MEN syndromes are familial disorders characterized by neoplastic changes that affect multiple endocrine organs. Changes may include hyperplasia, benign adenomas, and carcinomas.
There are two main types of MEN syndrome:
(Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN syndromes.)
The most salient clinical and genetic alterations of the multiple endocrine neoplasia (MEN) syndromes are shown in Table 1.
|Syndrome||Clinical Features/Tumors||Genetic Alterations|
|MEN type 1 (Wermer syndrome)||Parathyroid||11q13 (MEN1 gene)|
|Pancreatic islets:||Gastrinoma||11q13 (MEN1 gene)|
|Pituitary:||Prolactinoma||11q13 (MEN1 gene)|
|Other associated tumors (less common):||Carcinoid—bronchial and thymic||11q13 (MEN1 gene)|
|MEN type 2A (Sipple syndrome)||Medullary thyroid carcinoma||10q11.2 (RET gene)|
|MEN type 2B||Medullary thyroid carcinoma||10q11.2 (RET gene)|
A study documented the initial symptoms of MEN1 syndrome occurring before age 21 years in 160 patients. Of note, most patients had familial MEN1 syndrome and were followed up using an international screening protocol.
Germline mutations of the MEN1 gene located on chromosome 11q13 are found in 70% to 90% of patients; however, this gene has also been shown to be frequently inactivated in sporadic tumors. Mutation testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.
Clinical practice guidelines recommend that screening for patients with MEN1 syndrome begin by the age of 5 years and continue for life. The number of tests or biochemical screening is age specific and may include yearly serum calcium, parathyroid hormone, gastrin, glucagon, secretin, proinsulin, chromogranin A, prolactin, and IGF-1. Radiologic screening should include a magnetic resonance imaging of the brain and computed tomography of the abdomen every 1 to 3 years.[6,7,8]
A germline activating mutation in the RET oncogene (a receptor tyrosine kinase) on chromosome 10q11.2 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 MEN2A and MEN2B syndromes.
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]
A pentagastrin stimulation test can be used to detect the presence of medullary thyroid carcinoma in these patients, although management of patients is driven primarily by the results of genetic analysis for RET mutations.[14,17]
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 (refer to Table 1 in the PDQ summary on Childhood Thyroid Cancer Treatment for more information).
Guidelines for genetic testing of suspected patients with MEN2 syndrome and the correlations between the type of mutation and the risk levels of aggressiveness of medullary thyroid cancer have been published.[14,19]
|MEN2 Subtype||Medullary Thyroid Carcinoma||Pheochromocytoma||Parathyroid Disease|
|a Sources: de Krijger,Waguespack et al.,Brauckhoff et al.,and Eng et al.|
|MEN2A||95%||50%||20% to 30%|
Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975. 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:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer. 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 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years. 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.[5,6] 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 cancer, with other types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of 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.
Treatment options for childhood MEN syndromes, according to type, are as follows:
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. (Refer to the Interventions section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)
Relatives of patients with MEN2A undergo genetic testing in early childhood, 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]
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. 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 seem appropriate.
Complete removal of the thyroid gland is the recommended procedure for surgical management of medullary thyroid cancer in children because there is a high incidence of bilateral disease.
Hirschsprung disease has been associated with, in a small percentage of cases, 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.[21,22,23] 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.[23,24,25]
(Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN2A and MEN2B.)
Vandetanib (a kinase inhibitor). In a randomized phase III trial for adult patients with unresectable locally advanced or metastatic hereditary or sporadic medullary thyroid carcinoma treated with either vandetanib (a selective inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor) or placebo, vandetanib administration was associated with significant improvements in progression-free survival (PFS), response rate, disease control rates, and biochemical response. Children with locally advanced or metastatic medullary thyroid carcinoma were treated with vandetanib in a phase I/II trial. Of 16 patients, only one had no response and seven had a partial response. Three of those patients had subsequent disease recurrence; however, 11 of 16 patients treated with vandetanib remained on therapy at the time of the report. Subsequent follow-up analysis of this cohort revealed that 10 of 17 patients achieved a partial response, and an additional 6 individuals had stable disease. The median PFS for these patients was 6.7 years.
Selpercatinib (a RET inhibitor). A phase I/II trial of selpercatinib therapy for patients with RET-mutant cancers enrolled 55 patients with RET-mutant medullary thyroid cancer (age range, 17–84 years) who were previously treated with vandetanib and/or cabozantinib and 88 patients with RET-mutant medullary thyroid cancer (age range, 15–82 years) who were not previously treated with vandetanib or cabozantinib.
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, refer to 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 treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1A gene, located on chromosome 17. The syndrome is characterized by cardiac and cutaneous myxomas, pale brown to brown lentigines, blue nevi, primary pigmented nodular adrenocortical disease causing Cushing syndrome, and a variety of endocrine and nonendocrine tumors, including pituitary adenomas, thyroid tumors, and large cell calcifying Sertoli cell tumor of the testis.[1,2,3] There are published surveillance guidelines for patients with Carney complex that include cardiac, testicular, and thyroid ultrasonography.
For patients with the Carney complex, prognosis depends on the frequency of recurrences of cardiac and skin myxomas and other tumors.
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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.
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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>.
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Last Revised: 2022-02-25
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