Summary:A patientwith Cushing's syndromewhose clinical manifestations beganat approximately9 years of age was followed for a periodof four years.
ORIGINAL ARTICLES
in childhood Cushing's syndrome f.r.c.p.[c],
Donald W. f.r.c.p.
Killinger,
m.d., m.sc, ph.d.,
[c], Toronto
Summary: A patient with Cushing's syndrome whose clinical manifestations began at approximately 9 years of age was followed for a period of four years. Initial laboratory studies revealed urinary 170HCS and 17 KS levels which were elevated for her age, with a normal diurnal variation of plasma cortisol and normal suppression of urinary 170HCS by 1.5 mg. of dexamethasone daily. It was not until four years after the onset of the disease that laboratory studies unequivocally supported the diagnosis of Cushing's syndrome resulting in definitive therapy. Clinical features consisted primarily of cessation of growth, obesity, and hirsutism, with no evidence of protein depletion. It is suggested that the clinical and laboratory features of Cushing's syndrome in childhood may present differences from those found in the adult. Failure to recognize these differences may result in delay in therapy with subsequent persisting stigmata of the disorder. From the Department of Medicine, University of Toronto, and The Wellesley Hospital, Toronto, Ontario. Supported by The Medical Research Council of Canada (Grant no. 504-276-85) Reprint requests to: Dr. Killinger, The Wellesley Hospital, 160 Wellesley Street East, Toronto 5, Ontario.
Robert W. Hudson, m.d., and Robert
Volpe, m.d.,
f.a.c.p.,
Cushing's syndrome in childhood is an uncommon disorder with present¬ ing symptoms which may differ from those seen in the adult. In the majority of documented cases the syndrome has been caused by an adrenal neoplasm, but cases due to bilateral adrenal hyperplasia have been reported.1'6 The present study is of a proven case of bilateral adrenal hyperplasia in which the clinical manifestations began at about age 9, and whose clinical and laboratory findings presented diagnostic prob¬ lems. The persisting stigmata resulting from a delay in treatment of this syndrome indicate the importance of early diagnosis and definitive therapy. Materials and methods Plasma cortisol was determined by the method of Peterson, Karrer and Guerra,7 and urinary 17-hydroxycorticoids (17-OHCS) by the method of Reddy.8 Urinary 17-ketosteroids (17-KS) were determined by a modifi¬ cation of the Zimmerman reaction,9 and fractionation of urinary 17-ketosteroids was carried out by the method of Kirshner and Lipsett.10 Incubation studies and isolation of metabolites were carried out as
previously described.11 Report of Case
The patient, Miss P.G., was first seen in January, 1964 at 11 years of age with a two-year history of weight gain and cessation of growth. She had been perfectly normal as a child, with normal growth and development until age 9, when she noticed generalised weight gain, with fullness of her face and accumulation of fat in the supraclavicular and posterior cervical areas. Her weight gain was associated with hair growth over her face, abdomen and back, and complete cessation of growth. There were no visual disturbances, headaches, edema or abnormal pigmentation. The patient felt well and carried a full and active program without difficulty. Her behaviour was exemplary and she did extremely well at school. Her mother, father, and three siblings were of normal weight and height and were all considerably taller than the patient. There was no family history of developmental abnormalities or diabetes mellitus. Physical examination revealed a short (132.5 cm.), obese (46.8 kg.) young girl with a slightly plethoric, round face. There was abundant hair on her upper lip, cheeks and chin, with mild acne. There was accumulation of fat in the C.M.A. JOURNAL/JANUARY 22,
1972/VOL. 106
131
supraclavicular and posterior cervical areas, and the breasts were primarily adipose tissue with little or no duct tissue palpable. The thyroid gland was of normal size. Her blood pressure was 140/80 and auscultation of her heart revealed no abnormalities. Her abdomen was slightly obese but there was no evidence of striae. There was excessive hair growth over her lower abdomen extending up to the umbilicus, and to a less extent over her back, arms and legs. Her skin was of normal texture and there was no evidence of excessive bruising. There was no peripheral wasting and her legs were rather heavy in appearance (Fig. 1). Her external genitalia were normal with no evidence ofclitoral enlargement. Apart from the marked hirsutism there were no signs of virilization. Visual fields were normal. Laboratory tests revealed a hemoglobin of 12.7 g.%, leukocyte count of 14,000 per c.mm. and normal electrolytes, BUN and urinalysis. Results of thyroid function studies were slightly above the normal range with a serum protein-bound iodine (P.B.I.) of 7.5 /ig. % (normal 3.5 to 6.5), erythrocyte uptake of 131I-triiodothyronine (T3-RBC uptake) of 19.8% (normal 12.5 to 19%) and an 131I-thyroidal uptake of 46% (normal 10 to 40%). Clinically there was no evidence of thyroid overactivity. A glucose tolerance test gave a mildly diabetic type curve. Radiological examination of the chest and pituitary fossa was normal. An intravenous pyelogram showed normal renal func¬ tion without displacement of the kidneys. There was no evidence of bone demineralization on skeletal survey.
The following trivial names and abbreviations have been used in this work: dexamethasone 9a-fluoro-l 1ft 17a, =
21-trihydroxy-16a-methyl-pregn-l, 4-diene-3,20-dione; 1lfthydroxyandrostenedione 1 lfthydroxyandrost-4-ene, 3,17-dione; cortisol 1 lft 17a, 21-trihydroxy-pregn-4-ene-3, 20-dione; cortisone 11ft 21-dihydroxy-pregn-4-ene-3, 11, 20-trione; 9a-fluoro-hydrocortisone=9a-fluoro-l lft 17a, 21 -trihydroxy-pregn-4-ene-3,20-dione; =
=
=
etiocholanolone=5ftandrostane-3a-ol-17-one; androsterone=5a-androstostane-3a-ol-17-one;
pregnenolone=3fthydroxy-pregn-5- ene-20-one.
FIG. 1.Appearance of the patient at the time she was first seen in 1964 at age 11. 132 C.M.A. JOURNAL/JANUARY 22,
Studies of adrenal function in 1964 are shown in Fig. 4. The control values for 17-KS and 17-OHCS are elevated for a girl of this age.12 The administration of metyrapone (750 mg. six-hourly for six doses) resulted in a normal increase in both 17-KS and 17-OHCS, with a gradual return to baseline values. Infusion of ACTH 25 IU intravenously over a period of eight hours on two successive days resulted in a hyperactive 17-OHCS response and a normal 17-KS response. Dexamethasone 1.5 mg. daily was given for three days and resulted in suppression of both 17-KS and 17-OHCS. Plasma cortisol was elevated at 8 a.m. but a normal diurnal variation was observed. Initial management In spite of the fact that some of the clinical and laboratory features of classical Cushing's syndrome were absent, it was considered that the patient represented a case of adrenal hyper¬ plasia. A unilateral adrenalectomy was carried out with removal of a slightly enlarged gland weighing 5.5 g. Postoperative studies showed a 24-hour urinary excretion of 17-OHCS of 8.3 mg. and 17-KS of 4.8 mg. Thyroid function studies were normal. Following the operation there was a period of remission lasting about six months during which there was an improvement in her facial appearance, a decrease in the amount of hirsutism, and a growth of 2.5 cm. Her condition then gradually regressed with further weight gain to 58.1 kg. increased hirsutism and cessation of growth. Her obesity was generalised with no evidence of peripheral wasting and no striae. 1965 investigation Results of adrenal function studies in 1965 are shown in Fig. 5. Resting values for urinary 17-KS and 17-OHCS are again slightly elevated for a girl of this age. In response to metyrapone 750 mg. four-hourly for six doses there was an increase in the urinary 17-OHCS, indicating a normal pituitary response. Infusion of 25 IU of ACTH intravenously over a period of eight hours on two successive days resulted in a brisk response in urinary 17-OHCS and dexamethasone 1.5 mg. daily resulted in a
FIG. 2.Appearance of patient at age 14 prior FIG. 3.Appearance of patient 18 months after adrenalectomy.
to adrenalectomy in 1967.
1972/VOL. 106
normal suppression of urinary 17-OHCS. Estimation of plasma cortisol revealed high resting levels with loss of the usual evening decrease. Urinary FSH was undetectable in a 24-hour specimen. Radiological studies revealed a normal sella turcica, no evidence of demineralization and bone age compatible with
chronological age. In view of the conflicting results from the studies of adrenal suppression and stimulation and the inadequate clinical evidence of glucocorticoid excess it was considered that removal of her remaining adrenal gland at that time was not indicated. 1967 investigation When seen in May, 1967 at the age of 14, the patient's signs and symptoms were essentially unchanged (Fig. 2). Her weight was 57.3 kg. and her height 135 cm. Thyroid function studies were normal and a glucose tolerance test showed a diabetic curve: the blood glucose level, fasting, was 76 mg.%, and 159,191,128,123, 102 and 78 mg.% at 30 minutes, 1, 2, 3, 4 and 5 hours
respectively. Adrenal function studies on this occasion are shown in Fig. 6. The resting 17-OHCS are markedly elevated and the 17-KS are elevated for her age. The response of urinary 17-OHCS to metyrapone was brisk and infusion of ACTH on two successive days as previously described resulted in a hyperactive response. Dexamethasone at a dosage of 1.5 mg. daily now caused only slight suppression of urinary 17-OHCS, although a dosage of 8 Motmo 17 OHCS
FIG. 4.Adrenal function studies at the time of first admission in 1964. In this figure and also in Figs. 5 and 6 the dotted lines indicate the upper limit of normal for adults. The hatched areas extended below the base line indicate the periods of treatment and the black areas represent the duration of drug administration. The dosage of drugs is as stated in the text.
Plotmo 17 OHCS
5
Dgy
10
mg. daily produced suppression to well below half of the control levels. Diurnal variation of plasma cortisol was lost although some fluctuation was seen. Fractionation of urinary 17-ketos¬ teroids revealed the following values per 24 hours: androsterone 1.61 mg., etiocholanolone 2.48 mg., dehydroisoandrosterone 0.22 mg., 110-hydroxyandrosterone 1.46 mg., ll/?-hydroxy-etiocholanolone 3.50 mg., 11-ketoandrosterone 0.91 mg. and 11ketoetiocholanolone 1.75 mg. A skeletal survey showed generalized demineralization. There was evidence of early epiphysial narrowing at the elbows, wrists and knees compatible with a chronological age of 14 or 15. A second operation was performed at which the remaining hyperplastic adrenal gland weighing 9 g. was removed. There were no postoperative complications and the patient was dis¬ charged on a regimen of cortisone 12.5 mg. twice daily and 9-alphafluorohydrocortisone 0.1 mg. daily. Following total adrenalectomy there was a dramatic improvement in her clinical condition. Her facial appearance improved noticeably as shown in Fig. 3 and over the next 18 months her height increased by 10 cm. to 145 cm. There was complete disappearance of her facial hair and acne along with the onset of menstrual periods and breast development. The relatively high levels of urinary 11-oxygenated 17-ketos¬ teroids raised the question as to the source of these metabolites. Fukushima, Bradlow and Hellman13 have shown that 2 to 12% of injected cortisol is excreted in the form of 11-hydroxy or 11-ketoetiocholanolone. Bradlow and Gallagher14 found that 11/ft-hydroxyandrosterone was derived almost exclusively from 11/ft-hydroxyandrostenedione and that the conversion to this metabolite was of the order of 50 to 60%. Since this patient was excreting 1.4 mg. of 1 l/?-hydroxyandrosterone per 24 hours her production of 1 1/3-hydroxyandrostenedione can be roughly cal¬ culated at about 3 mg. per 24 hours. Incubation studies carried out on the hyperplastic adrenal tissue removed from this patient revealed that with 14C pregnenolone as a precursor the major product of metabolism was 11/3-hydroxyandrostenedione. This compound was formed in a yield of 12%. At present the biological significance of 11/3-hydroxyandrostenedione is un¬ known and the factors controlling its secretion are poorly understood, so that the biological effects of increased production of this compound on the clinical state cannot be determined.
Discussion The clinical features suggestive of Cushing's syndrome which were present in this case were: (1) cessation of growth, (2) obesity and (3) hirsutism. There was no evidence of bruising, thinning of skin, or peripheral wasting. The initial steroid studies also showed results which were different from those seen in classical Cushing's syndrome, i.e. normal diurnal variation of plasma cortisol and suppression of urinary 17-OHCS on a dose of dex¬ amethasone of 1.5 mg. daily. On the basis of the clinical
20 15
FIG. 5.Adrenal function studies in 1965. The clear spaces represent incomplete collections, and in the second treatment period a repeat metyrapone test was carried out, necessitated by the incomplete collections.
DEXAMtTHASONE
MET0NR0NE
Doy
10 5
15
20
FIG. 6.Adrenal function studies at the time of last admission in 1967.
C.M.A. JOURNAL/JANUARY 22,
1972/VOL. 106
133
features and elevated resting steroids it was felt that she probably had mild adrenal overactivity and one adrenal was removed and noted to be hyperplastic. Following the operation there was a transient improvement with subsequent recurrence. This sequence of events is similar to the observations of Silver and Ginsburg.' It was of interest that although the diurnal variation of plasma cortisol was abnormal in 1965, it was not until her last admission at the age of 14 (1967) that her urinary steroid response to dexamethasone became abnormal and the other steroid studies indicated unequivocal Cushing's syndrome. It is evident that there may be considerable difficulty in establishing a precise clinical and laboratory diagnosis in patients in this age group. Tests generally considered dependable in the investigation of adult Cushing's syndrome may be less valuable in juvenile onset of the condition as exemplified by this case. In six out of eight cases of proven Cushing's syndrome adrenal suppression with 2 mg. per day of dexamethasone was found to be normal.16 Streeten, Stevenson and Dalakos'6 have emphasized that suppressibility of the pituitary-adrenal axis should be tested with several doses of dexamethasone calculated on the basis of body weight (1-150 ,ug./kg.) which will produce submaximal suppression of urinary 17-OHCS. In this way a dose-response relationship between log-dose of dexamethasone/kg. body weight and urinary 17-OHCS/g. creatinine can be obtained. Although in the present case the suppression at a dose of dexamethasone of 25 ,tg./kg. was normal according to the criteria of Streeten, Stevenson and Dalakos, the accuracy of the dexamethasone suppression test may well be improved if the dose of dexamethasone is calculated on the basis of body weight, particularly in this age group. The present case and the two described by Schletter, Clift and Meyer6 underline the fact that one of the more prominent and potentially troublesome aspects of Cushing's syndrome in childhood is cessation of growth. This symptom was one of the earliest manifestations of the disorder in the present case, and definitive therapy resulted in rapid resumption in linear growth. The problem of growth retardation in patients with both endogenous and exogenous glucocorticoid excess has stimulated studies on the effect these hormones have on the rate of secretion and the metabolic effects of growth hormone. It has been shown in adults treated with glucocorticoids that there is a decreased release of growth hormone in response to insulin-induced hypoglycemia.'7'8 Similar results were found in a series of adult patients with Cushing's syndrome.1" Other studies, however, have demonstrated no change in growth hormone release with corticosteroid therapy,20 but showed an impaired response to the metabolic effects of growth hormone during treatment with glucocorticoids which could not be overcome by increasing the amount of growth hormone.2' Recent studies in 15 adult subjects with Cushing's syndrome revealed an impaired release of growth hormone to insulin hypoglycemia in some subjects but not in others, and the response did not depend on the etiology of the adrenal overactivity.22 The same authors found that some patients who did not respond to insulin hypoglycemia could respond to arginine stimulation. Morrow, Mellinger and Prendergastff found an impaired growth hormone release in patients whose clinical manifestations of Gushing's syndrome were most severe, but a normal response in others. In three juvenile patients with bilateral adrenal hyperplasia and growth retardation these authors found a normal growth hormone 134 C.M.A. JOURNAL/JANUARY 22, 1972/VOL. 106
response to insulin hypoglycemia. It was concluded from these studies that glucocorticoids in high titre could induce suppression of growth hormone release, but that suppressed growth hormone secretion was not essential for steroid-induced growth arrest. The importance of exercising definitive therapy before epiphysial fusion restricts further growth is demonstrated by the present case. Unilateral adrenalectomy was found to be inadequate in this patient, as well as in the case of Silver and Ginsburg.4 Since total adrenalectomy results in immediate cessation of the glucocorticoid excess and replacement therapy can be completely controlled, this is probably the treatment of choice. The excellent growth response in this case and in the two reported by Schletter, Clift and Meyer5 following adrenalectomy indicates that this therapy provides the capability for achieving maximum growth. In this situation the disadvantage of continuous replacement therapy is outweighed by the possibility of realizing optimum linear growth. The authors would like to thank Dr. J. C. Laidlaw who performed the plasma cortisol determinations and the initial 17ketosteroid, and 17-hydroxycorticoid determinations and Dr. John Bailey for his advice in the clinical management of this patient. We would also like to thank Mrs. Cheryl Cardiff for her expert technical assistance.
Resume Le syndrome de Cushing chez l'enfant Nous avons suivi pendant quatre annees un malade souffrant d'un syndrome de Cushing. Les premieres manifestations de la pathologie avaient commence alors que le malade etait age d'environ 9 ans. Les premieres epreuves de laboratoire avaient reve6l un taux urinaire des 17-cetosteroides et des 17-hydroxy-cortist6roides qui etaient 6leves pour un enfant de cet age, avec une variation diurne normale de l'hydrocortisone plasmatique et la suppression normale des 17-OHCS par une dose quotidienne de 1.5 mg. de dexamethasone. I1 a fallu attendre quatre ans apres le debut de la maladie pour que le laboratoire puisse confirmer sans equivoque le diagnostic du syndrome de Cushing et pour qu'on puisse appliquer le traitement specifique. Les principales caract6ristiques cliniques comportaient un arret de la croissance, de l'ob6site, de l'hirsutisme, maise aucun signe de deperdition protidique. Les auteurs croient que le tableau clinique et les epreuves pertinentes du syndrome de Cushing chez l'enfant sont diff6rents de ceux qu'on observe chez l'adulte. Le fait de ne pas tenir compte de ces diff6rences risque de retarder le traitement et de laisser apparaitre des stigmates persistants de la maladie. References 1. CHUTE AL, ROBINSON GC, DONAHUE WT: Cushing's Syndrome in Children. J Pediatr 34: 20-39, 1949 2. CHRISTY NP, LONGSON D, JAILER JW: Studies in Cushing's Syndrome: Observations on the response of plasma 17 hydroxycorticosteroid levels to corticotropin. AmJMed23: 910-916, 1957 3. LEVINE SZ, BARNETT HL, SHIBUYA M: Isosexual precocity in boys including a case of a gonadotrophin-producing teratoma. Adv Pediatr 8: 53-95, 1956 4. SILVER HK, GINSBURG MM: Cushing's Syndrome in an eight-yearold girl. Am J Dis Child 100: 123-129, 1960 5. SCHLETTER FE, CLIFT GV, MEYER R: Cushing's Syndrome in childhood: Report of two cases with bilateral adrenocortical hyperplasia, showing distinctive clinical features. J Clin Endocrinol Metab 27: 22-28, 1967 6. MORROW LB, MELLINGER RC, PRENDERGAST JJ: Growth hormone
7. 8. 9.
10.
11.
12. 13.
in hypersecretory diseases of the adrenal gland. J Clin Endocrinol Metab 29: 1364-1368, 1969 PETERSON RE, KARRER A, GUERRA SL: Determination of plasma hydrocortisone. Anal Chem 29: 144-149, 1957 REDDY WJ: Modification of the Reddy-Jenkins-Thorn method for the estimation of 17-hydroxycorticoids in urine. Metabolism 3, No 6,489-492, 1954 DREKTER BS, HEISLER A, STERN S: The determination of urinary steroids: The preparation of pigment-free extracts and the simplified procedure for the estimation of total 17-KS. J. Clin Endocrinol Metab 12: 55-65, 1952 KIRSCHNER MA, LIPSETT MB: The analysis of urinary steroids using gas-liquid chromatography. Steroids 3: 277-294, 1964 KILLINGER DW, SOLOMON S: Synthesis of pregnenolone sulfate, dehydroisoandrosterone sulfate, 1 7a-Hydroxypregnenolone sulfate, and A5-Pregnenetriol sulfate by the normal human adrenal gland. J Clin Endocrinol Metab 25: 290-293, 1965 MARGRAF HW, WEICHSELBAUM TE: Laboratory procedures in diagnosis of adrenal cortical disease in the adrenal cortex. Edited by AB Eisenstein, Boston, Little, Brown and Company, p 405 FUKUSHIMA DK, BRADLOW JH, HELLMAN L: Metabolic transformation of hydrocortisone-4-14C in normal men. JBiol Chem 235: 2246-2252, 1960
14. BRADLOW HL, GALLAGHER TF: Metabolism of l 1j hydroxy-W1androstene-3, 17-dione in man. J Biol Chem 229: 505-518, 1957 15. BAILEY J: Personal communication 16. STREETEN DH, STEVENSON CT, DALAKOS TG: The diagnosis of
17. 18.
19.
20. 21.
22.
hypercortisolism: Biochemical criteria differentiating patients from lean and obese normal subjects and from females on oral contraceptives. J Clin Endocrinol Metab 29: 1191-1211, 1969 HARTOG M, GAAFAR MA, FRASER R: Effect of corticosteroids on human growth hormone. Lancet 2: 376-378, 1964 FRANTZ AG, RABKIN MT: Human growth hormone, clinical measurement, response to hypoglycaemia and suppression by corticosteroids. N EnglJMed 271: 1375-1381, 1964 JAMES VHT, LANDON J, WYNN V: A fundamental defect of adrenocortical control in Cushing's Syndrome. J Endocrinol 40: 15-28, 1968 MORRIS HJ, JORGENSEN JR, JENKINS SA: Plasma growth hormone concentration in corticosteroid-treated children. J Clin Invest 47: 427-435, 1968 MORRIS HG, JORQUENSON JR, ERLICK H, et al: Metabolic effects of human growth hormone in corticosteroid-treated children. J Clin Invest 427: 436-451, 1968 STRAUCH G, MODIGLIANI E, LUTON JP, et al: Partial somatotrophin insufficiency in Cushing's syndrome. Acta Endocrinal 60: 121-129, 1969
The art of detachment, the virtue of method, and the quality of thoroughness may make you students, in the true sense of the word, successful practi-
tioners, or even great investigators, but your characters may still lack that which can alone give permanence to powers - the grace of humility ... As the divine Italian, at the very entrance to Purgatory, was led by his gentle master to the banks of the island and girt with a rush, indicating thereby that
he had cast off all pride and self-conceit, and was prepared for his perilous ascent to the realms above, so should you, now at the outset of your journey, take the reed of humility in your hands, in token that you appreciate the length
of the way, the difficulties to be overcome, and the fallibility of the faculties upon which you depend ... In these days of aggressive self-assertion, when the stress of competition is so keen and the desire to make the most of oneself so universal, it may seem a
little old-fashioned to preach the necessity of this virtue, but I insist for its own sake, and for the sake of what it brings, that a due humility should take the place of honour on the list.
C.M.A. JOURNAL/JANUARY 22, 1972/VOL. 106 135
