast cancer and the tumors of the pancreas, adrenal gland, thyroid and parathyroid glands, uterus, anterior mediastinum and lung. The pathological diagnosis of the resected breast was of invasive ductal carcinoma. Otherwise the pathological diagnosis was of calcitonin-producing pancreatic endocrine carcinoma, adrenal cortical adenoma, bilateral papillary thyroid carcinomas, parathyroid adenomas, uterine leiomyoma with adenomyosis, a thymic carcinoid tumor and lung hamatoma. Gene analysis was performed to determine the association between gene mutations and the development of tumors in this patient, and a germ-line MEN1 gene mutation was consequently detected. It could be assumed that MEN1 syndrome may have possibly predisposed the present patient to breast cancer. However, additional observations and further studies are required to demonstrate this association.

Chapter 23 - Familial pituitary tumors

Pituitary adenomas are benign intracranial neoplasms that present a major clinical concern due to hormone overproduction and/or tumor mass effects. The majority of pituitary adenomas occur sporadically; however, familial cases are increasingly being recognized, such as multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), and familial isolated pituitary adenoma (FIPA). Familial pituitary tumors appear to differ from their sporadic counterparts both in their genetic basis and in clinical characteristics. Evidence suggests that, especially in MEN1 and FIPA, tumors are more aggressive and affect patients at a younger age, therefore justifying the importance of early diagnosis, while in Carney complex pituitary hyperplasia is common. The genetic alterations responsible for the formation of familial pituitary syndromes include the MEN1 gene, responsible for about 80% of MEN1 cases, the regulatory subunit of the protein kinase A, PRKAR1A, responsible for about 70% of Carney complex cases, and AIP, the gene coding the aryl hydrocarbon receptor interacting protein, responsible for about 20% of FIPA cases. Rarely other genes have also been found responsible for familial pituitary adenoma cases. McCune-Albright syndrome (MAS) also has a genetic origin due to mosaic mutations in the G protein-coupled α subunit coded by the GNAS1 gene. In this chapter, we summarize the genetic and clinical characteristics of these familial pituitary syndromes and MAS.

Functioning glucagonoma associated with primary hyperparathyroidism: multiple endocrine neoplasia type 1 or incidental association?

BackgroundDiagnosis of multiple endocrine neoplasia type 1 (MEN1) is commonly based on clinical criteria, and confirmed by genetic testing. In patients without known MEN1-related germline mutations, the possibility of a casual association between two or more endocrine tumors cannot be excluded and subsequent management may be difficult to plan. We describe a very uncommon case of functioning glucagonoma associated with primary hyperparathyroidism (pHPT) in which genetic testing failed to detect germline mutations of MEN-1 and other known genes responsible for MEN1.Case presentationThe patient, a 65-year old woman, had been suffering for more than 1 year from weakness, progressive weight loss, angular cheilitis, glossitis and, more recently, skin rashes on the perineum, perioral skin and groin folds. After multidisciplinary investigations, functioning glucagonoma and asymptomatic pHPT were diagnosed and, since family history was negative, sporadic MEN1 was suspected. However, genetic testing revealed neither MEN-1 nor other gene mutations responsible for rarer cases of MEN1 (CDKN1B/p27 and other cyclin-dependent kinase inhibitor genes CDKN1A/p15, CDKN2C/p18, CDKN2B/p21). The patient underwent distal splenopancreatectomy and at the 4-month follow-up she showed complete remission of symptoms. Six months later, a thyroid nodule, suspected to be a malignant neoplasia, and two hyperfunctioning parathyroid glands were detected respectively by ultrasound with fine needle aspiration cytology and 99mTc-sestamibi scan with SPECT acquisition. Total thyroidectomy was performed, whereas selective parathyroidectomy was preferred to a more extensive procedure because the diagnosis of MEN1 was not supported by genetic analysis and intraoperative intact parathyroid hormone had revealed “adenoma-like” kinetics after the second parathyroid resection. Thirty-nine and 25 months after respectively the first and the second operation, the patient is well and shows no signs or symptoms of recurrence.ConclusionsDespite well-defined diagnostic criteria and guidelines, diagnosis of MEN1 can still be challenging. When diagnosis is doubtful, appropriate management may be difficult to establish.

Multiple endocrine neoplasia type 1- presenting multiple lipomas and hypoglycemia onset

SummaryBackground:Multiple endocrine neoplasia type 1 (MEN1), also called Wermer syndrome, is an autosomal dominant disorder characterized by tumors of the parathyroid glands, the anterior pituitary, and the endocrine pancreas.Case Report:Here, we report a case of MEN1. Our patient was a 44-year-old woman who manifested typical features of MEN1, including insulinoma, pituitary tumors, and parathyroidoma, and exhibited multiple lipomas and a gastrinoma with duodenal ulcers. She was admitted to our hospital because of recurrent massive bleeding of the upper gastrointestinal tract and hypoglycemia. The first operation for pituitary tumors was performed when she was 40 years old. According to these examinations and her clinical course, the patient was diagnosed with insulinoma and gastrinoma. She subsequently underwent surgery for the pancreatic tumors. The majority of these tumor cells were immunohistochemically positive for insulin and negative for glucagon.Conclusions:This case suggests that multiple lipomas, insulinoma and gastrinoma may provide clues for a diagnosis of MEN1.

Menin Missense Mutants Encoded by the MEN1 Gene that Are Targeted to the Proteasome: Restoration of Expression and Activity by CHIP siRNA

In multiple endocrine neoplasia type 1 (MEN1) characterized by tumors of parathyroid, enteropancreas, and anterior pituitary, missense mutations in the MEN1 gene product, menin, occur in a subset of cases. The mutant proteins are degraded by the proteasome. However, whether their expression and activity can be restored is not known. Our objective was to functionally characterize a panel of 16 menin missense mutants, including W423R and S443Y identified in new MEN1 families, with respect to protein stability, targeting to the proteasome and restoration of expression by proteasome inhibitors and expression and function by small interfering RNA technology. Flag-tagged wild-type (WT) and missense menin mutant expression vectors were transiently transfected in human embryonic kidney (HEK293) and/or rat insulinoma (Rin-5F) cells. The majority of mutants were short-lived, whereas WT menin was stable. Proteasome inhibitors MG132 and PS-341 and inhibition of the chaperone, heat-shock protein 70 (Hsp70), or the ubiquitin ligase, COOH terminus of Hsp70-interacting protein (CHIP), by specific small interfering RNA, restored the levels of the mutants, whereas that of WT menin was largely unaffected. Inhibition of CHIP restored the ability of mutants to mediate normal functions of menin: TGF-β up-regulation of the promoters of its target genes, the cyclin-dependent kinase inhibitors p15 and p21 as well as TGF-β inhibition of cell numbers. When the levels of missense menin mutants that are targeted to the proteasome are normalized they may function similarly to WT menin. Potentially, targeting specific components of the proteasome chaperone pathway could be beneficial in treating a subset of MEN1 cases.

Rare Germline Mutations in Cyclin-Dependent Kinase Inhibitor Genes in Multiple Endocrine Neoplasia Type 1 and Related States

Germline mutation in the MEN1 gene is the usual cause of multiple endocrine neoplasia type 1 (MEN1). However, the prevalence of identifiable germline MEN1 mutations in familial MEN1 cases is only 70%. Some cases may have a germline mutation in another gene such as the p27 cyclin-dependent kinase inhibitor (CDKI). The aim of the study was to investigate cases of MEN1 or related states for germline mutations in all CDKI genes. A total of 196 consecutive index cases were selected with clear or suspected MEN1 and no identifiable germline MEN1 mutation. Every case was analyzed for germline mutation in each of the seven CDKI genes. We identified benign polymorphisms of the CDKI genes and also 15 other initially unclassified sequence variants. After detailed gene/protein analysis, seven of these 15 variants were classified as probably pathological mutations. Three of these seven were probable mutations of p27. The remaining four were probable pathological mutations in three of the other CDKI genes, thereby implicating these three genes in the germline of human tumors. The identification rates for probably pathological mutations among the 196 index cases were similarly low for each of four CDKI genes: p15 (1%), p18 (0.5%), p21 (0.5%), and p27 (1.5%). No characteristic clinical subtype related to MEN1 was identified among the seven index cases and their families. Rare germline mutation in any among four (p15, p18, p21, and p27) of the seven CDKIs is a probable cause of MEN1 or of some related states.

Multiple Endocrine Neoplasia Type 1 with Multiple Leiomyomas Linked to a Novel Mutation in the MEN1 Gene

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited syndrome. MEN1 is characterized by the presence of functioning and nonfunctioning tumors or hyperplasia of the pituitary gland, parathyroid glands, and pancreatic islet cells. In addition, MEN1 carriers can have adrenal or thyroid tumors and non-endocrine tumors, such as lipomas, angiofibromas, and leiomyomas. Although leiomyoma is not a major component of MEN1, it is thought to occur more frequently than expected. However, there has been no report of a case of MEN1 with leiomyoma in Korea so far. This report describes a patient with multiple leiomyomas in MEN1. A 50-year-old woman was referred for further evaluation of elevated calcium levels and osteoporosis. Biochemical abnormalities included hypercalcemia with elevated parathyroid hormone. There was hyperprolactinemia with pituitary microadenoma in sella MRI. An abdominal MRI demonstrated adrenal nodules and leiomyomas in the bladder and uterus. Endoscopic ultrasonography demonstrated esophageal leiomyoma and pancreatic islet cell tumor. A subtotal parathyroidectomy with thymectomy was performed. Sequencing of the MEN1 gene in this patient revealed a novel missense mutation (D350V, exon 7). This is the first case of MEN1 accompanied with multiple leiomyomas, parathyroid adenoma, pituitary adenoma, pancreatic tumor, and adrenal tumor.

Mediastinal Seminoma in a Patient with Multiple Endocrine Neoplasia Type 1

A patient with multiple endocrine neoplasia type 1 (MEN1) developed a mediastinal seminoma. The patient was a 46-year-old man who presented with respiratory symptoms. A diagnosis of mediastinal seminoma was pathologically confirmed and a complete remission was achieved by chemotherapy. During his hospital stay, hyperparathyroidism and multiple pancreatic tumors associated with hypergastrinemia were found. A diagnosis of MEN1 was made genetically. Although patients with MEN1 manifest a variety of neoplastic disorders, no cases of concurrent seminoma and MEN1 have previously been reported. In addition, no etiological relationship between seminoma and MEN1 has yet been reported.

A Case of Multiple Endocrine Neoplasia Type 1 Combined with Papillary Thyroid Carcinoma

This is the first report of papillary thyroid carcinoma combined with multiple endocrine neoplasia type 1 (MEN1) in Korea. MEN1 is a hereditary disease comprising neoplastic disorders such as pituitary, parathyroid and pancreatic neuroendocrine tumor, such as gastrinoma. But papillary thyroid cancer was never regarded as its component before in Korea. Herein we present a 39-year-old woman who manifested typical features of MEN1 with a coincidental papillary thyroid carcinoma. Although the family history of MEN1 was definite, her genetic analysis of DNA had revealed no germline mutation in MEN1 gene locus. Unidentified culprit gene unable us further genetic study to find LOH (loss of heterogeneity) in 11q13, the possible explanation of papillary thyroid carcinoma as a new component of MEN1. As we have first experienced a case of MEN1 combined with papillary thyroid carcinoma in Korea, we report it with the review of literature.

THE IMPACT OF CLINICAL AND GENETIC SCREENINGS ON THE MANAGEMENT OF THE MULTIPLE ENDOCRINE NEOPLASIA TYPE 1

To perform clinical and genetic screening for multiple endocrine neoplasia type 1 (MEN1) in patients at the Academic Hospital of the University of São Paulo School of Medicine, and to analyze its impact on clinical management of patients with MEN1. The clinical diagnosis of MEN1 was made in accordance with the Consensus on multiple endocrine neoplasias. Mutation analysis of the entire MEN1 tumor suppressor gene and genetic screening of at-risk family members were performed by direct sequencing. To analyze the implementation of genetic diagnosis, the studied patients were separated into 3 groups: MEN1 index cases (group I), clinically diagnosed MEN1 cases (group II), and genetically diagnosed MEN1 cases (group III). In total, 154 individuals were clinically and genetically studied. We identified 12 different MEN1 mutations. Fifty-two MEN1 cases were identified: 13 in group I, 28 in group II, and 11 in group III. The mean age in group III (27.0 years) was significantly lower than in groups I (39.5 years) and II (42.4 years; P = 0.03 and P = 0.01, respectively). Patients in groups I and II mostly presented 2 or 3 MEN1-related tumors, while 81.8% of those in group III presented 1 or no MEN1-related tumor. Additionally, in group III, 45.4% of cases were asymptomatic, and no metastasis or death was verified. Surveillance for MEN1 mutations allowed the exclusion of 102 noncarriers, including a case of MEN1 phenocopy. Our data supports the benefits of clinical and genetic screening for multiple endocrine neoplasia type 1 in the management of this syndrome.