A l d o s t e r o n o m a in a Child With Localization by Adrenal Vein Aldosterone: Collective Review of the Literature By George Kafrouni, Marilyn D. Oakes, Arthur N. Lurvey, and Vincent DeQuattro

Y P E R A L D O S T E R O N I S M due to an aldosteronoma is very rare in childhood. Many cases of aldosterone-secreting tumors have been reported in adults; only five cases in children under the age of 16 have been collected from the world medical literature, j-5 The incidence of hypertension in childhood has been reported to be 2%. 6 Primary aldosteronoma is a potentially curable cause of hypertension, and careful investigation and work-up of hypertensive children is essential if an aldosteronoma is to be discovered and removed. We are reporting the sixth case of aldosteronoma in a child. The diagnosis was suggested by hypertension and hypokalemia and confirmed by increased urinary and plasma aldosterone and decreased plasma renin. The adenoma was localized before operation by adrenal venography and selective adrenal vein plasma aldosterone determination. Operative removal of the aldosteronoma from the right adrenal has been followed by complete relief of symptoms.

H

CASE REPORT

History A 10-yr-old black male was referred to the White Memorial Medical Center in June 1971. His parents first noted onset of enuresis and polydipsia up to 8 liters of fluid per day at 7 yr of age. He was found to be hypertensive on physical examination in school in December 1970. At age 989 he had an episode of carpopedal spasm that lasted about half an hour, and during the next 6 m o began to complain of fatigue, occasional headaches, a n d nausea. T h e initial work-up at another hospital in April 1971 showed a blood pressure of 200/100, serum potassium o f 1.4 meq/liter, and urine specific gravity of 1.005. He was placed on an aldosterone antagonist, spironolactone (Aldactone), 25 mg p.o.t.i.d., and reserpine 0.25 mg p.o.t.i.d., but his blood pressure remained elevated.

Physical Examination The child was well developed, well nourished, and in no acute distress. Blood pressure was 170/120 without significant pastural variation. Funduscopic examination was normal. The cardiac impulse was 2 cm lateral to the midclavicular line, and a grade I/VI blowing systolic m u r m u r was heard at the left sternal border. There was no edema and the rest of the physical examination was normal.

From the Departments of Surgery and Internal Medicine, White Memorial Medical Center, and the University of Southern CaliJbrnia School Of Medicine, Los A ngeles, Calif Supported in part by US General Clinical Research Center Grant RR-43 and NIH Trainee Grant A M-05176. Address Jbr reprint requests: George KaJrouni, M.D., 1710 Brooklyn A venue, Los Angeles, Calif 90033. ~c'~1975 by Grune & Stratton, Inc. Journal of Pediatric Surgery, Vol. 10, No. 6 (December), 1975

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Table 1. Preoperative Laboratory Results Test Serum potassium Serum sodium Daily urine output Urinary aldosterone excretion Plasma renin activity Regular sodium diet, supine overnight 20 meq sodium diet, standing 1 hr Water immersion test for nonsuppressible aldosteronism Preimmersion 2 hr partia ! immersion 4 hr partial immersion Aldosterone and cortisol concentration in the blood from adrenal veins and inferior vena cava (IVC) Serum aldosterone Left adrenal vein Right adrenal vein Low IVC Serum cortisol Left adrenal vein Right adrenal vein Low IVC

Patient's Results

Laboratory Normal Values

3.9-5.1 meqfliter

2.3-2.7 meq/liter > 140 meq/liter 2-6.5 liter/day 42-70 #g/day

135-148 meq/liter 0.6-2.0 liter/day < 26 # g / d a y (adults)

0.07 ng/ml/hr

0.7 • 0.05 ng/ml/hr

Nondetectable

2.9 • 1.2 ng/ml/hr

1030 ng/100 ml 930 ng/lO0 ml 1080 ng/100 ml

20-120 ng/lO0 ml 2.0-17.5 ng/100 ml

0.7 #g/100 ml 31.2 #g/100 ml 0.5 #g/100 ml

11.8/~g/t 00 m] 20.9/zg/100 ml 14.6 #g/100 ml

0.01-0.03 #g/100 ml (Normal range in peripheral veins; adrenal vein 10% higher) 5-25 #g/lO0 ml (Normal range in peripheral veins; adrenal vein 10% higher)

Laboratory Results ( Table 1 ) Results from laboratory investigations showed low serum potassium, ranging from 2.3 to 2.7 meq/liter. Serum sodium values were above 140 meq/liter. During hospitalization the patient's daily urine outpu't ranged from 2 to 6.5 liters/day. Urine potassium values were high, ranging from 45 to 62 m e q / 2 4 hr. Urinary aldosterone excretion rates when the patient was not receiving spironolactone ranged from 42 to 70 u g / d a y . Urine specific gravity was 1.003 and urine osmolality 271 m O s m / k g . Plasma renin activity measured while the patient was supine overnight and on a regular sodium diet (80 100 meq) was 0.07 n g / m l / h r . After 3 days on a 20-meq sodium diet and while standing for I hr, the patient's plasma renin was nondetectable. Electrocardiogram and chest x-ray film showed left ventricular hypertrophy. A water immersion test was performed by Dr. Milton Crane 7 at Loma kinda University School of Medicine. Although the test was performed while the patient was on a low sodium diet, the values were clearly abnormal compared to normal patients under the same conditions of immersion and diet. Plasma aldosterone was reported as 1030 ng/100 ml before immersion, 930 ng/100 ml after 2 hr of partial immersion, and 1080 ng/100 ml after 4 hr. (Normal values on a low sodium diet n.p.o. 12 hr, ambulatory 2 h r : 2 0 - 1 2 0 n g / 1 0 0 r n l b e f o r e i m m e r s i o n , 2.0 1 7 . 5 n g / 1 0 0 m l a f t e r 2 h r o f p a r t i a l i m m e r s i o n . ) Adrenal venography and aortography performed in August 1971 were reported as tbllows: "The right adrenal venogram disclosed a small normal gland at the inferior pole and 1.2 1.5-cm ovalshaped mass surrounded and described by venules in the upper pole of this gland (Fig. 1). Aortography demonstrated a suggestion of fine middle suprarenal arteries reaching the right adrenal gland directly from the abdominal aorta above the origin of the right renal artery. However, there was no perceptible t u m o r blush. The left adrenal venogram and aortogram demonstrated no mass lesion. Prior to venography, blood was obtained from the adrenal veins and the

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Fig. I. Right adrenal venogram demonstrating aldosteronoma. inferior vena cava. Aldosterone was increased in the right adrenal vein blood to 31.2 ~g/100 ml (normal, 0.Ol 0.03 ~g/100 ml).

Treatment Prior to surgery, the patient's blood pressure was maintained around 130/110 on the following medications: methyldopa, 250 mg p . o . q . i . d . ; spironolactone, 50 mg p . o . t . i . d . ; reserpine, 0.5 m g p.o.h.s.; potassium, 15-30 cc p.o.t.i.d.; and a 20-meq sodium diet. In January 1972, surgical exploration was undertaken t h r o u g h a bilateral subcostal abdominal incision. Examination of the right adrenal revealed an enlarged gland with a discrete nodule present. A right adrenalectomy was performed. The left adrenal was normal to palpation (Fig. 2).

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Fig. 2.

Pathologic specimen.

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KAFROUNI ET AL.

Pathologic Description The right adrenal gland weighed 9 g and measured 4.5 • 2.9 • 1.4 cm. Along the superior aspect of the gland was a well-circumscribed oval-shaped nodule measuring 1.8 • 1.3 x 1.2 cm. On sectioning, the nodule had a solid canary-yellow cut surface. The noninvolved portion of the adrenal gland appeared generally atrophic. Microscopic sections o f the adrenal gland showed a well-circumscribed nodule generally separated from the adjacent adrenal p a r e n c h y m a by a thin connective tissue layer. The nodule was m a d e up of uniform large cells with pale cytoplasm and small-rounded dark nuclei. The a r r a n g e m e n t of the cells is that of the glomerulosa and vesiculata layers of the adrenal cortex. There was no evidence of malignancy.

Postoperative Course The patient did well postoperatively; serum potassium values averaged 3.6 meq/liter, and he had no further problem with enuresis or polydipsia. His blood pressure gradually returned to normal and stabilized at 120/80 3 m o after surgery. At follow-up 2 yr later, blood pressure

was 98/80. DISCUSSION

The known described cases of childhood aldosteronoma under the age of 16 in the world literature are tabulated in Table 2. All patients except ours were white and female 9 Blood pressure was elevated in all patients. In two patients hypertension was noted on routine physical examination and s y m p t o m s were recognized only in retrospect. The most c o m m o n presenting complaint was polydipsia noted in four patients; three patients had enuresis; and two patients complained of headache and weakness. Nocturia was present in five of the six children. One patient presented with virilization due to other steroids produced by the same adrenal tumor. One patient was first seen for behavior problems and back pain. Serum potassium concentrations were low in five patients. The t u m o r was found in the left adrenal in two patients, and in the right in four. Surgical removal resulted in correction of serum electrolytes and normal blood pressure in each of the young patients. Conn, in 1954, reported the first case of primary aldosteronism associated with an adrenal a d e n o m a in an adult. 8'9 Ten years later, a series of 145 cases of primary aldosteronism in adults had been analyzed and the clinical characteristics well described, m S y m p t o m s in order of declining frequency were muscle weakness, polyuria/nocturia, headache, polydipsia, paresthesias, visual disturbances, intermittent paralysis, and tetany. Prominent physical findings were hypertension, retinopathy, cardiomegaly, positive Trousseau's sign, tetany, positive Chvostek's sign, and paralysis. Over 70~o of these cases were in the 35-50-yr age bracket, with a 70~o preponderance of females. Most patients were hypokalemic; renal function was normal in more than 60~,, but the ability to concentrate urine was decreased. There are several differences in the clinical picture of primary hyperaldosteronism in children from that seen in adults (see Table 2). In children the t u m o r was found in the right adrenal twice as often as the left; in adults the left adrenal most often contained the tumor. The cure rate after adrenalectomy is 100~,~ in children 9 Only 70~, of the adult patients were cured by surgical removal of the aldosteronoma, 5~,,, died, and 25~o were improved but not cured. Blood pressure and serum potassium levels returned to normal in all the pediatric patients, and they were all asymptomatic on follow-up examinations 9

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Primary aldosteronism is suspected in a hypertensive, hypokalemic patient who shows renal potassium loss on normal sodium intake. The diagnosis of aldosteronism is established by elevated, nonsuppressible plasma or urine aldosterone and concomitant depressed plasma renin activity. In patients with aldosteronoma, the excessive steroid concentration and resultant sodium retention inhibits production of renin by the juxtaglomerular cell of the kidney; therefore the concentration of renin is decreased and its release is suppressed. In our patient, the renin activity or the angiotensin ! generated per milliliter plasma per hour was one-tenth the normal value and was not detectable after renin stimulation. On the other hand, in renal vascular disease, as occurs in renal artery stenosis or in malignant hypertension, aldosteronism is a result of excessive renin production. In these patients, renin activity is elevated and increases further with the stimulation test. The most valuable diagnostic procedure for localization is combined adrenal venography and measurement of adrenal vein aldosterone levels. Although complications have been reported, ~'~2 this procedure can provide a definitive diagnosis. In Horton's and Finck's review of 21 adult cases, ~3 adrenal venography was diagnostic in three-fourths of the cases and measurement of adrenal vein aldosterone was diagnostic in all. The results of measuring the concentration of aldosterone in the adrenal vein blood of our patient were diagnostic both in regard to the type of aldosteronism present and the actual location of the tumor. Aldosterone production from the tumor suppresses aldosterone secretion from the remaining normal cortex. Thus the contralateral adrenal vein aldosterone will be equivalent to peripheral vein aldosterone concentration. If the aldosteronism is a result of bilateral adrenal hyperplasia, the aldosterone concentration of both adrenal veins will be increased. In our patient, right adrenal vein aldosterone was increased markedly, and left adrenal vein aldosterone concentration was equal to the peripheral vein concentration, indicating a right adrenal aldosteronoma. This is the first report of the use of adrenal vein catheterization in a pediatric patient to assist in the localization of an aldosteronoma. Adrenal venography and catheterization could help in localizing other rare ectopic tumors. Embryonic migration of adrenal tissue sometimes results in cortical rests in renal or gonadal tissue, and aldosterone-secreting adenoma in kidney tissue, ~4 and hyperaldosteronism due to an ovarian androblastoma ~5bare been described. Blood pressure and hypokalemia in our patient were controlled preoperatively with a low sodium diet, spironolactone, potassium, reserpine, and methyldopa. The operative approach to the adrenals has been well described. ~6 It may be possible to spare the patient unnecessary exploration o f the contralateral side with more experience in the use of adrenal vein catheterization to localize the tumor. SUMMARY

Hyperaldosteronism due to aldosteronoma is a rare but potentially curable form of pediatric hypertension. We have presented a patient who had symptoms of enuresis and fatigue, and in whom the diagnosis was suggested by low serum potassium and persistent hypertension. Diagnosis was confirmed by in-

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creased plasma and urinary aldosterone and decreased plasma renin. The tumor was localized with the aid of adrenal venography and catheterization, which s h o w e d g r e a t l y i n c r e a s e d p l a s m a a l d o s t e r o n e l e v e l s in t h e r i g h t a d r e n a l v e i n . The pathologic findings were totally reversed by right adrenalectomy. The clinical picture and results following surgical removal of aldosteronep r o d u c i n g t u m o r s i n six c h i l d r e n a r e r e v i e w e d . ACKNOWLEDGMENT

The authors would like to thank Milton G. Crane, M.D., for his kind assistance in performing the immersion test and the plasma aldosterone measurements; David Dee, M.D., for adrenal venography; Daantje Meijeir and Howard Hammar for laboratory assistance; and Wanda Rice for assistance in literature review and preparation of the manuscript.

REFERENCES 1. Orndahl G, H~kfelt B, Ljunggren E, et al: Two cases of primary aldosteronism: Comments on differential diagnosis and difficulties in screening. Acta Med Scand 165:445, 1959 2. Crane MG, Holloway JE, Winsor WG: Aldosterone-secreting adenoma: Report of a case in a juvenile. Ann Intern Med 54:280, 196t 3. Cavell B, Sandeghrd E, Hi3kfelt B: Primary aldosteronism due to an adrenal adenoma in a three-year-old child. Acta Paediatr Scand 53:205, 1964 4. Mora H, Cullen M, Bergadfi C, et al: Adenoma suprarenal con virilizaci6n e hiperatdosteronismo en una nifia de 10 afios. (Suprarenal adenoma with viribzation and hyperaldosteronism in a 10 year old girl.) Rev Argent Endocrinol Metab 11:117, 1965 5. Kelch RP, Connors MH, Kaplan SL, et al: A calcified aldosterone-producing tumor in a hypertensive, normokalemic, prepubertal girl. J Pediatr 83:432, 1973 6. koggie JMH: Systemic hypertension in children and adolescents: Causes and treatment. Pediatr Clin North Am 18:1273, 1971 7. Crane MG, Harris J J: Primary aldosteronism: Observations on water and electrolyte changes during partial immersion. J Clin Endocrinol Metab 37:790, 1973 8. Conn JW: Potassium-losing nephritis. Br Med J 2:1414, 1954

9. Conn JW: Presidential address. Part II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 45:6, 1955 10. Conn JW, Knopf RF, Nesbit RM: Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am J Surg 107: 159, 1964 11. Fisher CE, Turner FA, Horton R: Remission of primary hyperaldosteronism after adrenal venography. N Engl J Med 285:334, 1971 12. Bookstein JJ, Conn J, Reuter SR: lntraadrenal hemorrhage as a complication of adrenal venography in primary aldosteronism. Radiology 90:778, 1968 13. Horton R, Finck E: Diagnosis and localization in primary aldosteronism. Ann Intern Med 76:885. 1972 14. Flanagan M J, McDonald JH: Heretotopic adrenoeortical adenoma producing primary aldosteronism. J Urol 98:133, 1967 15. Ehrlich EN, Dominguez OV, Samuels LT, et al: Aldosteronism and precocious puberty due to an ovarian androblastoma (Sertoli cell tumor). J Clin Endocrinol Metab 23:358, 1963 16. Able LW: In Benson CD, Mustard WT, Ravitch M M, et al (eds): Pediatric Surgery. Chicago, Year Book, 1969, p 1107