Pheochromocytoma in Multiple Endocrine Neoplasia Type 2B

Multiple endocrine neoplasia type 2B (MEN2B) is an autosomal dominant disorder with age-related penetrance, and it represents approximately 5% of all MEN2 cases. MEN2B is characterized by medullary thyroid carcinoma (MTC) in all patients, adrenergic (epinephrine and metanephrine predominant) pheochromocytoma in 50%, mucocutaneous neuromas (typically involving the tongue, lips, and eyelids) in most patients, and by skeletal deformities (e.g., kyphoscoliosis, lordosis), joint laxity, myelinated corneal nerves, and intestinal ganglioneuromas. ^, MEN2B-associated tumors are caused by mutations in the rearranged during transfection (RET) protein’s intracellular domain. A single methionine-to-threonine missense pathogenic variant in exon 16 (p.Met918Thr; c.2753T>C) of the RET protooncogene is responsible for more than 95% of MEN2B cases. Another pathogenic variant, alanine to phenylalanine at codon 883 in exon 15 of the RET protooncogene, has been found in 4% of MEN2B cases.

Case Report

The patient was a 19-year-old man who had been troubled by episodic tachycardia of 10 minutes duration and occurring every other day for the past 1 year. At age 12 he was diagnosed with MEN2B when an ophthalmologist detected enlarged corneal nerves, which led to germline genetic testing that documented a pathogenic variant in the RET protooncogene (p.Met918Thr; c.2753T>C). As with most patients with MEN2B, no one else in the family carried the mutation. ^, Other stigmata of MEN2B were clearly evident, including mucocutaneous neuromas of the lips and tongue ( Fig. 46.1 ). At age 12 he underwent thyroidectomy for bilateral multicentric medullary thyroid carcinoma (MTC). Four lymph nodes contained metastatic MTC. The preoperative serum calcitonin concentration was 970 pg/mL and after surgery it improved to 41 pg/mL (normal, <15.9 pg/mL). At 15 years of age he underwent right adrenalectomy for multifocal pheochromocytoma (2 × 1.5 × 1.2 cm and 0.5 cm). He took no regular medications. What was of the most concern to the patient was the tongue mucocutaneous neuromas that were a constant irritation because he would inadvertently bite them. His blood pressure was 118/55 mm Hg, heart rate 68 beats per minute, and body mass index 18.6 kg/m ² .

INVESTIGATIONS

Preoperative laboratory studies are shown in Table 46.1 . The levels of metanephrine in the blood and urine were diagnostic of an adrenergic pheochromocytoma. Serum calcitonin was elevated at 168 pg/mL (normal, <15.9 pg/mL) and consistent with metastatic MTC. Adrenal computed tomography (CT) scan showed a multinodular left adrenal gland ( Fig. 46.2 ). Neck ultrasound and CT of the chest, abdomen, and pelvis did not localize the sites of persistent MTC.

TABLE 46.1

Laboratory Tests

Biochemical Test	Result	Reference Range
Sodium, mmol/L	141	135–145
Potassium, mmol/L	4.2	3.6–5.2
Creatinine, mg/dL	1.1	0.8–1.3
Plasma metanephrine, nmol/L	1.47	<0.5
Plasma normetanephrine, nmol/L	1.38	<0.9
Serum calcitonin, pg/mL	168	<15.9
24-Hour urine:
Metanephrine, mcg	490	<400
Normetanephrine, mcg	328	<900
Norepinephrine, mcg	28	<80
Epinephrine, mcg	4.5	<20
Dopamine, mcg	182	<400