Multiple Endocrine Neoplasia Type 2B (MEN2B) is a rare inherited disorder causing tumors in endocrine glands and other body tissues. It is the most severe subtype of multiple endocrine neoplasia, characterized by both benign and cancerous growths. These tumors affect hormone-producing glands, leading to various symptoms. MEN2B typically manifests before a child reaches 10 years of age.
Key Features and Manifestations
Individuals with MEN2B often present with distinct physical characteristics and clinical symptoms, including medullary thyroid carcinoma (MTC), a near-universal feature and aggressive thyroid cancer that frequently develops early in life, sometimes even during infancy. MTC originates from the calcitonin-producing C-cells of the thyroid gland. It can manifest as a lump in the neck, difficulty swallowing, hoarseness, or systemic symptoms like diarrhea and flushing due to excess hormone production.
Pheochromocytoma, a tumor of the adrenal glands, occurs in approximately 50% of MEN2B patients. These tumors produce excess adrenaline-like hormones, leading to symptoms such as high blood pressure, headaches, rapid heart rate, sweating, and anxiety. Most pheochromocytomas are benign but can cause health issues if left untreated.
Mucosal neuromas are characteristic benign growths present in nearly all MEN2B patients. They often appear as small, glistening bumps on the lips, tongue, and inside the mouth. These neuromas can also affect the eyelids and conjunctivae, sometimes causing thickened eyelids, everted (turned-out) eyelids, or difficulty producing tears. Numerous neuromas on the lips can lead to an enlarged or “blubbery” appearance.
Gastrointestinal ganglioneuromas, benign nerve growths in the digestive tract, are also common, affecting around 40% of patients. These growths can disrupt normal bowel function, leading to chronic issues such as constipation, diarrhea, abdominal pain, and sometimes an enlarged colon (megacolon). These gastrointestinal problems can be among the earliest signs of the syndrome, even in infancy.
Many individuals with MEN2B exhibit a “Marfanoid habitus,” characterized by a tall, slender build with disproportionately long limbs, fingers, and toes. They may also have joint hypermobility and skeletal abnormalities like spinal deformities (e.g., scoliosis, kyphosis). Other features include a high-arched palate and thick, myelinated corneal nerves visible upon eye examination.
Genetic Origins
Multiple Endocrine Neoplasia Type 2B is primarily caused by specific changes in the RET proto-oncogene. The RET gene provides instructions for a protein involved in cell growth and development, particularly in nerve cells. When mutated, its normal function is altered, leading to uncontrolled cell growth and tumor formation.
Over 95% of MEN2B cases are attributed to a single point mutation in the RET gene: a methionine-to-threonine substitution at codon 918 (M918T) in exon 16. Less common mutations, such as A883F in exon 15, can also cause MEN2B, though they may lead to a less aggressive form of medullary thyroid carcinoma. These mutations result in an overactive RET protein, continuously signaling cells to grow.
MEN2B follows an autosomal dominant inheritance pattern. A person only needs to inherit one copy of the mutated RET gene from either parent to develop the condition. Each child of an affected individual therefore has a 50% chance of inheriting the mutated gene.
While many cases are inherited, 50% to 95% arise from new, spontaneous mutations in the RET gene. These “de novo” mutations occur randomly and are not inherited from a parent, often originating in the paternal allele, particularly in children of older fathers. Such sporadic cases highlight the importance of genetic testing even without a family history.
Identification and Monitoring
Diagnosis of Multiple Endocrine Neoplasia Type 2B often begins with clinical suspicion based on characteristic physical features or a family history. Early detection and consistent monitoring are important due to the aggressive nature of medullary thyroid carcinoma (MTC) in MEN2B. Identifying at-risk individuals allows for proactive interventions that improve outcomes.
Genetic testing for the RET gene mutation is the definitive diagnostic method for MEN2B. A simple blood test identifies the specific mutation, typically the M918T variant, confirming the diagnosis with high accuracy. Genetic testing is also recommended for first-degree relatives to determine their risk, even if they show no symptoms.
Biochemical screening identifies associated tumors and monitors disease activity. Blood tests for calcitonin levels screen for MTC, as elevated levels indicate MTC or C-cell hyperplasia. For pheochromocytoma, blood plasma free metanephrines or 24-hour urine collection for fractionated metanephrines detect excess adrenal hormones.
Imaging studies locate and assess tumor extent. An ultrasound of the neck evaluates the thyroid gland for nodules or MTC. Magnetic resonance imaging (MRI) or computed tomography (CT) scans of the abdomen identify pheochromocytomas in the adrenal glands. For suspected metastatic MTC, CT scans of the chest and abdomen or other specialized scans like OctreoScan may be used.
Proactive screening of at-risk family members, especially children, is advised. For infants with high-risk RET mutations, genetic testing should be performed at or soon after birth. This early identification allows for timely prophylactic thyroidectomy, which can prevent aggressive, life-threatening MTC.
Management and Care
Management of Multiple Endocrine Neoplasia Type 2B involves a coordinated approach to address the syndrome’s various manifestations, with prophylactic thyroidectomy, the surgical removal of the entire thyroid gland, being widely recommended. It is often performed at a very young age, ideally before six months or within the first year of life. This early intervention occurs even before any signs of cancer appear, given the almost universal presence of medullary thyroid carcinoma (MTC) in MEN2B patients. This procedure improves survival rates by preventing MTC development and spread.
Pheochromocytomas, if present, require careful management, typically surgical removal. Before surgery, patients undergo medical preparation to control blood pressure and prevent complications from excess hormone release. If only one adrenal gland is affected, its removal may be considered. However, bilateral pheochromocytomas or later development of a tumor in the remaining gland may necessitate removal of both adrenal glands.
For advanced or metastatic MTC that cannot be surgically removed, targeted therapies are used. Medications like tyrosine kinase inhibitors (TKIs), including vandetanib and cabozantinib, block proteins that promote cancer cell growth and survival. These systemic treatments help control disease progression, though they are not curative and may have side effects. Newer RET inhibitors like selpercatinib and pralsetinib are also used for RET-mutated MTC.
Symptomatic management addresses gastrointestinal problems caused by ganglioneuromas. Constipation, diarrhea, and abdominal discomfort can often be managed with dietary adjustments, laxatives, and fiber supplements. In some cases, more intensive medical intervention or surgery may be needed to alleviate severe gastrointestinal symptoms.
Comprehensive care for MEN2B requires a multidisciplinary approach involving a team of specialists. This team typically includes endocrinologists, surgeons (endocrine, general, pediatric), oncologists, genetic counselors, and gastroenterologists. This collaborative effort ensures all aspects of the complex syndrome are addressed.
Lifelong surveillance is an ongoing aspect of care. After initial treatments, patients undergo regular monitoring for MTC or pheochromocytoma recurrence and new tumor development. This includes periodic blood tests for calcitonin and carcinoembryonic antigen (CEA) to detect MTC, and blood or urine tests for metanephrines to screen for pheochromocytoma. Regular imaging studies also detect any new growths or changes.