A 25-year-old man presents to his primary care provider for a routine appointment. He feels well and has no complaints. His medical and surgical history is significant for the reconstruction of a torn anterior cruciate ligament in his right knee. His family history is significant for a mother with “thyroid problems” and a father with coronary artery disease. The patient is an information technology specialist at a local company. He is sexually active with men. His temperature is 98.6°F (37.0°C), blood pressure is 124/82 mmHg, pulse is 71/min, and respirations are 12/min. On physical exam, the patient is tall and slender with a BMI of 21 kg/m2. A single nodule can be palpated on the patient’s thyroid. He has palpable cervical lymphadenopathy. On cardiac exam, he has a normal S1/S2 with no murmurs, rubs, or gallops, and his lungs are clear bilaterally. His abdomen is soft and non-tender without hepatosplenomegaly. A physical exam of the perioral region can be seen in Figure A. Which of the following additional findings is most likely to be found in this patient?
Elevated serum prolactin level
Elevated serum calcium level
Elevated plasma metanephrines
Fasting hypoglycemia
Elevated plasma metanephrines
This patient presents with tall stature, mucosal neuromas of the lips and tongue, an isolated thyroid nodule, and a family history of thyroid disease, which suggests a diagnosis of multiple endocrine neoplasia type 2 (MEN2B). MEN2B is also associated with pheochromocytomas, which cause elevated plasma metanephrines.

MEN2B is caused by a gain-of-function mutation in the RET proto-oncogene and presents with medullary carcinoma of the thyroid, pheochromocytoma, Marfanoid habitus, and mucosal neuromas. Medullary thyroid carcinoma (MTC) occurs in almost all patients with MEN2B and is often metastatic at the time of diagnosis. Patients should be screened for pheochromocytoma using plasma fractionated metanephrines at the time of diagnosis of MTC. Intestinal neuromas may also lead to intestinal manifestations such as chronic constipation and megacolon. Treatment is with surgical excision of malignant lesions and active screening for future development of tumors.

Castinetti et al. review the evidence regarding the diagnosis and treatment of MEN2B. They discuss how often the first presentation of this disease involves the diagnosis of medullary thyroid carcinoma. They recommend developing techniques for earlier diagnosis of this disease in order to allow for better survival.

Figure/Illustration A is a clinical photograph demonstrating mucosal neuromas, which are painless nodules on the lips or tongue (red circles). These findings are characteristically seen in multiple endocrine neoplasia type 2B.

Incorrect Answers:
Answer B: An elevated serum calcium level would suggest parathyroid hyperplasia, which is a feature of both type 1 and type 2A multiple endocrine neoplasia. Rather than hypercalcemia, this patient is likely to have an elevated serum calcitonin level due to his medullary thyroid carcinoma.

Answer C: An elevated serum prolactin level would suggest the presence of a prolactinoma, which is a pituitary tumor that may be seen in type 1 multiple endocrine neoplasia (MEN1). Other findings in this disorder include parathyroid and pancreatic tumors. Treatment is with surgical excision of malignant lesions.

Answer D: Fasting hypoglycemia would suggest the presence of an insulinoma, which is a less common pancreatic tumor that may be seen in MEN1. Other findings in this disorder include parathyroid and pancreatic tumors. Patients with an insulinoma require surgical excision in order to allow for proper glucose homeostasis.

Answer E: A positive fecal occult blood test would raise suspicion for colorectal cancer, which is a feature of Peutz-Jeghers syndrome (PJS). The extraintestinal manifestations of PJS include mucocutaneous pigmented macules on the lips and perioral region. Treatment is with screening for colorectal cancer and surgical excision of malignant lesions.

Bullet Summary:
Multiple endocrine neoplasia type 2B presents with medullary thyroid carcinoma, pheochromocytoma, Marfanoid habitus, and mucosal neuromas.