Multiple endocrine neoplasia type 2

Overview

Multiple Endocrine Neoplasia type 2 (MEN2) is a rare, inherited disorder characterized by the development of tumors in multiple endocrine glands, most notably the thyroid gland, adrenal glands, and parathyroid glands. MEN2 is divided into three clinical subtypes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). The hallmark feature of MEN2 in all forms is medullary thyroid carcinoma (MTC), a potentially aggressive cancer arising from parafollicular C cells of the thyroid that produce calcitonin.

MEN2 is caused by mutations in the RET proto-oncogene and is inherited in an autosomal dominant fashion. Early diagnosis and management, including prophylactic thyroidectomy in at-risk individuals, significantly improve outcomes. MEN2 is distinct from MEN1 and MEN4 in terms of genetic basis, tumor types, and clinical presentation.

Causes

The primary cause of MEN2 is a germline mutation in the RET proto-oncogene located on chromosome 10q11.2. This gene encodes a receptor tyrosine kinase that plays a role in cell growth and differentiation. Mutations lead to constitutive activation of the RET receptor, resulting in uncontrolled cellular proliferation and tumor formation.

Inheritance and Genetic Characteristics

• Autosomal dominant inheritance: One mutated copy of the RET gene is sufficient to cause the disorder.

• High penetrance: Most individuals with a RET mutation will eventually develop features of MEN2.

• Genotype-phenotype correlation: Specific RET mutations are associated with particular MEN2 subtypes and risk levels.

Genetic testing plays a critical role in the identification of carriers and in guiding prophylactic treatment strategies.

Symptoms

The symptoms of MEN2 vary depending on the subtype and the endocrine glands affected. All subtypes share a predisposition to medullary thyroid carcinoma, while other tumors are more subtype-specific.

1. Medullary Thyroid Carcinoma (MTC)

• Occurs in virtually all MEN2 patients

• May present with a neck mass, hoarseness, or symptoms of metastasis

• Can secrete calcitonin, leading to diarrhea or flushing (rare)

2. Pheochromocytoma (adrenal gland tumor)

• Seen in MEN2A and MEN2B (not FMTC)

• Causes episodic hypertension, headaches, palpitations, and sweating

• Usually benign but can cause life-threatening hypertensive crises if untreated

3. Hyperparathyroidism (in MEN2A)

• Caused by parathyroid hyperplasia or adenomas

• Leads to hypercalcemia, kidney stones, bone pain, and fatigue

4. MEN2B-Specific Features

• Marfanoid habitus (tall, slender build with long limbs and fingers)

• Mucosal neuromas (benign nerve tumors) on lips, tongue, eyelids, and gastrointestinal tract

• More aggressive and early-onset MTC (often in infancy or early childhood)

FMTC is considered a milder form with MTC as the sole clinical manifestation and typically later onset.

Diagnosis

Diagnosis of MEN2 is based on clinical presentation, family history, biochemical testing, imaging studies, and genetic confirmation of a RET mutation. Early identification, particularly through family screening, is vital for successful management.

1. Clinical Evaluation

• Family history of MEN2 or medullary thyroid carcinoma

• Presence of endocrine tumors or syndromic features (e.g., mucosal neuromas in MEN2B)

2. Biochemical Testing

• Calcitonin: Elevated in MTC

• Carcinoembryonic antigen (CEA): May be elevated in advanced MTC

• Plasma metanephrines: To screen for pheochromocytoma

• Serum calcium and PTH: For hyperparathyroidism

3. Imaging Studies

• Neck ultrasound for thyroid nodules

• CT or MRI of adrenal glands if pheochromocytoma is suspected

• Sestamibi scan or ultrasound for parathyroid glands

4. Genetic Testing

• Confirmation of RET mutation is definitive for MEN2

• Predictive testing of at-risk family members is essential

RET mutation analysis not only confirms the diagnosis but also guides the timing of prophylactic thyroidectomy and ongoing surveillance.

Treatment

Treatment of MEN2 focuses on surgical removal of tumors and ongoing surveillance for early detection of new or recurring neoplasms. Management differs slightly between subtypes but always includes proactive measures to prevent cancer-related complications.

1. Medullary Thyroid Carcinoma

• Total thyroidectomy: Often performed prophylactically in gene-positive children

• Lymph node dissection: If regional metastases are suspected

• Calcitonin and CEA monitoring: Post-surgical tumor marker surveillance

• Tyrosine kinase inhibitors (e.g., vandetanib, cabozantinib): For advanced or metastatic MTC

2. Pheochromocytoma

• Adrenalectomy: Surgical removal of the tumor(s)

• Preoperative alpha-adrenergic blockade: To prevent hypertensive crises during surgery

• Bilateral adrenalectomy may be necessary in some cases

3. Hyperparathyroidism (in MEN2A)

• Parathyroidectomy: For symptomatic or significant hypercalcemia

• Calcium and vitamin D monitoring after surgery

4. Supportive and Genetic Care

• Genetic counseling for patients and at-risk relatives

• Routine surveillance: Annual biochemical screening and imaging depending on mutation type

Management of MEN2B requires especially early and aggressive treatment due to the aggressive nature of MTC in this subtype.

Prognosis

The prognosis for MEN2 depends on the subtype, early detection, and management of tumors. With timely thyroidectomy and surveillance, the risk of cancer-related mortality can be significantly reduced, particularly in MEN2A and FMTC.

Prognosis by Subtype

• MEN2A: Good prognosis with early detection and management; lifelong monitoring needed

• MEN2B: Poorer prognosis due to aggressive and early-onset MTC; early surgery is critical

• FMTC: Best prognosis, as MTC is the only manifestation and typically slower-growing

Long-Term Outlook

• Survival improves significantly with prophylactic thyroidectomy in mutation carriers

• Persistent disease or metastases from MTC require targeted therapies

• Lifelong follow-up is essential to detect recurrences or new endocrine tumors

Thanks to advancements in genetic testing and early intervention, many individuals with MEN2 can live long and productive lives with proper treatment and surveillance strategies.