eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease

Multiple Endocrine Neoplasia, Type 2

Author: Melanie L Richards, MD, MPHE, Associate Professor, Department of Surgery, Mayo Clinic
Coauthor(s): 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; Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine
Contributor Information and Disclosures

Updated: Feb 19, 2010

Introduction

Background

Sipple first described an association between thyroid cancer and pheochromocytoma (benign tumor of the adrenal medulla) in 1961. The thyroid cancer found with pheochromocytoma was discovered to be a medullary carcinoma characterized by stromal amyloid in 1965. This familial constellation of pathology in conjunction with parathyroid hyperplasia was recognized as multiple endocrine neoplasia, type 2 (MEN 2) in 1968.

Although patients with mucosal neuromas were identified at this time, the distinction between MEN 2A and MEN 2B was not made until 1975.

• MEN 2A patients do not have the phenotypic abnormalities of mucosal neuromas and marfanoid habitus found in MEN 2B patients.
• MEN 2A patients also have a less virulent form of medullary thyroid carcinoma (MTC) than MEN 2B patients.
• MEN 2A patients may also have parathyroid hyperplasia, which is exceedingly rare in MEN 2B patients.

Pathophysiology

MEN 2 is a rare familial cancer syndrome caused by mutations in the RET proto-oncogene. Inherited as an autosomal dominant disorder, MEN 2 has 3 distinct subtypes, including MEN 2A, MEN 2B, and familial medullary thyroid carcinoma – only (FMTC-only). The subtypes are defined by the combination of tissues affected. Developmental abnormalities may also be present. By age 70 years, the penetrance rate is 70%. Genetic testing and clinical surveillance beginning in childhood provide the opportunity to treat the devastating and sometimes fatal complications of this disorder.¹

The RET proto-oncogene is 80 kilobase (kb) long and encodes a putative tyrosine kinase receptor. Its endogenous ligand may be the glial cell line–derived neurotrophic factor (GDNF), which appears to play a critical role in the normal function of pathways involved in enteric nervous system neurogenesis and renal organogenesis. Data suggest that an overrepresentation of mutant RET as an undefined second hit undefined event might trigger tumorigenesis. However, alterations in other genes might contribute to this overrepresentation of RET or impact on MEN 2-related tumor development through completely different mechanisms and pathways. 

Glandular hyperplasia begins with an increase of C cells located in the thyroid gland follicles and can progress to malignancy. Although they are benign, pheochromocytomas can cause a life-threatening hypertensive episode or arrhythmia.

Virtually all MEN 2A patients develop medullary thyroid carcinoma. This is often the first expressed abnormality and usually occurs in the second or third decade of life. The medullary thyroid carcinoma in MEN 2A patients is typically bilateral and multicentric, in contrast to sporadic medullary thyroid carcinoma, which is unilateral.

Pheochromocytomas are present in approximately half of MEN 2A patients. They are bilateral in 60-80% of patients, compared with 10% of patients with sporadic pheochromocytomas. Pheochromocytomas tend to be diagnosed at the same time as the medullary thyroid carcinoma or several years later (both primarily occurring in the second or third decade). The pheochromocytomas of MEN 2A patients are nearly all benign. Parathyroid hyperplasias are present in nearly half of patients but are less common than pheochromocytomas. In many patients, such hyperplasias can be clinically silent. However, as in other cases of hyperparathyroidism, symptoms can often be elucidated following comprehensive questioning.

Frequency

United States

The overall frequency is 1 case per 30,000-50,000 persons. In decreasing order of frequency, MEN occurs as follows: MEN 2A, FMTC-only, and MEN 2B.

Mortality/Morbidity

MEN 2A, MEN 2B, and FMTC-only elicit overlapping and distinct abnormalities. The characteristic tumor of MEN 2 MTC is present in all subtypes. Pheochromocytomas appear in both MEN 2A and MEN 2B patients. Primary hyperparathyroidism frequently develops in MEN 2A patients but rarely in those with MEN 2B. Gastrointestinal, skeletal, and dermatological abnormalities only occur in MEN 2B patients.

• Medullary thyroid carcinoma: The prognosis of medullary thyroid carcinoma is associated with the disease stage at the time of diagnosis. Because the penetrance of medullary thyroid carcinoma is nearly 100%, perform prophylactic thyroidectomy in infancy for patients with high-risk RET -mutations or by age 5 years in children with an identifiable RET mutation.^2,3 For patients who are at risk but who have not had genetic screening, perform annual biochemical screening.
• Pheochromocytoma: These benign tumors of the adrenal medulla occur in 50% of MEN 2 patients by the time they are in their late 30s; however, prevalence varies in different families. Pheochromocytomas develop in more than 50% of MEN 2B patients and can appear during early childhood. The earliest possible detection of these tumors can prevent a hypertensive crisis. Adrenalectomy should be considered when patients have biochemical confirmation and an adrenal mass or enlargement on imaging. A bilateral adrenalectomy is reserved for bilateral adrenal masses. Subtotal adrenalectomy remains controversial.^4,5
• Hyperparathyroidism: Extremely uncommon in MEN 2B patients, parathyroid hyperplasia affects 20-30% of MEN 2A patients. Patients may present with hypercalcemia and other vague symptoms.

Age

In MEN 2A patients, 50% of those with RET gene mutations develop the disease by age 50 years, and 70% develop the disease by age 70 years. Medullary thyroid carcinoma has been detected shortly after birth.

Clinical

History

The most important questions to ask relate to a family history of multiple endocrine neoplasms.

Patients may present with symptoms related to medullary thyroid carcinoma, hyperparathyroidism, or pheochromocytoma.

Clinical presentation is also related to the patient's age. A young patient with an identified RET proto-oncogene mutation will probably be asymptomatic. These patients generally have thyroid C-cell hyperplasia without progression to medullary carcinoma.

If a patient has thyroid medullary carcinoma, he or she may have a history of diarrhea from extensive disease. This may be related to elevated prostaglandin or calcitonin levels.

Virtually all index patients have medullary thyroid carcinoma at the time of diagnosis, although their clinical presentation may be consistent with pheochromocytoma or hyperparathyroidism.

Symptoms can include hypertension, episodic sweating, diarrhea, pruritic skin lesions, or compressive symptoms from a neck mass. Patients with hypercalcemia may present with constipation, polyuria, polydipsia, memory problems, depression, nephrolithiasis, glucose intolerance, gastroesophageal reflux, and fatigue, or they may have no symptoms. They may also lose bone density.

• Hypertension: If pheochromocytomas develop, an increase in blood pressure and heart rate may be the only signs. These increases can be chronic or episodic. Some patients have episodes of sweating and headaches.
• Chronic constipation: This constant finding in MEN 2B patients results from hyperplasia of the intrinsic autonomic ganglia in the intestinal wall. Infants may fail to thrive.
• Pruritic skin lesions: Cutaneous lichen amyloidosis in MEN 2A patients manifests as multiple pruritic, hyperpigmented, lichenoid papules in the scapular area of the back.⁶ They are associated with deposition of altered cytokeratins rather than of calcitoninlike peptides.

Physical

The physical signs of MEN 2 are extremely variable and often subtle.

• A neck mass or dominant thyroid nodule is discovered. Anterior neck lymph nodes are nontender, arise insidiously with progressive enlargement, and may signify regional metastasis.
• Blood pressure and heart rate may be elevated if a pheochromocytoma is present.
• Marfanoid habitus of high-arched palate, pectus excavatum, bilateral pes cavus, and scoliosis is observed in MEN 2B patients. Neuromas on the eyelids, conjunctiva, nasal and laryngeal mucosa, tongue, and lips are frequent findings. Patients also have prominent hypertrophied lips leading to a characteristic facies.
• Localized pruritus appears over the upper back in MEN 2B patients.

Causes

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

Point mutations associated with MEN 2A and FMTC-only were identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Almost all individuals with MEN 2B have an identical mutation in codon 918 of exon 16. Inheritance is autosomal dominant with variable penetrance and expressivity.

Substantiation of the genotype-phenotype correlation of inherited medullary thyroid carcinoma might lead to 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 medullary thyroid carcinoma in the long-term.⁷

• Search for CME/CE on This Topic »

• Multiple Endocrine Neoplasia (Pediatrics: General Medicine)
• Hyperaldosteronism (Pediatrics: General Medicine)
• Thyroid Cancer in Children (Otolaryngology and Facial Plastic Surgery)
• Glucagonoma (Endocrinology)

• Thyroid Problems Symptoms
• Endocrine System Center
• Thyroid Problems Treatment
• Thyroid Problems Causes
• Thyroid Problems Overview

• High-Protein/Low-Carb Diet Effective for Weight Loss in Type 2 Diabetes, But Merits Remain Unsubstantiated
• MRI Shows Brain Changes in Type 2 Diabetics
• Metformin Protects Against Cancer in Type 2 Diabetes

• Determination of Calcitonin Levels in C-cell Disease: Clinical Interest and Potential Pitfalls
• Catheter Ablation of Atrial Fibrillation in Patients with Diabetes Mellitus Type 2: Results From a Randomized Study Comparing Pulmonary Vein Isolation Versus Antiarrhythmic Drug Therapy
• Delineating Genetic Associations Between Obesity and Type 2 Diabetes

• Combination Therapy for Type 2 Diabetes
• Incretin Hormones in Diabetes and Metabolism Resource Center
• Hypogonadism Resource Center