Multiple endocrine neoplasia type 2A (MEN 2A) is a hereditary disease that is caused by the mutations of a RET proto-oncogene and is a subtype of MEN syndrome. Pathology arises in endocrine glands, and MEN 2A specifically causes medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism.
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 . 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  . 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 . 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 . 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 . Furthermore, the symptoms they produce are often insidious and may be paroxysmal . 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 .
Face, Head & Neck
- Episodic Headache
Pheochromocytoma can present as sustained or episodic hypertension, along with episodic headache, diaphoresis, palpitations, tachycardia, and anxiety. Primary hyperparathyroidism can manifest with symptoms of hypercalcemia or may be asymptomatic. [clinicaladvisor.com]
PHEO may account for hypertension, episodic headache, palpitations, nervousness, sweating and blanching of the skin due to excessive synthesis of epinephrine, norepinephrine and dopamine by the chromaffin cells of the adrenal gland. [ojrd.biomedcentral.com]
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:
- Measurement of serum calcitonin levels, which may be raised.
- Imaging studies consist of computerized tomography (CT), magnetic resonance imaging (MRI), and octreotide scanning.
- 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  .
- Imaging modalities used are CT, MRI, and positron emission tomography (PET) scans. CT is the least sensitive, while PET is the most sensitive test . A metaiodobenzylguanidine (MIBG) scan is also useful . These studies are used to localize the tumor and to check if it is bilateral.
- Small Bowel Mass
Surgical exploration identified a 5-cm pedunculated small-bowel mass approximately 25 cm from the ileocecal junction, as well as bilaterally firm ovaries. Bilateral oophorectomy revealed medullary thyroid cancer in both ovaries and fallopian tubes. [ncbi.nlm.nih.gov]
After treatment with α-blockers, he underwent a total bilateral laparoscopic adrenalectomy with CO 2 pneumoperitoneum; bilateral PHEO was confirmed by histopathological examination. [journals.plos.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]
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]
Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC indicating the necessity of a complete thyroid surgery for index cases with MTC and the early thyroidectomy for screened at risk subjects. [en.wikipedia.org]
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]
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]
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]
Immunohistochemistry of the tumor with ACTH confirmed the etiology of the ACTH secretion. Impaired glucose tolerance has been observed in patients with pheochromocytoma with an incidence of from 25~75%. [synapse.koreamed.org]
Summary Epidemiology Prevalence of MEN2A is approximately 1/40,000 and it accounts for about 70-80% of all cases of MEN2. [orpha.net]
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]
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Epidemiology The prevalence of M. catarrhalis colonisation is highly dependent on age. [patient.info]
However, none ever gained sufficient traction to merit continued use, and they are no longer used in the medical literature. The prevalence of MEN2B is not well established, but has been derived from other epidemiological considerations as 1 in 600,000 [en.wikipedia.org]
Effective strategies to prevent and treat AD remain elusive despite major efforts to understand its basic biology and clinical pathophysiology. [annualreviews.org]
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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.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]
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]
- Cohen MS, Moley JF. Surgical treatment of medullary thyroid carcinoma. J Intern Med. 2003;253(6):616–626.
- Callender GG, Rich TA, Perrier ND. Multiple endocrine neoplasia syndromes. Surg Clin North Am. 2008;88(4):863–895.
- 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.
- 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.
- 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.
- 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.
- Ilias I, Pacak K. Diagnosis, localization and treatment of pheochromocytoma in MEN 2 syndrome. Endocr Regul. 2009;43(2):89-93.
- 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.