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Multiple Endocrine Neoplasia, Type 2A (MEN 2A)

(MEN 2; Multiple Endocrine Adenomatosis, Type 2; Sipple Syndrome)

By

Lawrence S. Kirschner

, MD, PhD, The Ohio State University;


Pamela Brock

, MS, CGC, The Ohio State University

Reviewed/Revised Jun 2023
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Topic Resources

Multiple endocrine neoplasia, type 2A (MEN 2A) is an autosomal dominant syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, parathyroid hyperplasia or adenomas (causing hyperparathyroidism), and occasionally cutaneous lichen amyloidosis. Clinical features depend on the glandular elements affected. Familial medullary thyroid carcinoma is a distinct variant of MEN 2A. Diagnosis is confirmed by genetic testing. Hormonal and imaging tests help locate the tumors, which are removed surgically when possible.

Symptoms and Signs of MEN 2A

Clinical features depend on the type of tumor present (see table ).

Thyroid

Adrenal

Pheochromocytoma Pheochromocytoma A pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells typically located in the adrenals. It causes persistent or paroxysmal hypertension. Diagnosis is by measuring catecholamine... read more usually originates in the adrenal glands. Pheochromocytoma occurs in 40 to 50% of people within a MEN 2A kindred. In contrast to sporadic pheochromocytoma, the familial variety within MEN 2A begins with adrenal medullary hyperplasia and is multicentric and bilateral in > 50% of cases. Extra-adrenal pheochromocytomas are rare. Pheochromocytomas are almost always benign, but some tend to recur locally and account for significant morbidity and mortality.

Hypertensive crisis Hypertensive Emergencies A hypertensive emergency is severe hypertension (often defined as systolic blood pressure (BP) ≥ 180 mm Hg and/or diastolic blood pressure ≥ 120 mm Hg) with signs of damage to target organs... read more secondary to pheochromocytoma is a common manifestation. Hypertension in MEN 2A patients with pheochromocytoma is more often paroxysmal than sustained, in contrast to the usual sporadic case. Patients with pheochromocytomas may have paroxysmal palpitations, anxiety, headaches, or sweating; many are asymptomatic.

Parathyroid

Other manifestations

Cutaneous lichen amyloidosis, a pruritic, scaly, papular skin lesion, located in the interscapular region or on extensor surfaces, occurs in some MEN 2A-affected families. Hirschsprung disease Hirschsprung Disease Hirschsprung disease is a congenital anomaly consisting of a failure of neuronal colonization (and thus a failure of innervation) of the lower intestine, usually limited to the colon, resulting... read more Hirschsprung Disease is present in 2 to 5% of MEN 2A patients.

Diagnosis of MEN 2A

  • Serum calcitonin for medullary thyroid carcinoma

  • Serum calcium, 24-hour urine calcium, and parathyroid hormone for hyperparathyroidism

  • Plasma free metanephrines or urinary catecholamine and metanephrine levels for pheochromocytoma

  • Neck ultrasonography, with additional imaging as needed

  • Localization of pheochromocytoma with MRI or CT

  • Genetic testing

Serum calcitonin is a good marker for the presence of medullary thyroid carcinoma and can also be used as a biomarker to follow disease response and/or progression.

Neck imaging for localization of masses within the thyroid and parathyroid glands should begin with ultrasonography followed by CT, MRI, or radioisotope scanning as needed. Computed tomography (CT) or magnetic resonance imaging (MRI) is useful in localizing the pheochromocytoma or establishing the presence of bilateral lesions.

Many cases are identified during screening of family members of known cases. MEN 2A should also be suspected in patients with bilateral pheochromocytoma Pheochromocytoma A pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells typically located in the adrenals. It causes persistent or paroxysmal hypertension. Diagnosis is by measuring catecholamine... read more or at least 2 of its characteristic endocrine manifestations. The diagnosis can be confirmed with genetic testing. Although only 25% of medullary thyroid carcinoma Medullary Thyroid Carcinoma Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more cases are familial, genetic testing should be done in all patients with medullary thyroid carcinoma. RET mutations are found in virtually all patients with familial medullary thyroid cancer but are as high as approximately 7% in apparently sporadic cases (1 Diagnosis references Multiple endocrine neoplasia, type 2A (MEN 2A) is an autosomal dominant syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, parathyroid hyperplasia or adenomas (causing... read more Diagnosis references ).

Genetic screening

Genetic screening of family members of MEN 2A patients is the diagnostic test of choice; the availability of such testing has made biochemical screening for early medullary thyroid carcinoma largely obsolete. The specific RET mutation also predicts phenotypic characteristics such as aggressiveness of medullary thyroid carcinoma and presence of other endocrinopathies, so is important in clinical management; however, other factors, such as older age at onset and higher tumor stage at diagnosis, may be more predictive of disease aggressiveness (2 Diagnosis references Multiple endocrine neoplasia, type 2A (MEN 2A) is an autosomal dominant syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, parathyroid hyperplasia or adenomas (causing... read more Diagnosis references ).

Diagnosis references

  • 1. Wells SA Jr, Asa SL, Dralle H, et al: American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25(6):567–610, 2015.

  • 2. 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.

Treatment of MEN 2A

  • Surgical excision of identified tumors

  • Prophylactic thyroidectomy

In patients presenting with pheochromocytoma Diagnosis A pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells typically located in the adrenals. It causes persistent or paroxysmal hypertension. Diagnosis is by measuring catecholamine... read more and either medullary thyroid carcinoma Medullary Thyroid Carcinoma Thyroid cancer can derive from follicular cells or parafollicular C-cells. Most thyroid cancers manifest as asymptomatic nodules. Diagnosis is often by fine-needle aspiration biopsy but may... read more or hyperparathyroidism Diagnosis Hyperparathyroidism occurs when one or more of the parathyroid glands become overactive, causing elevated serum levels of parathyroid hormone and leading to hypercalcemia. Patients may be asymptomatic... read more , the pheochromocytoma should be removed first, even if asymptomatic because it greatly increases risk during other surgeries (1 Treatment references Multiple endocrine neoplasia, type 2A (MEN 2A) is an autosomal dominant syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, parathyroid hyperplasia or adenomas (causing... read more Treatment references ). Patients undergoing resection of a pheochromocytoma should receive adequate alpha blockade (typically using phenoxybenzamine, doxazosin, or prazosin) prior to surgery. Laparoscopic adrenalectomy, which has lower morbidity, is preferred to open laparotomy. Because bilateral pheochromocytomas are common, adrenal-sparing surgery may be appropriate in some patients (2 Treatment references Multiple endocrine neoplasia, type 2A (MEN 2A) is an autosomal dominant syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, parathyroid hyperplasia or adenomas (causing... read more Treatment references ).

Surgery for medullary thyroid carcinoma should include total thyroidectomy and central compartment lymph node dissection, with additional lymph node dissection if indicated based on preoperative imaging. Postsurgical assessment for residual or recurrent disease should include measurement of serum calcitonin and imaging with neck ultrasonography and, when indicated, CT or MRI of neck and chest, bone scan, or positron emission tomography (PET) scan.

Once medullary thyroid carcinoma has metastasized, tyrosine kinase inhibitors, including selpercatinib, cabozantinib, and vandetanib, can lengthen progression-free survival. Clinical trials of other tyrosine kinase inhibitors for metastatic medullary thyroid carcinoma are ongoing (3 Treatment references Multiple endocrine neoplasia, type 2A (MEN 2A) is an autosomal dominant syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, parathyroid hyperplasia or adenomas (causing... read more Treatment references ). Cytotoxic chemotherapy and radiation therapy are largely ineffective in lengthening survival but may slow disease progression. Postoperative adjuvant external beam radiation should be considered in patients at high risk of local recurrence and those at risk for airway obstruction. Some studies have shown lengthened survival with immunotherapy (eg, tumor-derived vaccines, tumor cell transfectants) and radioimmunotherapy (eg, radioisotope-coupled monoclonal antibodies).

Once genetic testing identifies a child as having a RET mutation, prophylactic thyroidectomy is recommended. Depending on the particular mutation, prophylactic thyroidectomy as early as the first months of life may be indicated. Medullary thyroid cancer can be cured or prevented by early thyroidectomy. There is a genotype-phenotype correlation for patients with RET mutations that may provide information about age of onset and clinical course of medullary thyroid cancer and this impact the timing of surgery for an affected child.

Psychological distress appears to be common and chronic in patients with MEN 2. Contributing factors include low amount of information on the disease, having children with the mutation, number of surgeries, and presence of comorbidities; psychological assessment to identify and treat affected individuals is recommended (4 Treatment references Multiple endocrine neoplasia, type 2A (MEN 2A) is an autosomal dominant syndrome characterized by medullary carcinoma of the thyroid, pheochromocytoma, parathyroid hyperplasia or adenomas (causing... read more Treatment references ).

Treatment references

  • 1. Wells SA Jr: Advances in the management of MEN2: From improved surgical and medical treatment to novel kinase inhibitors. Endocr Relat Cancer 25:T1–T13, 2018.

  • 2. Castinetti F, Qi XP, Walz AL, 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 15(6):648–655, 2014.

  • 3. Okafor C, Hogan J, Raygada M, et al: Update on Targeted Therapy in Medullary Thyroid Cancer. Front Endocrinol (Lausanne). 12:708949, 2021. doi:10.3389/fendo.2021.708949

  • 4. Rodrigues KC, Toledo RA, Coutinho FL, et al: Assessment of depression, anxiety, quality of life, and coping in long-standing multiple endocrine neoplasia type 2 patients. Thyroid 27(5):693–706, 2017.

Key Points

  • Most patients with multiple endocrine neoplasia, type 2A have medullary thyroid carcinoma, typically beginning in childhood.

  • Other manifestations are those of hormone excess, particularly hypertension due to pheochromocytoma and hypercalcemia due to hyperparathyroidism.

  • Patients should have genetic testing for RET proto-oncogene mutations and clinical evaluation for other tumors of the syndrome.

  • Tumors are excised when possible, beginning with any pheochromocytoma.

  • Prophylactic thyroidectomy is recommended; timing of the surgery may be influenced by the specific mutation.

More Information

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

  • Saravana-Bawan B, Pasternak JD. Multiple endocrine neoplasia 2: an overview. Ther Adv Chronic Dis 2022;13:20406223221079246. Published 2022 Feb 25. doi:10.1177/20406223221079246

Drugs Mentioned In This Article

Drug Name Select Trade
Dibenzyline
Cardura, Cardura XL
Minipress
Retevmo
Cabometyx , COMETRIQ
Caprelsa
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