title: Skeletal maturation in children with Cushing syndrome is not consistently delayed: the role of corticotropin, obesity, and steroid hormones, and the effect of surgical cure.
abstract: OBJECTIVE
  To assess skeletal maturity by measuring bone age (BA) in children with Cushing syndrome (CS) before and 1-year after transsphenoidal surgery or adrenalectomy, and to correlate BA with hormone levels and other measurements.
  
  
  METHODS
  This case series conducted at the National Institutes of Health Clinical Center included 93 children with Cushing disease (CD) (43 females; mean age, 12.3 ± 2.9 years) and 31 children with adrenocorticotropic hormone-independent CS (AICS) (22 females, mean age 10.3 ± 4.5 years). BA was obtained before surgery and at follow-up. Outcome measures were comparison of BA in CD vs AICS and analysis of the effects of hypercortisolism, insulin excess, body mass index, and androgen excess on BA.
  
  
  RESULTS
  Twenty-six of the 124 children (21.0%) had advanced BA, compared with the expected general population prevalence of 2.5% (P < .0001). Only 4 of 124 (3.2%) had delayed BA. The majority of children (76%) had normal BA. The average BA z-score was similar in the children with CD and those with AICS (0.6 ± 1.4 vs 0.5 ± 1.8; P = .8865). Body mass index SDS and normalized values of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androsteonedione, estradiol, and testosterone were all significantly higher in the children with advanced BA vs those with normal or delayed BA. Fifty-nine children who remained in remission from CD had follow-up BA 1.2 ± 0.3 years after transsphenoidal surgery, demonstrating decreased BA z-score (1.0 ± 1.6 vs 0.3 ± 1.4; P < .0001).
  
  
  CONCLUSIONS
  Contrary to common belief, endogenous CS in children appears to be associated with normal or even advanced skeletal maturation. When present, BA advancement in CS is related to obesity, insulin resistance, and elevated adrenal androgen levels and aromatization. This finding may have significant implications for treatment decisions and final height predictions in these children.
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD. Electronic address: lodishma@mail.nih.gov.
authors.forename: Maya B
authors.initials: MB
authors.lastname: Lodish
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Evgenia
authors.initials: E
authors.lastname: Gourgari
authors.affiliation: Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Bethesda, MD.
authors.forename: Ninet
authors.initials: N
authors.lastname: Sinaii
authors.affiliation: Department of Radiology, National Institutes of Health Clinical Center, Bethesda, MD.
authors.forename: Suvimol
authors.initials: S
authors.lastname: Hill
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Laura
authors.initials: L
authors.lastname: Libuit
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Mastroyannis
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Margaret
authors.initials: M
authors.lastname: Keil
authors.affiliation: Department of Pediatrics Warren Alpert Medical School of Brown University, Providence, RI.
authors.forename: Dalia L
authors.initials: DL
authors.lastname: Batista
authors.affiliation: Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000502:physiology*; D000365:Age Determination by Skeleton; D001846:Bone Development; D002648:Child; D003480:Cushing Syndrome / Q000150:complications / Q000503:physiopathology* / Q000601:surgery*; D005260:Female; D012739:Gonadal Steroid Hormones / Q000502:physiology*; D006801:Humans; D008297:Male; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D012739:Gonadal Steroid Hormones; D000324:Adrenocorticotropic Hormone