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the absence of patent hypercortisolism, and because some cases regress spontaneously, 2 we decided to postpone suppres- sive therapy. In March 2006, the patient’s urine and serum cortisol levels increased dramatically (Table). The diagnosis of adre- nocorticotropic hormone (ACTH)-independent hypercorti- solism was further supported by ultrasonography and mag- netic resonance imaging (MRI) showing slightly enlarged adrenal glands. Cerebral MRI did not reveal pituitary ade- noma. A dexamethasone-suppression test was not performed. Given the long-term side effects of hypercortisolism, espe- cially 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, 2,3 and metyrapone therapy is efficient but poorly tolerated. 1,2,4 Therefore, we propose this alterna- tive medication in cases of severe MAS complicated with hypercortisolism. Cecilia Heng Vong, MD Maguelone Forest, MD, PhD Marc Nicolino, MD, PhD Department of Pediatric Endocrinology and Metabolism Hopital Femme-Mere-Enfant Lyon/Bron, France 10.1016/j.jpeds.2008.12.003 REFERENCES 1. Gillis D, Rösler A, Hannon TS, Koplewitz BZ, Hirsch HJ. Prolonged remission of severe Cushing syndrome without adrenalectomy in an infant with McCune-Albright syndrome. J Pediatr 2008;152:882-4. 2. Kirk JM, Brain CE, Carson DJ, Hyde JC, Grant DB. Cushing’s syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome. J Pediatr 1999;134:789-92. 3. Shenker A, Weinstein LS, Moran A, Pescovitz OH, Charest NJ, Boney CM, et al. Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein GS. J Pediatr 1993; 123:509-18. 4. Halioui-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;12:1120-3. Reply To the Editor: The Letter to the Editor by Vong et al describing treatment of a child with McCune-Albright associated Cush- ing syndrome (MAS-CS) with ketoconazole stresses the pos- sible 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 adre- nalectomy, 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. However, for this infant, we preferred other medications, namely metyrapone and aminoglutethimide, despite their poorer tolerability be- cause of the potential hepatotoxicity of ketoconazole. 2-4 On admission at the age of 3 months, our patient’s liver enzymes were 1.5- to 8-fold greater than the upper limit of reference range (aspartate aminotransfarase, 91 IU/L; reference range, 2-60 IU/L; alanine aminotransferase [ALT], 201 IU/L; ref- erence range, 6-53 IU/L; gamma-glutamyl-transpeptidase, 796 IU/L; reference range, 10-80 IU/L; lactate dehydroge- nase, 1331; reference range, 300-620 IU/L), with albumin and total bilirubin levels in the reference range. We attributed the elevated enzyme levels to fatty liver associated with the massive obesity of Cushing syndrome, and later, after im- provement of the obesity, liver test results normalized. In a report from the United Kingdom about ketoconazole hep- atotoxicity, it was noted that in 2 of 3 associated deaths, the drug had been continued despite hepatitis. 2 The au- thors recommended that if serum transaminase levels rise Table. Hormonal findings in our patient 3/2003 10/2004 5/2005 3/2006 10/2006 6/2007 12/2007 6/2008 Age 2 years 3 years, 7 months 4 years, 2 months 5 years 5 years, 6 months 6 years, 3 months 6 years, 9 months 7 years, 3 months Serum cortisol level, nmol/L 8 hours 386 236 355 415 118 151 311 277 12 hours 365 293 358 954 157 211 291 255 20 hours 329 333 308 1245 114 252 224 341 0 hours — — 275 232 78 135 244 237 Urine free cortisol level, nmol/24 hours 66 — 115 2330 23 31.1 34.1 33 ACTH level, ng/L 8 hours 9 3 2 4 7 5 5 5 12 hours 6 3 2 3 8 5 5 5 20 hours 10 2 2 3 8 5 5 5 0 hours — — 1 2 1 5 5 5 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. 468 Letters to the Editor The Journal of Pediatrics • March 2009
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he absence of patent hypercortisolism, and because someases regress spontaneously,2 we decided to postpone suppres-ive therapy.
In March 2006, the patient’s urine and serum cortisolevels increased dramatically (Table). The diagnosis of adre-ocorticotropic hormone (ACTH)-independent hypercorti-olism was further supported by ultrasonography and mag-etic resonance imaging (MRI) showing slightly enlargeddrenal glands. Cerebral MRI did not reveal pituitary ade-oma. A dexamethasone-suppression test was not performed.iven the long-term side effects of hypercortisolism, espe-
ially on bone FD, treatment was initiated with ketoconazole2.5 mg/kg/day). Four months after the onset of treatment,he patient had very low cortisol urine and serum levels,ndicating strong adrenal suppression. This has persisted fort least 2 years, during which time liver function tests haveemained normal. Bilateral adrenalectomy increases morbidityn patients with MAS,2,3 and metyrapone therapy is efficientut poorly tolerated.1,2,4 Therefore, we propose this alterna-ive medication in cases of severe MAS complicated withypercortisolism.
Cecilia Heng Vong, MDMaguelone Forest, MD, PhD
Marc Nicolino, MD, PhDDepartment of Pediatric Endocrinology and Metabolism
Hopital Femme-Mere-EnfantLyon/Bron, France
10.1016/j.jpeds.2008.12.003
REFERENCES. Gillis D, Rösler A, Hannon TS, Koplewitz BZ, Hirsch HJ. Prolonged remission ofevere Cushing syndrome without adrenalectomy in an infant with McCune-Albrightyndrome. J Pediatr 2008;152:882-4.. Kirk JM, Brain CE, Carson DJ, Hyde JC, Grant DB. Cushing’s syndrome causedy nodular adrenal hyperplasia in children with McCune-Albright syndrome. J Pediatr999;134:789-92.
able. Hormonal findings in our patient
3/2003 10/2004 5
ge 2 years 3 years,7 months
4 y2
erum cortisol level, nmol/L8 hours 386 23612 hours 365 29320 hours 329 3330 hours — —
rine free cortisol level, nmol/24 hours 66 —CTH level, ng/L8 hours 9 312 hours 6 320 hours 10 20 hours — —
ormal ranges: serum cortisol, 8 a.m.: 373 � 117 mol/L, 8 p.m.: 100 to 250 nmol/L;
. Shenker A, Weinstein LS, Moran A, Pescovitz OH, Charest NJ, Boney CM, et al.evere endocrine and nonendocrine manifestations of the McCune-Albright syndrome t
68 Letters to the Editor
ssociated with activating mutations of stimulatory G protein GS. J Pediatr 1993;23:509-18.. Halioui-Louhaichi S, Azzabi O, Nefzi L, Ben Hariz M, Ben Mrad N, Ben Ammar, et al. Treatment with metyrapone of Cushing’s syndrome revealing McCune-lbright syndrome. Arch Pediatr 2005;12:1120-3.
eply
o the Editor:The Letter to the Editor by Vong et al describing
reatment of a child with McCune-Albright associated Cush-ng syndrome (MAS-CS) with ketoconazole stresses the pos-ible use of a pharmacological approach to MAS-CS. Weecently reported in The Journal about a patient with
AS-CS presenting in the first months of life with floridushingoid features.1 We had recommended bilateral adre-alectomy, but the parents did not consent to this procedure.he first drug we had considered as an alternative to surgeryas ketoconazole because one of us (A.R.) previously had
reated several adult patients with this drug for long periods,ith virtually no significant adverse effects. However, for this
nfant, we preferred other medications, namely metyraponend aminoglutethimide, despite their poorer tolerability be-ause of the potential hepatotoxicity of ketoconazole.2-4 Ondmission at the age of 3 months, our patient’s liver enzymesere 1.5- to 8-fold greater than the upper limit of reference
ange (aspartate aminotransfarase, 91 IU/L; reference range,-60 IU/L; alanine aminotransferase [ALT], 201 IU/L; ref-rence range, 6-53 IU/L; gamma-glutamyl-transpeptidase,96 IU/L; reference range, 10-80 IU/L; lactate dehydroge-ase, 1331; reference range, 300-620 IU/L), with albuminnd total bilirubin levels in the reference range. We attributedhe elevated enzyme levels to fatty liver associated with theassive obesity of Cushing syndrome, and later, after im-
rovement of the obesity, liver test results normalized. In aeport from the United Kingdom about ketoconazole hep-totoxicity, it was noted that in 2 of 3 associated deaths,he drug had been continued despite hepatitis.2 The au-
5 3/2006 10/2006 6/2007 12/2007 6/2008
ths5 years 5 years,
6 months6 years,
3 months6 years,
9 months7 years,
3 months
415 118 151 311 277954 157 211 291 255
1245 114 252 224 341232 78 135 244 237
2330 23 31.1 34.1 33
4 7 � 5 � 5 � 53 8 � 5 � 5 � 53 8 � 5 � 5 � 52 1 � 5 � 5 � 5
free cortisol, 30 to 60 nmol/24 hours; serum ACTH, � 50 ng/L at 8 a.m.
/200
ears,mon
355358308275115
2221
urine
hors recommended that if serum transaminase levels rise
The Journal of Pediatrics • March 2009
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ore than 3-fold higher than reference range, this treat-ent should be stopped.2 In our patient, the ALT level wasore than 4-fold the upper limit of the reference range,
nd we felt it would not be advisable to administer keto-onazole. Recent studies have described some of the cel-ular processes involved in ketoconazole toxicity, but areeyond the scope of this letter.3,4 The patient currentlyescribed by Vong et al presented in early childhood withilder clinical and biochemical features than those of our
atient, and therefore probably had no hepatic disease.learly, in this situation, ketoconazole would have been
he drug of choice.
David Gillis, MDAriel Rosler, MD
Benjamin Z. Koplewitz, MDHadassah Medical Center
Jerusalem, Israelgh
etters to the Editor
Tamara S. Hannon, MDChildren’s Hospital of Pittsburgh
Pittsburgh, Pennsylvania
Harry J. Hirsch, MDShaare-Zedek Medical Center
Jerusalem, Israel10.1016/j.jpeds.2008.12.004
REFERENCES. Gillis D, Rösler A, Hannon TS, Koplewitz BZ, Hirsch HJ. Prolonged remission ofevere Cushing syndrome without adrenalectomy in an infant with McCune-Albrightyndrome. J Pediatr 2008;152:882-4.. Lake-Bakaar G, Scheuer PJ, Sherlock S. Hepatic reactions associated with keto-onazole in the United Kingdom. Br Med J 1987;294:419-22.. Casley WL, Ogrodowezyk C, Larocque L, Jaentschke B, LeBlanc-Westwood C,enzies JA, et al. Cytotoxic doses of Ketoconazole affect expression of a subset of
epatic genes. J Toxicol Environ Health 2007;70:1946-55.. Rodriguez RJ, Buckholz J. Hepatotoxicity of ketoconazole in Sprague-Dawley rats:
lutathione depletion, flavin-containing monooxygenases-mediated bioactivation andepatic covalent binding. Xenobiotica 2003;33:429-41.469
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