3-Methoxytyramine, a Highly Sensitive Marker for Symptomatic Paraganglioma

Introduction:
Catecholamines are hormones produced from the chromaffin cells in the adrenal medulla and the sympathetic and parasympathetic systems. Paragangliomas are histologically similar tumors that form in the extra-adrenal paraganglia. Tumors that predominantly produce dopamine are rare and often pose a diagnostic challenge. We describe a patient with symptoms of catecholamine hypersecretion who was initially misdiagnosed with panic disorder and later found to have dopamine-only secreting paraganglioma.

Case Description:
68-year-old female with a history of hypertension, and hyperparathyroidism, presented to the hospital with two weeks history of pounding headaches, flushing, palpitations, and tremors. She was recently diagnosed with panic disorder. Her blood pressure was 213/100, and her heart rate was 64 beats/min. Imaging of her brain showed a 1.2 cm left carotid body tumor. Further testing showed plasma metanephrine and normetanephrine in the normal range; 26 pg/mL (12-27) and 76 pg/mL (24-145), respectively. Her urine epinephrine, norepinephrine, and dopamine were all normal; 3 ug/d (1-14), 110 ug/d (14-120), and 137 ug/d (71-485), respectively. Repeat testing showed normal plasma metanephrine and normetanephrine with normal urine epinephrine and dopamine and mildly elevated urine norepinephrine 125 ug/d. Her 24-hour urine 3-Methoxythyramine test was elevated at 348 mcg/24 hr ( <242). As a result, the patient was treated with an alpha blockade agent with plans for surgical removal of the paraganglioma. In addition, genetic testing will be performed.

Discussion:
Paragangliomas are extra-adrenal neuroendocrine tumors that produce norepinephrine, epinephrine, and rarely dopamine. These catecholamines are synthesized from tyrosine and undergo O-methylation to its metabolite products. The differences in catecholamine production reflect differences in the expression of the methylation enzymes in the catecholamine biosynthetic cascade.

Tumors that exclusively produce dopamine are extremely rare and often malignant. In most of the cases reported in the literature, patients were asymptomatic. However, in our case, the patient had apparent symptoms of catecholamine hypersecretion.

Patients with symptoms of catecholamine excess are often screened with urine or plasma measurements of normetanephrine and metanephrine alone, which will miss cases of dopamine hypersecretion. Furthermore, dopamine functions in the kidney as a natriuretic hormone and is excreted in significant amounts in the urine. Hence, urine dopamine is not a sensitive or specific marker for dopamine-secreting tumors. On the other hand, 3-methoxytyramine, the O-methylated metabolite of dopamine, is a more sensitive and specific marker for dopamine-secreting tumors.