Klinefelter syndrome (KS), a genetic disorder that occurs in 1/1000 males, is defined by the abnormal chromosome karyotype 47.XXY (extra X chromosome), and has characteristic physical and cognitive phenotypes evident in childhood. The KS physical phenotype includes testicular failure (androgen deficiency) and tall stature. The KS neurocognitive phenotype includes diminished motor function and language-based learning difficulties. The KS behavioral phenotype involves poor self-image and shyness. The neurodevelopmental deficits associated with KS likely reflect the influence of both androgen deficiency and genetic factors on development and represent a major impediment for living a normal life with KS. It is the goal of this clinical trial to determine whether this burden can be reduced by treatment early in childhood with androgen replacement. Androgen replacement is standard in adolescent and adult KS males but has not been used in younger, prepubertal KS boys. The Phase I study will establish that the androgen oxandrolone, an FDA-approved medication for children, is also safe in prepubertal KS boys. The Phase II study is the randomized clinical trial, in which we plan to study the effects of childhood androgen replacement on motor and cognitive aspects of the KS phenotype that may result from childhood androgen deficiency. This randomized, placebo-controlled study tests a novel intervention in this population: low-dose androgen (oxandrolone) treatment for two years in KS boys (n=120), ages of 4-12 years. We predict that KS boys treated with androgen for 24 months will have improved muscle strength, compared to the placebo-treated KS boys. Second, we predict that KS boys treated with androgen for 24 months will have improved aspects of motor function including response speed, simple repetitive movement, and complex nonrepetitive motor action, compared to the placebo-treated KS boys. Third, we predict that KS boys treated with androgen (oxandrolone) for 24 months will have improved aspects of language, including verbal memory and verbal fluency and fourth, we predict that KS boys treated with androgen for 24 months will have improved aspects of simple and complex attention, compared to the placebo-treated KS boys.

Public Health Relevance

OF THIS RESEARCH: KS is well suited for interventional studies because testicular failure is nearly universal in this disorder. Early androgen replacement is a reasonable, appropriate, and safe research treatment option in this androgen-deficient population. Therapeutic interventions for this relatively common disorder have not been forthcoming, and this proposal represents a unique opportunity to replace a missing hormone and potentially improve motor function and cognition. If successful, androgen replacement in the clinical management of KS would commence early in childhood rather than adolescence or adulthood. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050597-02
Application #
7217906
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Riddle, Robert D
Project Start
2006-05-01
Project End
2011-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
2
Fiscal Year
2007
Total Cost
$563,760
Indirect Cost
Name
Thomas Jefferson University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Davis, Shanlee M; Lahlou, Najiba; Cox-Martin, Matthew et al. (2018) Oxandrolone Treatment Results in an Increased Risk of Gonadarche in Prepubertal Boys With Klinefelter Syndrome. J Clin Endocrinol Metab 103:3449-3455
Foland-Ross, Lara C; Ross, Judith L; Reiss, Allan L (2018) Androgen treatment effects on hippocampus structure in boys with Klinefelter syndrome. Psychoneuroendocrinology 100:223-228
Davis, Shanlee M; Cox-Martin, Matthew G; Bardsley, Martha Z et al. (2017) Effects of Oxandrolone on Cardiometabolic Health in Boys With Klinefelter Syndrome: A Randomized Controlled Trial. J Clin Endocrinol Metab 102:176-184
Davis, S; Lahlou, N; Bardsley, M et al. (2016) Gonadal function is associated with cardiometabolic health in pre-pubertal boys with Klinefelter syndrome. Andrology 4:1169-1177
Davis, Shanlee M; Rogol, Alan D; Ross, Judith L (2015) Testis Development and Fertility Potential in Boys with Klinefelter Syndrome. Endocrinol Metab Clin North Am 44:843-65
Lepage, J-F; Hong, D S; Raman, M et al. (2014) Brain morphology in children with 47, XYY syndrome: a voxel- and surface-based morphometric study. Genes Brain Behav 13:127-34
Hong, David S; Hoeft, Fumiko; Marzelli, Matthew J et al. (2014) Influence of the X-chromosome on neuroanatomy: evidence from Turner and Klinefelter syndromes. J Neurosci 34:3509-16
Ross, Judith L; Roeltgen, David P; Kushner, Harvey et al. (2012) Behavioral and social phenotypes in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome. Pediatrics 129:769-78
Cordeiro, Lisa; Tartaglia, Nicole; Roeltgen, David et al. (2012) Social deficits in male children and adolescents with sex chromosome aneuploidy: a comparison of XXY, XYY, and XXYY syndromes. Res Dev Disabil 33:1254-63
Bryant, Daniel M; Hoeft, Fumiko; Lai, Song et al. (2012) Sex chromosomes and the brain: a study of neuroanatomy in XYY syndrome. Dev Med Child Neurol 54:1149-56

Showing the most recent 10 out of 18 publications