Abstract
Endogenous Cushing syndrome (endogenous hypercortisolemia) is a rare condition in children and adolescents. Its general incidence is 2–5 new cases per million of population per yr with a female to male preponderance of 9 to 1, and approximately 10% of these cases occur during childhood and adolescence. The clinical manifestations of the syndrome are different from those in adults, with generalized obesity and growth retardation being the prevailing signs. It is important to suspect the diagnosis, since, in many cases, the signs and symptoms are subtle, and it may take several months or years for the full clinical picture to develop. The diagnostic evaluation of the syndrome is complicated and still challenges the skills of physicians. Correct differential diagnosis, which is achieved by biochemical, imaging and catheterization studies, usually leads to successful treatment and cure. Early diagnosis is significant for prevention of the chronic deleterious effects of hypercortisolism especially on growth.
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Cushing H. The pituitary body and its disorders. Lippincott J.B., Philadelphia, 1912, p. 219.
Kamilaris T., Chrousos G.P. Adrenal diseases. In: Moore W.T., Eastman R. (Eds.), Diagnostic endocrinology. B.C. Decker Inc., Toronto, 1989, p. 79.
Magiakou M.A., Chrousos G.P. Corticosteroid therapy, nonendocrine disease and corticosteroid withdrawal. In: Bardin C.W. (Ed.), Current therapy in endocrinology and metabolism, ed. 5. Mosby Year Book Inc., 1994, p. 120–124.
Magiakou M.A., Chrousos G.P. Diagnosis and treatment of Cushing disease. In: Imura H. (Ed.), The pituitary gland, ed. 2. Raven Press, NY, 1994, p. 491.
Doppman J.L., Travis W.D., Nieman L., Miller D.L., Chrousos G.P., Gomez M.T., Cutler G.B., Loriaux D.L., Norton J.A. Cushing syndrome due to primary pigmented nodular adrenocortical disease: Findings at CT and MR imaging. Radiology 1989, 172: 415–420.
Doppman J.L., Nieman L.K., Travis W.D., Miller D.L., Cutler G.B. Jr., Chrousos G.P., Norton J.A. CT and MR imaging of massive macronodular adrenocortical disease: a rare cause of autonomous primary adrenal hypercortisolism. J. Comput. Assist. Tomogr. 1991, 15: 773–779.
Lacroix A., Bolte E., Tremblay J., Dupre J., Poitras P., Fournier H., Garon J., Garrel D., Bayard F., Taillefer R. Gastric inhibitory polypeptide — dependent cortisol hypersecretion — a new cause of Cushing’s syndrome. N. Engl. J. Med. 1992, 327: 974–980.
Danon M., Robboy S.L., Kim S., Scully R., Crawford J.D. Cushing syndrome, sexual precocity, and polyostotic fibrous dysplasia (Albright syndrome) in infancy. J. Pediatr. 1975, 87: 917–921.
Carey R.M., Varna S.K., Drake C.R., Thorner M.O., Kovacs K., Rivier J., Vale W. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing’s syndrome. N. Engl. J. Med. 1984, 311: 13–20.
Auchus R.J., Mastorakos G., Friedman T.C., Chrousos G.P. Corticotropin-releasing hormone production by a small cell carcinoma in a patient with ACTH-dependent Cushing syndrome. J. Endocrinol. Invest. 1994, 17: 447–452.
Malchoff C.D., Rosa J., DeBold C.R., Kozol R.A., Ramsby G.R., Page D.L., Malchoff D.M., Orth D.N. Adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia: an unusual cause of Cushing’s syndrome. J. Clin. Endocrinol. Metab. 1989, 68: 855–860.
Buckley N., Bates A.S., Broome J.C., Strange R.C., Perrett C.W., Burke C.W., Clayton R.N. P53 protein accumulates in Cushing’s adenomas and invasive non-functioning adenomas. J. Clin. Endocrinol. Metab. 1994, 79: 1518–1521.
Tsigos C., Chrousos G.P. Clinical presentation, diagnosis and treatment of Cushing’s syndrome. In: Current opinion in endocrinology and diabetes, Current Science, Philadelphia, 1995, p. 1.
Magiakou M.A., Mastorakos G., Oldfield E.H., Gomez M.T., Doppman J.L., Cutler G.B. Jr., Nieman L.K., Chrousos G.P. Cushing’s syndrome in children and adolescents. Presentation, diagnosis and therapy. N. Engl. J. Med. 1994, 331: 629–636.
Plotz C.M., Knowlton A.L., Ragan C. The natural history of Cushing syndrome. Am. J. Med. 1952, 13: 597–614.
Soffler L.J., Iannaccone A., Gabrilove J.L. Cushing’s syndrome: a study of fifty patients. Am. J. Med. 1961, 30: 129–146.
Murphy B.E.P. Clinical evaluation of urinary cortisol determinations by competitive protein-binding radioassay. J. Clin. Endocrinol. Metab. 1968, 28: 343–348.
Gomez M.T., Malozowski S., Winterer J., Chrousos G.P. Urinary free cortisol values in normal children and adolescents. J. Pediatr. 1991, 118: 256–258.
Schoneschofer M., Weber B., Oelkers W., Nahoul K., Mantero F. Measurement of urinary free 20 alpha-dihydrocortisol in biochemical diagnosis of chronic corticoidism. Clin. Chem. 1986, 32: 808–810.
Gafni R.I., Papanicolaou D.A., Nieman L.K. Nighttime salivary cortisol measurement as a simple, noninvasive, outpatient screening test for Cushing’s syndrome in children and adolescents. J. Pediatr. 2000, 137: 30–35.
Martinelli C.E. Jr., Sader S.L., Oliveira E.B., Daneluzzi J.C., Moreira A.C. Salivary cortisol for screening of Cushing’s syndrome in children. Clin. Endocrinol. (Oxf.) 1999, 51: 67–71.
Connolly C.K., Gore M.B.R., Stanley N., Wills M.R. Single-dose dexamethasone suppression in normal subjects and hospital patients. Br. Med. J. 1968, 2: 665–667.
Pavlatos F.C., Smilo R.P., Forsham P.H. A rapid screening test for Cushing’s syndrome. J. Am. Med. Ass. 1965, 193: 720–723.
Brown R.D., Van Loon G.R., Orth D.N., Liddle G.W. Cushing’s disease with periodic hormonogenesis: one explanation for paradoxical response to dexamethasone. J. Clin. Endocrinol. Metab. 1973, 36: 445–451.
Jubiz W., Meikle A.W., Levinson R.A., Mizutani S., West C.D., Tyler F.H. Effect of diphenyihydantoin on the metabolism of dexamethasone. N. Engl. J. Med. 1970, 283: 11–14.
Orth D.N. Adrenocorticotropic hormone (ACTH). In: Jaffe P.M., Behram H.R. (Eds.), Methods of hormone radioimmunoassay. Academic Press, New York 1978, p. 245.
Liddle G.W. Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing’s syndrome. J. Clin. Endocrinol. Metab. 1960, 20: 1539–1561.
Flack M.R., Oldfield E.H., Cutler G.B., Zweig M.H., Malley J.D., Chrousos G.P., Loriaux D.L., Nieman L.K. The use of urine free cortisol in the high dose dexamethasone suppression test for the differential diagnosis of Cushing’s syndrome. Ann. Intern Med. 1992, 116: 211–217.
Tyrrell J.B., Findling J.W., Aron D.C., Fitzgerald P.A., Forsham P.H. An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing’s syndrome. Ann. Intern. Med. 1986, 104: 180–186.
de Lange W.E., Sluiter W.J., Pratt J.J., Doorenbos H. Plasma 11-deoxycortisol, androstenedione, testosterone and ACTH in comparison with the urinary excretion of tetrahydro-11-deoxycortisol as indices of the pituitary-adrenal response to oral metyrapone. Acta Endocrinol. 1980, 93: 488–494.
Chrousos G.P., Schulte H.M., Oldfield E.H., Gold P.W., Cutler G.B. Jr., Loriaux DL. The corticotropin releasing factor stimulation test: an aid in the evaluation of patients with Cushing’s syndrome. N. Engl. J. Med. 1984, 310: 622–626.
Nieman L.K., Chrousos G.P., Oldfield E.H., Avgerinos P.C., Cutler G.B. Jr, Loriaux D.L. The ovine CRH test and the dexamethasone suppression test in the differential diagnosis of Cushing’s syndrome. Ann. Intern. Med. 1986, 105: 862–867.
Nieman L.K., Cutler G.B. Jr, Oldfield E.H., Loriaux D.L., Chrousos G.P. The ovine corticotropin-releasing hormone stimulation test is superior to the human corticotropin-releasing hormone stimulation test for the diagnosis of Cushing’s disease. J. Clin. Endocrinol. Metab. 1989, 69: 165–170.
Saris S.C., Patronas N.J., Doppman J.L., Loriaux D.L., Cutler G.B., Nieman L.K., Chrousos G.P, Oldfield E.H. Pituitary CT scanning in Cushing’s syndrome. Radiology 1986, 162: 775–777.
Dwyer A.J., Frank J.A., Doppman J.L., Oldfield E.H., Hickey A.M., Cutler G.B., Loriaux D.L., Schiable T.F. Gadolinium DTPA enhanced magnetic resonance imaging of pituitary adenomas in patients with Cushing’s disease: initial experience. Radiology 1987, 163: 421–426.
Doppman J.L., Frank J.A., Dwyer A.J., Oldfield E.H., Miller D.L., Nieman L.K., Chrousos G.P., Cutler G.B., Loriaux D.L. Gadolinium DPTA enhanced MR imaging of ACTH-secreting microadenomas of the pituitary gland. J. Comp. Assist. Tom. 1988, 12: 728–735.
Aron D.C., Findling J.W., Fitzgerald P.A., Brooks R.M., Fisher F.F., Forsham P.H., Tyrrell J.B. Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing’s syndrome-report of 2 cases and review of the literature. Am. J. Med. 1981, 71: 302–306.
Doppman J.L., Miller D.L., Dwyer A.J., Loughlin T., Nieman L., Cutler G.B., Chrousos G.P., Oldfield E.H., Loriaux D.L. Macronodular adrenal hyperplasia in Cushing’s disease. Radiology 1987, 166: 347–352.
Flack M.R., Chrousos G.P. Neoplasms of the adrenal cortex. In: Holland J.F., Frei Ill E., Bast R.C. Jr., Kufe D.W., Morton D.L., Weichselbaum R.R. (Eds.), Cancer medicine, ed. 3. Lea and Febiger, Philadelphia, 1993, p. 1147.
Herwig K.R., Schteingart D.E. Successful removal of adrenal remnant localized by I-19-iodocholesterol. J. Urol. 1974, 111: 713–714.
Doppman J.L., Nieman L.K., Miller D.L., Pass H.I., Chung R., Cutler G.B. Jr, Schauf M., Chrousos G.P., Norton J.A., Zirrsman H.A., Oldfield E.H., Loriaux D.L. Ectopic adrenocorticotropic hormone syndrome-localization studies in 28 patients. Radiology 1989, 172: 115–124.
Leinung M.C., Young W.F. Jr, Whitaker M.D., Scheithauer B.W., Tvastek V.F., Kvols L.K. Diagnosis of corticotropin-producing bronchial carcinoid tumors causing Cushing’s syndrome. Mayo Clin. Proe. 1990, 65: 1314–1321.
Miller D.L., Doppman J.L. Petrosal sinus sampling; technique and rationale. Radiology 1991, 178: 37–47.
Oldfield E.H., Chrousos G.P., Schulte H.M., Loriaux D.L., Schaaf M., Doppman J.L. Preoperative lateralization of ACTH secreting pituitary microadenomas by bilateral and simultaneous inferior petrosal sinus sampling. N. Engl. J. Med. 1985, 312: 100–103.
Oldfield E.H., Doppman J., Nieman L.K., Chrousos G.P., Miller D.L., Katz D.A., Cutler G.B., Loriaux D.L. Petrosal sinus sampling with and without corticotropin releasing hormone in patients with Cushing’s syndrome. N. Engl. J. Med. 1991, 325: 897–905.
Miller D.L., Doppman J.L., Peterman S.B., Nieman L.K., Oldfield E.H., Chang R. Neurologic complications of petrosal sinus sampling. Radiology 1992, 185: 143–147.
Findling J.W. Inferior petrosal sinus sampling: pros and cons; when and where. J. Endocrinol. Invest. 2000, 23: 193–195.
Bornstein S.R., Stratakis C.A., Chrousos G.P. Adrenocortical tumors. Recent advances in basic concepts and clinical management. Ann. Intern. Med. 1999, 130: 759–771.
Loriaux, D.L., Cutler G.B. Jr. Diseases of the adrenal glands. In: Kohier P.O. (Ed.), Clinical endocrinology. Wiley, New York, 1986, p. 167.
Tyrrell J.B., Brooks R.M., Fitzgerald P.A., Cofoid P.B., Forsham P.H., Wilson C.B. Cushing’s disease: Selective transsphenoidal resection of pituitary microadenomas. N. Engl. J. Med. 1978, 298: 753–758.
Salassa R.M., Laws E.R. Jr., Carpenter P.C., Northcutt R.C. Transsphenoidal removal of pituitary microadenoma in Cushing’s disease. Mayo Clin. Proc. 1978, 53: 24–28.
Malpalam T.J., Tyrrell J.B., Wilson C.B. Transsphenoidal microsurgery for Cushing disease: a report of 216 cases. Ann. Intern. Med. 1989, 109: 487–493.
Friedman R.B., Oldfield E.H., Nieman L.K., Chrousos G.P., Doppman J.L., Cutler G.B. Jr, Loriaux D.L. Repeat transsphenoidal surgery for Cushing’s disease. J. Neurosurg. 1989, 71: 520–527.
Hayashi M., Izawa M., Hiyama H., Nakamura S., Atsuchi S., Sato H., Nakaya K., Sasaki K., Ochiai T., Kubo O., Hori T., Takakura K. Gamma Knife radiosurgery for pituitary adenomas. Stereotact. Funct. Neurosurg. 1999, 72 (Suppl. 1): 111–118.
Kim S.H., Huh R., Chung J.W., Park Y.G., Chung S.S. Gamma Knife radiosurgery for functioning pituitary adenomas. Stereotact. Funct. Neurosurg. 1999, 72 (Suppl. 1): 101–110.
Schteingart D.E., Tsao H.S., Taylor C.I., McKenzie A., Victoria R., Therrien B.A. Sustained remission of Cushing’s disease with mitotane and pituitary irradiation. Ann. Intern. Med. 1980, 92: 613–619.
Jennings A.S., Liddle G.W., Orth D.N. Results of treating childhood Cushing’s disease with pituitary irradiation. N. Engl. J. Med. 1977, 297: 957–962.
Gomez M.T., Chrousos G.P. Cushing’s syndrome. In: Current therapy in endocrinology and metabolism, ed. 4. B.C. Decker, Toronto, 1991, p. 134.
Tabarin A., Navarranne A., Guerin J., Corcuff J.B., Parneix M., Roger P. Use of ketokonazole in the treatment of Cushing’s disease and ectopic ACTH syndrome. Clin. Endocrinol. (Oxf.) 1991, 34: 63–69.
Moore T.J., Dluhy R.G., Williams G.H., Cain J.P. Nelson’s syndrome: frequency, prognosis, and effect of prior pituitary irradiation. Ann. Intern. Med. 1976, 85: 731–734.
Doherty G.M., Nieman L.K., Cutler G.B. Jr, Chrousos G.P., Norton J.A. Time to recovery of the hypothalamic-pituitary-adrenal axis after curative resection of adrenal tumors in patients with Cushing’s syndrome. Surgery 1990, 108: 1085–1090.
Gomez M.T., Magiakou M.A., Mastorakos G., Chrousos G.P. The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic-pituitary-adrenal axis in patients with Cushing syndrome. J. Clin. Endocrinol. Metab. 1992, 77: 173–177.
Magiakou M.A., Mastorakos G., Gomez M.T., Rose S.R., Chrousos G.P. Suppressed spontaneous and stimulated growth hormone secretion in patients with Cushing’s disease before and after surgical cure. J. Clin. Endocrinol. Metab. 1994, 78: 131–137.
Hughes N.R., Lissett C.A., Shalet S.M. Growth hormone status following treatment for Cushing’s syndrome. Clin. Endocrinol. (Oxf.) 1999, 51: 61–66.
Magiakou M.A., Mastorakos G., Chrousos G.P. Final stature in patients with endogenous Cushing’s syndrome. J. Clin. Endocrinol. Metab. 1994, 79: 1082–1085.
Magiakou M.A., Mastorakos G., Zachman K., Chrousos G.P. Blood pressure in children and adolescents with Cushing’s syndrome before and after surgical cure. J. Clin. Endocrinol. Metab. 1997, 82: 1734–1738.
Stratakis C.A., Mastorakos G., Magiakou M.A., Papavasiliou E., Oldfield E.H., Chrousos G.P. Thyroid function in children with Cushing’s disease before and after transsphenoidal surgery. J. Pediatr. 1997, 131: 905–909.
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Magiakou, A., Chrousos, G.P. Cushing’s syndrome in children and adolescents: Current diagnostic and therapeutic strategies. J Endocrinol Invest 25, 181–194 (2002). https://doi.org/10.1007/BF03343985
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DOI: https://doi.org/10.1007/BF03343985