Pediatric Multiple Endocrine Neoplasia

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First reported in 1963 by Wermer, multiple endocrine neoplasia (MEN) syndromes, found in pediatric and adult patients, consist of rare, autosomal dominant mutations in genes that regulate cell growth. [1] Current classification recognizes type 1 and type 2 MEN, with the latter being divided into the subcategories type 2A MEN (Sipple syndrome) and type 2B MEN. (See Etiology.)

Menin protein, produced by the MENIN gene, is a tumor suppressor. Loss of this protein allows tumors to arise. Alternatively, Ret protein, produced by the RET gene, a proto-oncogene, can be constitutively activated, causing abnormal cell proliferation. (See Pathophysiology, Etiology, and Workup.) [2, 3]

Type 1 MEN is defined by hyperfunctioning tumors in the following:

All 4 parathyroid glands

Pancreatic islets – Eg, gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor (VIPoma), pancreatic polypeptide–producing tumor (PPoma)

Anterior pituitary – Eg, prolactinoma, somatotropinoma, corticotropinoma, nonfunctioning tumors

Other associated tumors include lipomas, angiofibromas, and those located in the adrenal gland cortex (rarely, in the adrenal medulla).

Type 2A MEN is defined by medullary thyroid carcinoma (MTC), pheochromocytoma (about 50% of cases), and hyperparathyroidism caused by parathyroid gland hyperplasia (about 20% of cases). (See Pathophysiology, Presentation, Workup, and Treatment.

Type 2B MEN is defined by MTC and pheochromocytoma. Associated abnormalities include mucosal neuromas, medullated corneal nerve fibers, and marfanoid habitus. (See Pathophysiology, Presentation, Workup, and Treatment.)

Familial MTC is hereditary MTC without other associated endocrinopathies, although adrenomedullary hyperplasia secondary to a germline RET mutation may still be present but undiagnosed.

The prevalence of MEN in adults is about 0.02-0.2 cases per 1000 population in the United States. Data for children are not available.

The male-to-female ratio for MEN is 2:1. Patients with hyperparathyroidism in type 1 MEN most often present at age 20-40 years, but the disease may appear in children younger than 10 years. However, all MEN syndromes are rare in children.

For patient education information, see Anatomy of the Endocrine System.

Families can locate an endocrinologist and access helpful information through the Hormone Foundation and the Endocrine and Metabolic Diseases Information Service, which is a service of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Hyperparathyroidism is the most common manifestation of type 1 MEN (80% of presentations); it results from hyperplasia of all 4 parathyroid glands. Abnormalities of parathyroid hormone (PTH) secretion may affect children younger than 10 years.

Islet-cell tumors that secrete predominantly gastrin are called gastrinomas; these tumors frequently metastasize. Children rarely have gastrinomas. Pituitary tumors (eg, as prolactinoma) can affect children as young as 5 years. Adrenal involvement includes silent adenomas, adrenocortical hyperplasia, cortisol-secreting adenomas, and, rarely, carcinomas.

In addition, pheochromocytomas have been reported in patients with type 1 MEN. Thymic and bronchial carcinoid tumors can also be associated with type 1 MEN. [4] Lipomas and angiofibromas may often lead to the diagnosis of type 1 MEN before the endocrine manifestations.

Type 2A MEN accounts for most cases of type 2 MEN. In general, type 2 MEN affects about 1 in 40,000 individuals, and fewer than 1000 kindreds are known worldwide. C-cell hyperplasia develops early in life and can be viewed as the precursor lesion for MTC, which often arises multifocally and bilaterally.

Pheochromocytomas are bilateral in 70% of cases and develop on the background of adrenomedullary hyperplasia secondary to an RET germline mutation. Biochemical manifestations, imaging manifestations, or both occur in about 50% of patients. The peak age at onset is approximately 40 years, but children as young as 10 years are reported.

Less than 25% of patients with type 2A MEN develop frank hyperparathyroidism; this condition is rare in childhood. Reasons for this low prevalence and discrepancy in type 2A MEN are unknown. Although various RET mutations can cause type 2A MEN, those mutations within exon 16 are most often reported in association with hyperparathyroidism.

Type 2B MEN represents about 5% of all cases of type 2 MEN. Patients have some aspects of a distinctive marfanoid phenotype and mucosal neuromas. MTC is relatively aggressive and frequently occurs in childhood; children as young as 12 months may develop MTC. Therefore, prophylactic thyroidectomy with lymph node dissection is recommended in children younger than 5 years who have a RET germline mutation in exon 16.

Pheochromocytomas also occur earlier than in patients with type 2A MEN, and patients have the same features arising in the context of adrenomedullary hyperplasia, multifocality, and, often, bilateral involvement. In contrast to MTC, which frequently metastasizes, metastatic pheochromocytomas rarely occur in patients with type 2 MEN (0-25%). An important parameter in this setting is the follow-up period and the time of first occurrence or diagnosis.

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The MENIN gene responsible for type 1 MEN has been localized to chromosome band 11q13; it produces a nuclear protein called menin, a tumor suppressor. The MENIN gene is ubiquitously expressed and is localized to the nucleus of cells; there is increasing evidence that menin may act in DNA repair or synthesis.

Patients with type 1 MEN possess a germline mutation in the MENIN gene and develop tumors when inactivation of the wild-type allele occurs, resulting in unsuppressed growth. Mutations are distributed over the entire coding region without showing any significant hot spot region. [5]

In type 1 MEN, neuroendocrine tumors can derive from various tissues, including the so-called APUD cells, as well as from pluripotent stem cells of these respective tissue (eg, pituitary tissue). [6] Most tumors arise in the pituitary gland and pancreatic islet cells. There is a lower incidence of parathyroid involvement in type 1 MEN compared with tumor rates in other tissues. However, patients with type 1 MEN–associated hyperparathyroidism tend to be younger than patients with sporadic primary hyperparathyroidism.

The genetic mutation in type 2 MEN occurs in a proto-oncogene called RET, located on band 10q11.2. RET encodes the tyrosine kinase RET protein subunit of a cell surface receptor. Activation of RET leads to hyperplasia of target cells in vivo. Subsequent secondary events then lead to tumor formation. RET is specifically expressed in neural crest–derived cells, such as the C cells in the thyroid gland and the chromaffin cells in the adrenal gland. The presence or absence of RET expression in parathyroid tissue is unknown.

There are typical genetic signatures for most cases of type 2 MEN. In type 2A MEN, 95% of RET mutations occur in exons 10, 11, and 14. Of patients with type 2B MEN, 95% have a point mutation in exon 16 (M918T). A second point mutation at codon 883 has been found in 2-3% of type 2B MEN cases. Interestingly, risk stratification strategies, targeting the age of development of medullary thyroid cancer, have been developed. These are based on the genomic signature of the RET mutation. Consensus guidelines for children with the highest risk mutations (eg, c.918,c.883) recommend total thyroidectomy and central lymph node dissection as early as 6 months after birth. [7] Mechanisms of tumorigenesis that have been elucidated show allelic imbalance between mutant and wild type RET alleles.

Most cases of MTC and/or pheochromocytoma are sporadic. Only about 10% of cases are hereditary and related to type 2 MEN.

So-called inactivating mutations due to deletions of RET are associated with congenital neurologic defects, such as aganglionic colon (ie, Hirschsprung disease). [8] Of interest, these mutations also occur on exons 10 and 11 (associated with type 2A MEN).

The prognosis is generally good in the presence of discrete parathyroid and pancreatic islet disease or pituitary adenoma. Pancreatic islet cell carcinoma and carcinoids are slowly progressive.

Patients with gastrinoma in type 1 MEN may have a prognosis better than that of patients with the sporadic form of the disease.

The prognosis depends on the stage of medullary thyroid cancer and is generally good after prophylactic thyroidectomy.

The prognosis for patients with type 2B MEN is worse than for patients with type 2A MEN because tumors, such as MTCs, are relatively aggressive, resulting in a 10-year survival rate of 50%.

Therefore, individuals with an RET germline mutation in exon 16 should undergo early prophylactic thyroidectomy and screening for pheochromocytomas. MTC may appear within the first year of life.

Death related to MEN can be caused by the following:

Complicated peptic ulcer disease

Metastases of endocrine pancreatic tumors

Severe hypercalcemia with arrhythmias

Metastatic MTC

Catecholamine release–related arrhythmias

Coronary heart disease

Stroke

Heart failure

Arrhythmias from cardiac myxomas

Zollinger-Ellison syndrome (ZES) is the major cause of morbidity and mortality in type 1 MEN. Mortality in type 2B MEN is mainly due to the aggressive nature of MTCs.

In a report on 103 patients with type 1 MEN, Doherty et al found that 46% of these individuals died from causes related to their endocrine tumors after a median of 47 years. [9]

Wermer P. Endocrine adenomatosis and peptic ulcer in a large kindred. Inherited multiple tumors and mosaic pleiotropism in man. Am J Med. 1963 Aug. 35:205-12. [Medline].

Eng C. RET proto-oncogene in the development of human cancer. J Clin Oncol. 1999 Jan. 17(1):380-93. [Medline].

Agarwal SK, Kennedy PA, Scacheri PC, Novotny EA, Hickman AB, Cerrato A, et al. Menin molecular interactions: insights into normal functions and tumorigenesis. Horm Metab Res. 2005 Jun. 37(6):369-74. [Medline].

Lim LC, Tan MH, Eng C, Teh BT, Rajasoorya RC. Thymic carcinoid in multiple endocrine neoplasia 1: genotype-phenotype correlation and prevention. J Intern Med. 2006 Apr. 259(4):428-32. [Medline].

Agarwal SK, Kester MB, Debelenko LV, et al. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet. 1997 Jul. 6(7):1169-75. [Medline].

Trouillas J, Labat-Moleur F, Sturm N, Kujas M, Heymann MF, Figarella-Branger D, et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am J Surg Pathol. 2008 Apr. 32(4):534-43. [Medline].

Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 Jun. 19(6):565-612. [Medline].

Decker RA, Peacock ML. Occurrence of MEN 2a in familial Hirschsprung’s disease: a new indication for genetic testing of the RET proto-oncogene. J Pediatr Surg. 1998 Feb. 33(2):207-14. [Medline].

Doherty GM, Olson JA, Frisella MM, Lairmore TC, Wells SA Jr, Norton JA. Lethality of multiple endocrine neoplasia type I. World J Surg. 1998 Jun. 22(6):581-6; discussion 586-7. [Medline].

Romero Arenas MA, Morris LF, Rich TA, Cote GJ, Grubbs EG, Waguespack SG, et al. Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism. J Pediatr Surg. 2014 Apr. 49 (4):546-50. [Medline].

Dreijerink KM, Goudet P, Burgess JR, Valk GD,. Breast-cancer predisposition in multiple endocrine neoplasia type 1. N Engl J Med. 2014 Aug 7. 371(6):583-4. [Medline].

Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep. 97(9):2990-3011. [Medline].

Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001 Dec. 86(12):5658-71. [Medline].

Thomas-Marques L, Murat A, Delemer B, Penfornis A, Cardot-Bauters C, Baudin E, et al. Prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. Am J Gastroenterol. 2006 Feb. 101(2):266-73. [Medline].

Triponez F, Dosseh D, Goudet P, Cougard P, Bauters C, Murat A. Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann Surg. 2006 Feb. 243(2):265-72. [Medline].

Anlauf M, Schlenger R, Perren A, Bauersfeld J, Koch CA, Dralle H, et al. Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. Am J Surg Pathol. 2006 May. 30(5):560-74. [Medline].

Castinetti F, Qi XP, Walz MK, Maia AL, Sansó G, Peczkowska M. Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol. 2014 May. 15(6):648-55. [Medline].

Kluijfhout WP, van Beek DJ, Verrijn Stuart AA, Lodewijk L, Valk GD, van der Zee DC, et al. Postoperative Complications After Prophylactic Thyroidectomy for Very Young Patients With Multiple Endocrine Neoplasia Type 2: Retrospective Cohort Analysis. Medicine (Baltimore). 2015 Jul. 94 (29):e1108. [Medline].

Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep. 97 (9):2990-3011. [Medline].

Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001 Dec. 86 (12):5658-71. [Medline].

Waguespack SG, Rich TA, Perrier ND, Jimenez C, Cote GJ. Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol. 2011 Aug 23. 7 (10):596-607. [Medline].

Wells SA Jr, Asa SL, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun. 25 (6):567-610. [Medline].

Chen H, Sippel RS, O’Dorisio MS, Vinik AI, Lloyd RV, Pacak K, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010 Aug. 39 (6):775-83. [Medline].

Alicia Diaz-Thomas, MD, MPH Associate Professor of Pediatrics, University of Tennessee Health Science Center College of Medicine

Alicia Diaz-Thomas, MD, MPH is a member of the following medical societies: Endocrine Society, International Society for Clinical Densitometry, Pediatric Endocrine Society, Tennessee Medical Association

Disclosure: Nothing to disclose.

Robert P Hoffman, MD Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children’s Hospital

Robert P Hoffman, MD is a member of the following medical societies: American College of Pediatricians, American Diabetes Association, American Pediatric Society, Christian Medical and Dental Associations, Endocrine Society, Midwest Society for Pediatric Research, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP (London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children’s Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other

Christian A Koch, MD, PhD, FACP, FACE Professor and Director, Division of Endocrinology, University of Mississippi Medical Center

Christian A Koch, MD, PhD, FACP, FACE is a member of the following medical societies: American Academy of Neurology, American Association of Clinical Endocrinologists, American College of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Society for Clinical Pharmacology and Therapeutics, American Society for Dermatologic Surgery, Endocrine Society, and German Diabetes Society

Disclosure: NovoNordisk Honoraria Consulting

Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds Other; Eli Lily Grant/research funds PI; NovoNordisk Grant/research funds PI

Klaus Radebold, MD, PhD Research Associate, Department of Surgery, Yale University School of Medicine

Klaus Radebold, MD, PhD is a member of the following medical societies: American Gastroenterological Association and New York Academy of Sciences

Disclosure: Nothing to disclose.

Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Pediatric Multiple Endocrine Neoplasia

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