Ketoconazole treatment for Cushing syndrome in McCune-Albright syndrome
2009; Elsevier BV; Volume: 154; Issue: 3 Linguagem: Inglês
10.1016/j.jpeds.2008.12.003
ISSN1097-6833
AutoresCecilia Heng Vong, Maguelone G. Forest, Marc Nicolino,
Tópico(s)interferon and immune responses
ResumoBased on our recent experience with a case of McCune-Albright syndrome (MAS), we propose an alternative medical treatment to that described by Gillis et al,1Gillis D. Rösler A. Hannon T.S. Koplewitz B.Z. Hirsch H.J. Prolonged remission of severe Cushing syndrome without adrenalectomy in an infant with McCune-Albright syndrome.J Pediatr. 2008; 152: 882-884Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar involving treatment with ketoconazole to avoid bilateral adrenalectomy. At age 6 months, our patient had severe fibrous dysplasia (FD) and hyperpigmented spots, confirmed by the findings of an arg201cys mutation on chromosome 20q13 in peripheral leucocytes. Later, the patient developed precocious puberty, which was controlled by aromatase inhibitors. At age 4 years, she was mildly obese. Her cortisol level was at the upper limit of normal with a loss of diurnal variation, whereas her corticotropin level was persistently low. She had no other cushingoid features, except for excessive adipose tissue and decreased muscle mass for age on dual-energy X-ray absorptiometry. In the absence of patent hypercortisolism, and because some cases regress spontaneously,2Kirk J.M. Brain C.E. Carson D.J. Hyde J.C. Grant D.B. Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.J Pediatr. 1999; 134: 789-792Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar we decided to postpone suppressive therapy.In March 2006, the patient's urine and serum cortisol levels increased dramatically (Table). The diagnosis of adrenocorticotropic hormone (ACTH)-independent hypercortisolism was further supported by ultrasonography and magnetic resonance imaging (MRI) showing slightly enlarged adrenal glands. Cerebral MRI did not reveal pituitary adenoma. A dexamethasone-suppression test was not performed. Given the long-term side effects of hypercortisolism, especially on bone FD, treatment was initiated with ketoconazole (2.5 mg/kg/day). Four months after the onset of treatment, the patient had very low cortisol urine and serum levels, indicating strong adrenal suppression. This has persisted for at least 2 years, during which time liver function tests have remained normal. Bilateral adrenalectomy increases morbidity in patients with MAS,2Kirk J.M. Brain C.E. Carson D.J. Hyde J.C. Grant D.B. Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.J Pediatr. 1999; 134: 789-792Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 3Shenker A. Weinstein L.S. Moran A. Pescovitz O.H. Charest N.J. Boney C.M. et al.Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein GS.J Pediatr. 1993; 123: 509-518Abstract Full Text PDF PubMed Scopus (272) Google Scholar and metyrapone therapy is efficient but poorly tolerated.1Gillis D. Rösler A. Hannon T.S. Koplewitz B.Z. Hirsch H.J. Prolonged remission of severe Cushing syndrome without adrenalectomy in an infant with McCune-Albright syndrome.J Pediatr. 2008; 152: 882-884Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 2Kirk J.M. Brain C.E. Carson D.J. Hyde J.C. Grant D.B. Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.J Pediatr. 1999; 134: 789-792Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 4Halioui-Louhaichi S. Azzabi O. Nefzi L. Ben Hariz M. Ben Mrad N. Ben Ammar B. et al.Treatment with metyrapone of Cushing's syndrome revealing McCune-Albright syndrome.Arch Pediatr. 2005; 12: 1120-1123Crossref PubMed Scopus (12) Google Scholar Therefore, we propose this alternative medication in cases of severe MAS complicated with hypercortisolism.TableHormonal findings in our patient3/200310/20045/20053/200610/20066/200712/20076/2008Age2 years3 years, 7 months4 years, 2 months5 years5 years, 6 months6 years, 3 months6 years, 9 months7 years, 3 monthsSerum cortisol level, nmol/L 8 hours386236355415118151311277 12 hours365293358954157211291255 20 hours3293333081245114252224341 0 hours——27523278135244237Urine free cortisol level, nmol/24 hours66—11523302331.134.133ACTH level, ng/L 8 hours93247< 5< 5< 5 12 hours63238< 5< 5< 5 20 hours102238< 5< 5< 5 0 hours——121< 5< 5< 5Normal ranges: serum cortisol, 8 a.m.: 373 ± 117 mol/L, 8 p.m.: 100 to 250 nmol/L; urine free cortisol, 30 to 60 nmol/24 hours; serum ACTH, < 50 ng/L at 8 a.m. Open table in a new tab Based on our recent experience with a case of McCune-Albright syndrome (MAS), we propose an alternative medical treatment to that described by Gillis et al,1Gillis D. Rösler A. Hannon T.S. Koplewitz B.Z. Hirsch H.J. Prolonged remission of severe Cushing syndrome without adrenalectomy in an infant with McCune-Albright syndrome.J Pediatr. 2008; 152: 882-884Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar involving treatment with ketoconazole to avoid bilateral adrenalectomy. At age 6 months, our patient had severe fibrous dysplasia (FD) and hyperpigmented spots, confirmed by the findings of an arg201cys mutation on chromosome 20q13 in peripheral leucocytes. Later, the patient developed precocious puberty, which was controlled by aromatase inhibitors. At age 4 years, she was mildly obese. Her cortisol level was at the upper limit of normal with a loss of diurnal variation, whereas her corticotropin level was persistently low. She had no other cushingoid features, except for excessive adipose tissue and decreased muscle mass for age on dual-energy X-ray absorptiometry. In the absence of patent hypercortisolism, and because some cases regress spontaneously,2Kirk J.M. Brain C.E. Carson D.J. Hyde J.C. Grant D.B. Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.J Pediatr. 1999; 134: 789-792Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar we decided to postpone suppressive therapy. In March 2006, the patient's urine and serum cortisol levels increased dramatically (Table). The diagnosis of adrenocorticotropic hormone (ACTH)-independent hypercortisolism was further supported by ultrasonography and magnetic resonance imaging (MRI) showing slightly enlarged adrenal glands. Cerebral MRI did not reveal pituitary adenoma. A dexamethasone-suppression test was not performed. Given the long-term side effects of hypercortisolism, especially on bone FD, treatment was initiated with ketoconazole (2.5 mg/kg/day). Four months after the onset of treatment, the patient had very low cortisol urine and serum levels, indicating strong adrenal suppression. This has persisted for at least 2 years, during which time liver function tests have remained normal. Bilateral adrenalectomy increases morbidity in patients with MAS,2Kirk J.M. Brain C.E. Carson D.J. Hyde J.C. Grant D.B. Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.J Pediatr. 1999; 134: 789-792Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 3Shenker A. Weinstein L.S. Moran A. Pescovitz O.H. Charest N.J. Boney C.M. et al.Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein GS.J Pediatr. 1993; 123: 509-518Abstract Full Text PDF PubMed Scopus (272) Google Scholar and metyrapone therapy is efficient but poorly tolerated.1Gillis D. Rösler A. Hannon T.S. Koplewitz B.Z. Hirsch H.J. Prolonged remission of severe Cushing syndrome without adrenalectomy in an infant with McCune-Albright syndrome.J Pediatr. 2008; 152: 882-884Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 2Kirk J.M. Brain C.E. Carson D.J. Hyde J.C. Grant D.B. Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome.J Pediatr. 1999; 134: 789-792Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 4Halioui-Louhaichi S. Azzabi O. Nefzi L. Ben Hariz M. Ben Mrad N. Ben Ammar B. et al.Treatment with metyrapone of Cushing's syndrome revealing McCune-Albright syndrome.Arch Pediatr. 2005; 12: 1120-1123Crossref PubMed Scopus (12) Google Scholar Therefore, we propose this alternative medication in cases of severe MAS complicated with hypercortisolism. Normal ranges: serum cortisol, 8 a.m.: 373 ± 117 mol/L, 8 p.m.: 100 to 250 nmol/L; urine free cortisol, 30 to 60 nmol/24 hours; serum ACTH, < 50 ng/L at 8 a.m. ReplyThe Journal of PediatricsVol. 154Issue 3PreviewThe Letter to the Editor by Vong et al describing treatment of a child with McCune-Albright associated Cushing syndrome (MAS-CS) with ketoconazole stresses the possible use of a pharmacological approach to MAS-CS. We recently reported in The Journal about a patient with MAS-CS presenting in the first months of life with florid Cushingoid features.1 We had recommended bilateral adrenalectomy, but the parents did not consent to this procedure. The first drug we had considered as an alternative to surgery was ketoconazole because one of us (A.R.) previously had treated several adult patients with this drug for long periods, with virtually no significant adverse effects. Full-Text PDF
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