Our Health Library information does not replace the advice of a doctor. Please be advised that this information is made available to assist our patients to learn more about their health. Our providers may not see and/or treat all topics found herein. This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER. MEN syndromes are familial disorders characterized by neoplastic changes that affect multiple endocrine organs.[1] Changes may include hyperplasia, benign adenomas, and carcinomas. There are two main types of MEN syndromes: For more information about MEN syndromes, see Genetics of Endocrine and Neuroendocrine Neoplasias. References: The main clinical features and genetic alterations of the multiple endocrine neoplasia (MEN) syndromes are shown in Table 1. MEN Type 1 (MEN1) Syndrome (Wermer Syndrome) MEN1 syndrome is an autosomal dominant disorder characterized by the presence of tumors in the parathyroid, pancreatic islet cells, and anterior pituitary. Diagnosis of this syndrome should be considered when two endocrine tumors listed in Table 1 are present. Clinical practice guidelines recommend that screening for patients with MEN1 syndrome begins by the age of 5 years and continues throughout life. The tests for screening are age specific and may include yearly serum calcium, parathyroid hormone, gastrin, glucagon, secretin, proinsulin, chromogranin A, prolactin, and IGF-1. Radiological screening should include magnetic resonance imaging of the brain and computed tomography of the abdomen every 1 to 3 years.[2,3,4] One study documented the initial presentation of MEN1 syndrome occurring before age 21 years in 160 patients.[5] Of note, most patients had familial MEN1 syndrome and were monitored using an international screening protocol. MEN1 germline mutations are found in 70% to 90% of patients; however, this gene is frequently inactivated in sporadic tumors.[7] Mutation testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.[8] MEN Type 2A (MEN2A) and MEN Type 2B (MEN2B) Syndromes A germline activating mutation in the RET oncogene (a receptor tyrosine kinase) is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN2A and MEN2B syndromes.[9,10,11]Table 2 describes the clinical features of these syndromes. MEN2A MEN2A is characterized by the presence of two or more endocrine tumors (see Table 1) in an individual or in close relatives.[12]RET mutations in these patients are usually confined to exons 10 and 11. The most-recent literature suggests that this entity should not be identified as a form of hereditary medullary thyroid carcinoma that is separate from MEN2A and MEN2B. Familial medullary thyroid carcinoma should be recognized as a variant of MEN2A, to include families with only medullary thyroid cancer who meet the original criteria for familial disease. The original criteria includes families of at least two generations with at least two, but less than ten, patients with RET germline mutations; small families in which two or fewer members in a single generation have germline RET mutations; and single individuals with a RET germline mutation.[13,14] MEN2B MEN2B is characterized by medullary thyroid carcinomas, parathyroid hyperplasias, adenomas, pheochromocytomas, mucosal neuromas, and ganglioneuromas.[12,15,16] The medullary thyroid carcinomas that develop in these patients are extremely aggressive. More than 95% of mutations in these patients are confined to codon 918 in exon 16, causing receptor autophosphorylation and activation.[17] Patients also have medullated corneal nerve fibers, distinctive faces with enlarged lips, and an asthenic Marfanoid habitus. A pentagastrin stimulation test can be used to detect medullary thyroid carcinoma in these patients. However, the patient management is driven primarily by the results of genetic analysis for RET mutations.[14,17] A review of 38 patients with genetically confirmed MEN2B at the National Institutes of Health identified eight patients who developed pheochromocytoma in the course of follow-up.[18] Pheochromocytoma was diagnosed at a mean age of 15.2 years (± 4.6 years; range, 10–25 years) and at a mean period of 4 years (± 3.3 years) after MEN2B diagnosis. Only one patient was diagnosed with pheochromocytoma as the initial manifestation of MEN2B after she presented with hypertension and secondary amenorrhea. The youngest patient diagnosed with pheochromocytoma in this cohort was an asymptomatic child aged 10 years. The authors of this study believe that the current guidelines to begin screening for pheochromocytoma at age 11 years are appropriate. A retrospective analysis identified 167 children with RET mutations who underwent prophylactic thyroidectomy. This group included 109 patients without a concomitant central node dissection and 58 patients with a concomitant central node dissection. Children were classified into risk groups by their specific type of RET mutation.[19] For more information, see Table 1 in Childhood Thyroid Cancer Treatment. In a small percentage of cases, Hirschsprung disease has been associated with the development of neuroendocrine tumors such as medullary thyroid carcinoma. RET germline inactivating mutations have been detected in up to 50% of patients with familial Hirschsprung disease and less often in the sporadic form.[20,21,22] Cosegregation of Hirschsprung disease and medullary thyroid carcinoma phenotype is infrequently reported, but these individuals usually have a mutation in RET exon 10. Patients with Hirschsprung disease are screened for mutations in RET exon 10. If such a mutation is discovered, a prophylactic thyroidectomy should be considered.[22,23,24] Guidelines for genetic testing of patients suspected of having MEN2 syndrome and the correlations between the type of mutation and the risk levels of aggressiveness of medullary thyroid cancer have been published.[14,25] References: Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life: For information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care. The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website. Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3,4,5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer. Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people. Therefore, all pediatric cancers are considered rare. The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows: Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers in children aged 0 to 14 years and 9.3% of the cancers in adolescents aged 15 to 19 years. These rare cancers are extremely challenging to study because of the low number of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers. References: Treatment options for childhood MEN syndromes, according to type, are as follows: MEN Type 1 (MEN1) Syndrome The treatment of patients with MEN1 syndrome is based on the type of tumor. The outcomes of patients with MEN1 syndrome are generally good provided adequate treatment can be obtained for parathyroid, pancreatic, and pituitary tumors. The standard approach to patients who present with hyperparathyroidism and MEN1 syndrome is genetic testing and treatment with a cervical resection of at least three parathyroid glands and transcervical thymectomy.[1] For more information, see the Interventions section in Genetics of Endocrine and Neuroendocrine Neoplasias. MEN Type 2 (MEN2) Syndromes The management of medullary thyroid cancer in children from families having MEN2 syndromes relies on presymptomatic detection of the RET proto-oncogene mutation responsible for the disease. MEN2A syndrome For children with MEN2A, thyroidectomy is commonly performed by approximately age 5 years or older if that is when a RET mutation is identified.[2,3,4,5,6,7] The outcomes for patients with MEN2A syndrome are generally good, although recurrences of medullary thyroid carcinoma and pheochromocytoma can occur.[8,9,10] A retrospective analysis identified 262 patients with MEN2A syndrome.[11] The median age of the cohort was 42 years and ranged from age 6 to 86 years. There was no correlation between the specific RET mutation identified and the risk of distant metastasis. Younger age at diagnosis did increase the risk of distant metastasis. Young children who are relatives of patients with MEN2A undergo genetic testing before the age of 5 years. Carriers undergo total thyroidectomy as described above, with autotransplantation of one parathyroid gland by a certain age.[12,13,14,15] MEN2B syndrome Patients with MEN2B syndrome have worse outcomes primarily because medullary thyroid carcinoma is more aggressive. Because of the increased severity of medullary thyroid carcinoma in children with MEN2B and in those with RET mutations in codons 883, 918, and 922, it is recommended that these children undergo prophylactic thyroidectomy in infancy.[3,16,17]; [18][Level of evidence C2] This can improve outcomes in patients with MEN2B.[19] Complete removal of the thyroid gland is the recommended surgical management of medullary thyroid cancer in children because there is a high incidence of bilateral disease. Targeted therapy Targeted therapy has been used for patients with the RET gene mutation and medullary thyroid cancer. Types of targeted therapy include the following: Vandetanib (a kinase inhibitor) A randomized phase III trial included adult patients with unresectable locally advanced or metastatic hereditary or sporadic medullary thyroid carcinoma who were treated with either vandetanib (a selective inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor) or placebo. The study found that vandetanib administration was associated with significant improvements in progression-free survival (PFS), response rate, disease control rates, and biochemical response.[20] Children with locally advanced or metastatic medullary thyroid carcinoma were treated with vandetanib in a phase I/II trial.[21] Selpercatinib (a RET inhibitor) A phase I/II trial of selpercatinib therapy included patients with RET-mutant cancers. The study enrolled 55 patients with medullary thyroid cancer (age range, 17–84 years) who were previously treated with vandetanib and/or cabozantinib and 88 patients with medullary thyroid cancer (age range, 15–82 years) who were not previously treated with vandetanib or cabozantinib.[23] References: Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website. The following are examples of national and/or institutional clinical trials that are currently being conducted: Patients with tumors that have molecular variants addressed by open treatment arms in the trial may be enrolled in treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website. The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above. This summary was reformatted. Special Considerations for the Treatment of Children With Cancer Revised text to state that between 1975 and 2020, childhood cancer mortality decreased by more than 50% (cited National Cancer Institute as reference 4 and Surveillance Research Program, National Cancer Institute as reference 5). Revised text to state that rare pediatric cancers account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years. Also revised text to state that most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers in children aged 0 to 14 years and 9.3% of cancers in adolescents aged 15 to 19 years. This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages. Purpose of This Summary This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric multiple endocrine neoplasia (MEN) syndromes. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions. Reviewers and Updates This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH). Board members review recently published articles each month to determine whether an article should: Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary. The lead reviewers for Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment are: Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries. Levels of Evidence Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Permission to Use This Summary PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]." The preferred citation for this PDQ summary is: PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/multiple-endocrine-neoplasia/hp-child-men-syndromes-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 31909948] Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images. Disclaimer Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page. Contact Us More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us. Last Revised: 2023-01-06 This information does not replace the advice of a doctor. Healthwise, Incorporated disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use and Privacy Policy. Learn how we develop our content. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.Topic Contents
Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment (PDQ®): Treatment - Health Professional Information [NCI]
General Information About Childhood Multiple Endocrine Neoplasia (MEN) Syndromes
Clinical Presentation, Molecular Features, and Diagnostic Evaluation
Syndrome Clinical Features/Tumors Genetic Alterations MEN type 1 (Wermer syndrome)[1] Parathyroid 11q13 (MEN1 gene) Pancreatic islets: Gastrinoma 11q13 (MEN1 gene) Insulinoma Glucagonoma VIPoma Pituitary: Prolactinoma 11q13 (MEN1 gene) Somatotropinoma Corticotropinoma Other associated tumors (less common): Carcinoid—bronchial and thymic 11q13 (MEN1 gene) Adrenocortical Lipoma Angiofibroma Collagenoma MEN type 2A (Sipple syndrome) Medullary thyroid carcinoma 10q11.2 (RET gene) Pheochromocytoma Parathyroid gland MEN type 2B Medullary thyroid carcinoma 10q11.2 (RET gene) Pheochromocytoma Mucosal neuromas Intestinal ganglioneuromatosis Marfanoid habitus MEN2 Subtype Medullary Thyroid Carcinoma Pheochromocytoma Parathyroid Disease a Sources: de Krijger,[26]Waguespack et al.,[14]Brauckhoff et al.,[16]and Eng et al.[21] MEN2A 95% 50% 20% to 30% MEN2B 100% 50% Uncommon Special Considerations for the Treatment of Children With Cancer
Treatment of Childhood Multiple Endocrine Neoplasia (MEN) Syndromes
Treatment Options Under Clinical Evaluation for Multiple Endocrine Neoplasia (MEN) Syndromes
Changes to This Summary (01 / 06 / 2023)
About This PDQ Summary
Our Health Library information does not replace the advice of a doctor. Please be advised that this information is made available to assist our patients to learn more about their health. Our providers may not see and/or treat all topics found herein.Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment (PDQ®): Treatment - Health Professional Information [NCI]