Multiple endocrine neoplasia type 2A (MEN 2A) is the most frequently occurring form of MEN 2, and many patients have a positive family history of endocrine cancers. Those with MEN 2A characteristically develop medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenomas or hyperplasia, with a prevalence of up to 95%, 50%, and 30% respectively. Symptoms arise as a result of the tumors present, however, some individuals may remain asymptomatic.

MTC is often the first clinical manifestation of the disease and usually becomes symptomatic by the third decade of life [1]. As MTC results from hyperplasia of the C-cells in the thyroid gland, diarrhea is a common complaint, albeit poor prognostic factor, resulting from hypersecretion of calcitonin [1] [2]. A neck mass is often seen on presentation, with symptoms of local spread such as difficulty swallowing, change in voice, neck pain, and dyspnea. Lymphadenopathy occurs as a result of tumor metastasis to the lymph nodes. The tumor has a propensity to metastasize, often to the liver, bones, and lungs [1]. This usually takes place before patients seek medical attention.

Pheochromocytomas are largely benign, and mainly arise from the adrenal glands and secrete catecholamines, although in MEN 2A they predominantly secrete adrenalin [3]. A minority of patients may present with pheochromocytoma as the first sign of disease, and in contrast to sporadic cases, they are more likely to be bilateral [4]. Furthermore, the symptoms they produce are often insidious and may be paroxysmal [5]. Typical manifestations include palpitations, tachycardia, hypertension, excessive sweating, headaches, anxiety, and hypertensive crisis.

Parathyroid adenomas may cause hypercalcemia, increased calcium excretion in urine, and renal stones. Some patients with MEN 2A additionally present with cutaneous lichen amyloidosis (CLA) often on the upper back, seen as dark itchy desquamating papules [6].

• Infertility

  PCOS is a leading cause of infertility. Precocious puberty. Abnormally early puberty that occurs when glands tell the body to release sex hormones too soon in life. [webmd.com]

  Recent studies have shown that RET is required for normal development of spermatogonia and, hence, normal sperm formation10 and a potential role for RET in therapies for male infertility has been proposed. [jmg.bmj.com]

• Anemia

  Glucagonoma: hyperglycemia characterized by inflammation of the tongue or stomach, anemia, weight loss, diarrhea, and blood clots. [encyclopedia.com]

• Rhinorrhea

  A 51-year-old woman with acute onset of facial pressure, rhinorrhea, and tooth pain: review of acute rhinosinusitis. JAMA. 2009 May 6. 301(17):1798-807. [Medline]. Roland PS, Kreisler LS, Reese B, et al. [medscape.com]

• Diarrhea

  Other findings include cervical lymphadenopathy, depressed mood, constipation, diarrhea, fatigue, headache, flushing, hypertension, memory impairment, pruritus, and palpitations. Thyroidectomy is a prophylactic measure. [visualdx.com]

  Diarrhea is the most frequent systemic symptom. Rare variants of MEN2A can be associated with cutaneous lichen amyloidosis (see this term) or excessive production of ACTH. [orpha.net]

  As MTC results from hyperplasia of the C-cells in the thyroid gland, diarrhea is a common complaint, albeit poor prognostic factor, resulting from hypersecretion of calcitonin. [symptoma.com]

  It may also cause gastrointestinal symptoms, such as constipation or diarrhea if the digestive tract is affected. [news-medical.net]

  These growths occur in the gastrointestinal tract and may cause swelling (distention) of the abdomen, diarrhea, constipation, and an abnormally enlarged colon (megacolon). [rarediseases.org]

Genetic testing is the preferred diagnostic test, performed on patients and their relatives as a screening test. It can also be performed antenatally. The presence of two of the neoplasms belonging to multiple endocrine neoplasia type 2A is enough to make a clinical diagnosis. Depending on the gene mutation found, the finding has a role in management and prognosis of the condition. Other screening tools include screening for MEN 2A characteristic tumors and their biochemical markers in family members yearly.
Laboratory and imaging studies for each of the tumors is as follows:
MTC

• Measurement of serum calcitonin levels, which may be raised.
• Imaging studies consist of computerized tomography (CT), magnetic resonance imaging (MRI), and octreotide scanning.

Pheochromocytoma

• Blood pressure measurements are important as patients may be hypertensive.
• Elevated levels of urine and serum catecholamines or their products (such as vanillylmandelic acid) are indicators of the tumor [5] [7].
• Imaging modalities used are CT, MRI, and positron emission tomography (PET) scans. CT is the least sensitive, while PET is the most sensitive test [7]. A metaiodobenzylguanidine (MIBG) scan is also useful [8]. These studies are used to localize the tumor and to check if it is bilateral.

Parathyroid adenoma

• Serum calcium and phosphate level requests may reveal hypercalcemia, hypophosphatemia. Parathyroid hormone (PTH) levels may be high.
• Imaging includes the use of single-photon emission CT (SPECT).

• Chlamydia

  Respiratory virus infection is present in approximately one-third of exacerbations and there is serologic evidence of infection with Chlamydia pneumoniae in 5 to 10% of exacerbations. [atsjournals.org]

Early detection and treatment are key to successful control. CONCLUSIONS: Identification of kindreds affected by this inherited disorder can result in improved detection and early treatment. [ncbi.nlm.nih.gov]

Learn more about treatment options for thyroid cancer. Recent studies of drugs that target the RET gene have shown promise for the treatment of medullary thyroid cancer that has spread to the lymph nodes, liver, lung or other places in the body. [cancer.net]

(See Workup and Treatment.) Prognosis Early treatment of medullary thyroid carcinoma (MTC) can prevent death, and careful monitoring for pheochromocytomas can decrease the chance of hypertensive episodes. [emedicine.medscape.com]

Evaluation by a specialist is necessary for accurate diagnosis and treatment, including knowing when to screen and when to consider surgical treatment. [chop.edu]

It is very important to accumulate cases with MEN 2A and investigate the phenotype and the prognosis in each mutation. [ncbi.nlm.nih.gov]

Conclusion: Patients of MEN2A with a C634A mutation and a L769L polymorphism in RET proto-oncogene may be presented in younger age and have poor prognosis. [endocrine-abstracts.org]

Lab tests were unremarkable, with the exception of a slightly increased calcium level, elevated PTH values, in a patient who was never investigated for a secondary etiology for hypertension. Calcitonin levels were normal. [journals.lww.com]

Etiology Missense mutations altering the conserved cysteine codons adjacent to the transmembrane domain of the RET proto-oncogene (10q11.2) have been identified in the germline DNA of patients with MEN2A. [orpha.net]

Patient history and laboratorial investigation do not support other etiologic diagnosis than hypercalcemia. [scielo.br]

(Etiology) MEN 2 Syndrome is caused by the mutation in the RET proto-oncogene on the chromosome 10; the proto-oncogene stimulates the proliferation of cancer cells. [dovemed.com]

Etiology Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. [emedicine.medscape.com]

Summary Epidemiology Prevalence of MEN2A is approximately 1/40,000 and it accounts for about 70-80% of all cases of MEN2. [orpha.net]

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] Epidemiology The overall frequency of MEN2 in the United States is 1 case per 30,000 [emedicine.medscape.com]

Existing data sources for clinical epidemiology: Danish registries for studies of medical genetic diseases. Clin Epidemiol. 2013;5:249–262. 15. Margraf RL, Crockett DK, Krautscheid PM, et al. [dovepress.com]

741) Paediatrics, Neonatology (687) Anatomy (684) Histology, Embryology (616) Surgery, Traumatology and Orthopaedics (603) Genetics (549) Infectology (472) Biophysics (454) Neurology (445) Microbiology (407) Dentistry (339) Cardiology, Angiology (304) Epidemiology [portal.mefanet.cz]

Epidemiology The prevalence of M. catarrhalis colonisation is highly dependent on age. [patient.info]

Effective strategies to prevent and treat AD remain elusive despite major efforts to understand its basic biology and clinical pathophysiology. [annualreviews.org]

Early total thyroidectomy remains effective in preventing the development of MTC in the long term. [3, 4, 5] Pathophysiology Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2. [emedicine.medscape.com]

Physiology and Pathophysiology (871) Internal Medicine (859) Medical Chemistry and Biochemistry (831) Pathology and Forensic Medicine (741) Paediatrics, Neonatology (687) Anatomy (684) Histology, Embryology (616) Surgery, Traumatology and Orthopaedics [portal.mefanet.cz]

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]. [emedicine.medscape.com]

Preventive surgery can be performed safely at that age and may be limited to total thyroidectomy when baseline calcitonin levels are normal. [ncbi.nlm.nih.gov]

Currently, there are no specific methods or guidelines to prevent Multiple Endocrine Neoplasia (MEN) Type 2, since it is a genetic condition Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing [dovemed.com]

Clinical recognition and accurate diagnosis of individuals and families who are at risk of harboring a germline RET mutation is critical for the prevention and management of potentially life-threatening neoplasms. [doi.org]

1. Cohen MS, Moley JF. Surgical treatment of medullary thyroid carcinoma. J Intern Med. 2003;253(6):616–626.
2. Callender GG, Rich TA, Perrier ND. Multiple endocrine neoplasia syndromes. Surg Clin North Am. 2008;88(4):863–895.
3. Modigliani E, Vasen HM, Raue K, et al. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med. 1995;238(4):363–367.
4. Rodriguez JM, Balsalobre M, Ponce JL, et al. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg. 2008;32(11):2520–2526.
5. Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med. 2005;257(1):60–68.
6. Seri M, Celli I, Betsos N, Claudiani F, Camera G, Romeo G. A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis. Clin Genet. 1997;51(2):86–90.
7. Ilias I, Pacak K. Diagnosis, localization and treatment of pheochromocytoma in MEN 2 syndrome. Endocr Regul. 2009;43(2):89-93.
8. Ilias I, Chen CC, Carrasquillo JA, et al. Comparison of 6-18F-fluorodopamine PET with 123I-metaiodobenzylguanidine and 111in-pentetreotide scintigraphy in localization of nonmetastatic and metastatic pheochromocytoma. J Nucl Med. 2008;49(10):1613–1619.