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Multiple Endocrine Neoplasia

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

  • Multiple endocrine neoplasia 1 (MEN type I) also known as Wermer's syndrome
  • Multiple endocrine neoplasia 2A (MEN type IIa) also known as Sipple Syndrome
  • Multiple endocrine neoplasia 2B (MEN type IIb)
  • Familial medullary thyroid carcinoma, (FMTC) is a similar inherited condition were medullary thyroid carcinoma may occur in several family members, though not necessarily with the other endocrine tumours seen in MEN.
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
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See also: Multiple endocrine neoplasia I (11q13)

Latest Research Publications

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

Liu Q, Tong D, Yuan W, et al.
Different RET gene mutation-induced multiple endocrine neoplasia type 2A in 3 Chinese families.
Medicine (Baltimore). 2017; 96(3):e5967 [PubMed] Free Access to Full Article Related Publications
BACKGROUD: Multiple endocrine neoplasia type 2A (MEN2A) is a condition with inherited autosomal dominant mutations in RET (rearranged during transfection) gene that predisposes the carrier to extremely high risk of medullary thyroid cancer (MTC) and other MEN2A-associated tumors such as parathyroid cancer and/or pheochromocytoma. Little is reported about MEN2A syndrome in the Chinese population.
METHODS: All members of the 3 families along with specific probands of MEN2A were analyzed for their clinical, laboratory, and genetic characteristics. Exome sequencing was performed on the 3 probands, and specific mutation in RET was further screened on each of the family members.
RESULTS: Different mutations in the RET gene were identified: C634S in Family 1, C611Y in Family 2, and C634Y in Family 3. Proband 1 mainly showed pheochromocytoma with MTC, both medullary thyroid carcinoma and pheochromocytoma were seen in proband 2, and proband 3 showed medullary thyroid carcinoma.
CONCLUSION: The genetic evaluation is strongly recommended for patients with a positive family history, early onset of age, or multiple sites of masses. If the results verified the mutations of RET gene, thyroidectomy should be undertaken as the guide for better prognosis.

Chi Z, Wu HH, Cramer H, et al.
Cytomorphological Features Useful to Prevent Errors in the Diagnosis of Pancreatic Adenocarcinoma by Fine Needle Aspiration Cytology.
Acta Cytol. 2017; 61(1):7-16 [PubMed] Related Publications
OBJECTIVES: Endoscopic ultrasound-guided fine-needle aspiration (FNA) is now widely used as a primary tool to diagnose pancreatic neoplasms. However, criteria that can reduce the risk of overdiagnosing pancreatic adenocarcinoma by FNA have not been adequately defined in the literature. This study aims to identify characteristic cytomorphological features that are helpful in distinguishing pancreatic adenocarcinoma from its mimics.
STUDY DESIGN: Five false-positive FNA cases (group A) diagnosed as adenocarcinoma (4 cases) and suspicious for adenocarcinoma (1 case) by FNA, were identified by searching our laboratory information system. Cytomorphological features of group A cases were compared to 12 true-positive, histologically confirmed FNA cases (group B).
RESULTS: Subsequent histological follow-ups of 5 misdiagnosed FNA cases showed 2 cases of intraductal papillary mucinous neoplasm with focal high-grade dysplasia, 1 case attributed to tumor contamination from a gastroesophageal junction adenocarcinoma, and 2 cases of pancreatic intraepithelial neoplasia (PanIN1/reactive change and PanIN2, respectively). Cytomorphological features present in both groups A and B included nuclear enlargement/overlapping, mild to moderate anisonucleosis, granular chromatin and prominent nucleoli. However, 1 or more of these 4 characteristic morphological features such as 3-dimensional cluster with cell disorientation, isolated malignant cells, irregular nuclear contour/nuclear grooves/notches (5% atypical cell population), and marked nuclear size variation 1:4 or higher was mainly present in adenocarcinoma.
CONCLUSIONS: A combination of at least 2 of these 4 characteristic cytomorphological features needs to be present before rendering an unequivocal diagnosis of adenocarcinoma. Using these strict cytological criteria would have eliminated these false-positive diagnoses.

Yamasaki M, Sato Y, Nomura T, et al.
Composite paraganglioma-ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2B: A case report.
Asian J Endosc Surg. 2017; 10(1):66-69 [PubMed] Related Publications
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal-dominant cancer syndrome with major components of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. MEN2B is the most aggressive and rarest of the MEN2 variants. Pheochromocytoma in MEN2 is virtually always located in the adrenal medulla, but MEN2-associated extra-adrenal pheochromocytomas (paraganglioma) are rare. A 59-year-old man who has been diagnosed with MEN2B consulted our hospital for surgical treatment of a 10-mm left adrenal mass and a 30-mm retroperitoneal mass. He had paroxysmal elevations in blood pressure and in urinary metanephrine and vanillylmandelic acid values. Laparoscopic excision of the left adrenal gland and retroperitoneal mass was performed. We experienced an extremely rare case of composite paraganglioma-ganglioneuroma concomitant with adrenal metastasis of medullary thyroid carcinoma in a patient with MEN2B.

Grey W, Hulse R, Yakovleva A, et al.
The RET E616Q Variant is a Gain of Function Mutation Present in a Family with Features of Multiple Endocrine Neoplasia 2A.
Endocr Pathol. 2017; 28(1):41-48 [PubMed] Related Publications
The REarranged during Transfection (RET) proto-oncogene is a receptor tyrosine kinase involved in growth and differentiation during embryogenesis and maintenance of the urogenital and nervous systems in mammals. Distinct mutations across hotspot RET exons can cause Multiple Endocrine Neoplasia Type 2A (MEN2A) characterised by development of medullary thyroid cancer (MTC), phaeochromocytoma (PCC) and primary hyperparathyroidism (PHPT), with a strong correlation between genotype and phenotype. Here, we report a 42-year-old man presented in the clinic with a unilateral PCC, with subsequent investigations revealing a nodular and cystic thyroid gland. He proceeded to thyroidectomy, which showed bilateral C-cell hyperplasia (CCH) without evidence of MTC. His brother had neonatal Hirschsprung disease (HSCR). Genetic testing revealed the presence of a heterozygous variant of unknown significance (VUS) in the cysteine-rich region of exon 10 in the RET gene (c.1846G>C, p.E616Q), in both affected siblings and their unaffected mother. Exon 10 RET mutations are known to be associated with HSCR and MEN2. Variants in the cysteine-rich region of the RET gene, outside of the key cysteine residues, may contribute to the development of MEN2 in a less aggressive manner, with a lower penetrance of MTC. Currently, a VUS in RET cannot be used to inform clinical management and direct future care. Analysis of RET(E616Q) reveals a gain of function mutant phenotype for this variant, which has not previously been reported, indicating that this VUS should be considered at risk for future clinical management.

Touska P, Srikanthan A, Amarasinghe K, Jawad S
Parathyroid adenoma arising within the sternocleidomastoid muscle: a rare complication of autotransplantation.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
A 19-year-old patient presented with slowly enlarging, painless, left-sided cervical mass. She had a background of multiple endocrine neoplasia 2B and had undergone a total thyroidectomy for medullary thyroid carcinoma during childhood. A cervical recurrence was therefore suspected. Ultrasonographic and MRI examination revealed a well-defined lesion within the left sternocleidomastoid muscle. Further evaluation with sestamibi and single-photon emission CT revealed elevated tracer uptake within the lesion. Cytological analysis, following ultrasound-guided sampling, revealed absent staining for calcitonin and blood samples confirmed a normal serum calcitonin level; however, the serum parathyroid hormone level was elevated. Overall, summative findings were consistent with a diagnosis of a parathyroid adenoma arising within the left sternocleidomastoid muscle. Given that this is not a location for a physiological parathyroid tissue, the adenoma might have arisen within the autotransplanted parathyroid tissue, injected into the muscular sheath during thyroidectomy. The clinical, radiological and pathological features are considered in this article.

Yang Z, Tan H, Sun Y, et al.
Intraoperative portal vein insulin assay combined with occlusion of the pancreas for complex pancreatogenous hypoglycemia: Two cases report.
Medicine (Baltimore). 2016; 95(26):e3928 [PubMed] Free Access to Full Article Related Publications
Intraoperative localization and confirmation of complete resection of the hypersecreting tissue are the 2 main challenges in the management of pancreatogenous hypoglycemia. Here, we report our experience with intraoperative portal vein insulin assay combined with occlusion of the pancreas in the management of pancreatogenous hypoglycemia. Clinical courses of 2 patients with biochemical evidence of a pancreatogenous hypoglycemia were studied. The preoperative diagnosis was multiple endocrine neoplasia 1 (MEN-1) and nesidioblastosis, respectively. Rapid intraoperative portal vein insulin assay combined with occlusion of the pancreas was used to localize and confirm complete excision of the hypersecreting tissue. Hypoglycemia was successfully treated in both the patients. In the MEN-1 patient, 2 small tumors in the head of pancreas were not resected, as they were deemed noninsulin secreting by intraoperative portal vein insulin assay, thus avoiding a total pancreatectomy. In the patient with nesidioblastosis, using intraoperative portal vein insulin assay combined with occlusion of the pancreas, an appropriate amount of pancreatic tissue was resected thereby avoiding recurrence and diabetes. This technique may be of particular value in patients with complex conditions such as MEN-1 and nesidioblastosis, to localize and achieve complete resection of hypersecreting pancreatic tissue.

Nell S, Brunaud L, Ayav A, et al.
Robot-assisted spleen preserving pancreatic surgery in MEN1 patients.
J Surg Oncol. 2016; 114(4):456-61 [PubMed] Related Publications
BACKGROUND: Multiple Endocrine Neoplasia type 1 (MEN1) patients often undergo multiple pancreatic operations at a young age.
OBJECTIVE: To describe robot-assisted and laparoscopic spleen-preserving pancreatic surgery in MEN1 patients, and to compare both techniques.
METHODS: Robot-assisted pancreatectomies of the DutchMEN1 study group and the Université de Lorraine, Nancy, France were compared to a historical cohort of laparoscopic treated MEN1 patients. Perioperative outcomes were compared.
RESULTS: A total of 21 MEN1 patients underwent minimally invasive pancreatic surgery for pancreatic neuroendocrine tumors, seven patients were subjected to robot-assisted surgery, and 14 patients underwent laparoscopic surgery. Demographics and clinical characteristics did not differ between the cohorts and no significant differences in operative outcomes were found. A high number of ISGPS grade B/C pancreatic fistulas were observed in both cohorts (38%), and no conversions were seen in the robot-assisted cohort (respectively 0% vs. 43%, P = 0.06). In one laparoscopic and one robot-assisted case the primary tumor was not resected.
CONCLUSIONS: Minimally invasive spleen-preserving surgery in MEN1 patients is safe and feasible. Patients who underwent robot-assisted surgery did not require conversion to open surgery. J. Surg. Oncol. 2016;114:456-461. © 2016 Wiley Periodicals, Inc.

Kwon EB, Jeong HR, Shim YS, et al.
Multiple Endocrine Neoplasia Type 1 Presenting as Hypoglycemia due to Insulinoma.
J Korean Med Sci. 2016; 31(6):1003-6 [PubMed] Free Access to Full Article Related Publications
Multiple endocrine neoplasia (MEN) mutation is an autosomal dominant disorder characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. The incidence of insulinoma in MEN is relatively uncommon, and there have been a few cases of MEN manifested with insulinoma as the first symptom in children. We experienced a 9-year-old girl having a familial MEN1 mutation. She complained of dizziness, occasional palpitation, weakness, hunger, sweating, and generalized tonic-clonic seizure that lasted for 5 minutes early in the morning. At first, she was only diagnosed with insulinoma by abdominal magnetic resonance images of a 1.3 x 1.5 cm mass in the pancreas and high insulin levels in blood of the hepatic vein, but after her father was diagnosed with MEN1. We found she had familial MEN1 mutation, and she recovered hyperinsulinemic hypoglycemia after enucleation of the mass. Therefore, the early genetic identification of MEN1 mutation is considerable for children with at least one manifestation.

Grajo JR, Paspulati RM, Sahani DV, Kambadakone A
Multiple Endocrine Neoplasia Syndromes: A Comprehensive Imaging Review.
Radiol Clin North Am. 2016; 54(3):441-51 [PubMed] Related Publications
MEN1, MEN2, and MEN4 comprise a series of familial disorders involving the simultaneous occurrence of tumors in more than one endocrine organ, collectively known as multiple endocrine neoplasia. Patients with this family of disorders develop tumors of the parathyroid gland, pancreas, pituitary gland, adrenal gland, and thyroid gland, along with miscellaneous neuroendocrine tumors of the respiratory and gastrointestinal tracts. Although some patients undergo early prophylactic surgical management, particularly in the setting of familial medullary thyroid carcinoma, many develop tumors later in life. These tumors are often discovered at imaging for screening purposes. Recognition of the imaging features of the known tumors is important for appropriate patient management.

Lopez CL, Albers MB, Bollmann C, et al.
Minimally Invasive Versus Open Pancreatic Surgery in Patients with Multiple Endocrine Neoplasia Type 1.
World J Surg. 2016; 40(7):1729-36 [PubMed] Related Publications
OBJECTIVE: The role of minimally invasive pancreatic surgery for pancreatic neuroendocrine neoplasms (pNENs) in patients with multiple endocrine neoplasia type 1 (MEN1) is not well defined. The aim of this study was to compare the outcome of minimally invasive versus open pancreatic resections in patients with MEN1.
MATERIALS AND METHODS: Prospectively collected data of MEN1 patients who underwent a primary distal pancreatic resection and/or enucleation for non-functioning pNENs or insulinoma were retrospectively analyzed regarding the outcome of minimally invasive or open pancreatic resections.
RESULTS: Thirty-three patients underwent primary pancreatic resection for either organic hyperinsulinism (n = 9, 27 %) or non-functioning pNENs >1 cm in size (n = 24, 73 %) between 1987 and 2015. 21 (64 %) patients underwent an open surgical (group 1) and 12 patients (36 %) a minimally invasive approach, either laparoscopic (n = 8) or robotic assisted (n = 4) (group 2). Both groups were comparable regarding age, gender, number, and size of pancreatic tumors. In both groups, the hyperinsulinism of all patients (9/9,100 %) could be cured and all NF-pNENs >1 cm could be resected. Group 2 had a significant shorter operative time (200 vs. 260 min; p = 0.036), less intraoperative blood loss (120 vs. 280 ml; p < 0.001), and a shorter hospital stay (11 vs. 15.5 days; p = 0.034). The rate of patients with postoperative complications, especially postoperative pancreatic fistulas, was not different between groups (62 % group 1 vs. 67 % group 2, p = 0.74).
CONCLUSION: Minimally invasive distal pancreatic resections and enucleations are feasible and safe in MEN1 patients with insulinoma or non-functioning pNENs.

Kotecka-Blicharz A, Hasse-Lazar K, Jurecka-Lubieniecka B, et al.
Occurrence of phaeochromocytoma tumours in RET mutation carriers - a single-centre study.
Endokrynol Pol. 2016; 67(1):54-8 [PubMed] Related Publications
INTRODUCTION: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant genetic syndrome caused by germline mutation in RET proto-oncogene. The most common mutations are in a cysteine rich domain. Phaeochromocytoma will develop in approximately 50% of RET proto-oncogene carriers.
MATERIAL AND METHODS: The studied population consisted of 228 RET proto-oncogene mutation carriers. Monitoring for the diagnosis of phaeochromocytoma was carried out in all patients with established genetic status. Mean time of follow up was 138 months. Surveillance consisted of periodically performed clinical evaluation, 24-hour urinary determinations of total metanephrines complementary with imaging (CT, MR, MIBG scintigraphy).
RESULTS: Phaeochromocytoma developed in 41 patients (18% of all RET proto-oncogene mutations carriers). The mean age of diagnosis for the whole cohort was 43 years. In eight cases phaeochromocytoma was the first manifestation of the MEN 2 syndrome. Only eight (20%) patients were symptomatic at diagnosis of phaeochromocytoma. The mean size of the tumour was 4.3 cm. There was no extra-adrenal localisation. We observed one case of malignant phaeochromocytoma.
CONCLUSIONS: In patients with MEN 2 syndrome phaeochromocytomas are usually benign adrenal tumours with high risk of bilateral development. Taking to account the latter risk and non-specific clinical manifestation of the neoplasm it is mandatory to screen all RET proto-oncogene mutations carriers for phaeochromocytoma.

Kihara M, Miyauchi A, Yoshioka K, et al.
Germline RET mutation carriers in Japanese patients with apparently sporadic medullary thyroid carcinoma: A single institution experience.
Auris Nasus Larynx. 2016; 43(5):551-5 [PubMed] Related Publications
OBJECTIVE: Genetic testing for RET germline mutation can be useful to distinguish whether a patient with medullary thyroid carcinoma (MTC) is genuinely sporadic or hereditary. Conducting a routine preoperative germline RET genetic screening for all patients with MTC has the clinical benefit, i.e., avoidance of unnecessary total thyroidectomy in the selected patients. We sought to clarify the incidence of germline RET mutation carriers in Japanese patients with apparently sporadic MTC and to address the differences in clinicopathological characteristics between true sporadic MTC and hereditary MTC in these patients, all of whom were treated at Kuma Hospital.
METHODS: A total of 134 patients with apparently sporadic MTC who underwent surgery between 1996 and 2014 were enrolled. All patients underwent a germline RET gene mutation analysis preoperatively.
RESULTS: Germline mutations in RET proto-oncogene were identified in 20 of the 134 (14.9%) apparently sporadic MTC patients. No significant difference in clinicopathological characteristics was observed between the patients with sporadic MTC (n=114) and those with hereditary MTC (n=20) except for the RET gene carriers' younger age at diagnosis and presence of multifocal and bilateral lesions.
CONCLUSION: Germline RET mutations were identified in 14.9% of Japanese patients with apparently sporadic MTC. No clearly decisive clinicopathological characteristics was observed to distinguish whether an apparently sporadic MTC case was genuinely sporadic or unconsciously hereditary. For the treatment strategy decision, it is advantageous to conduct a routine preoperative germline RET genetic screening for all patients with MTC, even if their MTC is apparently sporadic.

Pan Y, Lv J, Guo R, et al.
Pituitary Prolactinoma Imaged by 99mTc-Sestamibi SPECT/CT in a Multiple Endocrine Neoplasia Type 1 Patient.
Clin Nucl Med. 2016; 41(6):497-9 [PubMed] Related Publications
A 35-year-old woman who had undergone bilateral inferior parathyroidectomy for primary hyperparathyroidism was referred to our hospital to evaluate the cause of irregular menses, galactorrhea, and paroxysmal headache. Multiple endocrine neoplasia type 1 was then suspected for the high levels of plasma prolactin, parathyroid hormone, serum calcium, insulin, and related symptoms. A Tc-sestamibi SPECT/CT acquired to evaluate parathyroid glands unexpectedly revealed an increased accumulation in the pituitary gland, which was further confirmed by enhanced magnetic resonance imaging as a pituitary microadenoma. Bromocriptine treatment gradually reduced the prolactin level.

Morgat C, Vélayoudom-Céphise FL, Schwartz P, et al.
Evaluation of (68)Ga-DOTA-TOC PET/CT for the detection of duodenopancreatic neuroendocrine tumors in patients with MEN1.
Eur J Nucl Med Mol Imaging. 2016; 43(7):1258-66 [PubMed] Related Publications
CONTEXT: Somatostatin receptor scintigraphy with (111)In-pentetreotide (SRS) is used to detect duodenopancreatic neuroendocrine tumors (dpNETs) in multiple endocrine neoplasia type 1 (MEN1). However, SRS has limited sensitivity for this purpose. Positron emission tomography/computed tomography (PET/CT) with (68)Ga-DOTA-TOC has a higher rate of sporadic dpNETs detection than SRS but there is little data for dpNETs detection in MEN1.
PURPOSE: To compare the performances of (68)Ga-DOTA-TOC PET/CT, SRS and contrast-enhanced computed tomography (CE-CT) to diagnose dpNETs in MEN1.
DESIGN AND SETTING: Single-institution prospective comparative study
PATIENTS AND METHODS: Nineteen consecutive MEN1 patients (aged 47 ± 13 years) underwent (68)Ga-DOTA-TOC PET/CT, SRS, and CE-CT within 2 months in random order. Blinded readings of images were performed separately by experienced physicians. Unblinded analysis of CE-CT, combined with additional magnetic resonance imaging, endoscopic-ultrasound, (18)F-2-fluoro-deoxy-D-glucose ((18)F-FDG) PET/CT or histopathology results served as reference standard for dpNETs diagnosis.
RESULTS: The sensitivity of (68)Ga-DOTA-TOC PET/CT, SRS, and CE-CT was 76, 20, and 60 %, respectively (p < 0.0001). All the true-positive lesions detected by SRS were also depicted on (68)Ga-DOTA-TOC PET/CT. (68)Ga-DOTA-TOC PET/CT detected lesions of smaller size than SRS (10.7 ± 7.6 and 15.2 ± 5.9 mm, respectively, p < 0.03). False negatives of (68)Ga-DOTA-TOC PET/CT included small dpNETs (<10 mm) and (18)F-FDG PET/CT positive aggressive dpNETs. No false positives were recorded. In addition, whole-body mapping with (68)Ga-DOTA-TOC PET/CT identified extra-abdominal MEN1-related tumors including one neuroendocrine thymic carcinoma identified by the three imaging procedures, one bronchial carcinoid undetected by CE-CT and three meningiomas undetected by SRS.
CONCLUSIONS: Owing to higher diagnostic performance, (68)Ga-DOTA-TOC PET/CT (or alternative (68)Ga-labeled somatostatin analogues) should replace (111)In-pentetreotide in the investigation of MEN1 patients.

Concolino P, Costella A, Capoluongo E
Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years.
Cancer Genet. 2016 Jan-Feb; 209(1-2):36-41 [PubMed] Related Publications
This review will focus on the germline MEN1 mutations that have been reported in patients with MEN1 and other hereditary endocrine disorders from 2007 to September 2015. A comprehensive review regarding the analysis of 1336 MEN1 mutations reported in the first decade following the gene's identification was performed by Lemos and Thakker in 2008. No other similar papers are available in literature apart from these data. We also checked for the list of Locus-Specific DataBases (LSDBs) and we found five MEN1 free-online mutational databases. 151 articles from the NCBI PubMed literature database were read and evaluated and a total of 75 MEN1 variants were found. On the contrary, 67, 22 and 44 novel MEN1 variants were obtained from ClinVar, MEN1 at Café Variome and HGMD (The Human Gene Mutation Database) databases respectively. A final careful analysis of MEN1 mutations affecting the coding region was performed.

Latteyer S, Klein-Hitpass L, Khandanpour C, et al.
A 6-Base Pair in Frame Germline Deletion in Exon 7 Of RET Leads to Increased RET Phosphorylation, ERK Activation, and MEN2A.
J Clin Endocrinol Metab. 2016; 101(3):1016-22 [PubMed] Related Publications
CONTEXT: Multiple endocrine neoplasia type 2 (MEN2) is usually caused by missense mutations in the proto-oncogene, RET.
OBJECTIVE: This study aimed to determine the mutation underlying MEN2A in a female patient diagnosed with bilateral pheochromocytoma at age 31 years and with medullary thyroid carcinoma (MTC) 6 years later.
METHODS: Leukocyte DNA was used for exome and Sanger sequencing. Wild-type (WT) RET and mutants were expressed in HEK293 cells. Activation of MAPK/ERK and PI3K/AKT was analyzed by Western blotting and luciferase assay. The effect of RET mutants on cell proliferation was tested in a colony forming assay.
RESULTS: Exome sequencing revealed a 6-nucleotide/2-amino acid in-frame deletion in exon 7 of RET (c.1512_1517delGGAGGG, p.505_506del). In vitro expression showed that phosphorylation of the crucial tyrosine 905 was much stronger in the p.505_506del RET mutant compared with WT RET, indicating ligand-independent autophosphorylation. Furthermore, the p.505_506del RET mutant induced a strong activation of the MAPK/ERK pathway and the PI3K/AKT pathway. Consequently, the p.505_506del RET mutant cells increased HEK293 colony formation 4-fold compared with WT RET.
CONCLUSION: The finding of bilateral pheochromocytoma and MTC in our patient was highly suspicious of a RET mutation. Exome sequencing revealed a 6-base-pair deletion in exon 7 of RET, an exon not yet associated with MEN2. Increased ligand-independent phosphorylation of the p.505_506del RET mutant, increased activation of downstream pathways, and stimulation of cell proliferation demonstrated the pathogenic nature of the mutation. We therefore recommend screening the whole sequence of RET in MTC and pheochromocytoma patients with red flags for a genetic cause.

Bugalho MJ, Domingues R
Uncommon association of cerebral meningioma, parathyroid adenoma and papillary thyroid carcinoma in a patient harbouring a rare germline variant in the CDKN1B gene.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Multiple endocrine neoplasia type 4 (MEN 4) is a novel form of multiple endocrine neoplasia caused by mutations in the CDKN1B gene. Its clinical presentation includes MEN 1-related tumours such as parathyroid and anterior pituitary tumours in possible association with gonadal, adrenal, renal and thyroid tumours as well as facial angiofibromas, colagenomas and meningiomas. We describe the case of a patient with meningioma, papillary thyroid carcinoma, parathyroid adenoma and, additionally, Hürthle cell adenoma, cholesteatoma and uterine leiomyomas. Considering that this association could represent a MEN 4-like phenotype, we looked for germline mutations in the CDKN1B gene. A rare heterozygous single nucleotide substitution c.397C>A was identified. Its role as a susceptibility factor remains to be established.

Aydoğan Bİ, Yüksel B, Tuna MM, et al.
Distribution of RET Mutations and Evaluation of Treatment Approaches in Hereditary Medullary Thyroid Carcinoma in Turkey.
J Clin Res Pediatr Endocrinol. 2016; 8(1):13-20 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: This retrospective multicenter study, centrally conducted and supported by the Society of Endocrinology and Metabolism of Turkey, aimed to evaluate the impact of free RET proto-oncogene testing in medullary thyroid carcinoma (MTC) patients. Surgical timing, adequacy of the treatment, and frequency of prophylactic thyroidectomy (PTx) in mutation carriers were also assessed.
METHODS: Genetic testing for MTC and pheochromocytoma was conducted between July 2008 and January 2012 in 512 patients. Application forms and RET mutation analyses of these patients whose blood samples were sent from various centers around Turkey were assessed retrospectively. An evaluation form was sent to the physicians of the eligible 319 patients who had confirmed sporadic MTC, familial MTC (FMTC), multiple endocrine neoplasia type 2 (MEN2), or who were mutation carriers. Physicians were asked to give information about the surgical history, latest calcitonin levels, morbidity, mortality, genetic screening, and PTx among family members. Twenty-five centers responded by filling in the forms of 192 patients.
RESULTS: Among the 319 patients, RET mutation was detected in 71 (22.3%). Cys634Arg mutation was the most prevalent mutation (43.7%), followed by Val804Met in 18 patients (25.4%), and Cys634Tyr in 6 patients (8.5%). Among 192 MTC patients, the diagnosis was sporadic MTC in 146 (76.4%), FMTC in 14 (7.3%), MEN2A in 15 patients (7.9%), and MEN2B in one patient. The number of mutation carriers among 154 apparently sporadic MTC patients was 8 (5.2%). Ten patients were submitted to PTx out of twenty-four mutation carriers at a mean age of 35±19 years.
CONCLUSION: Turkish people have a similar RET proto-oncogene mutation distribution when compared to other Mediterranean countries. Despite free RET gene testing, the number of the PTx in Turkey is limited and relatively late in the life span of the carriers. This is mainly due to patient and family incompliance and incomplete family counselling.

van Leeuwaarde RS, van Nesselrooij BP, Hermus AR, et al.
Impact of Delay in Diagnosis in Outcomes in MEN1: Results From the Dutch MEN1 Study Group.
J Clin Endocrinol Metab. 2016; 101(3):1159-65 [PubMed] Related Publications
OBJECTIVE: Identifying a germline mutation in the multiple endocrine neoplasia type 1 (MEN1) gene in an index case has consequences for a whole family. Eligible family members should be offered genetic counseling and MEN1 mutation testing. Subsequently, clinical screening of mutation carriers according to the guidelines should be initiated. We assessed whether there is a lag time from MEN1 diagnosis of the index case to MEN1 diagnosis of family members. In addition, we determined whether this lag time was associated with an increased morbidity and mortality risk.
DESIGN: A cohort study was performed using the Dutch MEN1 database, including >90% of the Dutch MEN1 population >16 years of age (n = 393).
RESULTS: Fifty-eight MEN1 families were identified, of whom 57 were index cases and 247 were non-index cases (n = 304). The median lag time in MEN1 diagnosis of family members was 3.5 (range, 0-30) years. At the time of MEN1 diagnosis, 30 (12.1%) non-index cases had a duodenopancreatic neuroendocrine tumor, of whom 20% had metastases with a mean lag time of 10.9 years, in comparison with 7.1 years without metastases. Twenty-five (10.1%) non-index cases had a pituitary tumor, of whom 80% had a microadenoma and 20% had a macroadenoma, with mean lag times of 7.2 and 10.6 years, respectively. Ninety-five (38.4%) non-index cases had a primary hyperparathyroidism with a mean lag time of 9.5 years in comparison with seven patients without a primary hyperparathyroidism with a mean lag time of 3 years (P = .005). Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time.
CONCLUSION: There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members.

Perakakis N, Flohr F, Kayser G, et al.
Multiple endocrine neoplasia type 1 associated with a new germline Men1 mutation in a family with atypical tumor phenotype.
Hormones (Athens). 2016 Jan-Mar; 15(1):113-7 [PubMed] Related Publications
BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant hereditary disorder associated with the development of endocrine tumors due to reduced expression of the tumor suppressor protein menin. Recent studies indicate a general role of menin in carcinogenesis, affecting the prevalence and clinical course of common non-endocrine tumors such as breast cancer, hepatocellular carcinoma and melanoma. Here we report a new germline missense mutation of Men1 in a German family with atypical tumor phenotype over three generations. Based on the type of mutation, we discuss possible changes in menin function leading to atypical tumorigenesis and present the clinical significance of such findings.
CASE PRESENTATION: A German family with a history of primary hyperparathyroidism presented to our Hospital for further evaluation. Members of the family demonstrated many different atypical tumors, such as renal cell carcinoma, papillary thyroid cancer and prostate cancer. DNA sequencing from peripheral blood revealed a novel mutation: Ser38Cys [TCC>TGC] in exon 2, codon 38 of Men1. This novel mutation is located in a region of menin which is responsible for interactions with the transcription factor JunD. This factor has recently been associated with prostate cancer. DNA sequencing of two of the atypical tumors (prostate cancer, papillary thyroid cancer) did not reveal a loss of heterozygosity, indicating an impact on menin expression and function in the heterozygous state, in line with results in +/-Men1 mutant mice developing prostate cancer.
CONCLUSION: The results and clinical course of disease in this case indicate the potential role of menin in the development of non-endocrine or atypical-endocrine tumors in MEN1 patients. Further investigations are needed to clarify both the general role of menin and the importance of specific mutations in carcinogenesis. Nevertheless, in families with uncommon manifestations of the syndrome early diagnostic adjustments should be considered.

Aghdam MN, Abbaszadegan MR, Tafazoli A, et al.
Presence of the RET Cys634Tyr mutation and Gly691Ser functional polymorphism in Iranian families with multiple endocrine neoplasia type 2A.
Hormones (Athens). 2016 Jan-Mar; 15(1):65-72 [PubMed] Related Publications
PURPOSE: Multiple Endocrine Neoplasia type 2A (MEN2A) 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 germ line RET (REarranged in Transfection) mutation is required to make the diagnosis and initiate genetic counseling.
METHODS: We analyzed blood DNA from three Iranian families with three generations of MEN2A including 20 affected individuals with MTC and four with pheochromocytoma. RET hotspots were amplified in probands and sequenced for mutation detection.
RESULT: The causative mutation in all families was found to be the Cys634Tyr missense substitution. The presence of a functional SNP resulting in Gly691Ser was also detected in exon 11 of 15 affected cases. Four patients showed both of these RET variations.
CONCLUSION: Our study shows that the Cys634Tyr missense substitution and the Gly691Ser polymorphism are recurrent in Iranian patients, since our families are unrelated. All asymptomatic carriers of the Cys634Tyr high-risk activating mutation were referred for prophylactic thyroidectomy.

Singh Ospina N, Maraka S, Montori V, et al.
When and how should patients with multiple endocrine neoplasia type 1 be screened for thymic and bronchial carcinoid tumours?
Clin Endocrinol (Oxf). 2016; 84(1):13-6 [PubMed] Related Publications
Patients with multiple endocrine neoplasia type 1 (MEN1) are commonly evaluated for clinical manifestations of this syndrome with the rationale that early diagnosis and adequate treatment will result in improved survival and quality of life. Thymic and bronchial carcinoid tumours are uncommon but important manifestations of MEN1. Current practice guidelines recommend evaluation with computed tomography or magnetic resonance imaging scan of the chest every 1-2 years to detect these neoplasms. However, the certainty that patients will be better off (increased survival or quality of life) as a result of this case detection strategy is based on evidence at moderate-high risk of bias that yields only imprecise results of indirect relevance to these patients. In order to improve the care that patients with MEN1 receive, co-ordinated efforts from different stakeholders are required so that large, prospective, multicentre studies evaluating patient important outcomes are carried out.

Nilubol N, Weinstein LS, Simonds WF, et al.
Limited Parathyroidectomy in Multiple Endocrine Neoplasia Type 1-Associated Primary Hyperparathyroidism: A Setup for Failure.
Ann Surg Oncol. 2016; 23(2):416-23 [PubMed] Related Publications
BACKGROUND: Recently, some surgeons have suggested that minimally invasive parathyroidectomy guided by preoperative localizing studies of patients with multiple endocrine neoplasia type 1 (MEN1)-associated primary hyperparathyroidism (pHPT) provides an acceptable outcome while minimizing the risk of hypoparathyroidism. This study aimed to evaluate the outcome for MEN1 patients who underwent limited parathyroidectomy compared with subtotal parathyroidectomy.
METHODS: The authors performed a retrospective analysis of 99 patients with MEN1-associated pHPT who underwent at least one parathyroid operation at their institution. Preoperative imaging studies, intraoperative findings, and clinical outcomes for patients were compared.
RESULTS: A total of 99 patients underwent 146 operations. Persistent pHPT was significantly higher in patients whose initial operations involved removal of 1 or 2 glands (69 %) or 2.5 to 3 glands (20 %) compared with those who had 3.5 or more glands removed (6 %) (P < 0.01). Persistent pHPT occurred in 5 % of all operations that cumulatively removed 3.5 or more parathyroid glands compared with 40 % of operations that removed 3 or fewer glands (P < 0.01). The single largest parathyroid gland was correctly identified preoperatively in 69 % (22/32) of the patients. However, preoperative localizing studies missed enlarged contralateral parathyroid glands in 86 % (19/22) of these patients. Preoperative localizing studies missed the largest contralateral parathyroid gland in 16 % (5/32) of the patients.
CONCLUSIONS: Limited parathyroidectomy in MEN1 is associated with a high failure rate and should not be performed. Preoperative identification of a single enlarged parathyroid gland in MEN1 is not reliable enough to justify unilateral neck exploration because additional enlarged contralateral parathyroid glands are frequently missed.

Fyrsten E, Norlén O, Hessman O, et al.
Long-Term Surveillance of Treated Hyperparathyroidism for Multiple Endocrine Neoplasia Type 1: Recurrence or Hypoparathyroidism?
World J Surg. 2016; 40(3):615-21 [PubMed] Related Publications
BACKGROUND: Primary hyperparathyroidism (HPT) in multiple endocrine neoplasia type 1 (MEN1) is surgically treated with either a subtotal parathyroidectomy removing 3 or 3,5 glands (SPX), less than 3 glands (LSPX), or a total parathyroidectomy with autotransplantation (TPX). Previous studies with shorter follow-up have shown that LSPX and SPX are associated with recurrent HPT, and TPX with hypocalcemia and substitution therapy. We examined the situation after long-term follow-up (median 20,6 years).
METHODS: Sixty-nine patients with MEN1 HPT underwent 110 operations, the first operation being 31 LSPX, 30 SPX, and 8 TPX. Thirty patients underwent reoperative surgery in median 120 months later, as completion to TPX (n = 12), completion of LSPX to SPX (n = 9), extirpation of single glands (n = 3) still resulting in LSPX, and resection of forearm grafts (n = 3). Nine patients underwent a second, and 2 a third reoperation. In 24 patients genetic testing confirmed MEN1, and in the remaining heredity and phenotype led to the diagnosis.
RESULTS: TPX had higher risk for hypoparathyroidism necessitating substitution therapy, at latest follow-up 50%, compared to SPX (16% after 3-6 months; none at latest follow-up). Recurrent HPT was common after LSPX, leading to 24 reoperations in 17 patients. No need for substitution therapy after SPX indicated forthcoming recurrent disease. Not having hypocalcemia in the postoperative period and less radical surgery than TPX were significantly associated to risk for recurrence. Further, mutation in exon 3 in the MEN1 gene may eventually be linked to risk of recurrence.
CONCLUSION: LSPX is highly associated with recurrence and TPX with continuous hypoparathyroidism, also after long-term follow-up. SPX should be the chosen method in the majority of patients with MEN1 HPT.

Clark P
Multiple Endocrine Neoplasia Syndromes.
J Infus Nurs. 2015 Nov-Dec; 38 Suppl 6:S36-42 [PubMed] Related Publications
Multiple endocrine neoplasia (MEN) is a term used to describe a group of hereditary carcinoma syndromes. Patients carrying a characteristic autosomal dominant gene aberration exhibit various endocrine carcinomas, as well as other anatomical abnormalities. Unfortunately, familial endocrine carcinoma patients are too often unrecognized by primary care providers, resulting in delayed diagnosis and treatment, with profound consequences related to morbidity and mortality. This article will introduce the various MEN syndromes and the infusion nurse's role in the care of these individuals and their families.

McClurg SW, Wakely PE, Chio EG
Laryngeal neuromas in a case of multiple endocrine neoplasia type 2B.
Ear Nose Throat J. 2015 Oct-Nov; 94(10-11):E20-2 [PubMed] Related Publications
Mucosal neuromas of the larynx in the setting of multiple endocrine neoplasia type 2B (MEN-2B) are extremely rare; to the best of our knowledge, only 2 other cases have been previously reported in the world literature. We describe a new case, which occurred in a 30-year old woman who presented with dysphagia, dysphonia, and cough. On examination, she was found to have multiple laryngeal mucosal neuromas throughout the glottis and supraglottis. She underwent surgical resection of these lesions with resolution of her symptoms.

Alevizaki M, Saltiki K
Primary Hyperparathyroidism in MEN2 Syndromes.
Recent Results Cancer Res. 2015; 204:179-86 [PubMed] Related Publications
One of the components of trethe classical form of MEN2 syndromes is primary hyperparathyroidism (PHP). It occurs in 20-30% of the typical MEN2A syndrome. The prevalence is more rare in gene carriers as these frequently have familial MTC only. PHP is diagnosed more frequently in association with the exon 11, codon 634 mutation of the ret gene-so there is phenotype/genotype correlation. The clinical manifestations of PHP in MEN2 are usually mild and the peak age of diagnosis after the 3rd decade. The treatment is surgical excision of the enlarged gland(s). Although there can be multigland disease in the parathyroids, it is frequently the case that both hyperplasia and adenoma may coexist, or even a single adenoma may be found during the investigation and finally during the operation. Patients with MEN2 syndromes should be screened for PHP with serum calcium measurements. The intensity of the screening should be higher in those carrying the ret mutations most frequently associated with this manifestation.

Tsang VH, Tacon LJ, Learoyd DL, Robinson BG
Pheochromocytomas in Multiple Endocrine Neoplasia Type 2.
Recent Results Cancer Res. 2015; 204:157-78 [PubMed] Related Publications
Pheochromocytoma (PC) is a neuroendocrine tumor that originates from chromaffin cells of the adrenal medulla. The production of catecholamines, including epinephrine, norepinephrine and dopamine, may lead to haemodynamic instability. Over 30% of PCs are associated with germline mutations, including re-arranged in transfection (RET) mutations seen in multiple endocrine neoplasia type 2 (MEN2) syndromes. Around 40% of individuals with MEN2 develop PC, though it is rarely the presenting feature. Compared to sporadic PC, MEN2-associated PC is more likely to be epinephine secreting and demonstrate bilateral adrenal involvement, and is less likely to be malignant. The diagnosis of PC requires clinical suspicion and biochemical testing, followed by imaging studies. Novel nuclear medicine modalities, including FDG positron emission tomography (PET) and 68Ga DOTATATE PET have added to the conventional techniques of 123I-metaiodobenzylguanindine (MIBG) scintigraphy, computer tomography and magnetic resonance imaging. Treatment of PC is surgical and requires peri-operative alpha and, frequently, beta blockade. Novel surgical techniques, such as adrenal sparing surgery and a laparoscopic approach, have decreased peri-operative morbidity. Surveillance for PC is life long, due to the risk of metastatic disease.

Frank-Raue K, Raue F
Hereditary Medullary Thyroid Cancer Genotype-Phenotype Correlation.
Recent Results Cancer Res. 2015; 204:139-56 [PubMed] Related Publications
During the last two decades, there has been a marked expansion of our knowledge of both the basic and clinical aspects of multiple endocrine neoplasia type 2 (MEN2). There are two clinically distinct types of MEN2 syndrome, termed MEN2A and MEN2B. Within MEN2A, there are four variants: (i) classical MEN2A, represented by the uniform presence of MTC and the less frequent occurrence of pheochromocytoma, or primary hyperparathyroidism, or both; (ii) MEN2A with cutaneous lichen amyloidosis; (iii) MEN2A with Hirschsprung's disease; and (iv) familial medullary thyroid carcinoma (FMTC), i.e., families or individuals with only MTC. MEN2B is associated with MTC, pheochromocytoma, and mucosal neuromas. Hereditary MTC is caused by autosomal dominant gain of function mutations in the RET proto-oncogene. Specific RET mutations may suggest a predilection toward a particular phenotype and clinical course with a strong genotype-phenotype correlation. Based upon these genotype-phenotype correlations, RET mutations are now stratified into three risk levels, i.e., highest, high, and moderate risk, based on the penetrance and aggressiveness of the MTC. Children in the highest risk category should undergo thyroidectomy in their first year of life, and perhaps even in their first months of life. Children in the high-risk category should have ultrasound of the neck and calcitonin (CTN) measurement performed prior to thyroidectomy. Thyroidectomy should typically be performed at the age of 5 or earlier, depending on the presence of elevated serum CTN levels. However, heterogeneity in disease expression and progression within these groups varies considerably. To personalize disease management, the decision regarding the age of prophylactic thyroidectomy is no longer based upon genotype alone but is currently driven by additional clinical data, the most important being serum CTN levels; specifically, the decision to perform thyroidectomy should err on the safe side if the CTN level is elevated but below 30 pg/ml, especially in the moderate risk group. Personalized management also includes decisions about the best age to begin biochemical screening for pheochromocytoma and primary hyperparathyroidism.

Delorme S, Raue F
Medullary Thyroid Carcinoma: Imaging.
Recent Results Cancer Res. 2015; 204:91-116 [PubMed] Related Publications
Imaging plays an important role in early detection and staging of medullary thyroid carcinoma (MTC) as well as in follow-up to localize early recurrence. MTC is a rare, calcitonin-secreting thyroid malignancy often diagnosed by ultrasound and calcitonin screening as part of the routine workup for any thyroid nodule. If calcitonin is elevated, imaging studies are needed for preoperative staging, which dictates surgical management. This can be done by ultrasound of the neck and abdomen. Computed tomography (CT) or magnetic resonance imaging (MRI) studies for more distant disease are done preoperatively if calcitonin levels are higher than 500 pg/ml. Neither FDG-PET/CT nor F-DOPA-PET/CT are used routinely for preoperative staging but may contribute in doubtful individual cases. Postoperative elevated calcitonin is related to persistence or recurrence of MTC. Imaging studies to localize tumor tissue during postoperative follow-up include ultrasound, CT, MRI as well as PET studies. They should be used wisely, however, since treatment consequences are often limited, and even patients with persistent disease may survive long enough to accumulate significant radiation doses. Imaging studies are also useful for diagnosis of associated components of the hereditary MTC such as pheochromocytoma and primary hyperparathyroidism (pHPT).

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