Multiple Endocrine Neoplasia Type 2 (MEN2)

Multiple Endocrine Neoplasia Type 2 (MEN2)

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Multiple endocrine neoplasias type 2 (MEN2) is an inherited disorder characterized by the development of medullary thyroid cancer (MTC), parathyroid tumors, and pheochromocytoma.  MEN2 results from germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. There are two MEN2 syndromes: MEN2A and MEN2B. 

The MEN2A syndrome is further classified on the basis of the presence of associated conditions. Classical MEN2A is characterized by MTC, pheochromocytoma, and primary hyperparathyroidism. Three additional variants are MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease (HSCR), and familial medullary thyroid cancer (FMTC), which is diagnosed when the patient has a RET germline pathogenic variant and MTC but no family history of pheochromocytoma or hyperparathyroidism. [1]  

MEN2B is less common than MEN2A, accounting for 5% of MEN2 cases. It is characterized by more aggressive MTC (occurring in 100% of cases), pheochromocytoma (50%), mucosal neuromas (95%-98%) and intestinal ganglion neuromas (40%). Hyperparathyroidism is absent. In addition, nearly all patients have have a distinct marfanoid habitus. [2]

Substantiation of the genotype-phenotype correlation of inherited MTC may lead to the development of an individual approach to risk management in childhood genotype carriers, and research into potential modifying factors should take place. Early total thyroidectomy remains effective in preventing the development of MTC in the long term. [3, 4, 5]

 

 

Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2. Although its function is still unknown, the protein produced by RET is critical during embryonic development of the enteric nervous system and kidneys. RET consists of 3 domains, including a cysteine-rich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain. [6, 7]

The extracellular domain interacts with one of four ligands identified to date. These ligands—glial cell line–derived neurotrophic factor (GDNF), neurturin, persephin, and artemin—also interact with one of four coreceptors in the GDNF-family receptor–alpha family. GDNF appears to play a critical role in the normal function of pathways involved in enteric nervous system neurogenesis and renal organogenesis. The tyrosine kinase catalytic core is located in the intracellular domain and causes downstream signaling events through a variety of second-messenger molecules. [8]

MTC is a calcitonin-secreting tumor of the parafollicular or C cells of the thyroid. MTC develops in virtually all patients with MEN2A; it is is often the first expressed abnormality, with onset usually in the first to third decade of life. In patients with MEN2A, MTC is typically bilateral and multicentric and preceded by C-cell hyperplasia, in contrast to sporadic MTC, which is unilateral. [9]

Pheochromocytomas are present in approximately half of MEN2A patients. They are bilateral in 60-80% of cases, compared with 10% of sporadic pheochromocytomas. Pheochromocytomas tend to be diagnosed at the same time as MTC or several years later (with both occurring primarily in the second or third decade). The pheochromocytomas of MEN2A patients are nearly all benign. Even so, these lesions can cause life-threatening episodes of hypertension or arrhythmia.

Parathyroid hyperplasias are present in nearly half of patients with MEN2A but are less common than pheochromocytomas. In many patients, such hyperplasias can be clinically silent. However, as in other cases of hyperparathyroidism, comprehensive questioning will often elicit a history of symptoms.

Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Classical MEN2A is associated with germline missense mutations in RET codons 609, 611, 618, or 620 of exon 10 or codon 634 of exon 11, which map to the receptor’s extracellular cysteine-rich domain. MEN2A with cutaneous lichen amyloidosis is nearly always associated with mutation of codon 634, while patients with MEN2A and Hirschsprung disease typically harbor mutations involving RET exon 10. [10]  

Approximately 75% of MEN2B cases are sporadic and affected patients have de novo RET mutations, while 25% of cases occur in families with previous or current manifestations of MEN2B. Approximately 95% of patients with MEN2B have RET germline mutations in exon 16 (codon M918T) and fewer than 5% have RET germline mutations in exon 15 (codon A883F). [1]  

The overall frequency of MEN2 in the United States is 1 case per 30,000-50,000 population. In decreasing order of frequency, MEN occurs as follows: MEN2A, MEN2A with FMTC only, and MEN 2B.

In MEN2A patients, 50% of those with RET gene mutations develop disease by age 50 years, and 70% develop the disease by age 70 years. MTC has been detected shortly after birth in MEN2B. (See Workup and Treatment.)

Early treatment of medullary thyroid carcinoma (MTC) can prevent death, and careful monitoring for pheochromocytomas can decrease the chance of hypertensive episodes.

MTC, the characteristic tumor of MEN2, is present in all subtypes. Pheochromocytomas appear in MEN2A and MEN2B patients. Primary hyperparathyroidism frequently develops in patients with MEN2A but rarely in those with MEN2B. Gastrointestinal, skeletal, and dermatologic abnormalities occur only in patients with MEN2B.

Almost all published reports on MEN2B concern patients with the RET codon M918T mutation. Little is known about the clinical behavior of patients with the RET codon A883F mutation. Recent reports, however, suggest that patients with the A883F codon mutation have a more indolent natural course compared with that of M918T carriers and that pheochromocytomas manifests later in A883F carriers than in M918T carriers. [11]

The prognosis in patients with MTC varies in part with the disease stage at the time of diagnosis. In addition, MTC associated with MEN2B is the most aggressive, whereas FMTC in the absence of other endocrine malignancies is the least aggressive. [9]   

Because the penetrance of MTC is nearly 100%, prophylactic thyroidectomy in infancy is indicated for patients with high-risk RET mutations or by age 5 years in children with an identifiable RET mutation. [12, 13] Patients who are at risk but who have not had genetic screening should undergo annual biochemical screening.

The 5- and 10-year survival rates in patients with MTC and MEN 2A are approximately 90% and 75%, respectively.

These benign tumors of the adrenal medulla occur in 50% of patients with MEN2 by the time they are in their late 30s; however, prevalence varies in different families. Pheochromocytomas develop in more than 50% of patients with MEN2B and can appear during early childhood. The earliest possible detection of these tumors can prevent a hypertensive crisis. The risk of malignancy is low (<5%).<ref>14</ref>

Adrenalectomy should be considered when patients have biochemical confirmation and an adrenal mass or enlargement on imaging. Bilateral adrenalectomy is reserved for bilateral adrenal masses. Patients become adrenal insufficient following bilateral adrenalectomy. Even patients who receive appropriate information on the management of their chronic adrenal insufficiency are at risk of addisonian crisis, which is a life-threatening emergency that may occur when the patient does not increase the replacement dosage when a major stress occurs. On the other hand, excessive steroid replacement is associated with premature osteoporosis, hypertension, and diabetes. [14]

 

Adhering to a surveillance program lessens disease complications. Order genetic counseling for the patient so that gene testing and reproductive options can be discussed. For patient education information, see Thyroid Problems.

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

[Guideline] American Society of Clinical Oncology. Multiple Endocrine Neoplasia Type 2. Cancer.net. Available at https://www.cancer.net/cancer-types/multiple-endocrine-neoplasia-type-2. November 2015; Accessed: May 26, 2018.

Raue F, Frank-Raue K. Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management. Hormones (Athens). 2009 Jan-Mar. 8(1):23-8. [Medline]. [Full Text].

Moley JF, Skinner M, Gillanders WE, Lairmore TC, Rowland KJ, Traugott AL, et al. Management of the Parathyroid Glands During Preventive Thyroidectomy in Patients With Multiple Endocrine Neoplasia Type 2. Ann Surg. 2015 Oct. 262 (4):641-6. [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].

Verrienti A, Carbone A, Bellitti P, Fabiano MC, De Rose RF, Maranghi M, et al. A NOVEL DOUBLE MUTATION VAL648ILE AND VAL804LEU OF RET PROTO-ONCOGENE IN MULTIPLE ENDOCRINE NEOPLASIA TYPE 2. Endocr Pract. 2015 Aug 6. [Medline].

Zupan A, Glavač D. The development of rapid and accurate screening test for RET hotspot somatic and germline mutations in MEN2 syndromes. Exp Mol Pathol. 2015 Aug 29. [Medline].

National Cancer Institute. Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)–Health Professional Version. Cancer.gov. Available at https://www.cancer.gov/types/thyroid/hp/medullary-thyroid-genetics-pdq#link/_114_toc. May 15, 2018; Accessed: May 26, 2018.

[Guideline] National Comprehensive Cancer Network. NCCN Guidelines: Neuroendocrine and Adrenal Tumors. Version 2.2108. NCCN.org. Available at https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. May 4, 2018; Accessed: May 26, 2018.

Li Y, Simonds WF. Endocrine neoplasms in familial syndromes of hyperparathyroidism. Endocr Relat Cancer. 2016 Jun. 23 (6):R229-47. [Medline]. [Full Text].

Mathiesen JS, Habra MA, Bassett JHD, Choudhury SM, Balasubramanian SP, Howlett TA, et al. Risk Profile of the RET A883F Germline Mutation: An International Collaborative Study. J Clin Endocrinol Metab. 2017 Jun 1. 102 (6):2069-2074. [Medline]. [Full Text].

Lallier M, St-Vil D, Giroux M, et al. Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome. J Pediatr Surg. 1998 Jun. 33(6):846-8. [Medline].

van Heurn LW, Schaap C, Sie G, et al. Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children. J Pediatr Surg. 1999 Apr. 34(4):568-71. [Medline].

Castinetti F, Taieb D, Henry JF, Walz M, Guerin C, Brue T, et al. MANAGEMENT OF ENDOCRINE DISEASE: Outcome of adrenal sparing surgery in heritable pheochromocytoma. Eur J Endocrinol. 2016 Jan. 174 (1):R9-18. [Medline]. [Full Text].

Gagel RF, Levy ML, Donovan DT, et al. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med. 1989 Nov 15. 111(10):802-6. [Medline].

Alegría-Landa V, Jo-Velasco M, Robledo M, Requena L. Dermal Hyperneury and Multiple Sclerotic Fibromas in Multiple Endocrine Neoplasia Type 2A Syndrome. JAMA Dermatol. 2017 Dec 1. 153 (12):1298-1301. [Medline].

Ilias I, Pacak K. Diagnosis, localization and treatment of pheochromocytoma in MEN 2 syndrome. Endocr Regul. 2009 Apr. 43(2):89-93. [Medline].

Pacak K, Eisenhofer G, Ilias I. Diagnosis of pheochromocytoma with special emphasis on MEN2 syndrome. Hormones (Athens). 2009 Apr-Jun. 8(2):111-6. [Medline]. [Full Text].

Taïeb D, Sebag F, Barlier A, et al. 18F-FDG avidity of pheochromocytomas and paragangliomas: a new molecular imaging signature?. J Nucl Med. 2009 May. 50(5):711-7. [Medline].

Yoshida S, Imai T, Kikumori T, et al. Long term parathyroid function following total parathyroidectomy with autotransplantation in adult patients with MEN2A. Endocr J. 2009 Aug. 56(4):545-51. [Medline].

Castinetti F, Qi XP, Walz MK, et al. 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].

[Guideline] National Comprehensive Cancer Network. NCCN Guidelines: Thyroid Cancer. Version 1.2018. NCCN.org. Available at https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. May 22, 2018; Accessed: May 26, 2018.

[Guideline] Kesserwan C, Friedman Ross L, Bradbury AR, Nichols KE. The Advantages and Challenges of Testing Children for Heritable Predisposition to Cancer. Am Soc Clin Oncol Educ Book. 2016. 35:251-69. [Medline]. [Full Text].

Risk Level

RET codon Mutation

Possible Diagnoses

Prophylactic Thyroidectomy

Recommendations

Follow-up

Highest Risk (HST)

M918T+All MEN2B

MEN2B

Within the first year of life or the first months of life based upon specialist and parental discussions. The ability to identify and preserve or transplant parathyroid glands determines level VI dissection.

Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually; begin screening for pheochromocytoma at age 11 yr

High Risk (H)

C634, A883F

MEN2A

At or before age 5 yr, to be determined on the basis of serum Ctn

Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually. Begin screening for pheochromocytoma at age 11.

Moderate Risk (MOD)

All other mutations

MEN2A

When serum Ctn becomes elevated or in childhood to avoid lengthy evaluation period.

Evaluate every 6 months for 1 year. Annual follow-ups thereafter if serum Ctn is normal or undetectable. Begin screening for pheochromocytoma at age 16 yr

Melanie L Richards, MD, MPHE Professor, Department of Surgery, Mayo Clinic

Melanie L Richards, MD, MPHE is a member of the following medical societies: American Association of Endocrine Surgeons, American College of Surgeons, International Association of Endocrine Surgeons, Southwestern Surgical Congress, Western Surgical Association

Disclosure: Nothing to disclose.

Suzanne M Carter, MS Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine

Suzanne M Carter, MS is a member of the following medical societies: American Bar Association

Disclosure: Nothing to disclose.

Susan J Gross, MD, FRCSC, FACOG, FACMG Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine

Susan J Gross, MD, FRCSC, FACOG, FACMG is a member of the following medical societies: American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, American Society of Human Genetics, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Ruth Freeman, MD, Director of Menopause Research and Treatment Center, Professor, Departments of Medicine and Obstetrics and Gynecology, Montefiore Medical Center, Albert Einstein College of Medicine

Ruth Freeman, MD is a member of the following medical societies: American College of Clinical Endocrinologists

Disclosure: Nothing to disclose.

Romesh Khardori, MD, PhD Professor and Director, Division of Endocrinology, Metabolism, and Molecular Medicine, Southern Illinois University School of Medicine

Romesh Khardori, MD, PhD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society of Andrology, Endocrine Society, and Illinois State Medical Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

Multiple Endocrine Neoplasia Type 2 (MEN2)

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