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Case Reports

CUSHING’S SYNDROME IN CHILDREN ASSOCIATED WITH ADRENAL CORTICAL CARCINOMA

A Case Report with Review of the Literature

GRACE H. GUIN, M.D. and ENID F. GILBERT, M.B.B.S., Washington, D.C.

T HE ASSOCIATION of adrenal tumors with the clinical picture now identified as Cushing’s syndrome was first observed by Cooke * in 1756. Cushing,2 in 1932, collected 12 similar cases and con- cluded that pituitary basophilism was the underlying lesion. Cushing’s original con- cept has been modified as a result of subse- quent investigations .; In the pediatric age group Cushing’s syndrome is most fre- quently caused by malignant adrenal tu- mors. Basophilic adenomas of the pituitary, while rare, have been reported in children in the absence of adrenal pathology.# The only case of Cushing’s syndrome in a child caused by adrenal hyperplasia was described by Chute and his colleagues 14 and occurred in a girl 8 years of age. Albright and Forbes § believe that all cases of Cushing’s syndrome in infancy are caused by malig- nant adrenal tumors. Recently, however, Powell 15 has observed an infant, age 3 months, with Cushing’s syndrome who was found at autopsy to have bilateral adrenal adenomas.

It is the purpose of this paper to review the reported cases of carcinoma of the ad- renal cortex causing Cushing’s syndrome in children and to add a case studied in this hospital which is believed to be the youngest case reported to date.

Submitted for publication April 5, 1956.

From the Department of Pathology, The Chil- dren’s Hospital of The District of Columbia.

* Cooke, W., cited by Hicks, J. B.1

+ References 3-8.

# References 5, 9-13.

§ Albright, F., and Forbes, A. P., personal communication with the authors.

Report of Case

A 3-month-old white girl was admitted to The Children’s Hospital of the District of Columbia on Aug. 31, 1954, because of obesity beginning 6 weeks prior to admission. The family history revealed that the mother, age 27 years, had suf- fered from diabetes since the age of 4 years. Dur- ing her adolescence the disease was controlled with difficulty, and she experienced many episodes of diabetic coma. Following coma, her first preg- nancy terminated in May, 1951, by the delivery of a 1136 gm. (21/2 lb.) stillborn boy. The pa- tient herein described was the result of the second gestation. There were no episodes of coma during the course of this second pregnancy. The mother’s blood sugar during this pregnancy ranged from 79 to 165 mg/100 ml., dropping to 54 mg/100 ml. on the day of delivery. During the day of delivery the total 24-hour excretion of glucose was 150 mg. The maximum daily dose of insulin was 105 units. No additional hormone therapy was given during pregnancy. The mother at 8 months’ ges- tation was delivered by Cesarean section of a girl weighing 2700 gm. (6 1b. 3 oz.). The in- fant’s blood sugar was low at birth but rose to 120 mg/100 ml. by the third day. For two months prior to admission the infant had been irritable and was treated with phenobarbital. Six weeks prior to admission the parents considered the infant to be obese. For three weeks prior to ad- mission the patient was noted to have an eczema- toid and acneform rash on the cheeks. She had been on a low fat formula. Food intake had not been excessive. At 10 weeks she weighed 4100 gm. (9 1b.) and on admission 5500 gm. ( 12 1b.).

On physical examination the temperature was 99.8 F (rectal), pulse rate 108, and respiration rate 28 per minute. The systolic blood pressure ranged from 115 to 210 mm. Hg. The infant was obese, showing a buffalo hump and moon face. There was no axillary or pubic hair and no abnormality of the external genitalia other than slight clitoral hypertrophy. There was hirsutism of the upper lip and an erythematous papular rash over the face and neck. The heart was not enlarged to percussion, and no murmurs were heard. The abdomen was distended, and the liver was palpable 4.0 cm. below the right costal mar-

gin. A firm mass 4.0 cm. in diameter unattached to the liver was palpated to the right of the um- bilicus. X-ray examination revealed marked osteoporosis of the entire skeletal system (Fig.

Fig. 1 .- X-ray showing osteoporosis of verte- brae, pelvis, and femora.

1). X-rays of the chest and abdomen were normal. An intravenous pyelogram indicated secre- tory activity of both kidneys. An electrocardio- gram was interpreted as showing left axis deviation with prolongation of the Q-T interval. This was thought to represent hypopotassemia.

The hemogram was as follows: hemoglobin 11.8 gm/100 ml., white blood cells 22,700/cu. mm .; differential count, 67% polymorphonuclear leuco- cytes, 29% lymphocytes, and 4% monocytes. A total eosinophile cell count was zero per cubic millimeter. The fasting blood sugar was 115 mg/100 ml .; plasma sodium 116,9 mEq/L; po- tassium 3.0 mEq/L; chlorides 76.0 mEq/L; cal- cium 10.5 mg/100 ml., blood urea nitrogen 26 mg/100 ml., and CO2 combining power 22 mEq/L. The urinary excretion of 11-oxycorticosteroids was 2.4 mg. in 12 hours and the 17-ketosteroids 1.7 mg. in 12 hours.|| For two days prior to surgery and on the morning of the operation she received 50 mg. of cortisone intramuscularly and 30 mEq. of potassium ion by mouth. On the ninth hospital day, while the patient was under hypo-

|| The normal 24-hour excretion of 11-oxycorti- costeroids using the formaldehydrogenic method is 0.5-1.5 mg. The normal 24-hour excretion of 17-ketosteroids for this age is less than 1 mg.

thermic anesthesia, an exploratory laparotomy was performed. A tumor replacing the right adrenal gland was found and removed. For three days postoperatively the patient’s systolic blood pressure ranged between 190 and 210 mm.Hg. Her blood sugar dropped to 55 mg/100 ml. about seven hours postoperatively. She received 10 ml. of adrenal cortical extract, 50 mg. cortisone, intravenous fluids, a blood transfusion, and tetracycline (Ach- romycin) hydrochloride 75 mg. every eight hours and procaine penicillin 1,200,000 units daily. Ap- proximately four hours following surgery, blebs and bullae appeared on the skin of all extremities. Pseudomonas aeruginosa and Proteus vulgaris were cultured from the surgical wound and from the skin lesions. ,

Her condition deteriorated on the third post- operative day and clinical signs of pneumonia be- came evident. There was abdominal distention and a weak cry. The infant died on the fourth post- operative day after several episodes of apnea.

Pathological Summary .- The surgical specimen consisted of a tumor which was encapsulated, ovoid, nodular, moderately soft, pinkish gray, weighing 105 gm. and measuring 8.0×5.5×3.5 cm. On section the tissue was reddish tan and lobulated with softened hemorrhagic areas (Fig. 2).

Microscopically, the cells were polyhe- dral, forming solid alveolar groups and cords separated by capillaries and thin fib- rous tissue septa. The capsule was invaded and areas of hemorrhage and necrosis were present. The majority of tumor cells were of uniform size with large hyperchromatic nuclei and a fair amount of pale cytoplasm. Mitotic figures were rare. No chromaffin was seen following fixation in chrome salts or using Gomori’s stain. Oil Red O stain revealed minute amounts of fat. The diag- nosis was cortical carcinoma of the right adrenal gland (Figure 3). The tissue was submitted to Dr. Fred W. Stewart, Memo- rial Center, New York, who concurred in the diagnosis.

Postmortem examination was performed three hours after death. At autopsy the in- fant weighed 5557 gm., measured 22 cm., and presented the classical habitus and facies of Cushing’s syndrome. A few acne- form lesions were noted on each cheek and a thin line of fine dark hair outlined the upper lip. Except for slight clitoral en-

Fig. 2 .- Right adrenal cortical tumor.

Fig. 3. - Microscopic appearance of adrenal cortical carcinoma; mag. × 115.

largement the genitalia were those of a fe- male infant. No axillary or pubic hair was present. Superficial necrotic areas and blebs measuring up to 1.5 cm. were present over the left heel, right leg, and upper ab- domen. Postmortem blood culture grew Pseudomonas aerugenosa. Subcutaneous fat averaged 3.0 cm. over the thorax and

2.5 cm. over the abdomen. The heart was twice the normal weight, and the left ven- tricle was hypertrophied. Miliary abscesses were present in the lungs and many branches of the pulmonary artery were filled with emboli of tumor cells which were identical in appearance to those seen in the original tumor (Fig. 4). The liver

Fig. 4 .- Adrenal cor- tical carcinoma metas- tatic in blood vessel of lung; mag. × 115.

Fig. 5 .- Anterior pit- uitary gland showing Crooke's hyaline change of the basophilic cells; mag. × 650.

was studded throughout with unencapsu- lated foci of tumor cells similar in appear- ance to those described above.

The thyroid, thymus, spleen, and lymph nodes were not remarkable. The pancreas weighed 10 gm. and measured 8.5×1.0X 0.5 cm. The islets of Langerhans were numerous throughout the gland. The right adrenal was surgically absent. The left adrenal weighed 1.5 gm. and measured

1.0×0.4×0.3 cm. Oil Red O stain revealed more lipid in the zona glomerulosa than in the remaining zones. The kidneys were normal except for a few hyaline casts in the collecting tubules. The vagina, uterus, tubes, and ovaries were infantile. The brain was not remarkable except for a 4.0×3.0X 2.0 cm. subdural blood clot overlying the right frontal area. The pituitary gland was grossly normal. Microscopically, the acid-

Clinical and Pathological Findings in Malignant Tumors of

Serial No.	Publication Yr. of	Authors	Sex	Age of Patient, Yr.	Age &t Onset, Yr.	Typical	Obesity	Striae	Hirsutism	Virilism	Blood Pressure	Osteo- porosis	Weakness	Blood Sugar Increased	Eosinopenia
1	1905	Bullock and Sequeira 17	F	11	10		+	+	+	+	+	-	--
2	1927	Kennedy and Lister 1ª	F	13	12 12		+		+	-.	..	--	-.	+
3	1930	Schweizer and Senet 1.	F	7	6 12		+	--	+	+	150/90	..
4	1933	Van der Bogert "	F	2	9 mo.		+		+	+	160/110
5	1936	Little 21	F	7 72	3 12		+	--	+	+	120/80	+	+
6	1936	Rasmussen **	M	13	?		+	+	+	+	+	+ .		+
7	1939	Crooke and Callow 23 (Case 2)	F	6	6		+	+	+	+	180/145	-
8	1940	Gross :4 (Case 4)	F	10%	10		-	..	+	-	160/120	--	+	+
9	1940	Gross 24	F	314	3		+	-.	--	-	260/190	--	--	+
10	1943	(Case 5) Farber and others 2	M	15	14		+	+	+	+	190/156	+	+
														+
11	1948	Glanzmann **	F	3%	2		+	+	+	+	175/88	+	-.	+
12	1949	Walters and Sprague **	M	114	?		+			+
13	1949	Walters and Sprague ??	F	3 4/12	?		+	-.		+	--
14	1951	Walters and Sprague "	F	15 mo.	--		..	..		--	--
15	1951	Walters and Sprague "	F	17 mo.			--
16	1950	Wilkins 20	F	5 mo.	3 mo.		+	--	+	+	180/120			+
17	1951	Garrett & o	F	2	1		+	--	+	-	210/110 200/160 --	Delayed		+
18	1951	(Case 1) Garrett **	M	2	1		+	-	+	+
	1951	(Case 2)										ossification
19		Garrett :0 (Case 4)	M	12	11 72		+	+	+	+	160/110	-	+		+
20	1952	Talbot *1	M	8 72 mo.	612	mo.	+	--	+	+	150/90	--			+
21	1952	Talbot $1	M	6	6		+	--	+	+	130/100	--
22	1952	Harrison 3: Picard and others 33	F	10 14	832 13 1/2		+ + ៛	+	+ Female dis- tribution	+	150/80 210/150 185/135 210/140	-- +
23	1952		M
								-		Feminiza- tion			+	+
24	1952	Wilkins :4	F	3	2 12		+	--	+	+	138/110		--	+	--
25	1953	Davies **	M	2 12	2		+	-	+	-	200/140	-		-	+
26	1953	Grob and others "	F	4	1		+	+	+	-	145/110	--	+	-	1%
27	1953	Falk 37	F	10 mo.	10 mo.		+	+	+	-	220/140	+	--	+	..
28	1955	Fèvre and others **	F	2 12	13 mo.		+	+	+	+	120/80	-	--	+	--
29	1956	Guin and Gilbert	F	3 mo.	6 wk.		+	+	+	+	190/210 systolic	+	+	+	+

the Adrenal Cortex Producing Cushing’s Syndrome in Children

Urinary Secretion of Hormones		External Genitalia	Right Adrenal	Left Adrenal	Change in Pituitary Crook's Hyaline	Pancreas	Histopathology	Status
17-KS	11-OCS
		Clitoris enlarged	Enlarged	Tumor			Adrenal cortical carcinoma	Autopsy: metastases to liver and lungs
		Clitoris not en-	Small	Tumor			Hypernephroma,	Autopsy: metastases to
		larged; labia					adrenal cortex	lungs
		enlarged
		Clitoris and labia enlarged	Tumor					Autopsy: invasion of right kidney, metastases to lungs
		Clitoris enlarged;	Tumor	Large			Adrenal cortical	Autopsy
		vulva prominent					carcinoma
				Tumor			Carcinoma of left	Autopsy: metastases to liver
							adrenal	and lungs
				Tumor	+		Carcinoma of left adrenal	Autopsy
Up to		Enlarged		Tumor	+		Carcinoma of left	Autopsy: metastases to liver
850 mg.							adrenal	lymph nodes and in-
			Tumor				Carcinoma of adrenal cortex	vasion of left kidney Autopsy
		Normal		Tumor			Carcinoma of adrenal cortex	Autopsy
		+	Tumor		+		Carcinoma of adrenal cortex	Autopsy
+ ☒		Enlargement of		Tumor			Histologic descrip-	Autopsy
		of penis					tion consistent with
							carcinoma of adrenal cortex
4.1							Carcinoma of adrenal cortex	Surgery
6.2							Carcinoma of	Surgery
							adrenal cortex
3.0							Carcinoma of adrenal cortex
1.1							Adrenal cortical
							carcinoma
6.8			Tumor				Adrenal cortical	Surgery and autopsy; me-
62			? rt. or lt.				carcinoma	tastases to liver and lungs
Less than			Tumor	Normal			Carcinoma of	Surgery
1 mg.							adrenal cortex
		Normal	Tumor	Tumor			Carcinoma of	Autopsy: metastases to
							adrenal cortex	para-aortic nodes
51.3	3.5; estrogens	Adult	Tumor				Carcinoma of	Surgical exploration; me-
60.5	greater than						adrenal cortex	tastases to liver; died; No
	20 rat units							autopsy.
15		Enlargement of	Tumor				Carcinoma of	Surgical exploration
		penis and scrotum					adrenal cortex
6.6	0.2	Enlargement of	Tumor				Carcinoma of	Surgical exploration
		penis					adrenal cortex
150-256			Tumor	Normal	+		Carcinoma of	Autopsy at age 30; me-
							adrenal cortex	tastases to lungs
32	Folliculin	Penis small and	--	Tumor			Carcinoma of	Surgery, punch biopsy, x-ray,
	275 Y	atrophic; small					adrenal cortex	pulmonary metastases
		testis; gyneco-
		mastia
11.2		Enlarged penis	Not	Normal			Carcinoma of	Surgical exploration
			present				aberrant adrenal
							tissue in right
							lobe of liver
1.43-8.4		Normal	Extreme				Adrenal cortical	Autopsy: umbilical nodule
			autolysis				carcinoma of	and peritoneal deposits of
							aberrant adrenal	adrenal carcinoma; me-
1.4-2.5		Normal		Tumor			tissue Adrenal cortical	tastases to liver Surgical removal of tumor
							carcinoma
10-20			Tumor				Adrenal cortical carcinoma	Autopsy: No metastases
	0.55	Enlarged clitoris	Tumor	Not found	+		Adrenal cortical	Autopsy: No metastases
3.4	4.8	Slightly enlarged	Tumor	Normal	+	Increased	carcinoma Adrenal cortical	Autopsy: Metastases to
		clitoris				islets	carcinoma	liver and lungs

CUSHING’S SYNDROME IN CHILDREN

ophilic cells were increased in number. The basophilic cells were numerically normal but were increased in size. A Russell 16 stain revealed hyalinized cytoplasm with enlarged eccentric nuclei (Fig. 5). The pars intermedius and pars posterior were not remarkable.

Comment

Cushing’s syndrome, whether in children or adults, reflects a hyperadrenocorticism with respect to cortocoids.5 The somatic alterations include buffalo type of obesity, plethora, moon face, striae, hirsutism, hy- pertension, cessation of growth, and atrophy of skin, muscle, and bone. Osteoporosis is commonly found and usually involves the vertebrae, ribs, pelvis, and less frequently the skull. In addition, a diabetic glucose tol- erance curve, eosinopenia, and elevated blood and urinary corticoids are found. The fasting blood sugar is usually within normal limits. When diabetes is present it is in- sulin resistant. Alterations in the hemo- gram include hemoglobin values between 15 and 17 gm/100 ml., and 5,000,000 to 7,000,000 erythrocytes per cubic millimeter. Total eosinophile counts are usually below 100 per cubic millimeter.3

Hyperadrenocorticism is reflected in the increased production of corticosteroids, which causes disturbances in carbohydrate metabolism, and excess of androgenic ste- roids which results in hirsutism, acne, en- largement of the external genitalia, and other symptoms of virilism. Variation in amounts of these two steroids accounts for the frequent occurrence of mixed forms. It is not our purpose to review the physio- pathology of Cushing’s syndrome, since it has been amply recorded elsewhere.[

The literature was searched for all au- thenticated cases of adrenal cortical carci- noma associated with Cushing’s syndrome in children in whom the disease began be- fore the age of 14 years. Twenty-eight cases were found, and the authors have added one of their own, believed to be the

youngest reported to date. The data on these patients are presented in the Table. Any attempt to tabulate the cases of ad- renal cortical carcinoma with Cushing’s syndrome in a comprehensive fashion is limited by the degree of completeness of the reported cases. The cases of Walters and Sprague,27 although not fully described in the literature, have been cited by Forbes and Albright 28 as authentic cases of Cush- ing’s syndrome due to adrenal cortical car- cinoma and have therefore been included.

Several cases of adrenal cortical tumors were omitted from this Table because suffi- cient clinical or histological evidence was lacking on which to establish an unequivocal diagnosis. Although the cases of Tele- sius,# Ogle 40 and Pitman,41 Dickinson,* Weisse,42 Allibone 43 (two cases) had adrenal cortical carcinoma, they were re- ported as showing only obesity and hirsu- tism. These cases have been excluded. The cases of Fox 44 and Birrell 45 have been omitted as they showed only obesity, hirsut- ism, and clitoral enlargement, while the cases of Cooke,; Bevern and Römkild,# Walker,§ and Lundh 48 have been excluded because of insufficient histological descrip- tion. Kis-Varday 49 recorded a case of neuroblastoma of the adrenal gland in a 17-year-old girl with Cushing’s syndrome whose symptoms began at the age of 14. This case was omitted because of the his- tologic diagnosis.

Of the 29 tabulated cases, 20 were fe- males and 9 were males. Eighteen patients died, and all but one of these came to au- topsy ; however, histologic confirmation of adrenal cortical carcinoma on this patient had been previously obtained surgically. Nine patients underwent surgery. As of February, 1956, the patient reported by

T References 4, 5, 6, and 8.

# Telesius, cited by Linser.30

* Dickinson, W. H., cited by Bullock and Se- queira.17

¡ Cooke, E., cited by Bullock and Sequeira.17 # Bevern and Römkild, cited by Neurath.40

§ Walker, cited by Richards.47

Wilkins 34 is well, without evidence of dis- ease.||

The range of urinary excretion of 17-ke- tosteroids is wide in all age groups and may be influenced by a variety of clinical set- tings.8 The urinary excretion of 17-ketos- teroids was ascertained in 17 patients and found to be elevated in 15. Estimations of plasma and urinary 17-hydroxycorticoids and urinary 17-ketosteroids provides the most accurate measurement of adrenocorti- cal activity.[ Recently, several investiga- tors # have demonstrated a persistent elevation of the urinary and plasma 17- hydroxycorticosteroids and the urinary 17- ketosteroids after ACTH stimulation in patients with adrenal cortical carcinoma. This is in contradistinction to patients with adrenal cortical hyperplasia and adrenal cor- tical adenomas and appears to provide an ac- curate method of differentiating benign from malignant lesions. Forbes and Al- bright 28 in a study of 90 patients found the highest excretion of 17-ketosteroids in pa- tients with malignant tumors. The inci- dence of virilism was also high in these patients. A diagnosis of carcinoma of the adrenal cortex is strongly suggested when the 17-ketosteroid excretion exceeds 30 mg. per 24 hours.58 The alpha 17-ketosteroids are elaborated by both the adrenal cortex and male gonads, whereas the beta 17-ketos- teroids are produced only by the adrenal cortex. Talbot 59 and co-workers have sug- gested that an increase in the excretion of beta ketosteroids occurs in adrenal cor- tical carcinoma. The 17-hydroxycorticoid , excretion was determined in only 4 of the 29 patients and was found to be elevated in each instance.

Only one example 33 of feminization was found in this series of collected cases, and this was presumably the result of increased secretion of estrogens. One other case (Garrett,30 Case 4) showed increased uri-

| Wilkins, L., personal communication with the authors.

T References 50 and 51.

# References 52-57.

nary excretion of estrogens without clini- cal evidence of feminization.

Crooke 60 noted the association of a hya- line change in the basophilic cells of the pituitary in patients with Cushing’s syn- drome. This change, however, is not yet fully understood. In the cases tabulated, the hyaline change was noted in six of the eight cases in which it was sought. Eisen- hardt and Thompson 61 studied the pituitary glands of 90 patients with Cushing’s syn- drome and found Crooke’s hyaline change to be present in all cases. Hyperplasia of the islet cells of the pancreas has been noted previously in patients with adrenal cortical carcinomas. Heinbecker 62 believed that hyperplasia of the islets of Langerhans in Cushing’s syndrome was the result of an imbalance among the acidophilic cells, which he considered to be hypofunctioning. In the present case the picture is further com- plicated by the fact that the patient’s mother was diabetic. Maternal diabetes with the development of carcinoma and Cushing’s syndrome in the infant suggests an endocri- nological relationship. Hyperplasia of the islets of Langerhans in infants born to dia- betic and prediabetic mothers has been ex- tensively studied,* and an increase in the size and weight of the adrenal glands has been observed in these infants .; An in- crease in the number of eosinophilic cells in the anterior hypophysis # together with hyperplasia of the female sex organs has also been described.§

Adrenal cortical carcinoma, though rare, is the most frequent cause of Cushing’s syndrome in infants and children. The finding of elevated plasma and urinary cor- ticosteroids following ACTH stimulation should aid in the differential diagnosis of adrenal cortical tumors.

Summary

The case of an infant with Cushing’s syndrome due to adrenal cortical carcinoma

* References 63-65.

References 66 and 67.

# References 66, 68-70.

§ References 71 and 72.

CUSHING’S SYNDROME IN CHILDREN

is presented. Symptoms in this patient be- gan at the age of 6 weeks, making it the youngest patient with this disease reported to date. The fact that the mother of the infant had diabetes is of special interest.

Twenty-four cases of adrenal cortical carcinoma associated with Cushing’s syn- drome in children under 14 years of age are selected from the literature and tabu- lated.

Persistent elevations of plasma and urinary 17-hydroxycorticosteroids and uri- nary 17-ketosteroids after ACTH stimula- tion provide an additional aid for the diagnosis of adrenocortical carcinoma.

This patient was admitted on the service of Drs. C. Francis Scalessa and W. Dabney Jarman. Drs. E. Clarence Rice and Theodore Winship provided advice and criticism for this report. Edward Riggs supplied the histological preparations.

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1. Hicks, J. B .: Adenoma of the Adrenal Cor- tex with Report of a Case, New England J. Med. 199:1140, 1928.

2. Cushing, H .: The Basophil Adenomas of the Pituitary Body and Their Clinical Manifesta- tions (Pituitary Basophilism), Bull. Johns Hopkins Hosp. 50:137, 1932.

3. Cooke, A. C .: A Change in the Basophil Cells of the Pituitary Gland Common to Condi- tions Which Exhibit the Syndrome Attributed to Basophil Adenoma, J. Path. & Bact. 41 :339, 1935.

4. Albright, F .: The Harvey Lectures, Series 38, Lancaster, Pa., The Science Press, 1943-1944.

5. Heinbecker, P .: The Pathogenesis of Cush- ing’s Syndrome, Medicine 23:225, 1944.

6. Kepler, E. J .: The Relationship of “Crooke’s Changes” in the Basophilic Cells of the Anterior Pituitary Body to Cushing’s Syndrome (Pitui- tary Basophilism), J. Clin. Endocrinol. 5:70, 1945. 7. Soffer, L. J .: Diseases of the Adrenals, Philadelphia, Lea & Febiger, 1946.

8. Soffer, L. J .: Clinical and Experimental Studies on Adrenal Cortical Hyperfunction, Bull. New York Acad. Med. 24:32, 1948.

9. Bauer, T., and Wassing, H .: Zur Frage der Adipositas hypophysaria (Basophiles Adenoma der Hypophyse), Wien. klin. Wchnschr. 26:1236, 1913.

10. Bishop, P. M. F., and Close, M. B .: A Case of Basophile Adenoma of the Anterior Lobe of the Pituitary: “Cushing’s Syndrome,” Guy’s Hosp. Rep. 82:143, 1932.

11. Wright, C. A., and Courville, C .: Pituitary Basophilism: A Discussion of Additional Factors in Relation to 4 Cases, M. Rec. 141:191, 1935.

12. Freyberg, R. H .; Barker, P. S .; Newburg, L. H., and Coller, F. A .: Pituitary Basophilism (Cushing’s Syndrome) : Report of a Verified Case with a Discussion of the Differential Diag- nosis and Treatment, Arch. Int. Med. 58:187, 1936.

13. Shoykhet, A. I., and Palchewsky, E. I .: Cushing’s Syndrome, Klin. med. 15:1113, 1937.

14. Chute, A. L .; Robinson, G. C., and Dona- hue, W. L .: Cushing’s Syndrome in Children, J. Pediat. 34:20, 1949.

15. Powell, L. W. Jr .; Newman, S., and Hooker, J. W .: Cushing’s Syndrome: Report of a Case in an Infant 12 Weeks Old, A. M. A. Am. J. Dis. Child. 90:417, 1955.

16. Russell, D .: Histological Technique for Intracranial Tumors, London, Oxford University Press, 1939, p. 39.

17. Bullock, W., and Sequeira, J. H .: On the Relation of the Suprarenal Capsules to the Sexual Organs, Tr. Path. Soc. London 56:189, 1905.

18. Kennedy, C. M., and Lister, W. A .: Case of Suprarenal Hypernephroma, Lancet 2:749, 1927.

19. Schweizer, F .; Senet, O., and Llambías, A .: Un caso de hirsutismo, Arch. argent. de pediat. 1:550, 1930.

20. Van der Bogert, F .: Virilism and Hyper- tension in Infancy Associated with Adrenal Tu- mor, J. Pediat. 3:629, 1933.

21. Little, A. A .: Carcinoma of the Adrenal Cortex, J. Pediat. 9:62, 1936.

22. Rasmussen, A. T .: The Relation of the Basophilic Cells of the Human Hypophysis to Blood Pressure, Endocrinology 20:673, 1936.

23. Crooke, A. C., and Callow, R. K .: Differ- ential Diagnosis of Forms of Basophilism (Cush- ing’s Syndrome), Particularly by Estimation of Urinary Androgens, Quart. J. Med. 8:233, 1939.

24. Gross, R. E .: Neoplasms Producing En- docrine Disturbance in Childhood, Am. J. Dis. Child. 59:579, 1940.

25. Farber, J. E .; Gustina, F. J., and Postoloff, A. V .: Cushing’s Syndrome in Children: Re- view of the Literature and Report of a Case, Am. J. Dis. Child. 65:593, 1943.

26. Glanzmann, E .: Interrenale Syndrome im Kindesalter, Ann. Pædiat. 171:335, 1948.

27. Walters, W., and Sprague, R. G .: Hyper- functioning Tumors of the Adrenal Cortex : Study of 9 Cases, J. A. M. A. 141 :653, 1949.

28. Forbes, A. P., and Albright, F .: Compari- son of 17-Ketosteroid Excretion in Cushing’s Syndrome Associated with Adrenal Tumors and with Adrenal Hyperplasia, J. Clin. Endocrinol. 11:926, 1951.

29. Wilkins, L .: The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adoles- cence, Springfield, Ill., Charles C Thomas, Pub- lisher, 1950.

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