53 summer months and when he was more active.

He noted the pattern of distribution of the

54 sweating to be generalized, but mostly affecting the upper half of his body. Further work-up

55 included normal thyroid studies (free T4 1 ng/dL (0.78-1.33 ng/dL)) and a negative purified

56 protein derivative (PPD) skin test for tuberculosis. A 24-hour urine collection for norepinephrine

57 was 1,002 ug/24 hours (0-135 ug/24 hours), 24-hour urine epinephrine was 10 ug/24 hours (0-

58 20 ug/24 hours) and a 24-hour urine dopamine level was 301 ug/24 hours (0-510 ug/24 hours).

59 Plasma normetanephrine level was 2873 pg/mL (0-145 pg/mL) and a norepinephrine level was

60 2869 pg/mL (0-874 pg/mL). Other catecholamine levels and their degradation products were

of
61 within normal limits as follows: plasma metanephrine value of 53 pg/mL (0-62 pg/mL), plasma

ro
62 epinephrine <15 pg/mL (0-62), and plasma dopamine level of <30 pg/mL (0-48 pg/mL) (see

63
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Table 1). The plasma metanephrines, 24-hour urine metanephrines and urine catecholamines
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64 were assayed with liquid chromatography/tandem mass spectrometry. The plasma
lP

65 catecholamines were assayed by high pressure liquid chromatography with electrochemical

na

66 detection of the frozen plasma specimen. A CT scan with enhanced Hounsfield units of 129

67 demonstrated a 4.0 x 3.1 x 4.3cm left adrenal mass. Despite normotensive blood pressures of
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68 close to 120/80 mmHg on previous office visits, the patient was noted to have a blood pressure
Jo

69 reading of 150/80 mmHg in an office visit prior to surgery after the diagnosis had been

70 established, potentially indicating paroxysmal hypertension that had not been unmasked on

71 prior visits. He underwent a surgical resection of the pheochromocytoma after treatment with

72 doxazosin 1mg for alpha-adrenergic blockade pre-operatively with resolution of hypertension

73 and metoprolol 12.5mg perioperatively. Pathology confirmed a completely excised

74 pheochromocytoma. The diaphoresis resolved within 4 weeks after resection of

75 pheochromocytoma. He underwent genetic testing for hereditary cancer syndromes and tested

76 negative for 14 possible gene mutations, including MEN1, NF1, RET, SDHx, and VHL.

77

78 Discussion:
79 Herein we present a 20-year-old man with a norepinephrine-secreting pheochromocytoma who

80 presented with diaphoresis as the major symptom but lacked overt hypertension, headache,

81 flushing, tachycardia, or other features of pheochromocytoma. Unlike 40-45% of patients

82 between ages 11 and 20 [5], this patient also did not appear to have an underlying genetic

83 predisposition. The differential diagnosis for this patient with generalized sweating included

84 lymphoma, adrenal insufficiency, tuberculosis, thyrotoxicosis and pheochromocytoma.

85 Lymphoma was less likely due to normal WBC differential. The lack of fatigue, nausea, weight

86 loss or evidence of orthostatic hypotension put adrenal insufficiency lower on the differential.

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87 Tuberculin skin test was negative ruling out tuberculosis. Thyroid studies were normal

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88 eliminating hyperthyroidism. A pheochromocytoma became the most likely diagnosis, despite no

89
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other signs and symptoms of catecholamine excess, and was confirmed with the laboratory
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90 data, CT scan, and pathology.
lP

91
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92 Pheochromocytomas are primarily tumors of the medulla of the adrenal gland and secrete

93 catecholamines (norepinephrine and epinephrine). They are associated with significant

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94 cardiovascular morbidity and mortality in up to 20% of those afflicted [6,7]. The signs and
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95 symptoms noted above (hypertension, headache, flushing, tachycardia, etc.) have been

96 attributed to the direct effects of catecholamines systemically, including on vascular smooth

97 muscle and the central nervous system. For example, it is well known that norepinephrine has a

98 high affinity for alpha-1 receptors which are primarily responsible for vasoconstriction and thus

99 hypertension is a common finding in pheochromocytoma. Epinephrine traditionally has stronger

100 affinity for the beta receptors, particularly beta-2 receptors, at lower physiologic levels, but at

101 higher concentrations, also will bind alpha receptors. Both norepinephrine and epinephrine have

102 some affinity for beta-1 receptors which can induce tachycardia. The excess catecholamines, as

103 described, are the primary cause of the cardiovascular morbidity and mortality associated with

104 pheochromocytoma. Cardiovascular sequelae include arrhythmias, myocardial infarction,