Study of Psychological and Motor Effects of Testosterone in Adolescents With XXY/Klinefelter Syndrome

Klinefelter syndrome (47,XXY) is the most common chromosomal abnormality in humans and occurs
in approximately 1 in 650 males. Testosterone deficiency develops during adolescence in the
majority of individuals with XXY. However, there are no previous studies that evaluate the
psychological and motor effects of testosterone replacement therapy in adolescents with XXY.

The study researchers are interested in learning if testosterone therapy initiated in early
puberty in XXY (KS) will lead to improvements in psychological and/or motor skills. They are
also interested in learning if genetic variations of the androgen receptor gene or the
parent-of-origin of the extra X chromosome influence the response to testosterone therapy.

Specific psychological factors to be studied include verbal and nonverbal cognitive skills,
attention, executive function (organization, problem-solving skills, inhibition), anxiety,
language, self-esteem, and other behavioral factors. Motor skills to be studied include gross
and fine motor skills, motor coordination, and motor planning.

Participants in the study will be randomized to one of two treatment groups, receiving either
testosterone gel or placebo, for 12 months. 60% of the study group will receive testosterone,
and 40% will receive placebo.

The research participants, parents/caregivers, and the members of the study team will be
blinded to the treatment group, and will not know whether they are receiving testosterone gel
or placebo treatments.

The supervising endocrinologist for the study will not be blinded and will know which
patients are in the testosterone and placebo groups. This will allow him to monitor results
to determine if participants in the placebo group may develop a significant need for
testosterone therapy during the study period. If this occurs, the patient will be switched to
the testosterone group and will continue to be monitored in the study.

All participants will be evaluated at the beginning of the study and at 1, 3, 6, and 12
months. Travel costs are included. Evaluations will include a combination of psychological
and motor skills testing, questionnaires completed by the parent/caregiver and study
participant, physical examinations, and blood draws for safety monitoring and genetic
studies.

Participation in the trial will last one year and includes 5 clinic visits to the
eXtraordinarY Kids Clinic at Children's Hospital Colorado in Denver.

Inclusion Criteria:

- Males with 47,XXY

- Participants must be in early puberty (Tanner stage II-III)

- Age 8 - 18 will be considered, but eligibility will be determined by review of
laboratory results, bone age X-ray, and physical examination to determine stage of
puberty

- All racial and ethnic groups

Exclusion Criteria:

- Other genetic variations of Klinefelter syndrome (48,XXXY, 48,XXYY, 49,XXXXY). The
investigator has other studies for these groups and we encourage interested
individuals with these disorders to contact us about other available studies.

- 47,XXY plus another genetic disorder

- Non-English speaking individuals (because the psychological tests are administered in
English)

- Participants with a medical history of blood clotting problems, blindness, deafness,
or cancer