What Is Endocrine Neoplasia Type 2?
What Is Endocrine Neoplasia Type 2?
Endocrine neoplasia type 2 or multiple endocrine neoplasia type 2 (MEN2) is a rare inherited condition, which is caused due to mutation in RET gene. It presents with increased risk of developing certain cancers including pheochromocytoma, medullary thyroid carcinoma (MTC) and parathyroid tumors. Multiple endocrine neoplasia type 2 is further divided into 2 types, namely, multiple endocrine neoplasia type 2A and multiple endocrine neoplasia type 2B. (1)
Multiple endocrine neoplasia type 2A is the most common of the both subtypes accounting for 95% of the total cases of MEN2. The classical MEN2A consists of medullary thyroid carcinoma, pheochromocytoma and primary hyperparathyroidism. Other types include MEN2A with cutaneous lichen amyloidosis, MEN2A with Hirschsprung disease and familial medullary thyroid cancer. Familial medullary thyroid cancer patients are positive for RET germline mutations and have medullary thyroid cancer, but do not have any family history of pheochromocytoma or hyperparathyroidism.
Multiple endocrine neoplasia type 2B is less common accounting for around 5% of all multiple endocrine neoplasia type 2 cases. When present it consists of more aggressive form of medullary thyroid cancer that occurs in almost 100% cases, mucosal neuromas occurring in 95-98% cases, pheochromocytoma occurring in about 50% of cases, and intestinal ganglion neuromas is present in about 40% cases. There is absence of hyperparathyroidism. Most of these patients have typical marfanoid habitus (combination of symptoms that resemble those of Marfan syndrome).
Clinical Presentation Of MEN2
The clinical presentation of MEN2A is highly varied depending on the involvement of the underlying glands and also on the severity of the condition. The commonly affected glands are the thyroid gland, parathyroid glands and adrenal glands, which lead to medullary thyroid carcinoma, parathyroid hyperplasia (hyperparathyroidism) and pheochromocytoma respectively.
Medullary thyroid carcinoma is present exclusively in all the cases of multiple endocrine neoplasia type 2. It is a calcitonin secreting tumor and leads to C cell hyperplasia, which acts as a precursor of medullary thyroid carcinoma. The onset is around 10-30 years of age. Young patients usually do not present with any symptoms as they have thyroid C cell hyperplasia without any progression to medullary thyroid carcinoma. Patients may present with chronic diarrhea and neck mass.
Pheochromocytoma is usually present in nearly half of the patients of MEN2A with bilateral predilection, but can be found unilaterally in about 10% cases. The onset is around 20-30 years of age. Nearly all the cases of pheochromocytoma are benign; however, 4% cases can be malignant. It can lead to severe hypertension, increased heart rate, arrhythmias along with episodes of sweating and headaches.
Parathyroid hyperplasia is less common than pheochromocytoma. They may not present with any symptoms; however, 20-30% patients may have hyperparathyroidism. Hypercalcemia may lead to fatigue, constipation, glucose intolerance, polydipsia, polyuria, kidney stones, GERD, memory problems, depression or they maybe asymptomatic along with loss of bone density.
MEN2A patients with Hirschsprung disease have impairment of GI peristalsis that may lead to constipation, bloating, loss of appetite, vomiting and enlarged colon. Chronically, it may lead to diarrhea, dehydration and growth failure.
MEN2A patients with cutaneous lichen amyloidosis present with multiple, itchy, scaly, lichenoid papules that are hyperpigmented, mostly present in the back area due to deposition of amyloids.
Patients with MEN2B present with multiple neuromas on the conjunctiva, eyelids, mucosa of nose, larynx, lips, tongue, palate, and pharynx. Neuromas can cause enlarged and prominent lips, typical facial characteristics including anteverted eyelids, coarse and elongated face and broad based nose. Symptoms also include distention of abdomen, diarrhea, constipation, enlarged colon, failure to grow along with localized itching over the upper back area. It also consists of marfanoid habitus features, which includes tall stature, long arms and legs, long and thin fingers and toes. The patients may also have muscle weakness, loose joints, sunken breastbone and abnormal spine curvature. The treatment of multiple endocrine neoplasia type 2 is usually surgery with the removal of thyroid gland, parathyroid gland and adrenal glands.