Search

Multiple endocrine neoplasia type 2B is a rare autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, pheochromocytoma, Marfan-like fatigue, a peculiar face with thickening of the lips, mucosal neuromas on the lips and tongue, and gastrointestinal phenomena. Most patients harbor pathological variants of the RET gene. Herein, we present the first case of a 14 year-old boy who experienced small intestinal volvulus along with a megacolon, and he was diagnosed with multiple endocrine neoplasia type 2B. The patient complained of constipation since he was 2 years old and slowly progressive abdominal distension at school age. At 14 years of age, he presented with remarkable megacolon mimicking Hirschsprung's disease and complicated with small intestinal volvulus. The volvulus was successfully repaired, and the particularly dilated transverse colon was resected following a rectal biopsy. Histopathological evaluation of the resected transverse colon revealed to be compatible with ganglioneuromatosis. After emergency surgery, the patient was diagnosed with multiple endocrine neoplasia type 2B with medullary thyroid carcinoma, and a de novo variant of RET was confirmed. Gastroenterologists should consider it when treating patients with constipation, especially those with megacolon. Therefore, timely diagnosis may lead to appropriate treatment of medullary thyroid carcinoma and improve mortality., (© 2024. The Author(s).)

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare autosomal dominant hereditary cancer syndrome which is characterized by the appearance of medullary thyroid carcinoma (MTC), pheochromocytoma, parathyroid adenomas, ganglioneuromas of the digestive tract, and musculoskeletal abnormalities. The case is presented of a 31-year-old male patient with numerous polyps in the colon described as ganglioneuromas which are ectodermal neoplasms emerging from a proliferation of ganglionic cells of the sympathetic nervous system. The results show elevated levels of normetanephrine, which is an endogenous catecholamine metabolite, and has high diagnostic sensitivity as well as specificity in pheochromocytoma detection. The patient underwent partial thyreoidectomy due to a nodular goiter. He was admitted to the Department of Gastroenterology to lead a diagnostic pathway towards MEN 2B.

Tumor-to-tumor metastasis is a rare phenomenon in which primary tumor cells metastasize to other tumors. Herein, we report an extremely rare case of tumor-to-tumor metastasis of medullary thyroid carcinoma to a paraganglioma in a patient with multiple endocrine neoplasia type 2B. Based on genetic examination, a 36-year-old woman was diagnosed with multiple endocrine neoplasia type 2B when she was 24 years old. She had a history of total thyroidectomy for medullary thyroid carcinoma and bilateral adrenalectomy for pheochromocytomas, which were performed when she was 15 years and 29 years old, respectively. Follow-up computed tomography demonstrated a retroperitoneal tumor of 30 mm in diameter beside the left kidney and a liver tumor of 16 mm in diameter located in segment 6. The retroperitoneal and liver tumors were surgically resected and examined by a pathologist. Histological examination revealed the classic Zellballen pattern in the retroperitoneal tumor, rendering the diagnosis of a paraganglioma recurrence. Inside the tumor, a white nodule positive for carcinoembryonic antigen, weakly positive for calcitonin, and negative for tyrosine hydroxylase, was identified and diagnosed as a metastatic medullary thyroid carcinoma with high malignant potential. The liver lesion was diagnosed as a metastasis of the medullary thyroid carcinoma. This is the first report of tumor-to-tumor metastasis of medullary thyroid carcinoma to paraganglioma in a patient with multiple endocrine neoplasia type 2B twenty years after total thyroidectomy.

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare variant of hereditary tumor syndromes caused by germinal mutations in the proto-oncogene RET. One of the components of the syndrome is multiple neurinomas, the early detection of  which is not always given due attention. We present a description of the case of MEN 2B, manifested in the first months of life by intestinal ganglioneuromatosis. The disease presented with chronic constipation, including episodes of intestinal obstruction that required repeated surgical interventions. MEN 2B was suspected at the age of 15. At the time of diagnosis, an increase in serum calcitonin levels was noted (1041 pg/ml, norm <9.5 pg/ml), and a node in the thyroid gland was also determined (1,3*1,0*1,2 see, TIRADS 5), subsequently verified as a neoplasm of C-cells. By DNA analysis, a pathogenic variant p.Met918Thr, typical for MEN2 B, was detected in the RET gene. No signs of pheochromocytoma were found at the time of investigation. The patient underwent a thyroidectomy with lymphadenectomy. The difficulties of early diagnosis of sporadic cases of MEN 2B due to the nonspecificity of gastrointestinal manifestations of the disease are discussed.

Background: We describe early and typical nonendocrine symptoms of Multiple Endocrine Neoplasia type 2B (MEN2B) presented in our patients with de novo M918T mutation in the RET proto-oncogene in early childhood, however, the diagnosis of MEN2B and medullary thyroid carcinoma (MTC) was confirmed late, in the second decade of life. In this paper, we emphasize the possibility of growth retardation, growth hormone (GH) deficiency and ovarian teratoma as a new symptom of MEN2B., Case Reports: Advanced MTC with palpable mass on the neck and nonendocrine symptoms such as marfanoid habitus, thickened lips, mucosal neuromas led to the diagnosis in case 1 at the age of 13 years and GH deficiency and nonendocrine symptoms in case 2 at the age of 11 years. The earliest feature of MEN2B was alacrima and constipation. Patient 1 was operated on for a slipped femoral capital epiphysis and for a cystic ovarian teratoma., Conclusions: Improved awareness of nonendocrine signs of MEN2B could lead to earlier diagnosis, when surgical cure of MTC is possible. Alacrima is the first sign of MEN2B. We confirmed the possibility of growth retardation and GH deficiency in MEN2B, which had been previously rarely described. We suggest that patients with MEN2B may develop cystic ovarian teratoma, to the best of our knowledge, which has never been described so far in the literature. The results of this study could be used to guide further diagnosing of MENB2 at the early stage for better clinical outcome. We emphasize that MEN2B carries a risk for development of cystic ovarian teratoma as a novel tumor in this disease.

Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Multiple endocrine neoplasia type 2B (MEN 2B) is mainly caused by M918T RET germline mutation, and characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and non-endocrine features. However, the diagnosis and treatment are usually delayed., Methods: This study reports 5 Chinese pedigrees with 5 individuals harboring germline RETM918T, and systematically reviewed previous Chinese literature reported., Results: All 5 patients initially presented MTC, but none had biochemically cured postoperatively. 2 also presented bilateral PHEO after adrenal-sparing surgery, 1 needed steroid replacement. Further, a total of 32 MEN 2B patients from literature were clustered with 28 available for analysis. 26 (92.8%) were diagnosed by endocrine-related symptoms; the remaining 2 (7.2%) due to RET testing and oral symptoms, respectively. 25 patients underwent thyroidectomy with/without neck lymph node dissection at the mean age of (23.3 ± 10.4) years. Histopathological examination revealed MTC (100%). Of them, 17 had definite TNM stage, with 1 in stage III and others in IV. Other information of MEN 2B-related symptoms included penetrance of PHEO (60.7%), constipation (32.1%), Hirschsprung disease (25%), alacrima (17.8%), mucosal ganglioneuroma (96.4%) and marfanoid habitus (71.4%). 19 patients were verified harboring RET-M918T (c.2753T>C), of whom 15 (78.9%) were de novo mutation. The other 9 were clinically diagnosed as MEN 2B., Discussion & Conclusion: The initial diagnosis of MEN 2B is relatively later, and diagnosed by non-endocrine components is extremely lower. Recognition of MEN 2B and its non-endocrine-related components is still the utmost requirement for a Chinese physician. Combined RET screening and serum calcitonin detection can facilitate early diagnosis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: To describe clinical, anterior segment optical coherence tomography (AS-OCT), in vivo confocal microscopy (IVCM), histopathologic, and immunohistochemical findings in a patient with multiple endocrine neoplasia type 2b (MEN 2b) syndrome., Materials and Methods: Retrospective case report of a patient with MEN 2b., Results: A 31-year-old male diagnosed with MEN 2b presented with eye redness, burning, and visible conjunctival mass in both eyes. The patient's past medical history revealed that he underwent bilateral adrenalectomy and total thyroidectomy. Genetic testing revealed M918T heterozygous mutation in the RET proto-oncogene. Corrected visual acuity was 20/20 in both eyes. Anterior segment examination revealed bilateral thickened lid margins, ectropion, blepharitis, conjunctival injection, temporal and inferonasal subconjunctival lesions with corneal invasion, corneal neovascularization, and marked corneal nerves. AS-OCT showed a subepithelial mixed reflective lobular mass in both eyes. Hyperreflective and noticeable thickened stromal corneal nerves were observed on IVCM in the left eye. After incisional biopsy of the right perilimbal lesions, histopathological examination revealed that lesions consisted of spindle cells in hypocellular bundles with no atypia and mitosis. Immunohistochemical examination revealed diffuse staining with S100, focal staining with synaptophysin, and no staining with neurofilament protein. These findings were considered compatible with a benign nerve sheath tumor, probably schwannoma., Conclusions: We present clinical, AS-OCT, IVCM, histopathological, and immunohistochemical findings in a patient with MEN 2b. To our knowledge, this is the first case of a conjunctival schwannoma diagnosed histopathologically in MEN 2b.

Background: Medullary thyroid carcinomas (MTC) account for 3% to 5% of all thyroid cancers. In most cases, MTC is hereditary and occurs as part of the multiple endocrine neoplasia (MEN) type 2A and 2B syndromes. There is a strong genotype-phenotype correlation associated with the respective RET mutations, making risk-adapted management possible., Procedure: We report the prospectively collected data on children and adolescents of the multicenter nonrandomized German GPOH-MET registry. Children and adolescents with MTC and C-cell hyperplasia (CCH) were included., Results: From 1997 to June 2019, a total of 57 patients with MTC and 17 with CCH were reported. In patients with MTC, median follow-up was five years (range, 0-19) and median age at diagnosis 10 years (range, 0-17). Overall survival and event-free survival (EFS) were 87% and 52%, respectively. In total 96.4% of patients were affected by MEN2 syndromes, which was in 37/42 MEN2A and 3/28 MEN2B (M918T mutation) inherited. EFS in MEN2A was 78%, and in MEN2B 38% (P < 0.001). In multivariate analyses, lymph node (LN) status and postoperatively elevated calcitonin were significant prognostic factors for EFS. Notably, modest-risk mutation carriers presented with MTC at a rather young age, without raised calcitonin, and LN metastases., Conclusions: Identification of children carrying de novo RET M918T mutations by means of the characteristic phenotype is crucial to detect MTC at an early stage, which will be associated with improved survival. As calcitonin levels may be false-negative and modest-risk mutation carriers present with a variable phenotype, particular attention should be paid to these children., (© 2020 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals, Inc.)

Background: Multiple endocrine neoplasia (MEN) 2B is characterized by early development of aggressive medullary thyroid carcinoma (MTC), visible physical stigmata, and associated symptoms. In most cases, de novo mutations are revealed. There are premonitory symptoms and stigmata that enable early diagnosis, before an inoperable MTC develops. The German Society for Paediatric Oncology and Haematology (GPOH)-Malignant Endocrine Tumours (MET) registry maintains records of children with MTC in Germany since 1997., Methods: Children with a diagnosis of MTC in MEN 2B recorded in the GPOH-MET study were analyzed retrospectively. Stigmata and symptoms associated with MEN 2B were examined., Results: From inception through 2017, 24 patients aged 0.2-17.3 years were included. Symptoms affecting the oral/dental (88.0%), musculoskeletal (79.2%), and gastrointestinal (70.8%) systems were recognized most frequently. Gastrointestinal and musculoskeletal symptoms preceded symptoms of MTC. Twelve patients had short stature. Regarding the prevalence of single symptoms, neuromas of the lips and the oral cavity were mentioned most frequently. Five patients died from MTC. Patients diagnosed by tumor symptoms showed more advanced disease than those with disease detected by other means. Children diagnosed via associated stigmata and symptoms or positive family history had significantly improved overall survival (OS) compared to children diagnosed via symptoms of MTC (OS 100% vs 53.3%)., Conclusions: In children with MEN 2B, oral/dental, musculoskeletal, and gastrointestinal symptoms are most common. If children are diagnosed via associated symptoms and stigmata, OS is improved. Most of the children were diagnosed with growth disturbances; this finding requires verification and ranging in other patient cohorts., (© 2019 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Background: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection., Methods: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features., Findings: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs., Interpretation: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Diffuse intestinal ganglioneuromatosis is a rare condition associated with MEN2B. It is also seen in conditions like neurofibromatosis type 1 and Cowden syndrome. This is a report of a patient who underwent total colectomy with end ileostomy creation for a megacolon. He was diagnosed to have diffuse ganglioneuromatosis on histological examination of the resected segment of colon. The definitive management of diffuse ganglioneuromatosis is to resect and anastomose., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Multiple endocrine neoplasia (MEN) is an uncommon genetic syndrome transmitted as an autosomal dominant condition characterized by multiple tumors or hyperplasia of neuroendocrine tissues. MEN type 2b (MEN2B) often has clinical signs of marfanoid facial appearance and mucosal neuromas of the head. This report describes the diagnosis of MEN2B in a previously undiagnosed 9 year old who presented for biopsy of an oral lesion., (Published by Elsevier Inc.)

Background: Multiple endocrine neoplasia type 2B (MEN2B) is an extremely rare syndrome mainly caused by RET918 germline mutations. MEN2B typically causes medullary thyroid carcinoma (MTC), pheochromocytoma, and unique physical characteristics including mucosal neuroma, distinctive facial appearance, and Marfanoid habitus. Most patients have abdominal symptoms such as bloating, intermittent constipation, and diarrhea. MTC is the most important determinant of mortality in patients with MEN2B. Establishing the diagnosis of MEN2B at a curative stage of MTC is crucial., Case Presentation: We have encountered four patients with MEN2B. Two were hereditary cases from the same family, and two were considered de novo cases with phenotypically normal parents. Mean age at diagnosis was 25.5 years (range, 13-39 years). Although all patients had shown mucosal neuroma on the lips and tongue, in addition to gastrointestinal symptoms from infancy, diagnoses were made from symptomatic MTC even for the hereditary patients (our index case was a 14-year-old girl, whose mother was subsequently diagnosed with advanced MTC). Genetic tests for RET mutations revealed the M918T mutation in all patients. Two patients developed pheochromocytoma, two died from distant metastases of MTC, and two received treatment for multiple metastases of MTC (one with vandetanib)., Conclusions: In our patients with MEN2B, prophylactic or early thyroidectomy could not be performed. The characteristic phenotype associated with MEN2B is almost always seen prior to detection of MTC or pheochromocytoma. Knowledge about the non-endocrine manifestations of MEN2B needs to be shared among pediatricians and gastroenterologists.

Multiple Endocrine Neoplasia Type 2B (MEN2B) is a cancer-predisposing syndrome that affects patients with germline RET mutations. The clinical spectrum of the syndrome includes medullary thyroid carcinoma (MTC) and pheochromocytoma. Currently, there is no satisfactory model recapitulating all the features of the disease especially at the level of stem cells. We generated induced pluripotent stem cells (iPSCs) from a patient with RET mutation at codon 918 who developed pheochromocytoma and MTC. These iPSC had normal karyotype, harboured the RET M918T mutation and expressed pluripotency hallmarks. A comprehensive pathological assessment of teratoma was performed after injection in immunodeficient mice., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Medullary thyroid carcinoma (MTC) is a rare cancer during childhood. MTC is sporadic in approximately 80% of cases and hereditary in 20%. When hereditary, it can be associated with other endocrine neoplasias and/or typical nonendocrine diseases, thus configuring the multiple endocrine neoplasia (MEN) syndromes. Children with clinically obvious MTC belong to MEN 2A or 2B families, related to RET mutations. The standard treatment is total thyroidectomy and central neck dissection. However, treatment of advanced MTC has not yet been standardized, even if a new tyrosine kinase inhibitor specific to RET mutation has changed the outcome of such patients. Vandetanib plays a role in the treatment of children with metastatic, locally advanced and nonoperable MTC, with good tolerance. We report the 5-year treatment of an 11-year-old patient, with vandetanib and without thyroid surgery., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Ganglioneuromatous proliferation in the gastrointestinal tract is a rare occurrence and is usually associated with specific syndrome complexes such as multiple endocrine neoplasia Type 2B or von Recklinghausen's disease. We report here a case of diffuse intestinal ganglioneuromatosis, presenting as intestinal obstruction and chronic constipation in an 11-year-old boy. Sporadic cases of intestinal ganglioneuromatosis in the absence of any systemic manifestations are a very rare cause of enteric motility disorders in childhood, and we discuss the pathological and clinical significance of this finding. Histopathological identification of this uncommon cause of a common pediatric problem is important since the condition is amenable to surgical treatment.

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy of the thyroid C cells that occurs in hereditary and sporadic clinical settings. Metastatic spread commonly occurs to cervical and mediastinal lymph nodes. MTC cells do not concentrate radioactive iodine and are not sensitive to hormonal manipulation, and therefore surgery is the most effective option for curative therapy, reduction in tumor burden, or effective palliation. In patients undergoing preventative surgery for hereditary MTC, central lymph node dissection should be considered if the calcitonin level is elevated. Preservation of parathyroid function in these young patients is of paramount importance. In patients with established primary tumors, systematic surgical removal of lymph node basins (compartmental dissection) should be guided by ultrasound mapping of lymph node metastases and level of serum calcitonin. A "berry-picking" approach is discouraged. Newly approved targeted molecular therapies offer wider treatment options for patients with progressive or metastatic disease., (© 2015 American Cancer Society.)

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.

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.

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.

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).

Purpose: This paper intends to review for the oral and maxillofacial surgery community the MEN abnormalities generally, to emphasize the maxillofacial abnormalities peculiar to the MEN2B variant particularly, and to demonstrate the importance of early recognition of its most important component, medullary thyroid carcinoma., Patients and Methods: The findings in five individuals with confirmed diagnoses of MEN2B are arranged to demonstrate the various manifestations of the disorder, and together represent the largest single group in the oral and maxillofacial surgery literature to date., Results: Tabulation of the patients' individual findings demonstrates the variants and severity of the disorder, discloses findings not previously emphasized in the literature, and stresses the significance of early recognition of medullary thyroid carcinoma., Conclusion: The evidence in this study group suggests that the oral mucosal lesions are more commonly neurofibromas than neuromas as previously reported, that the characteristic dental central diastemas may occur independent of tongue size or the presence of oral soft tissue lesions, and that the characteristic apertognathia potentially requires surgical correction., (Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Multiple endocrine neoplasia (MEN) type 2 syndrome is an autosomal dominant inherited disease caused by mutations of the RET proto-oncogene, and is clinically divided into three phenotypes: MEN2A, MEN2B, and familial medullary thyroid carcinoma. Although multiple mucosal neuromas are commonly observed in patients with MEN2B, there are only a few reports of laryngeal neuroma. We present here a rare case of laryngeal mucosal neuromas with MEN2B., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A relationship between the palisaded encapsulated neuroma (PEN) and the mucocutaneous neuroma seen in multiple endocrine neoplasia (MEN) 2b syndrome has been noted. We experienced a case of multiple mucocutaneous neuromas including both MEN 2b type neuromas and PENs. We evaluated the histopathologic and immunohistochemical features of 48 lesions in this patient. The lesions were histopathologically classified into 3 groups: (1) MEN 2b type neuroma (18 lesions), (2) PEN (22 lesions), and (3) an intermediate form of the 2 conditions (8 lesions). The intermediate form was classified into 2 subtypes: 1 type characterized by PEN nodules made up of assembled neuroma fascicles neighboring MEN 2b type neuroma fascicles and the other type characterized by more broad nerve fascicles than those seen in typical MEN 2b type neuroma. The idea that PEN is a progressive form of MEN 2b type neuroma may be speculative. Instead, the present study suggests that the observation of hybrid MEN 2b type neuroma/PEN in association with MEN 2b type neuroma and PEN may be a characteristic finding in cases of multiple mucocutaneous neuromas. The view that MEN 2b type neuroma and PEN lie within a spectrum of the same disease entity may be an overstatement; however, the present study suggests that PEN is basically a neural hamartoma/benign neoplasm, like MEN 2b type neuroma, and that there is a close relationship between the 2 conditions in terms of their histogenesis.

Purpose: This "consensus statement" aims to summarise the current evidence-based knowledge as to "timing" and planning the "extent" of thyroid surgery in terms of an optimal balance between the prevention of thyroid malignancy (involving metastasis) and the risks associated with more extended surgery (permanent hypoparathyroidism, permanent paralysis of the recurrent laryngeal nerve). Surgery "in time" is influenced by genetic findings and age. Basal (and stimulated) calcitonin levels may individualise the timing and extent of surgery., Materials and Methods: The review of English-language studies addressing the management of REarranged during Transfection proto-oncogene mutation carriers including the time, extent of thyroid surgery and results. Evidence is mostly obtained from well-designed, non-experimental descriptive investigations, such as comparative, correlation and case-control studies (level III) with a grading of recommendation B, or from expert committee reports or opinions and/or the clinical experience of respected authorities (level IV) with a grading of recommendation C, respectively., Results: "Risk level D" includes multiple endocrine neoplasia 2B cases. Thyroidectomy is recommended within the first year of life, preferably as soon as possible, due to the very early transformation of C cell hyperplasia to more aggressive tumours. Calcitonin levels may be less helpful. In patients with codon 634 mutations (risk level C), thyroidectomy between ages 2 and 4 years has been proposed based upon evidence of age-dependent and codon-specific progression of early medullary thyroid cancer. In "risk level B" (codons 609, 611, 618, 620, 630 and 804), tandem mutation (804-778) patients should undergo thyroidectomy before the age of 6 years. "Risk level A" includes patients with mutations in codons 321, 515, 533, 600, 603, 606, 635, 649, 666, 768, 776, 790, 791, 804 (single mutation), 833, 844, 861, 891 or 912. Surgery may be postponed until the age of 10 years. However, postponing surgery and avoiding central (level VI) neck dissection in patients with risk levels A to C are only justified in families with a less aggressive MTC history and in combination with the results of basal (and calcium- or pentagastrin-stimulated) serum calcitonin levels. The moment of transition from C cell hyperplasia to MTC seems to occur when calcitonin levels rise. In patients with normal basal and stimulated calcitonin levels, the chance of micro-MTC increases significantly., Conclusions: Hereditary C cell disease acts as a model to apply the results of bedside genetic testing, age and calcitonin levels (genotype-age-calcitonin-concept) for the individual timing of thyroid surgery and its extent.

In infants at risk of multiple endocrine neoplasia type 2B (MEN2B) the American Thyroid Association recommends genetic testing as soon as possible after birth and that thyroidectomy should be performed in MEN2B RET-mutation positive individuals as soon as possible and if possible within the first year of life. We present a ten-month-old girl with MEN2B who had prophylactic thyroidectomy. The surgical specimen showed medullary thyroid carcinoma. This case emphasizes the need for early diagnosis and prophylactic thyroidectomy in MEN2B patients.

Medullary thyroid carcinoma (MTC) originates from thyroid parafollicular C cells, and it accounts for 5% of thyroid malignancies. MTC is sporadic in approximately 80% and hereditary in 20% of cases. When hereditary it can be associated with other benign endocrine neoplasias and/or typical nonendocrine diseases, thus configuring the multiple endocrine neoplasia syndromes (type 2, MEN2/familial MTC, FMTC). Sporadic MTC is usually diagnosed in adult life. Children with clinically evident MTC are belonging to MEN2 families, particularly MEN2A and MEN2B. Children belonging to families with FMTC are usually identified by RET genetic screening shortly after birth or during childhood but they likely develop MTC later in adult life. A genotype-phenotype correlation has been observed between RET mutations and MEN2 syndromes. As for adults, the diagnosis of childhood MTC is based on serum calcitonin (Ct) and neck ultrasound with fine-needle aspiration if a thyroid nodule is present. The standard treatment is total thyroidectomy and central neck node dissection but, according to recent evidence, if the basal Ct is <30 pg/ml or following the institutional cutoff the neck node dissection can be avoided. For advanced metastatic cases, vandetanib has been demonstrated to be effective in children as well as adults.

Background: Multiple endocrine neoplasia type 2B (MEN2B) is the rarest and most aggressive form of MEN2. MEN2B cases usually carry either an M918T or A883T mutation of the RET, but to date, there are 3 atypical MEN2B caused by tandem mutations., Methods and Results: A 32-year-old woman with no family history of medullary thyroid carcinoma (MTC) presented with a neck tumor and multiple mucosal nodules. She was diagnosed with MEN2B. Genetic analyses of RET revealed that she had 2 mutations, Q781R and V804M. Subclone and genetic analyses revealed that Q781R was on the paternal allele and V804M was a de novo. In silico analysis of the tandem mutations showed a high prediction score., Conclusions: We describe a novel combination of tandem RET mutations (Q781R/V804M) in a MEN2B-like patient. In silico analysis showed a high prediction score, which was compatible with the clinical phenotype in the present case., (Copyright © 2012 Wiley Periodicals, Inc., A Wiley Company.)

Objective: Primary gastrointestinal neuropathies are a heterogeneous group of enteric nervous system (ENS) disorders that continue to cause difficulties in diagnosis and histological interpretation. Recently, an international working group published guidelines for histological techniques and reporting, along with a classification of gastrointestinal neuromuscular pathology. The aim of this article was to review and summarize the key issues for pediatric gastroenterologists on the diagnostic workup of congenital ENS disorders. In addition, we provide further commentary on the continuing controversies in the field., Results: Although the diagnostic criteria for Hirschsprung disease are well established, those for other forms of dysganglionosis remain ill-defined. Appropriate tissue sampling, handling, and expert interpretation are crucial to maximize diagnostic accuracy and reduce interobserver variability. The absence of validated age-related normal values for neuronal density, along with the lack of correlation between clinical and histological findings, result in significant diagnostic uncertainties while diagnosing quantitative aberrations such as hypoganglionosis or ultrashort Hirschsprung disease. Intestinal neuronal dysplasia remains a histological description of unclear significance., Conclusions: The evaluation of cellular quantitative or qualitative abnormalities of the ENS for clinical diagnosis remains complex. Such analysis should be carried out in laboratories that have the necessary expertise and access to their own validated reference values.

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.

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., (©2013 AACR.)