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Suprarenal tumor (Cushing's syndrome)
SUPRARENAIJ TUMOR (CUSHING'S SYNDROME)
M. G. PETERMAN, M.D. MILWAUKEE, ~VIS. HE ease of this patient is reported he had bilateral suprarenal tumors, but he did not conform completely to the clinical picture as described by Albright. The obesity was marked and developed rapidly, but was definitely associated with an excessively abnormal appetite; the fat accumulation involved not only the face, neck, trunk, and abdomen, but also the extremities. The muscular weakness was not marked; the osteoporosis was of moderate degree. In contradistinction to impotency, this boy had precocious pube r t y and virilism. Tumors of the suprarenal gland produce a definite well-known entity conveniently called Cushing's syndrome. The literature is replete with ease reports of this condition and exhaustive studies have been made. In Albright's second paper on the subject he specified certain clinical manifestations and states that " t h e diagnosis would be questionable in any ease which did not have the first three of these manifestations. They are: (1) diabetes, which is usually mild and often only demonstrable as the responsiveness to an alimentary hyperglycemia (i.e., decreased sugar tolerance), but which is resistant to insulin; (2) muscular weakness, with a low creatinine excretion as an indication of decreased muscle mass; (3) osteoporosis, especially of the
T because
spine (not to be confused with osteitis fibrosa generalisata or with osteomalaeia since the serum phosphatase level is normal rather than high), associated with hyperca]cinuria ear]y in the disease and, in many instances, with nephrolithiasis; (4) a thin, reddish (?) (transparent) skin, easy bruisability, often large purplish striae, a marked susceptibility to skin infection; (5) impotence in men and amenorrhea in women; (6) mild to moderate obesity, with a tendency f o r the fat to be deposited in the neck and face (mostly in the face) and to spare the extremities; (7) mild hirsutism without other evidence of virilism (clitoris not enlarged, thyroid eartilage and voice normal in females), usually but not always associated with a slight to moderate elevation in the urinary excretion of the 17-ketosteroids; (8) mild erythroeytosis (red count circa 5.8 M) without increased blood volume; (9) hypertension and arteriosclerosis often accompanied by coronary heart disease and vascular disease of the kidneys. ''1 This paper presents a thorough study of the problem. Among the other papers there were thirtythree well-studied cases presented by Kttowlto~ 2 in 1953. The electrolyte disturbances in Cushing's syndrome were reviewed by Sprague and Power a in 1953. Subtotal adrenalectomy for Cushing"s syndrome was re59
60
T H E J O U R N A L OF PEDIATRICS
viewed in detail by P r i e s t l y and associates ~ in 1951. Twenty-nine cases were presented. Other p e r t i n e n t reports concerning the s y n d r o m e are listed. ~ CASE REPORT
A 10-year-old boy was first seen on Aug. 23, 1951. He was b o r n Sept. 3, 1941, a f u l l - t e r m i n f a n t of the first p r e g n a n c y , with a n o r m a l labor and
F i g . 1.
delivery and a birth weight of 6 pounds 8 ounces. The physical and m e n t a l d e v e l o p m e n t were considered to be normal. The b o y h a d chicken p o x in 1947 and a mild ease of measles in 1948. The tonsils a n d adenoids were r e m o v e d w h e n he was 2 y e a r s of age. I n the p a s t two y e a r s the b o y h a d been gaining w e i g h t steadily at the r a t e of a b o u t 5 pounds a month. P r e v i o u s to this he was considered to be nervous and under-
weight. He had g r o w n in two years f r o m 60 to 168 pounds. The seeo n d a r y sex c h a r a c t e r s h a d been noted to develop. On examination, this b o y weighed 154 p o u n d s and measu r e d 52 in. in height (Pig. 1). Nutrition was f a i r ; m e n t a l response, exeellent. The blood pressure was 120/100. The left u p p e r central ineisor was missing. The tonsils were out d e a n . The genitals were n o r m a l in size b u t the pubie hair showed a female t y p e of distribution. The urine was n e g a t i v e ; the blood count was normal. The blood W a s s e r m a n n was n e g a t i v e ; sedimentation r a t e was normal, t i e was obviously obese but most of his excess weight was in the t r u n k , w i t h a " b u f f a l o h u m p " over his u p p e r thoracic spine. His face was r o u n d with r e d eheeks. There were striae in the axillae and in the groins. The extremities were thin and slightly weak. He was r e f e r r e d to M i l w a u k e e C h i l d r e n ' s H o s p i t a l on Aug. 25, 1951, where the following o b s e r v a t i o n s were m a d e : X - r a y s of the kidneys, ureters, and b l a d d e r were n e g a t i v e or normal. A n intravenous p y e l o g r a m was negative. X - r a y s of the long bones showed a moderate degree of osteoporosis. X - r a y s of the wrist showed a bone age of 10 years. E x a m i n a t i o n of the f u n d i and of the visual fields showed no abnormalities. The basal metabolic r a t e was -24. Blood pressure in the hospital r a n g e d f r o m 145/80 to 180/130. On Sept. 11, 1951, the e p i n e p h r i n e tolerance test showed a f a s t i n g blood s u g a r level of 139.5; a f t e r the injection of 4 minims of 1 to 1,000 crystalline epinephrine: in 15 m i n u t e s 154 mg., in 30 minutes 176 rag. Three d a y s later, a careful cheek on the blood pressure showed the following: supine--right arm 190/144, left arm 184/130; sitting u p - - r i g h t a r m 174/]36, left a r m 180/ 132; s t a n d i n g - - r i g h t a r m 174/132, left arm ]82/146. S e p t e m b e r 10 det e r m i n a t i o n of the steroids b y Dr. It. L. Mason of the Mayo Clinic was r e p o r t e d as follows: 17-ketosteroids 6.4 rag. in t w e n t y - f o u r hours, eor-
PETERMAN:
SUPRARENAL
ticosteroids 0.127 rag. in t w e n t y - f o u r hours. The serum cholesterol was 337 nag. The alkali reserve was 58.9 vol. per cent; sodium chloride 561 rag.; sodium 150 meq.; phosphorus 6.2 meq. The glucose tolerance test showed a fasting level of 122 rag. (capillary blood). A f t e r 100 Gin. of glucose the following changes were noted: one-half hour, 187 mg.; one hour, 210 mg.; two hours, 167 rag.; t h r e e hours, 156 rag. ; f o u r hours, 165 mg. Ten units of insulin was then injected. I n one-half hour the blood sugar was 154 rag. The T h o r n test on S e p t . 7, 1951, showed the following reaction: 225 rag. of A C T H injected i n t r a v e n o u s l y at 9:00 A.M., 44 eosinophils; a t 12:00 noon, 31 eosinophils. On September 11, before 9:00 A.M., 78 eosinophils; in one-half hour, 34 eosinophils. A diagnosis of Cushing's syndrome or adenoma of the suprarenals was made. Dr. W. W. Engstrom saw this boy in consultation Sept. 8, 1951, and concurred in the diagnosis. Dr. Philip Seefeld saw the boy on September 11 and also concurred in the diagnosis. On September 11 the epinephrine tolerance showed the following: before the injection, blood sugar level 139.5 rag.; after the injection of 4 minims of 1 to 1,000 crystalline epinephrine, in 15 minutes the sugar was 154 rag.; 30 minutes, 176 rag. On September 13, Dr. Philip Seefeld did a total adrenaleetomy on the left side. The adrenal measured 5 b y 2.5 by 1.5 era. It was d a r k red with some n o d u l a r i t y on the surface (Fig. 2). Cut section showed cortical adenoma I cm. in diameter. Microscopic examination b y Dr. Gorton Ritchie showed the following: " T h e cortex was largely replaced b y masses of large cells with round nuclei and eosinophilic granular cytoplasm. Some cells were much larger t h a n average and contain hyperchromic nuclei with v e r y prominent nuc]eo]i. A few of the cel]s were vacuolated, the vacuoles being fine and uniform in size. Some of the t u m o r cells contain finely granular brownish p i g m e n t ; an occasional
61
TUMOR
maerophage contains Mumps of yellow brownish pigment. Many groups of small cells with doubly staining nuclei were present and among these there were m a n y pigment-eontainir/g phagocytes. No mitotic figures seen. The normal eortieM cells appear somewhat crowded and greatly reduced in n u m b e r but were otherwise not significantly altered. The medulla was normal in appearance. The cells of the adenoma described above
F i g . 2.
were similar to those found in the androgenic or ' X zone' in the adrenal cortex of the newborn infant. Multiple androgenic adenoma of the adrenal c o r t e x . " Postoperatively on the first day the patient was given 50 rag. of cortisone every four hours. On September 14 this was changed to e v e r y six hours, and ascorbie acid was added, 250 rag. three times a day, On September 15 the cortisone was continued e v e r y eight hours and "DOCA R" (desoxyeorticosterone) was added 5 rag. daily, and sodimn chloride, 1 Gin., was given e v e r y eight hours. On September 16 cortisone
62
THE
JOURNAL
was given, 50 rag. every twelve hours, and sodium chloride, I Gin. e v e r y twelve hours. On September 18 sodium chloride was discontinued. Cortisone was given, 25 rag. e v e r y twelve hours. On September 20 the cortisone was given 25 rag. once a day. The cortisone was discontinued four days later. On September 26, a twentyfour-hour urine specimen was sent to Dr. H. L. Mason at the Mayo Clinic, who r e p o r t e d the following determinations: 17-ketosteroids, 1.8 rag.; cortieosteroids, 1.01 rag. The following day the glucose tolerance test on capillary blood showed the following: fasting, 135 rag.; after 100 grams of glucose given b y mouth, in one-hMf hour the blood sugar was 187 rag. ; in one hour, 171 rag.; two hours, 165 rag.; three hours, 141 rag. The boy was discharged from the hospital Sept. 29, 1951. He was seen at m y office Nov. 2, 1951, at which time he weighed 146 pounds and measured 52 inches. He had a voracious appetite and was eating an exceptionally large amount of food. Blood pressure was 142/110. It was impossible for the parents to control the b o y ' s intake of food. At t h a t time, two months a f t e r surgery, x-ray treatment to the p i t u i t a r y glands was advised. Six t r e a t m e n t s were given in three weeks. There was a complete loss of hair over the temporal areas on both sides. B y December 29 the weight had dropped to 1381/2 pounds. The blood pressure was 118/80; the skin seemed to be much better, but the pseudogynecomastia was increased and the breasts were r a t h e r pendulous. On Jan. 10, 1952, the 17ketosteroids were 1.5 rag. B y Febr u a r y 8 the weight had f u r t h e r decreased to 126 pounds; the height was 521~ inches. The blood pressure, however, was increasing, 132/80. The ache was much i m p r o v e d ; there were no striae. The pubic hair had become sparse. B y April 11, 1952, the weight was 1213~ pounds, the height 523/~ inches. Blood pressure was 122/70. The pubic hair was growing up in the midline. B y J u l y 2, 1952,
OF
PEDIATRICS
the weight was 1 2 7 ~ pounds, height 531/2 inches. There was no acne. The breasts were larger. There was no more hyperkeratosis on the lateral b o r d e r of the arms. There were no striae. The blood pressure was 134/ 82. The 17-ketosteroids were 3.5 nag. The p a t i e n t was r e a d m i t t e d to the Milwaukee Children's Hospital Oct. 20, 1952, and three days later Dr. Seefeld did a subtotal removal of the right s u p r a r e n a l gland. The pathologic findings were the same as those in the left suprarenal gland. Immediately a f t e r operation the blood pressure was 120/48, pulse 100. At 6:30 P.~. the blood pressure was 114/ 80. Following this the daily blood pressures ranged from 130/70 to 114/ 70. He was given cortisone immediately a f t e r operation in the following dosage: preoperative, 25 rag. at 12:00 noon, at 6:00 p.~., and 10:00 P.M. He was given 100 rag. intramuscuIarly just before operation and then 50 rag. by mouth e v e r y six hours. A f t e r s u r g e r y he was given 100 rag. i n t r a m u s c u l a r l y at 6:00 P.~. and 50 mg. intramuscularly every four hours. The following day the dosage was increased to 50 rag. cortisone e v e r y six hours. On October 25 this was changed to e v e r y eight hours. On October 27 the intramuscular injections were discontinued and he was given 50 rag. of cortisone orally every 8 hours; October 29, 25 rag. every eight hours; October 30, 12.5 rag. every eight hours; November 1, 10 rag. e v e r y eight hours; November 4, 5 rag. e v e r y eight hours; November 5, 5 nag. e v e r y twelve hours; November 8, 10 rag. e v e r y eight hours. November 9 he was discharged f r o m the hospital on 10 rag. e v e r y eight hours. B y November 20 the weight was 137 pounds, height 531/~ inches. Blood pressure was 120/70. At t h a t time the boy was p u t on cortisone, 1215 rag. e v e r y twelve hours. B y December 20, 1952, the weight was 1273/~ pounds, the height 53 89 inches. Blood pressure 120/70. The weight b y Janu a r y 6 was 1253A pounds and the height 54 inches. Blood pressure
PETERMAN:
SUPRARENAL
115/60. The cortisone was given, 25 rag. in the morning and 12.5 mg. in the evening. On J a n u a r y 20 the weight and height were the same. The boy had regained his strength and his appetite was good. Blood pressure 120/80. The eortisone was reduced to 12.5 rag. twice a day. tie was then given some Dexedrine ("Spansules tr 0.01 Gin. every morning. B y Feb. 20, 1953, the weight was 1161/2 pounds, height 541/s inches. There were no complaints and the ap-
521
'
63
TUMOR
had weak spells about twice a day, one fainting spell on Mareh 26. Blood pressure was 100/60. The face appeared mueh thinner, and the mother was advised to give cortisone, 12.5 rag., twice a day if necessary (Fig. 3). On April 1, 1952, an electroencephalogram was done and a satisfactory record was obtained. This showed a basle frequency of 8 per seeond. During light sleep there were a number of bursts of 14 and 6 per seeond positive spikes in the temporal lobe leads.
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Fig. 3.
petite was curbed; however, the boy had become a behavior problem in school. Following his first operation the sehool work had deteriorated and the behavior problem increased. At this time he developed an unusual interest in sexual activity and needed to be watehed closely. IIe seemed to have erections but they were not of long duration. The cortisone was reduced to 12.5 rag. morning only. After one week the boy complained of severe ringing in the ears and he
There was random spiking in the oeeipital region throughout the record. There was a big build-up on hyperventilation, with larval bursts of spike wave activity. Phenacemide (Phenurone), 0.25 Gin., was given every twelve hours. On April 15, 1953, the mother reported that the school work was still poor and deteriorating rapidly. On a dosage of 12.5 rag. cortisone the boy was sleepy; when he was given 12.5 rag. twice a day he beeame much more active if
64
THE JOURNAL OF PEDIATRICS
not drowsy, but was a v e r y disturbing element in school. H e w a s t h e n p u t on cortisone, 12.5 rag. in the morning and 6.25 rag. in the evening. The p h c n a c e m i d e was iner'eased to 0.25 Gm. e v e r y eight hours. The weight was down to ]061fiz pounds, height 55 inches. Blood pressure was 106/68. There w e r e loose folds of skin a n d
and the cortisone was increased to 25 rag. in the m o r n i n g and 12.5 Gin. in the evening. B y Sept. 1, 1955, the boy r e t u r n e d , weighing 128 p o u n d s ; his height was 581~ inches. H e had been well. a n d w a n t e d to p l a y football on the school team. He h a d become careless about his diet a n d indifferent to his weight.
Fig. 4.
Fig. 5.
the breasts were r a t h e r pendulous. There were no striae. Sedimentation r a t e was n o r m a l ; blood count was normal. B y M a y 26, 1953, the w e i g h t was 1021/~, height 55 inches. There were no s t r i a e ; the skin h u n g in loose folds. The b r e a s t s a n d nipples w e r e large. The blood count was normal. Blood p r e s s u r e was 102/70. The behavior w a s still b a d ; t h e r e f o r e the P h e n u r o n e was discontinued: The cortisone was continued at 12.5 Gin. e v e r y twelve hours. The w e i g h t d r o p p e d to 9 8 8 9 pounds Oct. 24, 1953. (Figs. 4 a n d 5.) There was a complaint of weakness in the a f t e r n o o n
DISCUSSION
This p a t i e n t made a r a p i d weight gain of five pounds p e r m o n t h and an increase f r o m 60 to 168 pounds at 10 y e a r s of age when his height was fifty-two inches. He had a t y p i c a l r o u n d ( " m o o n " ) face, a f a t neck, well-developed pendulous breasts, but also m a r k e d f a t deposits on the extremities, as m a y be seen in the photograph. The basal metabolism was low; the b l o o d pressure was high until a f t e r operation, w h e n it d r o p p e d
PETERMAN:
SUPRARENAL
to n o r m a l . A f t e r t h e f i r s t o p e r a t i o n a n d r e m o v a l of t h e l e f t s u p r a r e n a l t u m o r a n a t t e m p t w a s m a d e to c o n t r o l the blood pressure and symptoms by irradiation over the pituitary gland. The blood pressure dropped to 118/80, b u t t h e p s e u d o g y n e c o m a s t i a increased considerably. The blood p r e s s u r e t h e n i n c r e a s e d to 1 3 4 / 8 2 a n d a s u b t o t a l r e m o v a l of t h e r i g h t s u p r a r e n a l g l a n d w a s done. Following this, t h e b l o o d p r e s s u r e g r a d u a l l y dec r e a s e d to 115/60. H o w e v e r , t h e behavior problem had become serious a n d e v e n t u a l l y t h e b o y b e c a m e a dist u r b i n g e l e m e n t in school. W i t h cooperation it was possible to keep the weight and blood pressure near norm a l on s m a l l doses o f c o r t i s o n e (2.5 mg. t w i c e a d a y ) . However, when the boy moved out of the city and c o o p e r a t i o n a n d c o n t r o l w e r e lost, t h e w e i g h t i n c r e a s e d f r o m 9 8 8 9 p o u n d s in O c t o b e r , 1953, to 128 p o u n d s in S e p t e m b e r , 1955. REFERENCES
1. Albright, Fuller: Cushing's Syndrome. Its Pathological Physiology, Its Relationship to the Adreno-Genital Syndrome, and Its Connection With the Problem of the Reaction of the Body to Injurious Agents ( " A l a r m Reaction" of Selye), Harvey Lectures 38: 123, 1943. 2. Knowlton, Abbie L: Cushing's Syndrome, Bull. New York Acad. 1V[ed. 29: 441, 1953. 3. Sprague, Randall G., and Power, Marschelle It.: Itypopotassemla and Other Electrolyte Disturbances in Cushing's Syndrome~ Journal-Lancet 73: 217, 1953.
TUMOR
65
4. Priestly,
James T., Sprague, Randall G., Waiters, Waltman, and Salassa, Robert M.: Subtotal Adrenalectomy for Cushing's Syndrome: A Preliminary Report of 29 Cases, Ann. Surg. 134: 464, 1951. 5. Giannlco, Orazlo, and Zilli, E.: Prothrombin, Fibrinogen, Proteinemla and u in Eight Cases of Cushing's Syndrome, Policlinico (sezione pratica) 56: 963, 1949. Cochran, J. G., Watson, R. D., and Reid, J.: Mild Cushing's Syndrome Due to Aspirin, Brit. M. J. 1: 1411, 1950. Rush, Jack T., and Forsee, James It.: Cushing's Syndrome Associated With Adenoma of the Adrenal Cortex, l~[il. Surg. 108: 319, 1951. Poutasse, Eugene F., and McCullagh, E. Perry: Cushing's Syndrome, J. Urol. 68: 779, 1952. Sheehan, H. L., Sumners, V. K., and Nichols, John: D.D.D. Therapy in Cushing's Syndrome, Lancet 1: 312, 1953. Sheldon, W. H., Golden:, A., and Beady, P. I(.: Cushing's Syndrome Produced by a Pituitary
Basophil
Carcinoma
With
Hepatic Metastases, Am. J. Med. 17: 134, 1954. Bastenie~ P. A., and Godon, C.: Pregnancy Accompanied by Transient Diabetes and Cushing's Syndrome, Bruxellesm6dical 34: 1618, 1954. Bishop, P. M. F., Glover, F. N., de ]Vfowbray, R. 1% and Thorne, IV[. G.: The Treatment of Cushing's Syndrome, Lancet 2: 1137, 1954. Beck, R. N., Montgomery, D. A. D., and Welbourn, R. B.: Cushing's Syndrome. Six Cases Treated Surgically, Lancet 2: 1140, 1954. Skrimshire, J. F. P.: Radiotherapy of Cushing's Syndrome, Lancet 1: 270, 1955. Cohen, Sheldon B.: Cushing's Syndrome Associated With Congenital Hydrocephalus and Spastic Paraplegia, Bull. Menninger Clin. 19: 53, 1955. Cope, C. L., and t~arrlson, 1%. J.: Effect of 9a-Fluorohydrocortisone on Adrenal Hyperfunction ]n Cushing's Syndrome, Brit. M. J. 2: 457, 1955. Greenlee, Ralph G.: Hyperfunetion of the Adrenal Cortex, 1VI. Clin. North America 39: 1081, 1955.
M. G. PETERMAN, M.D. MILWAUKEE, ~VIS. HE ease of this patient is reported he had bilateral suprarenal tumors, but he did not conform completely to the clinical picture as described by Albright. The obesity was marked and developed rapidly, but was definitely associated with an excessively abnormal appetite; the fat accumulation involved not only the face, neck, trunk, and abdomen, but also the extremities. The muscular weakness was not marked; the osteoporosis was of moderate degree. In contradistinction to impotency, this boy had precocious pube r t y and virilism. Tumors of the suprarenal gland produce a definite well-known entity conveniently called Cushing's syndrome. The literature is replete with ease reports of this condition and exhaustive studies have been made. In Albright's second paper on the subject he specified certain clinical manifestations and states that " t h e diagnosis would be questionable in any ease which did not have the first three of these manifestations. They are: (1) diabetes, which is usually mild and often only demonstrable as the responsiveness to an alimentary hyperglycemia (i.e., decreased sugar tolerance), but which is resistant to insulin; (2) muscular weakness, with a low creatinine excretion as an indication of decreased muscle mass; (3) osteoporosis, especially of the
T because
spine (not to be confused with osteitis fibrosa generalisata or with osteomalaeia since the serum phosphatase level is normal rather than high), associated with hyperca]cinuria ear]y in the disease and, in many instances, with nephrolithiasis; (4) a thin, reddish (?) (transparent) skin, easy bruisability, often large purplish striae, a marked susceptibility to skin infection; (5) impotence in men and amenorrhea in women; (6) mild to moderate obesity, with a tendency f o r the fat to be deposited in the neck and face (mostly in the face) and to spare the extremities; (7) mild hirsutism without other evidence of virilism (clitoris not enlarged, thyroid eartilage and voice normal in females), usually but not always associated with a slight to moderate elevation in the urinary excretion of the 17-ketosteroids; (8) mild erythroeytosis (red count circa 5.8 M) without increased blood volume; (9) hypertension and arteriosclerosis often accompanied by coronary heart disease and vascular disease of the kidneys. ''1 This paper presents a thorough study of the problem. Among the other papers there were thirtythree well-studied cases presented by Kttowlto~ 2 in 1953. The electrolyte disturbances in Cushing's syndrome were reviewed by Sprague and Power a in 1953. Subtotal adrenalectomy for Cushing"s syndrome was re59
60
T H E J O U R N A L OF PEDIATRICS
viewed in detail by P r i e s t l y and associates ~ in 1951. Twenty-nine cases were presented. Other p e r t i n e n t reports concerning the s y n d r o m e are listed. ~ CASE REPORT
A 10-year-old boy was first seen on Aug. 23, 1951. He was b o r n Sept. 3, 1941, a f u l l - t e r m i n f a n t of the first p r e g n a n c y , with a n o r m a l labor and
F i g . 1.
delivery and a birth weight of 6 pounds 8 ounces. The physical and m e n t a l d e v e l o p m e n t were considered to be normal. The b o y h a d chicken p o x in 1947 and a mild ease of measles in 1948. The tonsils a n d adenoids were r e m o v e d w h e n he was 2 y e a r s of age. I n the p a s t two y e a r s the b o y h a d been gaining w e i g h t steadily at the r a t e of a b o u t 5 pounds a month. P r e v i o u s to this he was considered to be nervous and under-
weight. He had g r o w n in two years f r o m 60 to 168 pounds. The seeo n d a r y sex c h a r a c t e r s h a d been noted to develop. On examination, this b o y weighed 154 p o u n d s and measu r e d 52 in. in height (Pig. 1). Nutrition was f a i r ; m e n t a l response, exeellent. The blood pressure was 120/100. The left u p p e r central ineisor was missing. The tonsils were out d e a n . The genitals were n o r m a l in size b u t the pubie hair showed a female t y p e of distribution. The urine was n e g a t i v e ; the blood count was normal. The blood W a s s e r m a n n was n e g a t i v e ; sedimentation r a t e was normal, t i e was obviously obese but most of his excess weight was in the t r u n k , w i t h a " b u f f a l o h u m p " over his u p p e r thoracic spine. His face was r o u n d with r e d eheeks. There were striae in the axillae and in the groins. The extremities were thin and slightly weak. He was r e f e r r e d to M i l w a u k e e C h i l d r e n ' s H o s p i t a l on Aug. 25, 1951, where the following o b s e r v a t i o n s were m a d e : X - r a y s of the kidneys, ureters, and b l a d d e r were n e g a t i v e or normal. A n intravenous p y e l o g r a m was negative. X - r a y s of the long bones showed a moderate degree of osteoporosis. X - r a y s of the wrist showed a bone age of 10 years. E x a m i n a t i o n of the f u n d i and of the visual fields showed no abnormalities. The basal metabolic r a t e was -24. Blood pressure in the hospital r a n g e d f r o m 145/80 to 180/130. On Sept. 11, 1951, the e p i n e p h r i n e tolerance test showed a f a s t i n g blood s u g a r level of 139.5; a f t e r the injection of 4 minims of 1 to 1,000 crystalline epinephrine: in 15 m i n u t e s 154 mg., in 30 minutes 176 rag. Three d a y s later, a careful cheek on the blood pressure showed the following: supine--right arm 190/144, left arm 184/130; sitting u p - - r i g h t a r m 174/]36, left a r m 180/ 132; s t a n d i n g - - r i g h t a r m 174/132, left arm ]82/146. S e p t e m b e r 10 det e r m i n a t i o n of the steroids b y Dr. It. L. Mason of the Mayo Clinic was r e p o r t e d as follows: 17-ketosteroids 6.4 rag. in t w e n t y - f o u r hours, eor-
PETERMAN:
SUPRARENAL
ticosteroids 0.127 rag. in t w e n t y - f o u r hours. The serum cholesterol was 337 nag. The alkali reserve was 58.9 vol. per cent; sodium chloride 561 rag.; sodium 150 meq.; phosphorus 6.2 meq. The glucose tolerance test showed a fasting level of 122 rag. (capillary blood). A f t e r 100 Gin. of glucose the following changes were noted: one-half hour, 187 mg.; one hour, 210 mg.; two hours, 167 rag.; t h r e e hours, 156 rag. ; f o u r hours, 165 mg. Ten units of insulin was then injected. I n one-half hour the blood sugar was 154 rag. The T h o r n test on S e p t . 7, 1951, showed the following reaction: 225 rag. of A C T H injected i n t r a v e n o u s l y at 9:00 A.M., 44 eosinophils; a t 12:00 noon, 31 eosinophils. On September 11, before 9:00 A.M., 78 eosinophils; in one-half hour, 34 eosinophils. A diagnosis of Cushing's syndrome or adenoma of the suprarenals was made. Dr. W. W. Engstrom saw this boy in consultation Sept. 8, 1951, and concurred in the diagnosis. Dr. Philip Seefeld saw the boy on September 11 and also concurred in the diagnosis. On September 11 the epinephrine tolerance showed the following: before the injection, blood sugar level 139.5 rag.; after the injection of 4 minims of 1 to 1,000 crystalline epinephrine, in 15 minutes the sugar was 154 rag.; 30 minutes, 176 rag. On September 13, Dr. Philip Seefeld did a total adrenaleetomy on the left side. The adrenal measured 5 b y 2.5 by 1.5 era. It was d a r k red with some n o d u l a r i t y on the surface (Fig. 2). Cut section showed cortical adenoma I cm. in diameter. Microscopic examination b y Dr. Gorton Ritchie showed the following: " T h e cortex was largely replaced b y masses of large cells with round nuclei and eosinophilic granular cytoplasm. Some cells were much larger t h a n average and contain hyperchromic nuclei with v e r y prominent nuc]eo]i. A few of the cel]s were vacuolated, the vacuoles being fine and uniform in size. Some of the t u m o r cells contain finely granular brownish p i g m e n t ; an occasional
61
TUMOR
maerophage contains Mumps of yellow brownish pigment. Many groups of small cells with doubly staining nuclei were present and among these there were m a n y pigment-eontainir/g phagocytes. No mitotic figures seen. The normal eortieM cells appear somewhat crowded and greatly reduced in n u m b e r but were otherwise not significantly altered. The medulla was normal in appearance. The cells of the adenoma described above
F i g . 2.
were similar to those found in the androgenic or ' X zone' in the adrenal cortex of the newborn infant. Multiple androgenic adenoma of the adrenal c o r t e x . " Postoperatively on the first day the patient was given 50 rag. of cortisone every four hours. On September 14 this was changed to e v e r y six hours, and ascorbie acid was added, 250 rag. three times a day, On September 15 the cortisone was continued e v e r y eight hours and "DOCA R" (desoxyeorticosterone) was added 5 rag. daily, and sodimn chloride, 1 Gin., was given e v e r y eight hours. On September 16 cortisone
62
THE
JOURNAL
was given, 50 rag. every twelve hours, and sodium chloride, I Gin. e v e r y twelve hours. On September 18 sodium chloride was discontinued. Cortisone was given, 25 rag. e v e r y twelve hours. On September 20 the cortisone was given 25 rag. once a day. The cortisone was discontinued four days later. On September 26, a twentyfour-hour urine specimen was sent to Dr. H. L. Mason at the Mayo Clinic, who r e p o r t e d the following determinations: 17-ketosteroids, 1.8 rag.; cortieosteroids, 1.01 rag. The following day the glucose tolerance test on capillary blood showed the following: fasting, 135 rag.; after 100 grams of glucose given b y mouth, in one-hMf hour the blood sugar was 187 rag. ; in one hour, 171 rag.; two hours, 165 rag.; three hours, 141 rag. The boy was discharged from the hospital Sept. 29, 1951. He was seen at m y office Nov. 2, 1951, at which time he weighed 146 pounds and measured 52 inches. He had a voracious appetite and was eating an exceptionally large amount of food. Blood pressure was 142/110. It was impossible for the parents to control the b o y ' s intake of food. At t h a t time, two months a f t e r surgery, x-ray treatment to the p i t u i t a r y glands was advised. Six t r e a t m e n t s were given in three weeks. There was a complete loss of hair over the temporal areas on both sides. B y December 29 the weight had dropped to 1381/2 pounds. The blood pressure was 118/80; the skin seemed to be much better, but the pseudogynecomastia was increased and the breasts were r a t h e r pendulous. On Jan. 10, 1952, the 17ketosteroids were 1.5 rag. B y Febr u a r y 8 the weight had f u r t h e r decreased to 126 pounds; the height was 521~ inches. The blood pressure, however, was increasing, 132/80. The ache was much i m p r o v e d ; there were no striae. The pubic hair had become sparse. B y April 11, 1952, the weight was 1213~ pounds, the height 523/~ inches. Blood pressure was 122/70. The pubic hair was growing up in the midline. B y J u l y 2, 1952,
OF
PEDIATRICS
the weight was 1 2 7 ~ pounds, height 531/2 inches. There was no acne. The breasts were larger. There was no more hyperkeratosis on the lateral b o r d e r of the arms. There were no striae. The blood pressure was 134/ 82. The 17-ketosteroids were 3.5 nag. The p a t i e n t was r e a d m i t t e d to the Milwaukee Children's Hospital Oct. 20, 1952, and three days later Dr. Seefeld did a subtotal removal of the right s u p r a r e n a l gland. The pathologic findings were the same as those in the left suprarenal gland. Immediately a f t e r operation the blood pressure was 120/48, pulse 100. At 6:30 P.~. the blood pressure was 114/ 80. Following this the daily blood pressures ranged from 130/70 to 114/ 70. He was given cortisone immediately a f t e r operation in the following dosage: preoperative, 25 rag. at 12:00 noon, at 6:00 p.~., and 10:00 P.M. He was given 100 rag. intramuscuIarly just before operation and then 50 rag. by mouth e v e r y six hours. A f t e r s u r g e r y he was given 100 rag. i n t r a m u s c u l a r l y at 6:00 P.~. and 50 mg. intramuscularly every four hours. The following day the dosage was increased to 50 rag. cortisone e v e r y six hours. On October 25 this was changed to e v e r y eight hours. On October 27 the intramuscular injections were discontinued and he was given 50 rag. of cortisone orally every 8 hours; October 29, 25 rag. every eight hours; October 30, 12.5 rag. every eight hours; November 1, 10 rag. e v e r y eight hours; November 4, 5 rag. e v e r y eight hours; November 5, 5 nag. e v e r y twelve hours; November 8, 10 rag. e v e r y eight hours. November 9 he was discharged f r o m the hospital on 10 rag. e v e r y eight hours. B y November 20 the weight was 137 pounds, height 531/~ inches. Blood pressure was 120/70. At t h a t time the boy was p u t on cortisone, 1215 rag. e v e r y twelve hours. B y December 20, 1952, the weight was 1273/~ pounds, the height 53 89 inches. Blood pressure 120/70. The weight b y Janu a r y 6 was 1253A pounds and the height 54 inches. Blood pressure
PETERMAN:
SUPRARENAL
115/60. The cortisone was given, 25 rag. in the morning and 12.5 mg. in the evening. On J a n u a r y 20 the weight and height were the same. The boy had regained his strength and his appetite was good. Blood pressure 120/80. The eortisone was reduced to 12.5 rag. twice a day. tie was then given some Dexedrine ("Spansules tr 0.01 Gin. every morning. B y Feb. 20, 1953, the weight was 1161/2 pounds, height 541/s inches. There were no complaints and the ap-
521
'
63
TUMOR
had weak spells about twice a day, one fainting spell on Mareh 26. Blood pressure was 100/60. The face appeared mueh thinner, and the mother was advised to give cortisone, 12.5 rag., twice a day if necessary (Fig. 3). On April 1, 1952, an electroencephalogram was done and a satisfactory record was obtained. This showed a basle frequency of 8 per seeond. During light sleep there were a number of bursts of 14 and 6 per seeond positive spikes in the temporal lobe leads.
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Fig. 3.
petite was curbed; however, the boy had become a behavior problem in school. Following his first operation the sehool work had deteriorated and the behavior problem increased. At this time he developed an unusual interest in sexual activity and needed to be watehed closely. IIe seemed to have erections but they were not of long duration. The cortisone was reduced to 12.5 rag. morning only. After one week the boy complained of severe ringing in the ears and he
There was random spiking in the oeeipital region throughout the record. There was a big build-up on hyperventilation, with larval bursts of spike wave activity. Phenacemide (Phenurone), 0.25 Gin., was given every twelve hours. On April 15, 1953, the mother reported that the school work was still poor and deteriorating rapidly. On a dosage of 12.5 rag. cortisone the boy was sleepy; when he was given 12.5 rag. twice a day he beeame much more active if
64
THE JOURNAL OF PEDIATRICS
not drowsy, but was a v e r y disturbing element in school. H e w a s t h e n p u t on cortisone, 12.5 rag. in the morning and 6.25 rag. in the evening. The p h c n a c e m i d e was iner'eased to 0.25 Gm. e v e r y eight hours. The weight was down to ]061fiz pounds, height 55 inches. Blood pressure was 106/68. There w e r e loose folds of skin a n d
and the cortisone was increased to 25 rag. in the m o r n i n g and 12.5 Gin. in the evening. B y Sept. 1, 1955, the boy r e t u r n e d , weighing 128 p o u n d s ; his height was 581~ inches. H e had been well. a n d w a n t e d to p l a y football on the school team. He h a d become careless about his diet a n d indifferent to his weight.
Fig. 4.
Fig. 5.
the breasts were r a t h e r pendulous. There were no striae. Sedimentation r a t e was n o r m a l ; blood count was normal. B y M a y 26, 1953, the w e i g h t was 1021/~, height 55 inches. There were no s t r i a e ; the skin h u n g in loose folds. The b r e a s t s a n d nipples w e r e large. The blood count was normal. Blood p r e s s u r e was 102/70. The behavior w a s still b a d ; t h e r e f o r e the P h e n u r o n e was discontinued: The cortisone was continued at 12.5 Gin. e v e r y twelve hours. The w e i g h t d r o p p e d to 9 8 8 9 pounds Oct. 24, 1953. (Figs. 4 a n d 5.) There was a complaint of weakness in the a f t e r n o o n
DISCUSSION
This p a t i e n t made a r a p i d weight gain of five pounds p e r m o n t h and an increase f r o m 60 to 168 pounds at 10 y e a r s of age when his height was fifty-two inches. He had a t y p i c a l r o u n d ( " m o o n " ) face, a f a t neck, well-developed pendulous breasts, but also m a r k e d f a t deposits on the extremities, as m a y be seen in the photograph. The basal metabolism was low; the b l o o d pressure was high until a f t e r operation, w h e n it d r o p p e d
PETERMAN:
SUPRARENAL
to n o r m a l . A f t e r t h e f i r s t o p e r a t i o n a n d r e m o v a l of t h e l e f t s u p r a r e n a l t u m o r a n a t t e m p t w a s m a d e to c o n t r o l the blood pressure and symptoms by irradiation over the pituitary gland. The blood pressure dropped to 118/80, b u t t h e p s e u d o g y n e c o m a s t i a increased considerably. The blood p r e s s u r e t h e n i n c r e a s e d to 1 3 4 / 8 2 a n d a s u b t o t a l r e m o v a l of t h e r i g h t s u p r a r e n a l g l a n d w a s done. Following this, t h e b l o o d p r e s s u r e g r a d u a l l y dec r e a s e d to 115/60. H o w e v e r , t h e behavior problem had become serious a n d e v e n t u a l l y t h e b o y b e c a m e a dist u r b i n g e l e m e n t in school. W i t h cooperation it was possible to keep the weight and blood pressure near norm a l on s m a l l doses o f c o r t i s o n e (2.5 mg. t w i c e a d a y ) . However, when the boy moved out of the city and c o o p e r a t i o n a n d c o n t r o l w e r e lost, t h e w e i g h t i n c r e a s e d f r o m 9 8 8 9 p o u n d s in O c t o b e r , 1953, to 128 p o u n d s in S e p t e m b e r , 1955. REFERENCES
1. Albright, Fuller: Cushing's Syndrome. Its Pathological Physiology, Its Relationship to the Adreno-Genital Syndrome, and Its Connection With the Problem of the Reaction of the Body to Injurious Agents ( " A l a r m Reaction" of Selye), Harvey Lectures 38: 123, 1943. 2. Knowlton, Abbie L: Cushing's Syndrome, Bull. New York Acad. 1V[ed. 29: 441, 1953. 3. Sprague, Randall G., and Power, Marschelle It.: Itypopotassemla and Other Electrolyte Disturbances in Cushing's Syndrome~ Journal-Lancet 73: 217, 1953.
TUMOR
65
4. Priestly,
James T., Sprague, Randall G., Waiters, Waltman, and Salassa, Robert M.: Subtotal Adrenalectomy for Cushing's Syndrome: A Preliminary Report of 29 Cases, Ann. Surg. 134: 464, 1951. 5. Giannlco, Orazlo, and Zilli, E.: Prothrombin, Fibrinogen, Proteinemla and u in Eight Cases of Cushing's Syndrome, Policlinico (sezione pratica) 56: 963, 1949. Cochran, J. G., Watson, R. D., and Reid, J.: Mild Cushing's Syndrome Due to Aspirin, Brit. M. J. 1: 1411, 1950. Rush, Jack T., and Forsee, James It.: Cushing's Syndrome Associated With Adenoma of the Adrenal Cortex, l~[il. Surg. 108: 319, 1951. Poutasse, Eugene F., and McCullagh, E. Perry: Cushing's Syndrome, J. Urol. 68: 779, 1952. Sheehan, H. L., Sumners, V. K., and Nichols, John: D.D.D. Therapy in Cushing's Syndrome, Lancet 1: 312, 1953. Sheldon, W. H., Golden:, A., and Beady, P. I(.: Cushing's Syndrome Produced by a Pituitary
Basophil
Carcinoma
With
Hepatic Metastases, Am. J. Med. 17: 134, 1954. Bastenie~ P. A., and Godon, C.: Pregnancy Accompanied by Transient Diabetes and Cushing's Syndrome, Bruxellesm6dical 34: 1618, 1954. Bishop, P. M. F., Glover, F. N., de ]Vfowbray, R. 1% and Thorne, IV[. G.: The Treatment of Cushing's Syndrome, Lancet 2: 1137, 1954. Beck, R. N., Montgomery, D. A. D., and Welbourn, R. B.: Cushing's Syndrome. Six Cases Treated Surgically, Lancet 2: 1140, 1954. Skrimshire, J. F. P.: Radiotherapy of Cushing's Syndrome, Lancet 1: 270, 1955. Cohen, Sheldon B.: Cushing's Syndrome Associated With Congenital Hydrocephalus and Spastic Paraplegia, Bull. Menninger Clin. 19: 53, 1955. Cope, C. L., and t~arrlson, 1%. J.: Effect of 9a-Fluorohydrocortisone on Adrenal Hyperfunction ]n Cushing's Syndrome, Brit. M. J. 2: 457, 1955. Greenlee, Ralph G.: Hyperfunetion of the Adrenal Cortex, 1VI. Clin. North America 39: 1081, 1955.