Incidence and clinical relevance of RET proto-oncogene germline mutations in pheochromocytoma patients.

BACKGROUND: Autosomal dominant cancer syndrome--multiple endocrine neoplasia type 2 (MEN 2), may exist more often than expected in patients with pheochromocytoma. Germline mutations identified recently in MEN 2 can be revealed by genetic screening. OBJECTIVE: To evaluate the frequency of RET (rearranged during transfection) mutations in patients with pheochromocytoma. DESIGN AND METHODS: We genetically screened germline mutations in the RET proto-oncogene and clinically re-evaluated patients with pheochromocytoma. A pentagastrin test and other biochemical studies were performed in all patients. SETTING: Department of Internal Medicine and Hypertension, The Medical University of Warsaw, Warsaw, Poland and the Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany. PARTICIPANTS: Seventy seven unselected patients with pheochromocytoma (19 men, 58 women, mean age: 51.55 +/- 1.5 years; pheochromocytoma confirmed histopathologically) out of 162 diagnosed and treated in the years 1957-1998 in the Department of Internal Medicine and Hypertension in Warsaw, Poland. The other 85 patients did not respond to the written invitation. MAIN OUTCOME MEASURES: The finding of RET mutations and diagnosis of MEN 2 in patients with pheochromocytoma. RESULTS: Genetic testing revealed germline mutations in the RET proto-oncogene in six patients (7.8%). All carriers had mutation of exon 11, codon 634: TGC to CGC. In four patients with this mutation, medullary thyroid carcinoma (MIC) was diagnosed and in three cases, surgically treated. Biochemical parameters: parathormone 31.88 +/- 2.87 pg/ml, calcitonin: 0 min 0.23 +/- 0.14 ng/ml; 2 min 0.49 +/- 0.21 ng/ml; 5 min 0.48 +/- 0.21 ng/ml, metoxycatecholamines: 601.62 +/- 42.71 microg/24h, epinephrine: 1.94 +/- 0.17 microg/24h, norepinephrine 13.96 +/- 1.3 microg/24h, carcinoembryonic antigen (CEA) 9.94 +/- 4.3 ng/ml. Ambulatory blood pressure monitoring (ABPM): systolic blood pressure (SBP): 116 +/- 1.9 mmHg, diastolic blood pressure (DBP): 73.7 +/- 0.9 mmHg. Clinical, biochemical and imaging procedures did not reveal any recurrence of pheochromocytoma in the 77 patients studied. CONCLUSIONS: Patients with pheochromocytoma should be genetically screened for mutations of the RET proto-oncogene. These patients should undergo clinical screening for MEN 2. In addition, genetic studies can be useful for the screening of the families of the carriers.

Alterations in plasma neuropeptide Y immunoreactivity and catecholamine levels during surgical removal of pheochromocytoma.

BACKGROUND: Neuropeptide Y, an abundant neurohormone present with catecholamines in the adrenal medulla, is a potent non-adrenergic vasoconstrictor and a vascular growth factor. OBJECTIVE: To determine the mechanism of the release from, and possible role of neuropeptide Y in, pheochromocytomas, compared with those of catecholamines. METHODS: Plasma and tumour levels of neuropeptide Y-immunoreactivity (by, radioimmunoassay) and of noradrenaline and adrenaline (by a radioenzymatic method) in 29 patients (19 women and 10 men, aged 22-68 years) were measured during surgical removal of the tumour, during alpha-adrenergic and beta-adrenergic blockade. Arterial systemic blood samples were withdrawn before the ligation of the vessels supplying the tumour, during its surgical manipulations and after its removal, while haemodynamics was monitored. RESULTS: Plasma neuropeptide Y levels in 17 patients (58.6%, group I) significantly increased during manipulations of the pheochromocytoma and returned completely to normal after its removal. This response was independent of the plasma neuropeptide Y immunoreactivity manipulation and was correlated to increases in plasma noradrenaline (r = 0.638, P < 0.02) but not adrenaline levels. Manipulation-induced increases in plasma neuropeptide Y-immunoreactivity were associated with greater neuropeptide Y content in tumours (r = 0.508, P < 0.05) but neither plasma nor tumour levels of neuropeptide Y immunoreactivity were correlated to tumour mass. Plasma levels of neuropeptide Y immunoreactivity in the remaining 12 patients (41.4%, group II) remained unchanged throughout the experimental period, while levels of circulating catecholamine rose. In all, in spite of our attempt at complete adrenergic blockade, tumour manipulation elevated arterial blood pressure and these changes were significantly correlated to increases in levels of catecholamines in patients in both groups but also to plasma neuropeptide Y immunoreactivity in patients in group I. CONCLUSION: Pheochromocytomas exhibit different patterns of secretion. For about half of the patients either the secretion of neuropeptide Y is uncoupled from that of catecholamines or its secretion could be obscured by an increase in degradation of neuropeptide Y to inactive fragments undetectable by radioimmunoassay.

Heart rate variability in pheochromocytoma.

The results of our study show that parasympathetic tone was higher in patients with pheochromocytoma than in patients with primary hypertension. An unusual spectral form of vagal activity was seen during excessive beta-adrenergic stimulation, while persistent hypertension with an excessive alpha-adrenergic stimulation was responsible for low cardiac sympathetic tone, probably due to desensitization of beta-adrenergic receptors.

Platelet norepinephrine and epinephrine concentration in patients with pheochromocytoma.

Platelet and plasma catecholamine concentrations were determined in 17 patients with surgically proven pheochromocytoma (mean age 42.3 years); in 31 patients with borderline hypertension (mean age 35.3 years) and in 9 healthy controls (mean age 39.3 years). Both platelet norepinephrine and epinephrine were significantly increased in patients with pheochromocytoma when compared with hypertensive and control groups (P less than .001). No correlation between platelet and plasma catecholamines was detected in all studied groups. The diagnostic accuracy of platelet catecholamine in pheochromocytoma is limited since increased platelet norepinephrine was found in 35.5% and increased platelet epinephrine was found in 19.4% of patients with essential hypertension.

Blood pressure, plasma NPY and catecholamines during physical exercise in relation to menstrual cycle, ovariectomy, and estrogen replacement.

Some evidences indicate that the female sex hormones protect against the development of cardiovascular diseases. Modulation of sympathetic activity may be one of the possibilities. We investigated the influence of treadmill stress on blood pressure (BP) and plasma neuropeptide Y (NPY), norepinephrine (NE) and epinephrine (E) concentrations in 11 normotensive, menstruating women in the follicular (HWf) and luteal (HWl) phases and in eight ovariectomized women, before (OVX) and after estrogen supplementation (OVXe). Both at rest and during exercise there were no differences in BP between HWf and HWl and between OVX and OVXe. During stress BP was significantly lower in HWf and HWl than in OVX but not in OVXe. NPY did not differ significantly between the groups of women either at rest or during activity. We did not observe differences in resting and stimulated NE and E between HWf and HWl and between OVX and OVXe. Neither resting nor activated NE and E differed between the groups, except higher stimulated NE in OVX than in HWf. These results suggest that the female sex hormones may modulate the BP response to dynamic exercise. Our data support evidence that this influence may be exerted by circulating catecholamines and not by NPY.

Circulating neuropeptide Y in humans: relation to changes in catecholamine levels and changes in hemodynamics.

Neuropeptide-Y (NPY) is a sympathetic cotransmitter, which causes vasoconstriction, decreases coronary blood flow and decreases cardiac output. Circulating immunoreactive NPY (ir-NPY) levels increase with exercise, in patients admitted to the coronary care unit, and during thoracic surgery, and may play a role in postoperative hemodynamics. We studied changes in ir-NPY, epinephrine (E) and norepinephrine (NE) arterial plasma levels, and their correlation to simultaneous hemodynamic measurements at 8 perioperative time points in 13 patients undergoing open heart surgery. Changes in circulating ir-NPY negatively correlated with changes in systemic vascular resistance index (SVRI), mean arterial pressure (MAP) and mean pulmonary arterial pressure (MPAP) (P < 0.05), suggesting that the hemodynamic changes were the cause of the changes in ir-NPY levels, inducing overflow of NPY into the circulation via sympathetic activation. Changes in NE and E levels positively correlated with changes in heart rate (HR), SVRI and MPAP. Changes in E levels also positively correlated with changes in stroke volume index (SVI), central venous pressure (CVP) and cardiac index (CI). NE levels correlated well with E levels, but catecholamine levels did not correlate with ir-NPY levels. These results suggest, that the elevation in circulating NPY levels previously noted in patients with heart failure and acute myocardial infarction may reflect changes in NPY overflow and/or clearance secondary to increased sympathetic activity and to hemodynamic changes.

The urinary excretion of 3-methoxy-4-hydroxyphenylglycól in acute myocardial infarction.

Urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), noradrenaline, adrenaline and vanillylmandelic acid (VMA) was studied in 30 patients with acute myocardial infarction. The excretion of MHPG was higher in patients with myocardial infarction than in the control group, with no difference between uncomplicated and complicated courses of the disease. The excretion of MHPG showed a negative although not significant correlation with noradrenaline and VMA during the first days of infarction and a statistically significant positive correlation on the 5th day of the disease. The possible causes of the changes observed are discussed.

Effect of removal of phaeochromocytoma on diurnal variability of blood pressure, heart rhythm and excretion of catecholamines.

Ambulatory 24 hour blood pressure and ECG monitoring with simultaneous estimation of the urinary excretion of noradrenaline and adrenaline were performed in seven patients with phaeochromocytoma, before and after removal of the tumour. Mean blood pressure during eight 3-hour periods, mean heart rate, and noradrenaline and adrenaline excretion during four 6-hour periods were estimated. Mean blood pressure before surgery did not show any significant circadian changes. After surgery both systolic and diastolic blood pressures were significantly lower at night than in the daytime periods. In contrast, mean heart rate before surgery was significantly lower at night than in the morning, and this relationship was greater after surgery. Ventricular arrhythmias during 24 hour monitoring were noted in three patients before and in six after surgery. These findings suggest that profound disturbances of autonomic blood pressure regulation improve after removal of phaeochromocytoma, and that ventricular arrhythmias, except for paroxysmal symptoms, tend to be less frequent before than after surgery.

Heart rate variability before sudden blood pressure elevations or complex cardiac arrhythmias in phaeochromocytoma.

In phaeochromocytoma, sudden hypertensive or arrhythmic episodes are believed to be associated with excessive free catecholamine excretion. However, lack of correlation between blood pressure (BP) and plasma catecholamine levels has been reported. Therefore an attempt was made to assess the sympathovagal balance before and during episodes of BP elevation or complex cardiac arrhythmias in this disease. Ten patients with phaeochromocytoma and 10 matched controls with essential hypertension underwent simultaneous 24 h Holter ECG and BP monitoring. BP elevation was diagnosed when the BP exceeded the mean 24 h values by 40 mm Hg systolic or 30 mm Hg diastolic, respectively. Heart rate variability (HRV) was measured for 5 min periods 1 h before, 15 min before and during 13 episodes of BP elevation in phaeochromocytoma and 13 episodes in the control group, as well as at 1 h, 15 min and immediately before five arrhythmic events in phaeochromocytoma. In phaeochromocytoma, vagal activity measured 1 h before BP elevation was markedly higher than in control hypertensives. However, in both groups at 15 min before and during the hypertensive events, the vagal tone decreased significantly. In contrast, just before the arrhythmic events HRV remained unaltered with a slight insignificant increase in sympathetic activity. We conclude that in phaeochromocytoma, pronounced BP elevations during daily activities are preceded by a parasympathetic withdrawal, similar to the findings in essential hypertension. Such a sequence does not seem to precede sudden complex arrhythmic events in phaeochromocytoma.

Influence of alpha-adrenergic blockade on ventricular arrhythmias, QTc interval and heart rate variability in phaeochromocytoma.

There are strong experimental evidences that alpha 1-adrenergic stimulation significantly influences cardiac arrhythmogenesis, especially during myocardial ischaemia and reperfusion. However, anti-arrhythmic effects of alpha-blockade in humans were scarcely utilised. Thus the purpose of our study was to assess these effects in patients with phaeochromocytoma. In 22 patients simultaneous 24 h ECG and blood pressure (BP) monitoring, as well as estimation of the urinary 24 h free catecholamine excretion, were performed twice: before and during the treatment with the non-selective alpha-blocker, phenoxybenzamine. The heart rate variability was measured during four 5 min periods, at 10.00, 16.00, 22.00 and 04.00. During alpha-blockade systolic blood pressure (SBP) decreased from 137.6 +/- 23.8 to 126.5 +/- 15.7 mm Hg (P < 0.01), heart rate increased from 83.0 +/- 9.9 to 88.5 +/- 10.0/min (P < 0.02) and duration of QTc interval unsignificantly increased. Incidence of frequent or repetitive ventricular arrhythmias was significantly higher before treatment (in 9 vs 3 of 22 patients, P < 0.05). Heart rate variability significantly decreased during the treatment, with regard to all parameters, representing both the sympathetic and parasympathetic activity. We conclude that non-selective alpha-blockade significantly decreases the incidence of frequent or repetitive ventricular arrhythmias in patients with phaeochromocytoma, although the lack of QTc interval shortening suggests that the effect of class I drugs may participate in the anti-arrhythmic effects of phenoxybenzamine. Moreover, non-selective alpha-blockade in phaeochromocytoma significantly diminishes vagal activity.

Endothelin-1 and neuropeptide Y plasma concentrations in renal venous blood of hypertensive patients with unilateral renal artery stenosis.

The aim of the study was to investigate endothelin-1 (ET-1) and neuropeptide Y (NPY) plasma concentrations in renal venous blood of hypertensive patients with unilateral renal artery stenosis (URAS). The study was performed in 22 patients with URAS and 18 patients diagnosed as essentially hypertensive. In each subject renal arteriography and renal vein catheterisation was performed. Blood samples for ET-1, NPY and plasma renin activity (PRA) were withdrawn from renal veins and vena cava inferior, and for ET-1 and NPY from the aorta. Patients with URAS were divided in two subgroups according to the renal vein renin ratio. Both in nine patients with URAS and ratio > 1.5 and in 13 patients with URAS and ratio < 1.5, ET-1 and NPY plasma concentrations evaluated in renal venous blood of the ischaemic kidney were not different from those assessed in the contralateral side, in vena cava inferior and in the aorta. In essential hypertension, the mean ET-1 and NPY plasma concentrations of both renal veins were not different from the ET-1 and NPY plasma values assessed in renal vein of stenosed and contralateral side, vena cava and aorta of patients with URAS with and without activation of the renin system. Our study indicates that chronic ischaemia does not affect ET-1 and NPY plasma concentrations in renal venous blood of hypertensive URAS patients both with and without activation of the renin system.

Pheochromocytoma--the catecholamine dependent hypertension.

Pheochromocytoma is a unique type of hypertension caused by excessive production of catecholamines by the chromaffin tumor. Pheochromocytoma, a potentially life-threatening disease, is a rare cause of hypertension. The incidence varies from 0.1 to 0.8% of hypertensive population. The author's experience is based on 138 patients treated in one institution from 1956 to 1995. Hormonal activity of pheochromocytoma varies considerably, influencing the pattern, of blood pressure and the clinical symptoms. It is emphasized that different other humoral mechanisms may play a role in the pathophysiology of this type of endocrine hypertension. Biochemical tests and non-invasive localizing methods are essential for the definite diagnosis of pheochromocytoma. A great progress has been made in this respect during the last three decades. Surgical removal of the tumor is the only definite therapy with low morbidity and mortality.

Immunomorphological studies and cytometric DNA ploidy in diagnostics of pheochromocytoma.

The aim of the study was to define features indicating malignancy in pheochromocytoma through analysis of clinical data, immunomorphological and nuclear DNA ploidy patterns with flow cytometry. The studied group consisted of 33 patients with hypertension and adrenal gland tumor. In all patients 24 hr measurements of adrenaline, noradrenaline, dopamine and their metabolites were taken and the content of these substances in the tumor tissue was measured. Morphologically most pheochromocytomas displayed alveolar pattern with polyhedral cells with clear cytoplasm. Nuclear pleomorphism was infrequent and mitotic figures were rare. In 5 tumors areas of ganglioneuromatous differentiation were present with neurofilament expression. Morphological features indicating malignancy were noted--vascular emboli of tumor cells, capsular infiltration and foci of necrosis. However, in the patient with metastases evident during operation, none of those features was found in the tumor sample. All pheochromocytomas expressed neuroendocrine markers (chromogranin A, synaptophysin and NSE) and most also vimentin. Reactivity of other markers was negligible. In DNA ploidy studies in 22/33 cases there was DNA diploid (normal) pattern. The patient with metastases belonged to this group. In 3 cases there were aneuploid tumor cells on histograms and in 8 increased number of tetraploid cells. The follow-up period of our patients was 1-43 months.

[Is there a correlation between serum dopamine level and blood pressure during upright posture?]. / Czy istnieje wspólzaleznosc miedzy stezeniem dopaminy we krwi i cisnieniem tetniczym podczas pionizacji?

In the face known antihypertensive action of small dopamine (DA) concentrations, serum free and conjugated dopamine levels were determined during orthostatic impulse. It was also estimated, whether correlation between blood pressure changes and serum dopamine concentration existed under those conditions. 9 patients with borderline hypertension, 8 with fixed hypertension and 5 healthy volunteers (control group) underwent the 10 minute passive tilt up test. It caused significant decrease of free DA concentration in healthy men as well as in those with borderline hypertension and conjugated DA level in both groups of patients with primary hypertension. Blood pressure increased only in patients with borderline hypertension. Most expressed changes in dopamine concentration were also observed in those patients and they only had increased serum DBH activity. Blood pressure changes inversely correlated with changes of serum free and/or conjugated DA levels in the control group and in patients with primary hypertension. Authors stated basing on this study results, that serum DA level lowering caused by the orthostatic impulse can be one of phenomenons enable adaptation for a vertical position.

[Are there correlations of hormonal activity in pheochromocytoma and serum as well as erythrocyte sodium and potassium concentrations in patients with pheochromocytoma]. / Czy istnieje wspólzaleznosc miedzy czynnoscia hormonalna guza chromochlonneego a stezeniem sodu i potasu we krwi i erytrocytach u chorych z pheochromocytoma?

Interrelationship between serum Na+, K+ concentrations and the excretion of norepinephrine (NA), epinephrine (A) in the urine was studied in 69 patients aged 15-69 with pheochromocytoma (PH), and between serum Na+, K+ concentrations and serum NA, A levels in 53 patients. Furthermore, in 15 patients correlation between Na+, K+ concentrations in erytrocytes and serum NA, A levels was estimated. Na+ and K+ concentrations were determined using photometric analysis, NA and A excretion in the urine using fluorometric method and in blood by radiometry. Hypokalemia and hyponatremia were stated in 22% and 19% of patients with PH, respectively. Only in patients with electrolytic disorders correlation of serum as well as erythrocyte Na+ concentrations with serum NA level and between serum K+ and A concentrations were proved. In the part of studied patients with PH, the NA and A excess induced disorders of electrolytic homeostasis.

[Free serotonin level in the blood of patients with borderline and essential hypertension]. / Stezenie wolnej serotoniny we krwi u chorych z nadcisnieniem tetniczym granicznym i utrwalonym.

Serotonin appears to play an important part in the pathogenesis of essential hypertension. Various studies have shown, that the metabolism of serotonin may be disturbed in some pathological conditions for example in hypertension. It concerns also the changed mechanisms of uptake and release of serotonin. The certain blood vessels may become more hypersensitive to the vasoconstrictor effects of serotonin in patients with hypertension than in normal subjects. During chronic treatment with ketanserin, S2-serotonergic antagonist, blood pressure is reduced in spontaneously hypertensive rats and in humans. This fact can also indicate indirectly, that that serotonin plays a part in the pathogenesis of essential hypertension. The aim of the study was to determine the concentration of free serotonin (S) in the blood of 15 patients with sustained essential hypertension in the mean age 32.8 +/- 1.8, of 23 patients with borderline essential hypertension in the mean age 29.0 +/- 3.0 and of 10 normal subjects in the mean age 31.1 +/- 1.7 years. Plasma free serotonin was determined by fluorometric method. All patients and controls were investigated at the hospital. They were on normosodium diet, without drugs for last two weeks. The fasting blood samples were collected in the supine position. Free serotonin blood concentration was significantly higher in hypertensive group than in normal subjects. The important difference of serotonin blood concentration between two groups of hypertensive patients was noticed. It was significantly higher in group of patients with sustained hypertension, than in group with borderline hypertension (p less than 0.05). Our results are similar to the observations of other authors.(ABSTRACT TRUNCATED AT 250 WORDS)

[Correlations between catecholamines and prostaglandins in patients with primary arterial hypertension and pheochromocytoma in basic conditions and after administration of clonidine]. / Wspólzaleznosc miedzy katecholaminami i prostaglandynami u chorych z nadcisnieniem tetniczym pierwotnym i z guzem chromochlonnym w warunkach podstawowych i po klonidynie.

Authors assessed correlation between venous blood catecholamines and prostaglandins concentrations before and after inhibition of sympathetic activity by clonidine in patients with primary hypertension or pheochromocytoma. 30 patients with essential uncomplicated hypertension and 11 with pheochromocytoma underwent the study. The control group consisted of 6 healthy volunteers. Serum norepinephrine (NA), epinephrine (A), prostaglandins: PGE2 PGF2 alpha and prostacyclin metabolite -6-keto-PGF1 alpha were determined before and 3 hours after oral administration of 0.3 mg clonidine. Negative correlation was stated between basic serum norepinephrine and 6-keto-PGF1 alpha concentrations in patients with pheochromocytoma, which could indicate prostacyclin metabolism disorders during persistent hypercatecholaminemia . There was no correlation between catecholamines and prostaglandins during the inhibition of sympathetic activity in patients with pheochromocytoma as well as essential hypertension. The positive correlation was observed between changes in serum NA and PGF2 alpha levels in patients with borderline hypertension. Thus, one may suppose, that correlation between na excretion and vasoconstrictive PGF2 proved in acute experiments, becomes evident within the early stage of hypertension also during sympathetic activity inhibition.

[Primary arterial hypertension. Treatment with captopril and function of the left heart ventricle, concentration of catecholamine in blood and activity of renin]. / Pierwotne nadcsnienie tetnicze. leczenie kaptoprylem a czynnosc lewej komory serca, stezenie katecholamin we krwi i aktywnosc reniny.

We evaluated the effect of captopril treatment on left ventricular mass (LVM) and function in sustained mild-to-moderate primary hypertension. In 16 men aged 34.5 +/- 6.4 yrs. M-mode echo and pulsed wave Doppler recordings were obtained prior to and after 2 months captopril treatment (50-150 mg daily). No significant changes in heart rate, systolic blood pressure, ejection fraction, fractional shortening, cardiac output, LVM and Doppler-derived indices of mitral inflow were observed. Diastolic blood pressure measured during examination fell from 102.2 +/- 13.3 to 90.3 +/- 9 mmHg (p less than 0.026). No consistent correlations between catecholamines and indexes of left ventricular function were found. Two-month captopril therapy in mild-to-moderate hypertension results in diastolic blood pressure lowering with no effect on LVM or left ventricular function.

[Correlations of atrial natriuretic peptide and catecholamine levels in the blood during surgical removal of pheochromocytoma]. / Wspólzaleznosc miedzy stezeniem przedsionkowego peptydu natriuretycznego a katecholaminami we krwi w czasie operacyjnego usuniecia guza chromochlonnego.

Atrial natriuretic peptide concentrations (ANP) were determined in 4 patients with pheochromocytoma during its surgical removal. There was no correlation among ANP level, plasma catecholamines concentrations and blood pressure. Increase of plasma ANP concentration after tumor removal can be explained by simultaneously observed hypervolemia. It proves that ANP secretion mostly depends on enlarged central blood volume.

[Evaluation of the usefulness for measuring catecholamines and their principle metabolites in the diagnosis of pheochromocytoma]. / Ocena przydatnosci oznaczania katecholamin i ich glównych metabolitów w diagnostyce guzów chromochlonnych.

Objective of the study was assessment of the usefulness of determination of noradrenaline (NA) and adrenaline (A) in urine and blood as well as the total methoxycatecholamines (MNA +MA), vanillylmandelic acid (VMA), DOPA and dopamine (DA) urinary excretion in diagnosis of pheochromocytoma. The experience based on 155 patients with pheochromocytoma (105F, 50M, age 18-82 yrs) diagnosed in the Department of Hypertension and Angiology Academy of Medicine in Warsaw will be discussed. In all patients excluding 2 cases pheochromocytoma has been proven histopathologically. The most considerable diagnostic usefulness of MNA + MA indication was proven. MNA + MA was increased in 96.6 patients. In 89.6% patients an increased excretion of NA and A or one of this catecholamines was demonstrated. An increased excretion of VMA was demonstrated in 75%. The excretion of DOPA and dopamine was tested in 120 cases. An increased excretion of DA was shown in 31% and DOPA in 16%.