Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Childhood Multiple Endocrine Neoplasia (MEN) Syndromes

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 syndrome:

• Type 1.
• Type 2.
  • Type 2A.
    • Familial medullary thyroid carcinoma.
  • Type 2B.

(Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information about MEN syndromes.)

References:

1. de Krijger RR: Endocrine tumor syndromes in infancy and childhood. Endocr Pathol 15 (3): 223-6, 2004.

Clinical Presentation, Diagnostic Evaluation, and Molecular Features

The most salient clinical and genetic alterations of the multiple endocrine neoplasia (MEN) syndromes are shown in Table 1.

Table 1. Multiple Endocrine Neoplasia (MEN) Syndromes With Associated Clinical and Genetic Alterations

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

• 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.

  A study documented the initial symptoms of MEN1 syndrome occurring before age 21 years in 160 patients.[2] Of note, most patients had familial MEN1 syndrome and were followed up using an international screening protocol.

  1. Primary hyperparathyroidism. Primary hyperparathyroidism, the most common symptom, was found in 75% of patients, usually only in those with biological abnormalities. Primary hyperparathyroidism diagnosed outside of a screening program is extremely rare, most often presents with nephrolithiasis, and should lead the clinician to suspect MEN1.[2,3]
  2. Pituitary adenomas. Pituitary adenomas were discovered in 34% of patients, occurred mainly in females older than 10 years, and were often symptomatic.[2]
  3. Pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors were found in 23% of patients. Specific diagnoses included insulinoma, nonsecreting pancreatic tumor, and Zollinger-Ellison syndrome. The first case of insulinoma occurred before age 5 years.[2]
  4. Malignant tumors. Four patients had malignant tumors (two adrenal carcinomas, one gastrinoma, and one thymic carcinoma). The patient with thymic carcinoma died before age 21 years from rapidly progressive disease.

  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.[4] Mutation testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.[5]

  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]

• MEN type 2A (MEN2A) and MEN type 2B (MEN2B) syndromes:

  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.

  • MEN2A: MEN2A is characterized by the presence of two or more endocrine tumors (refer to Table 1) in an individual or in close relatives.[12]RET mutations in these patients are usually confined to exons 10 and 11.
    • Familial Medullary Thyroid Carcinoma: Familial medullary thyroid carcinoma is diagnosed in families with medullary thyroid carcinoma in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. RET mutations in exons 10, 11, 13, and 14 account for most cases.

      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 body habitus.

    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).[18]

  • In the highest-risk category, medullary thyroid carcinoma was found in five of six children (83%) aged 3 years or younger.
  • In the high-risk category, medullary thyroid carcinoma was present in 6 of 20 children (30%) aged 3 years or younger, 16 of 36 children (44%) aged 4 to 6 years, and 11 of 16 children (69%) aged 7 to 12 years (P = .081).
  • In the moderate-risk category, medullary thyroid carcinoma was seen in one of nine children (11%) aged 3 years or younger, 1 of 26 children (4%) aged 4 to 6 years, 3 of 26 children (12%) aged 7 to 12 years, and 7 of 16 children (44%) aged 13 to 18 years (P = .006).

  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]

Table 2. Clinical Features of Multiple Endocrine Neoplasia Type 2 (MEN2) Syndromes^a

MEN2 Subtype	Medullary Thyroid Carcinoma	Pheochromocytoma	Parathyroid Disease
a Sources: de Krijger,[20]Waguespack et al.,[14]Brauckhoff et al.,[16]and Eng et al.[21]
MEN2A	95%	50%	20% to 30%
MEN2B	100%	50%	Uncommon

References:

1. Thakker RV: Multiple endocrine neoplasia--syndromes of the twentieth century. J Clin Endocrinol Metab 83 (8): 2617-20, 1998.
2. Goudet P, Dalac A, Le Bras M, et al.: MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines. J Clin Endocrinol Metab 100 (4): 1568-77, 2015.
3. Romero Arenas MA, Morris LF, Rich TA, et al.: Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism. J Pediatr Surg 49 (4): 546-50, 2014.
4. Farnebo F, Teh BT, Kytölä S, et al.: Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 83 (8): 2627-30, 1998.
5. Field M, Shanley S, Kirk J: Inherited cancer susceptibility syndromes in paediatric practice. J Paediatr Child Health 43 (4): 219-29, 2007.
6. Thakker RV: Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 24 (3): 355-70, 2010.
7. Vannucci L, Marini F, Giusti F, et al.: MEN1 in children and adolescents: Data from patients of a regional referral center for hereditary endocrine tumors. Endocrine 59 (2): 438-448, 2018.
8. Thakker RV, Newey PJ, Walls GV, et al.: Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97 (9): 2990-3011, 2012.
9. Sanso GE, Domene HM, Garcia R, et al.: Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer 94 (2): 323-30, 2002.
10. Alsanea O, Clark OH: Familial thyroid cancer. Curr Opin Oncol 13 (1): 44-51, 2001.
11. Fitze G: Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr Surg 14 (6): 375-83, 2004.
12. Puñales MK, da Rocha AP, Meotti C, et al.: Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid 18 (12): 1261-8, 2008.
13. Wells SA, Asa SL, Dralle H, et al.: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 (6): 567-610, 2015.
14. Waguespack SG, Rich TA, Perrier ND, et al.: Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol 7 (10): 596-607, 2011.
15. Skinner MA, DeBenedetti MK, Moley JF, et al.: Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 31 (1): 177-81; discussion 181-2, 1996.
16. Brauckhoff M, Gimm O, Weiss CL, et al.: Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg 28 (12): 1305-11, 2004.
17. Sakorafas GH, Friess H, Peros G: The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy. Endocr Relat Cancer 15 (4): 871-84, 2008.
18. Machens A, Elwerr M, Lorenz K, et al.: Long-term outcome of prophylactic thyroidectomy in children carrying RET germline mutations. Br J Surg 105 (2): e150-e157, 2018.
19. Kloos RT, Eng C, Evans DB, et al.: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19 (6): 565-612, 2009.
20. de Krijger RR: Endocrine tumor syndromes in infancy and childhood. Endocr Pathol 15 (3): 223-6, 2004.
21. Eng C, Clayton D, Schuffenecker I, et al.: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276 (19): 1575-9, 1996.

Special Considerations for the Treatment of Children With Cancer

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:

• Primary care physicians.
• Pediatric surgeons.
• Radiation oncologists.
• Pediatric medical oncologists/hematologists.
• Rehabilitation specialists.
• Pediatric nurse specialists.
• Social workers.
• Child-life professionals.
• Psychologists.

(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.[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 2010, childhood cancer mortality decreased by more than 50%.[3] 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.[4] 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:

• A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than 2 cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than 2 cases per 1 million people were also included in the very rare group because there is a lack of knowledge and expertise in the management of these tumors.[7]
• The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancer, melanoma and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinoma, nasopharyngeal carcinoma, and most adult-type carcinomas such as breast cancer, colorectal cancer, etc.).[8] These diagnoses account for about 4% of cancers diagnosed in children aged 0 to 14 years, compared with about 20% of cancers diagnosed in adolescents aged 15 to 19 years.[9]

  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.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 1, 2022.
3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
4. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr.
5. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017.
6. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017.
7. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019.
8. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010.
9. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2012. National Cancer Institute, 2015. Also available online. Last accessed June 22, 2021.

Treatment of Childhood Multiple Endocrine Neoplasia (MEN) Syndromes

Treatment options for childhood MEN syndromes, according to type, are as follows:

1. MEN type 1 (MEN1) syndrome: Treatment of patients with MEN1 syndrome is based on the type of tumor. The outcome of patients with MEN1 syndrome is 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] (Refer to the Interventions section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)

2. 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 mutation is identified.[2,3,4,5,6,7] The outcome for patients with MEN2A syndrome is also generally good, yet the possibility exists for recurrence of medullary thyroid carcinoma and pheochromocytoma.[8,9,10] A retrospective analysis identified 262 patients with MEN2A syndrome.[11] 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.

     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]

   • MEN2B syndrome: Because of the increased virulence of medullary thyroid carcinoma in children with MEN2B and in those with 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: 3iiiDii] Patients who have MEN2B syndrome have a worse outcome primarily because of more aggressive medullary thyroid carcinoma. Prophylactic thyroidectomy has the potential to improve the outcome in patients with MEN2B.[19]

     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.[20] 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.[26] 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.[27] 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.[28]

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.[29]

• For the previously treated cohort, 69% of patients achieved an objective response, and the median duration of response had not been reached, with a median follow-up of 14 months.
• For the cohort of patients who were not previously treated, 73% of patients achieved an objective response, with a median duration of response of 22.0 months.
• The most common grades 3 to 4 treatment-related adverse events were hypertension (12%), increased alanine aminotransferase (ALT) (10%) and aspartate aminotransferase (AST) (7%), diarrhea (3%), and prolonged QT interval (2%).
• Selpercatinib was approved by the U.S. Food and Drug Administration (under accelerated approval) for the treatment of adult and pediatric patients aged 12 years and older with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy.[30]

References:

1. Romero Arenas MA, Morris LF, Rich TA, et al.: Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism. J Pediatr Surg 49 (4): 546-50, 2014.
2. Skinner MA, Moley JA, Dilley WG, et al.: Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 353 (11): 1105-13, 2005.
3. Skinner MA: Management of hereditary thyroid cancer in children. Surg Oncol 12 (2): 101-4, 2003.
4. Fitze G: Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr Surg 14 (6): 375-83, 2004.
5. Learoyd DL, Gosnell J, Elston MS, et al.: Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf) 63 (6): 636-41, 2005.
6. Guillem JG, Wood WC, Moley JF, et al.: ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol 24 (28): 4642-60, 2006.
7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 2.2019. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2019. Available online with free subscription. Last accessed June 08, 2020.
8. Lallier M, St-Vil D, Giroux M, et al.: Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome. J Pediatr Surg 33 (6): 846-8, 1998.
9. Dralle H, Gimm O, Simon D, et al.: Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World J Surg 22 (7): 744-50; discussion 750-1, 1998.
10. Skinner MA, Wells SA: Medullary carcinoma of the thyroid gland and the MEN 2 syndromes. Semin Pediatr Surg 6 (3): 134-40, 1997.
11. Voss RK, Feng L, Lee JE, et al.: Medullary Thyroid Carcinoma in MEN2A: ATA Moderate- or High-Risk RET Mutations Do Not Predict Disease Aggressiveness. J Clin Endocrinol Metab 102 (8): 2807-2813, 2017.
12. Heizmann O, Haecker FM, Zumsteg U, et al.: Presymptomatic thyroidectomy in multiple endocrine neoplasia 2a. Eur J Surg Oncol 32 (1): 98-102, 2006.
13. Frank-Raue K, Buhr H, Dralle H, et al.: Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype. Eur J Endocrinol 155 (2): 229-36, 2006.
14. Piolat C, Dyon JF, Sturm N, et al.: Very early prophylactic thyroid surgery for infants with a mutation of the RET proto-oncogene at codon 634: evaluation of the implementation of international guidelines for MEN type 2 in a single centre. Clin Endocrinol (Oxf) 65 (1): 118-24, 2006.
15. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 1.2018. Fort Washington, Pa: National Comprehensive Cancer Network, 2018. Available online with free subscription. Last accessed July 5, 2018.
16. Leboulleux S, Travagli JP, Caillou B, et al.: Medullary thyroid carcinoma as part of a multiple endocrine neoplasia type 2B syndrome: influence of the stage on the clinical course. Cancer 94 (1): 44-50, 2002.
17. Sakorafas GH, Friess H, Peros G: The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy. Endocr Relat Cancer 15 (4): 871-84, 2008.
18. Zenaty D, Aigrain Y, Peuchmaur M, et al.: Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B. Eur J Endocrinol 160 (5): 807-13, 2009.
19. Brauckhoff M, Machens A, Lorenz K, et al.: Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective. Ann Surg 259 (4): 800-6, 2014.
20. Makri A, Akshintala S, Derse-Anthony C, et al.: Pheochromocytoma in Children and Adolescents With Multiple Endocrine Neoplasia Type 2B. J Clin Endocrinol Metab 104 (1): 7-12, 2019.
21. Decker RA, Peacock ML, Watson P: Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet 7 (1): 129-34, 1998.
22. Eng C, Clayton D, Schuffenecker I, et al.: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276 (19): 1575-9, 1996.
23. Fialkowski EA, DeBenedetti MK, Moley JF, et al.: RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds. J Pediatr Surg 43 (1): 188-90, 2008.
24. Skába R, Dvoráková S, Václavíková E, et al.: The risk of medullary thyroid carcinoma in patients with Hirschsprung's disease. Pediatr Surg Int 22 (12): 991-5, 2006.
25. Moore SW, Zaahl MG: Multiple endocrine neoplasia syndromes, children, Hirschsprung's disease and RET. Pediatr Surg Int 24 (5): 521-30, 2008.
26. Wells SA, Robinson BG, Gagel RF, et al.: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30 (2): 134-41, 2012.
27. Fox E, Widemann BC, Chuk MK, et al.: Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res 19 (15): 4239-48, 2013.
28. Kraft IL, Akshintala S, Zhu Y, et al.: Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib. Clin Cancer Res 24 (4): 753-765, 2018.
29. Wirth LJ, Sherman E, Robinson B, et al.: Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med 383 (9): 825-835, 2020.
30. Eli Lilly and Company: RETEVMO (selpercatinib): Prescribing Information. Indianapolis, Ind: Lilly USA, LLC, 2020. Available online. Last accessed September 28, 2020.

Treatment Options Under Clinical Evaluation for Multiple Endocrine Neoplasia (MEN) Syndromes

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:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.

  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.

• LIBRETTO-001 (NCT03157128) (Phase I/II Study of LOXO-292 in Patients With Advanced Solid Tumors, RET Fusion–Positive Solid Tumors, and Medullary Thyroid Cancer): This is a phase I/II, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of selpercatinib (also known as LOXO-292) administered orally to patients with advanced solid tumors, including RET fusion–positive solid tumors, medullary thyroid cancer, and other tumors with RET activation.

Carney Complex

Carney complex is an autosomal dominant syndrome caused by mutations in the PPKAR1A gene, located on chromosome 17.[1] 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.

References:

1. Wilkes D, Charitakis K, Basson CT: Inherited disposition to cardiac myxoma development. Nat Rev Cancer 6 (2): 157-65, 2006.
2. Carney JA, Young WF: Primary pigmented nodular adrenocortical disease and its associated conditions. Endocrinologist 2: 6-21, 1992.
3. Ryan MW, Cunningham S, Xiao SY: Maxillary sinus melanoma as the presenting feature of Carney complex. Int J Pediatr Otorhinolaryngol 72 (3): 405-8, 2008.

Changes to This Summary (02 / 25 / 2022)

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.

Editorial changes were made to this summary.

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® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

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:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

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:

• Denise Adams, MD (Children's Hospital Boston)
• Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

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>.

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: 2022-02-25