Multiple Endocrine Neoplasia
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Multilpe endocrine neoplasia (MEN) are rare fimilial (inherited) conditions affecting the glands of the endocrine system:

MEN I typically affects parathyroid, the pancreas, and the pituitary while MEN IIa and MEN IIb are associated with medullary thyroid carcinoma.

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Endocrine Cancers
Thyroid Cancer

Information Patients and the Public (6 links)

Information for Health Professionals / Researchers (7 links)

See also: Multiple endocrine neoplasia I (11q13)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Păun DL, Poiană C, Petriş R, et al.
Multiple endocrine neoplasia type 2A: case report.
Chirurgia (Bucur). 2013 Nov-Dec; 108(6):900-3 [PubMed] Related Publications
Multiple endocrine neoplasia type 2A (MEN 2A) is a complex autosomal dominant inherited syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary parathyroid hyperplasia. In patients with only one or two clinical features, identification of a germline RET(REarranged in Transfection) mutation or the identification of the clinical features of MEN 2A in other first degree relatives is required to make the diagnosis. We present the case of a family with MEN 2A syndrome confirmed by genetic analysis which identified RET gene mutation in 634 codon in father - DV - aged 48 years and also in daughter DM -aged 20 years. The specific feature in this case is that the index case was the daughter (diagnosed and operated for pheochromocytoma at the age of 19 years), the father being diagnosed later with medullary thyroid carcinoma by mutational screening in all family members. This family supports the phenomenon of anticipation, in which severity increases and the age of onset decreases in successive generations, the syndrome being discovered earlier and with a worse prognostic in the daughter.

Related: Thyroid Cancer RET

Piver D, Ronot M, Guedj N, et al.
Case 200: Gastric enterochromaffinlike cell tumors in a patient with type 1 multiple endocrine neoplasia.
Radiology. 2013; 269(3):940-4 [PubMed] Related Publications
History A 55-year-old man presented with chronic epigastric pain lasting for about 1 year and without fever or vomiting. The abdomen was soft and tender at physical examination. Laboratory tests revealed unremarkable liver function, normal hemoglobin level, and normal amylase level. White blood cell count was normal, and there was no inflammatory syndrome. The patient's medical history included pancreatic gastrinoma resected by means of left pancreatectomy 31 years before, hyperparathyroidism treated with subtotal parathyroidectomy 24 years before, and a slowly growing lung mass known for 9 years. Esophagogastroduodenoscopy was performed because of a suspected gastroduodenal ulcer. The results showed numerous small (<10 mm) gastric and duodenal ulcers and multiple 10-15-mm polypoid gastric masses. Contrast material-enhanced dual-phase multidetector row computed tomography (CT) of the chest and abdomen was performed with a 64-section CT scanner (LightSpeed VCT; GE Healthcare, Milwaukee, Wis). Technical parameters for CT were as follows: pitch, 0.98; section thickness and reconstruction interval, 1.25 mm; 120 kVp; and variable milliamperage determined by x-, y-, and z-axis dose modulation. After an unenhanced abdominal scan, iobitridol, a nonionic iodinated contrast agent containing 350 mg of iodine per milliliter (Xenetix 350; Guerbet, Aulnay-sousbois, France), was administered intravenously through a 16-18-gauge catheter. A 120-mL dose of the contrast agent was injected via an antecubital vein at a rate of 4 mL/sec. No oral contrast medium was administered. After preliminary unenhanced abdominal scanning, arterial and portal venous phase acquisitions were obtained 45 and 80 seconds after initiation of contrast medium injection.

Related: Stomach Cancer Gastric Cancer

Gonçalves TD, Toledo RA, Sekiya T, et al.
Penetrance of functioning and nonfunctioning pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 in the second decade of life.
J Clin Endocrinol Metab. 2014; 99(1):E89-96 [PubMed] Related Publications
CONTEXT: Data are scarce on the penetrance of multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-PETs) and insulinomas in young MEN1 patients. A potential positive correlation between tumor size and malignancy (2-3 cm, 18%; >3 cm, 43%) has greatly influenced the management of MEN1 adults with NF-PETs.
OBJECTIVE: The aim of the study was to estimate the penetrance of NF-PETs, insulinomas, and gastrinomas in young MEN1 carriers.
DESIGN: The data were obtained from a screening program (1996-2012) involving 113 MEN1 patients in a tertiary academic reference center.
PATIENTS: Nineteen MEN1 patients (aged 12-20 y; 16 patients aged 15-20 y and 3 patients aged 12-14 y) were screened for NF-PETs, insulinomas, and gastrinomas.
METHODS: Magnetic resonance imaging/computed tomography and endoscopic ultrasound (EUS) were performed on 10 MEN1 carriers, magnetic resonance imaging/computed tomography was performed on five patients, and four other patients underwent an EUS.
RESULTS: The overall penetrance of PETs during the second decade of life was 42% (8 of 19). All eight PET patients had NF-PETs, and half of those tumors were multicentric. One-fifth of the screened patients (21%; 4 of 19) harbored at least one large tumor (>2.0 cm). Insulinoma was detected in two NF-PET patients (11%) at the initial screening; gastrinoma was not present in any cases. Six of the 11 (54%) screened patients aged 15-20 years who underwent an EUS had NF-PETs. Potential false-positive EUS results were excluded based on EUS-guided biopsy results, the reproducibility of the NF-PET findings, or the observation of increased tumor size during follow-up. Distal pancreatectomy and the nodule enucleation of pancreatic head tumors were conducted on three patients with large tumors (>2.0 cm; T2N0M0) that were classified as grade 1 neuroendocrine tumors (Ki-67<2%).
CONCLUSIONS: Our data demonstrated high penetrance of NF-PETs in 15- to 20-year-old MEN1 patients. The high percentage of the patients presenting consensus criteria for surgery for NF-PET alone or NF-PET/insulinoma suggests a potential benefit for the periodic surveillance of these tumors in this age group.

Related: Cancer of the Pancreas Pancreatic Cancer MEN1

Kurozumi A, Okada Y, Arao T, et al.
Case of multiple endocrine neoplasia 2B with probable ectopic adrenocorticotropic hormone-secreting liver metastasis from medullary thyroid carcinoma.
J UOEH. 2013; 35(3):193-9 [PubMed] Related Publications
A 31 year old woman was diagnosed with multiple endocrine neoplasia (MEN) 2B at 10 years old. Dark pigmentation gradually developed on her skin and her serum adrenocorticotropic hormone (ACTH) was high, suggesting concurrent ectopic ACTH syndrome (EAS). Corticotropin-releasing hormone (CRH) loading test ruled out Cushing's disease and supported the diagnosis of EAS. Multiple low attenuation mass in the liver was observed in a computed tomography (CT) scan, and was suspected as ectopic ACTH-secreting metastatic tumor from medullary thyroid carcinoma (MTC). ACTH production by MTC is relatively rare, particularly in patients with MEN; patients with ectopic ACTH-secreting liver metastatic tumor from MTC in MEN 2B have never been reported previously.

Related: Thyroid Cancer

Thosani S, Ayala-Ramirez M, Palmer L, et al.
The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2.
J Clin Endocrinol Metab. 2013; 98(11):E1813-9 [PubMed] Related Publications
CONTEXT: Pheochromocytoma (PHEO) occurs in 50% of patients with multiple endocrine neoplasia type 2 (MEN2). It is unknown if the presence of PHEO is associated with more aggressive medullary thyroid cancer (MTC).
OBJECTIVE: To present our experience with MEN2 PHEO and evaluate whether PHEO impacts MTC overall survival in patients with RET codon 634 mutations.
DESIGN: We performed a retrospective chart review of MEN2 patients at MD Anderson Cancer Center from 1960 through 2012.
PATIENTS: The study group comprised 85 patients (group 1) with MEN2-associated PHEO. Of these, 59 patients (subgroup 1) with RET codon 634 mutations were compared to 48 patients (group 2) with RET codon 634 mutations, but without MEN2-associated PHEO.
MAIN OUTCOME MEASURES: Of 85 patients with MEN2 and PHEO, 70 had MEN2A and 15 had MEN2B. Median age at PHEO diagnosis was 32 years. The initial manifestation of MEN2 was MTC in 60% of patients, synchronous MTC and PHEO in 34%, and PHEO in 6% of patients. Of patients, 72% had bilateral PHEO, and most tumors were synchronous (82%). Subgroup analysis of MEN2 patients with and without PHEO, who were carriers of RET codon 634, the most common mutation with PHEO, showed no significant differences in the stage of MTC at initial diagnosis. The median follow-up time for patients with PHEO was 249 months and without PHEO was 67 months (P < .01). Survival analyses among RET 634 carriers did not show shorter survival for patients with PHEO. The median survival time for patients with PHEO was 499 months and without PHEO was 444 months (P < .05).
CONCLUSIONS: PHEO in MEN2 patients are usually bilateral and unlikely to be metastatic. Subgroup analysis of patients with RET 634 mutations with and without PHEO showed that PHEO was not associated with a more advanced stage of MTC at diagnosis or a shorter survival.

Related: Thyroid Cancer RET

Asha HS, Seshadri MS, Rajaratnam S
Hypertensive crisis in a patient with thyroid cancer.
Natl Med J India. 2012 Nov-Dec; 25(6):339-40 [PubMed] Related Publications
Phaeochromocytomas may be discovered incidentally when patients present with hypertensive crisis during general anaesthesia. A 49-year-old man underwent thyroidectomy 25 years ago and was diagnosed to have spindle cell carcinoma of the thyroid. He presented with recent onset of hoarseness of voice and was found to have a vocal cord nodule. He developed a hypertensive crisis during surgery. He was subsequently evaluated and found to have bilateral phaeochromocytoma. Further evaluation revealed a RET proto-oncogene mutation at codon 634 consistent with multiple endocrine neoplasia (MEN)-2A.

Related: Thyroid Cancer

de Laat JM, Pieterman CR, Weijmans M, et al.
Low accuracy of tumor markers for diagnosing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 patients.
J Clin Endocrinol Metab. 2013; 98(10):4143-51 [PubMed] Related Publications
CONTEXT: The assessment of tumor markers for diagnosing pancreatic neuroendocrine tumors (pNET) in multiple endocrine neoplasia type 1 (MEN1) patients is advised in the current guidelines but has never been validated for this purpose.
OBJECTIVE: The objective of the study was to assess the diagnostic accuracy of chromogranin A (CgA), pancreatic polypeptide (PP), and glucagon for pNET in MEN1.
DESIGN: This was a diagnostic study.
SETTING: The study was conducted at Dutch university medical centers from 2008 to 2011, representing 90% of the total Dutch MEN1 population.
PATIENTS AND METHODS: Patients for whom data on tumor markers in combination with the reference standard (ie, radiological imaging) were available between 2008 and 2011 were included. The reference standard for the presence of pNET was pathology or detection on magnetic resonance imaging, computed tomography, or endoscopic ultrasound confirmed on subsequent imaging, irrespective of modality at follow-up.
MAIN OUTCOME MEASURES: The area under the receiver-operating characteristic curve (AUC), positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, sensitivity, and specificity were calculated for each marker.
RESULTS: For the analysis of PP, CgA, and glucagon, 73, 81, and 94 patients were available, respectively. The AUC for CgA was 0.48 [95% confidence interval (CI) 0.35-0.61] with a sensitivity 0.33 and a specificity 0.73; the AUC for glucagon was 0.58 (95% CI 0.46-0.70) with a sensitivity 0.43 and a specificity 0.73; and the AUC for PP was 0.64 (95% CI 0.50-0.77) with a sensitivity 0.36 and a specificity 0.74. Age, imaging modality, tumor size, and number did not influence the outcomes.
CONCLUSION: The diagnostic accuracy of the tumor markers CgA, PP, and glucagon for pNET in MEN1 is low.

Related: Cancer of the Pancreas Pancreatic Cancer

Manchester CS
Multiple endocrine neoplasia: the enigma of MEN.
AACN Adv Crit Care. 2013 Jul-Sep; 24(3):304-13 [PubMed] Related Publications
Multiple endocrine neoplasia (MEN) is an array of tumors found in various endocrine glands throughout the human body. A wide spectrum of clinical manifestations accompanies this syndrome. The complexities of the glandular function and subtle development of symptoms can cause the diagnosis to be missed, and individuals with MEN can be an enigma to the care team. Appropriate differential diagnosis and assessment are critical for these individuals to receive optimal care. An interprofessional team of health care providers, including an endocrinologist and an advanced practice endocrine nurse, must work in concert to orchestrate a plan of care across the continuum. Those specialized nurses who encounter individuals with MEN in a critical care setting are positioned to support the patient, the family, and the care team through this maze of multiple endocrinopathies and tumors.

Rowland KJ, Chernock RD, Moley JF
Pheochromocytoma in an 8-year-old patient with multiple endocrine neoplasia type 2A: implications for screening.
J Surg Oncol. 2013; 108(4):203-6 [PubMed] Related Publications
Childhood pheochromocytoma in the setting of multiple endocrine neoplasia type 2 (MEN2) remains rare and has not been reported under the age of 12. We present an 8-year-old female with known MEN 2A, C634Y RET mutation, diagnosed with a 6 cm pheochromocytoma requiring laparoscopic adrenalectomy. Given this patient's age at diagnosis, screening guidelines should recommend annual screening beginning at age 8 for patients with MEN 2B or MEN 2A codons 630 or 634 RET mutations.

Related: Cancer Screening and Early Detection RET

Qi XP, Zhao JQ, Du ZF, et al.
Prophylactic thyroidectomy for MEN 2-related medullary thyroid carcinoma based on predictive testing for RET proto-oncogene mutation and basal serum calcitonin in China.
Eur J Surg Oncol. 2013; 39(9):1007-12 [PubMed] Related Publications
INTRODUCTION: Early and normative surgery is the only curative method for multiple endocrine neoplasia type 2 (MEN 2)-related medullary thyroid carcinoma (MTC).
AIMS: To study the timing of prophylactic total thyroidectomy (TT) for MEN 2-related MTC with different RET mutations in a Chinese population, and to compare the sensitivity and accuracy of fully-automated chemiluminescence immunoassay (FACLIA) and radioimmunoassay (RIA) for serum calcitonin (Ct).
METHODS: We collected 24 asymptomatic individuals from 8 unrelated Chinese families with MEN 2, and analyzed RET mutation and Ct levels. Then we performed TT on 17 of the 24 individuals, including TT (2/17), TT with bilateral level VI lymph-node dissection (B-LND(VI); 12/17) and TT with B-LND(VI) + modified unilateral/bilateral/local neck dissection (3/17).
RESULTS: Histopathology revealed bilateral/unilateral MTC in 15/17 (88.2%; median diameter, 1.0 cm) and bilateral C-cell hyperplasia in 2/17 (11.8%; p.V292M/R67H/R982C and p.C618Y). Lymph-node metastasis/fibro-adipose tissue invasion (p.C634R) or solely fibro-adipose tissue invasion (p.C634Y) were found in 2/17 (11.8%). Elevated pre-surgical Ct (pre-Ct) was identified by FACLIA in 17/17 (median age, 24.0), while pre-Ct by RIA was found in only 6/15 (P < 0.001). The median follow-up was 22.0 months, during which 16/17 had no abnormality (one p.C634R individual had elevated Ct), and another 7 carriers still had consistently undetectable Ct by FACLIA.
CONCLUSIONS: Our study highlights the importance and feasibility of individualized prophylactic TT for MEN 2-related MTC, based on predictive integrated screening of RET and pre-Ct levels. Besides, we recommend FACLIA to measure Ct for earlier diagnosis, treatment and follow-up monitoring of MTC.

Related: Thyroid Cancer RET

López CL, Langer P, Waldmann J, et al.
Shortness: an unknown phenotype of multiple endocrine neoplasia type 1.
Eur J Endocrinol. 2013; 169(1):133-7 [PubMed] Related Publications
OBJECTIVE: An observation of shortness among the female participants of a regular screening program in multiple endocrine neoplasia type 1 (MEN1) patients has raised the question as to whether shortness represents a phenotype characteristic of the disease.
METHODS: The body height (cm) of genetically confirmed MEN1 patients at the time of diagnosis was compared with the body height of their unaffected relatives (parents, siblings, and children), the midparental body height, and the body height of the age-matched German population. Univariate analysis of the clinical variables was performed using the t-test, Mann–Whitney U test, and ANOVA as appropriate, and multivariate analysis was performed as a logistic regression analysis. P values <0.05 were considered statistically significant.
RESULTS: The mean body height of 22 female MEN1 patients (mean age 33.5 years) was 161 +/- 5 cm and thus significantly lesser than the body heights of their unaffected female relatives (mean 165.5 +/- 7.3 cm, P=0.027) and the age-matched German female population (mean 167 cm, P=0.0001) and mid-parental height (177.5 cm, P<0.0001). The mean body height of 24 male MEN1 patients (mean age 34.8 years) was also lesser (177 +/- 6.5 cm) than the average body height of German males in this age group (180 cm, P=0.031) and tended to be lesser than that of their unaffected male relatives (178.5 +/- 5.8 cm, P=0.0915) and the mid-parental body height (177.5 cm, P=0.124).
CONCLUSIONS: Small body height is a yet unrecognized phenotype characteristic of MEN1 patients, especially in women. The mechanisms behind this phenotypical characteristic warrant further investigation.

Related: MEN1

Versnick M, Popadich A, Sidhu S, et al.
Minimally invasive parathyroidectomy provides a conservative surgical option for multiple endocrine neoplasia type 1-primary hyperparathyroidism.
Surgery. 2013; 154(1):101-5 [PubMed] Related Publications
BACKGROUND: Many authors advocate routine subtotal parathyroidectomy or total parathyroidectomy and autotransplantation for patients with multiple endocrine neoplasia type 1 (MEN1). Many of these patients are young and recurrence may take decades. Four-gland parathyroid exploration carries a higher risk of complication than minimally invasive parathyroidectomy (MIP). The aim of this study was to assess the role of selective removal of only abnormal glands for MEN1 in the era of MIP.
METHODS: For this retrospective, cohort study we collected data on patients undergoing parathyroidectomy for MEN1 from an endocrine surgery database. We reviewed preoperative localization studies, operative findings, histopathology, and clinical outcomes.
RESULTS: Twenty-six patients underwent parathyroidectomy for MEN1-associated hyperparathyroidism over the 23-year study period. Six of 10 (60%) patients in the total parathyroidectomy group and 4 of 10 (40%) patients in the subtotal parathyroidectomy group developed hypocalcemia. The subtotal and total parathyroidectomy groups both had a recurrence rate of 30% with a mean follow-up rate of 106 and 133 months, respectively. The MIP group had no hypocalcemia or recurrence with a mean follow-up of 19 months.
CONCLUSION: MIP with excision of only documented abnormal parathyroid glands provides an acceptable outcome for patients with MEN1, avoiding the potential for permanent hypoparathyroidism in young patients. It is accepted that recurrent disease is inevitable in these patients; however, such recurrence may take decades to occur and may be able to be dealt with by a further focused procedure.

Marx SJ
Multiplicity of hormone-secreting tumors: common themes about cause, expression, and management.
J Clin Endocrinol Metab. 2013; 98(8):3139-48 [PubMed] Article available free on PMC after 01/08/2014 Related Publications
CONTEXT: Multiplicity of hormone-secreting tumors occurs in a substantial portion of hormone-excess states. Multiplicity increases the difficulty of management and drives the selection of special strategies.
EVIDENCE ACQUISITION: This is a synthesis from publications about tumor development and expression, and also about types of clinical strategy for hormone-secreting tumors.
EVIDENCE SYNTHESIS: Comparisons were made between patient groups with solitary tumors vs those with multiple tumors. Major themes with clinical relevance emerged. Usually, tumor multiplicity develops from a genetic susceptibility in all cells of a tissue. This applies to hormone-secreting tumors that begin as either polyclonal (such as in the parathyroids of familial hypocalciuric hypercalcemia) or monoclonal tumors (such as in the parathyroids of multiple endocrine neoplasia type 1 [MEN1]). High penetrance of a hereditary tumor frequently results in bilaterality and in several other types of multiplicity. Managements are better for the hormone excess than for the associated cancers. Management strategies can be categorized broadly as ablation that is total, subtotal, or zero. Examples are discussed for each category, and 1 example of each category is named here: 1) total ablation of the entire tissue with effort to replace ablated functions (for example, in C-cell neoplasia of multiple endocrine neoplasia type 2); 2) subtotal ablation with increased likelihood of persistent disease or recurrent disease (for example, in the parathyroid tumors of MEN1); or 3) no ablation of tissue with or without the use of pharmacotherapy (for example, with blockers for secretion of stomach acid in gastrinomas of MEN1).
CONCLUSIONS: Tumor multiplicity usually arises from defects in all cells of the precursor tissue. Even the optimized managements involve compromises. Still, an understanding of pathophysiology and of therapeutic options should guide optimized management.

Fox E, Widemann BC, Chuk MK, et al.
Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma.
Clin Cancer Res. 2013; 19(15):4239-48 [PubMed] Related Publications
PURPOSE: Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC.
EXPERIMENTAL DESIGN: We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m(2) administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m(2)/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit.
RESULTS: Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%-75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects.
CONCLUSION: Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m(2)/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.

Related: Thyroid Cancer RET

Bihan H, Murat A, Fysekidis M, et al.
The clinical spectrum of RET proto-oncogene mutations in codon 790.
Eur J Endocrinol. 2013; 169(3):271-6 [PubMed] Related Publications
OBJECTIVE: Due to a strong genotype-phenotype correlation, the timing of prophylactic thyroidectomy in rearranged during transfection (RET) gene mutation carriers is usually dictated by genetic analysis.
SUBJECTS AND METHODS: We report a nationwide retrospective study of the clinical data of 77 French patients from 19 families with a mutation in codon 790 of the RET proto-oncogene.
RESULTS: The average age at diagnosis was 35.6 years ± 20.5. Thirty-nine patients were women. Fifty-five patients underwent operations for the treatment of medullary thyroid carcinoma (MTC) at the mean age of 38 years (4-82 years). The mean follow-up duration was 89 months. TNM staging was as follows: T0NxMx in 19, TxNxMx in 1, T1NxMx in 22, T1N1Mx in 8, T2N1Mx in 1 and T3N1Mx in four patients. In the T1/x-Nx group, 96% were considered cured after surgery. In the N1 group (n=13), six patients had multifocal disease and five patients were cured. Age and gender were not significant predictors of remission. Twenty-two patients did not undergo an operation (age 1.5-78 years); among them, 11 patients had a mean basal calcitonin (CT) level of 9.8 pg/ml (2-24) after 53 months of follow-up. One patient had been operated on for phaeochromocytoma (PHEO), and their CT level remained normal for 262 months.
CONCLUSIONS: This study confirms that RET 790 mutation is associated with a non-aggressive form of multiple endocrine neoplasia type 2, as 28% of the patients were followed up without thyroidectomy, 25% had been thyroidectomised with no tumour being detected and even patients with MTC had slow-evolving disease. Moreover, only one patient had PHEO, and no-one had primary hyperparathyroidism.

Related: France Thyroid Cancer RET

Wells SA, Pacini F, Robinson BG, Santoro M
Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update.
J Clin Endocrinol Metab. 2013; 98(8):3149-64 [PubMed] Related Publications
CONTEXT: Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded greatly. In this manuscript, we summarize how recent discoveries have enhanced our understanding of the molecular basis of these diseases and led to improvements in the diagnosis and management of affected patients.
EVIDENCE ACQUISITION: We reviewed the English literature through PubMed from 2000 to the present, using the search terms medullary thyroid carcinoma, multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin.
EVIDENCE SYNTHESIS: Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent findings from studies of large kindreds with these syndromes have clouded the relationship between genotype and phenotype, primarily because of the varied clinical presentation of different families with the same RET mutation. This clinical variability has also confounded decisions about the timing of prophylactic thyroidectomy for MTC, the dominant endocrinopathy associated with these syndromes. A distinct advance has been the demonstration through phase II and phase III clinical trials that molecular targeted therapeutics are effective in the treatment of patients with locally advanced or metastatic MTC.
CONCLUSIONS: The effective management of patients with MEN2A, MEN2A, and FMTC depends on an understanding of the variable behavior of disease expression in patients with a specific RET mutation. Information gained from molecular testing, biochemical analysis, and clinical evaluation is important in providing effective management of patients with either early or advanced-stage MTC.

Related: Thyroid Cancer RET

Sabetkish N, Tavangar SM
An unusual combination of parathyroid adenoma, medullary and papillary thyroid carcinoma.
Acta Med Iran. 2013; 51(5):337-40 [PubMed] Related Publications
The coexistence of medullary thyroid carcinoma (MTC), papillary thyroid carcinoma (PTC) and parathyroid adenoma is an uncommon clinical entity. Here, we report a case of MTC, PTC, and parathyroid adenoma diagnosed incidentally on a routine physical examination of the neck for the work-up of diabetes. The patient had neither symptoms of hypercalcemia nor those related to MTC and PTC.

Related: Parathyroid Cancer Thyroid Cancer

Nilubol N, Weisbrod AB, Weinstein LS, et al.
Utility of intraoperative parathyroid hormone monitoring in patients with multiple endocrine neoplasia type 1-associated primary hyperparathyroidism undergoing initial parathyroidectomy.
World J Surg. 2013; 37(8):1966-72 [PubMed] Related Publications
BACKGROUND: Intraoperative parathyroid hormone monitoring (IOPTH) is a widely used adjunct for primary hyperparathyroidism (pHPT). However, the benefit of IOPTH in familial pHPT, such as in multiple endocrine neoplasia type I (MEN1), remains unclear.
METHODS: We performed a retrospective analysis of 52 patients with MEN1-associated pHPT undergoing initial parathyroidectomy with IOPTH monitoring at our institution. Parathyroid hormone (PTH) levels were measured before skin incision and 10 min after resection of the last parathyroid gland. Variables analyzed included percent drop of PTH from baseline and the final PTH level compared to the normal reference range (RR).
RESULTS: A total of 52 patients underwent initial subtotal parathyroidectomy with IOPTH. An IOPTH decrease cutoff of ≥75 % from baseline had the highest biochemical cure rate (87 %). In the remaining 13 % who met this cutoff, all had persistent pHPT, with ≥90 % drop of PTH from baseline. The remaining patients, who did not meet the ≥75 % cutoff, were cured. Follow-up was available for three of four patients with final IOPTH levels above the RR: one had persistent pHPT, two had hypoparathyroidism (50 %). When a postresection PTH level was within the RR, 88 % of patients were cured. While considered cured from pHPT, 7 % of patients in this group developed permanent hypoparathyroidism. When the final PTH level dropped below the RR, 28 % developed permanent hypoparathyroidism.
CONCLUSIONS: A cutoff in IOPTH decrease of ≥75 % from baseline has the highest biochemically cure rate in patients with pHPT associated with MEN1. However, a 75 % cutoff in IOPTH decrease does not exclude persistent pHPT. The absolute IOPTH value does not accurately predict postoperative hypoparathyroidism.

Sattar MA, Hadi HI, Ekramuddoula FM, Hasanuzzaman SM
A 9 years boy with MEN-2B variant of medullary thyroid carcinoma.
Mymensingh Med J. 2013; 22(2):406-9 [PubMed] Related Publications
To highlight a rare disease like multiple endocrine neoplasia (MEN)-2B variant of medullary thyroid carcinoma and to optimize the management option in such cases, we present a nine year old boy with thyroid swelling, cervical lymphadenopathy and thick lips. His calcitonin level was raised. Investigation's results of the boy were as following fine needle aspiration cytology (FNAC) was medullary carcinoma of thyroid, preoperative calcitonin was >2000pg/ml, post operative histopathological report was medullary carcinoma. Total thyroidectomy with aggressive initial neck surgery may reduce the recurrence and increase better prognosis and survival rate. Calcitonin is used as diagnostic and follow-up marker.

Related: Thyroid Cancer

Stamatakos M, Paraskeva P, Katsaronis P, et al.
Surgical approach to the management of medullary thyroid cancer: when is lymph node dissection needed?
Oncology. 2013; 84(6):350-5 [PubMed] Related Publications
OBJECTIVE: Medullary thyroid cancer (MTC) is a rare and particularly aggressive type of thyroid cancer of neuroendocrine origin. It occurs in hereditary and sporadic forms and its aggressiveness is related to the clinical presentation and the type of RET mutation.
METHODS: In this article, we present the criteria, as reviewed in contemporary literature, regarding lymph node dissection and radical neck dissection in patients with either sporadic or hereditary MTC.
RESULTS: Early diagnosis and treatment remains the key to a 100% cure rate.
CONCLUSIONS: Routine central lymph node dissection is the minimum procedure recommended for all sporadic and hereditary MTCs. Routine lateral lymph node dissection on either side is necessary when lymph node metastases are found in the central neck compartment.

Related: Thyroid Cancer

Lee M, Pellegata NS
Multiple endocrine neoplasia type 4.
Front Horm Res. 2013; 41:63-78 [PubMed] Related Publications
A few years ago a novel multiple endocrine neoplasia syndrome, named multiple endocrine neoplasia type 4 (MEN4), was discovered thanks to studies conducted on a MEN syndrome in the rat (named MENX). The rat and the human syndromes are both caused by germline mutations in the Cdkn1b/CDKN1B gene, respectively. This gene encodes p27Kip1, a putative tumor suppressor which binds to and inhibits cyclin/cyclin-dependent kinase complexes, thereby preventing cell cycle progression. MEN4 patients carry heterozygous mutations at various residues of p27Kip1 and present with endocrine lesions mainly belonging to a MEN1-like spectrum: their most common phenotypic features are parathyroid and pituitary adenomas. Recently, germline mutations in p27kip1 were also identified in patients with a sporadic parathyroid disease presentation. In vitro functional analysis of several CDKN1B sequence changes identified in MEN4 patients detected impaired activity of the encoded p27Kip1 variant proteins (e.g. reduced expression, mislocalization or poor binding to interaction partners), thereby highlighting the characteristics of the protein which are critical for tumor suppression. Although the number of MEN4 patients is low, the discovery of this syndrome has demonstrated a novel role for CDKN1B as a tumor susceptibility gene for neuroendocrine tumors. Here, we review the clinical characteristics of the MEN4 syndrome and the molecular phenotype of the associated p27Kip1 mutations.

Related: Parathyroid Cancer Pituitary Tumors

Espiard S, Bertherat J
Carney complex.
Front Horm Res. 2013; 41:50-62 [PubMed] Related Publications
Carney complex is a rare, dominantly inherited multiple endocrine neoplasia syndrome, affecting endocrine glands as the adrenal cortex (causing Cushing's syndrome), the pituitary and the thyroid. It is associated with many other nonendocrine tumors, including cardiac myxomas, testicular tumors, melanotic schwannoma, breast myxomatosis, and abnormal pigmentation (lentiginosis) or myxomas of the skin. The gene located on the CNC1 locus was identified 12 years ago as the regulatory subunit 1A (R1A) of the protein kinase A (PRKAR1A) located at 17q22-24. Inactivating heterozygous germline mutations of PRKAR1A are observed in about two thirds of Carney complex patients with some genotype-phenotype correlation useful for follow-up and prognosis. More rarely, mutations of phosphodiesterase genes have been reported in patients presenting mainly with Cushing's syndrome. In vitro and in vivo studies help to understand how R1A inactivation leads to tumorigenesis. PRKAR1A appears to be a relatively weak tumorigenic signal which can cooperate with other signaling pathways and tumor suppressors.

Related: Pituitary Tumors

Lodish M
Multiple endocrine neoplasia type 2.
Front Horm Res. 2013; 41:16-29 [PubMed] Related Publications
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal-dominant cancer syndrome characterized by variable penetrance of medullary thyroid carcinoma(MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT). MEN2 consists of two clinical subtypes, MEN2A and MEN2B. Familial medullary thyroid cancer is now viewed as a phenotypic variant of MEN2A with decreased penetrance for PHEO and PHPT rather than a distinct entity. All subtypes are caused by gain-of-function mutations of the RET proto-oncogene. Genotype-phenotype correlations exist that help predict the presence of other associated endocrine neoplasms as well as the timing of thyroid cancer development. Recognition of the clinical entity in individuals and families at risk of harboring a germline RET mutation is crucial for the management and prevention of associated malignancies. Recent guidelines released by the American Thyroid Association regarding the management of MTC will be summarized in this chapter.

Related: Thyroid Cancer

Agarwal SK
Multiple endocrine neoplasia type 1.
Front Horm Res. 2013; 41:1-15 [PubMed] Related Publications
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant tumor syndrome characterized by the occurrence of tumors in multiple endocrine tissues and nonendocrine tissues. The three main endocrine tissues most frequently affected by tumors are parathyroid (95%), enteropancreatic neuroendocrine (50%) and anterior pituitary (40%). Tumors are caused by a heterozygous germline-inactivating mutation in the MEN1 gene (1st hit) followed by somatic inactivating mutation or loss of the normal copy of the gene (2nd hit), leading to complete loss of function of the encoded protein menin. Most of the disease features and tumors are recapitulated in mouse models with heterozygous germline loss of the Men1 gene. Also, tissue-specific tumors are observed in mouse models with homozygous somatic loss of the Men1 gene specifically in MEN1-associated endocrine tissues. Hence, mouse models could serve as possible surrogates for studying MEN1 and related states. To gain insights into MEN1 pathophysiology, menin-interacting partners and pathways have been identified to investigate its tumor suppressor and other functions. Also, the 3D crystal structure of menin has been deciphered which could be useful to reveal the relevance of MEN1 gene mutations and menin's interactions. This chapter covers clinical, genetic and basic findings about the MEN1 syndrome, MEN1 gene and its product protein menin.

Related: Parathyroid Cancer JUND MEN1 MLL gene

Balachandran K, Kamalanathan S, Gopalakrishnan S, Murugananadham K
Multiple endocrine neoplasia 2B: delayed presentation, rapid diagnosis.
BMJ Case Rep. 2013; 2013 [PubMed] Related Publications
Multiple endocrine neoplasia (MEN) refers to the synchronous or metachronous development of tumours in two or more endocrine organs. MEN 2B is associated with medullary thyroid carcinoma and phaeochromocytoma along with classic morphological features such as marfanoid habitus and mucosal neuromas. Dominantly inherited germline mutations involving the REarranged during Transfection (RET) proto-oncogene are responsible. Affected patients usually present in childhood with thyroid mass or gastrointestinal symptoms. We describe the case of a 28-year-old man who presented to us with metastatic medullary thyroid carcinoma. He lacked the classic marfanoid habitus, but had mucosal neuromas and thickened corneal nerves. Whole-body metaiodobenzyl guanidine scan (MIBG) showed tracer uptake in adrenal and thyroid-confirming phaeochromocytoma and medullary thyroid carcinoma. This case exemplifies the late presentation of multiple endocrine neoplasia 2B and emphasises the need to screen all cases of medullary thyroid carcinoma for phaeochromocytoma.

Related: Thyroid Cancer

Ito T, Igarashi H, Uehara H, et al.
Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors.
Medicine (Baltimore). 2013; 92(3):135-81 [PubMed] Article available free on PMC after 01/05/2014 Related Publications
Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking.To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%-14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled literature series, the main causes of MEN1-related deaths were due to the malignant nature of the PETs, followed by the malignant nature of thymic carcinoid tumors. These results differ from the results of a number of the literature series, especially those reported before the 1990s. The causes of non-MEN1-related death for the 2 series, in decreasing frequency, were cardiovascular disease, other nonendocrine tumors > lung diseases, cerebrovascular diseases. The most frequent non-MEN1-related tumor deaths were colorectal, renal > lung > breast, oropharyngeal. Although both overall and disease-related survival are better than in the past (30-yr survival of NIH series: 82% overall, 88% disease-related), the mean age at death was 55 years, which is younger than expected for the general population.Detailed analysis of causes of death correlated with clinical, laboratory, and tumor characteristics of patients in the 2 series allowed identification of a number of prognostic factors. Poor prognostic factors included higher fasting gastrin levels, presence of other functional hormonal syndromes, need for >3 parathyroidectomies, presence of liver metastases or distant metastases, aggressive PET growth, large PETs, or the development of new lesions.The results of this study have helped define the causes of death of MEN1 patients at present, and have enabled us to identify a number of prognostic factors that should be helpful in tailoring treatment for these patients for both short- and long-term management, as well as in directing research efforts to better define the natural history of the disease and the most important factors determining long-term survival at present.

Related: Cancer of the Pancreas Pancreatic Cancer USA MEN1

Guo Y, Xu H, Ren Z, et al.
Genetic analysis of a Chinese Han family with multiple endocrine neoplasia type 2A.
Indian J Biochem Biophys. 2013; 50(1):26-31 [PubMed] Related Publications
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder that can be distinguished as three different syndromes: multiple endocrine neoplasia type 2A (MEN2A), MEN2B and familial medullary thyroid carcinoma (FMTC). This disorder is usually caused by the mutations of the rearranged during transfection protooncogene gene (RET) or the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1). To investigate the genetic cause in a Chinese Han family with MEN2A and the genotype-phenotype correlations, nine members belonging to 3 generations of MEN2A family with 5 affected subjects underwent genetic analysis. Standard GTG-banded karyotype analysis and sequencing of the RET and NTRK1 genes were performed to identify the genetic cause of this family. A heterozygous mutation p.Cys634Arg in the RET gene was identified in 5 patients with MEN2A and one asymptomatic family member. The phenotype of patients was that of classic MEN2A, characterized by medullary thyroid carcinoma and phaeochromocytoma. The clinical features of all cases with RET mutations varied greatly, including onset age of clinical manifestations, severity and comorbidities. Thus, this study not only identified the hereditary nature of the MEN2A in the cases, but also discovered a family member harboring the same p.Cys634Arg mutation, who was unaware of his condition. These finding may provide new insights into the cause and diagnosis of MEN2A and have implications for genetic counseling.

Related: RET

Gurung B, Feng Z, Iwamoto DV, et al.
Menin epigenetically represses Hedgehog signaling in MEN1 tumor syndrome.
Cancer Res. 2013; 73(8):2650-8 [PubMed] Related Publications
Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumor syndrome that includes susceptibility to pancreatic islet tumors. This syndrome results from mutations in the MEN1 gene, encoding menin. Although menin acts as an oncogenic cofactor for mixed lineage leukemia (MLL) fusion protein-mediated histone H3 lysine 4 methylation, the precise basis for how menin suppresses gene expression and proliferation of pancreatic beta cells remains poorly understood. Here, we show that menin ablation enhances Hedgehog signaling, a proproliferative and oncogenic pathway, in murine pancreatic islets. Menin directly interacts with protein arginine methyltransferase 5 (PRMT5), a negative regulator of gene transcription. Menin recruits PRMT5 to the promoter of the Gas1 gene, a crucial factor for binding of Sonic Hedgehog (Shh) ligand to its receptor PTCH1 and subsequent activation of the Hedgehog signaling pathway, increases repressive histone arginine symmetric dimethylation (H4R3m2s), and suppresses Gas1 expression. Notably, MEN1 disease-related menin mutants have reduced binding to PRMT5, and fail to impart the repressive H4R3m2s mark at the Gas1 promoter, resulting in its elevated expression. Pharmacologic inhibition of Hedgehog signaling significantly reduces proliferation of insulinoma cells, and expression of Hedgehog signaling targets including Ptch1, in MEN1 tumors of mice. These findings uncover a novel link between menin and Hedgehog signaling whereby menin/PRMT5 epigenetically suppresses Hedgehog signaling, revealing it as a target for treating MEN1 tumors.

Related: Signal Transduction MEN1

Qari F
RET codon 618 mutations in Saudi families with multiple endocrine neoplasia Type 2A and familial medullary thyroid carcinoma.
Ann Saudi Med. 2013 Mar-Apr; 33(2):155-8 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Certain diseases such as multiple endocrine neoplasia (MEN) 2A, MEN 2B, familial and sporadic medullary thyroid carcinoma (MTC) and renal dysgenesis are related to abnormalities of the RET protein. Our aim was to evaluate the frequency of RET mutation in 10 Saudi families with MEN type 2A and familial MTC.
DESIGN AND SETTING: A cross-sectional prospective study of patients followed up at King Abdulaziz University Hospital and King Abdulaziz Medical City, Jeddah, between March 2001 and March 2011.
PATIENTS AND METHODS: Genomic DNA was isolated from peripheral blood leukocytes of all subjects by standard procedures. Exons 10, 11, 13, 14 and 16 of the RET proto-oncogene were analyzed by single-strand conformation polymorphism, direct DNA sequencing and/or restriction enzyme analysis.
RESULTS: We screened 79 subjects for the RET mutation. Of which 43 subjects had hereditary MTC were en.rolled in this study. MEN type 2A was identified in 25 subjects; MTC was diagnosed in all 25 subjects (100%), pheochromocytoma in 13 subjects (52%) and hyperparathyroidism in 4 subjects (16%). The most frequent genotype in patients with MEN 2A syndrome was a codon 618 mutation (46.6%), followed by a codon 634 mutation (44.2%). Among the 5 families with MEN 2A, 3 had a mutation at codon 634, whereas 2 had a mutation at codon 618.
CONCLUSION: The most frequent RET proto-oncogene mutation in our series was in codon 618 (exon 10).

Related: Thyroid Cancer RET

Funayama T, Sakane M, Yoshizawa T, et al.
Tanycytic ependymoma of the filum terminale associated with multiple endocrine neoplasia type 1: first reported case.
Spine J. 2013; 13(8):e49-54 [PubMed] Related Publications
BACKGROUND CONTEXT: Ependymoma associated with multiple endocrine neoplasia type 1 (MEN-1) is an extremely rare clinical entity. To the best of our knowledge, only five cases of ependymoma associated with MEN-1 have been previously described. Furthermore, there has been no case of tanycytic ependymoma of the filum terminale associated with MEN-1.
PURPOSE: The present case report illustrates a 53-year-old man with tanycytic ependymoma of the filum terminale associated with MEN-1. We review the literature on ependymoma with MEN-1 and tanycytic ependymoma of the cauda equina region and also discuss the risk of recurrence.
STUDY DESIGN: A case report.
METHODS: The patient presented with complaints of nocturnal pain in the lower back, accompanied by numbness around the anus and intermittent claudication for approximately 1 year. Magnetic resonance imaging (MRI) identified an intradural-enhancing, large mass lesion at the level from Th12 to L2 vertebrae, with a cranial cystic lesion.
RESULTS: Open-door laminoplasty of the Th12, L1, and L2 and en bloc tumor resection with thickened filum terminale were performed. Histopathologic examination of the tumor specimens showed tanycytic ependymoma (World Health Organization Classification Grade II). At the time of the 2-year and 8-month follow-up examination, MRI did not show tumor recurrence.
CONCLUSIONS: This is the first reported case of this clinical entity. A careful follow-up of patients with this unusual tumor is strongly recommended.

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