TESTO: Testosterone Effects on Short-Term Outcomes in Infants With XXY

XXY (also known as Klinefelter syndrome) is the most common chromosomal abnormality in males,
affecting 1/600 boys. The extra X chromosome leads to insufficient development of the
testicles and subsequent testosterone deficiency. Males with XXY also have a high risk for
developmental delays, learning disabilities, and cardiovascular disease. An essential
question is how much of this risk is because of testosterone deficiency and could therefore
be reduced by testosterone supplementation, particularly during critical periods of
development.

In typical male development, there is a surge of testosterone in the first few months of
life, commonly known as the "mini-puberty period of infancy." This testosterone surge may be
critical for neurodevelopmental and cardiometabolic programming throughout life. Recently
there has been increased off-label use of testosterone in infants with XXY, however neither
the short or long term safety or efficacy have been evaluated. This study aims to quantify
the short term effects of testosterone treatment in infants with XXY on neurodevelopment,
growth, body composition, testicular function, and safety parameters. This is a double blind
randomized placebo controlled trial of testosterone injections 25 mg every 4 weeks for 3
doses in boys with XXY enrolled between 1 and 3 months of age. Outcomes including body fat
percentage, scaled motor developmental scores, growth velocity, testicular hormone
concentrations, specific metabolites, and safety parameters will be assessed 12 weeks into
the study. The groups will then cross-over (all subjects will receive testosterone during the
study period) and the outcomes will be reassessed 24 weeks into the study. The secondary
questions the investigators will answer with this cross-over is 1) whether benefits in the
treatment group at 12 weeks are sustained at 24 weeks, and 2) whether the same benefits are
seen if treated after the mini-puberty period.

Inclusion Criteria:

- Male infants with 47,XXY karyotype identified prenatally who are 4-12 weeks old (31 to
90 days of age). 47,XXY must be from a diagnostic test such as Chorionic Villus
Sampling (CVS), amniocentesis, or post-natal blood/tissue. Non-invasive prenatal
screening results alone will not be accepted.

Exclusion Criteria:

- >20 percent mosaicism for a normal cell line

- Gestational age at birth <36 weeks

- Birth weight <2.5th percentile or >97.5 percentile for age (small or large for
gestational age)

- History of thrombosis in self or a first degree relative

- Exposure to androgen therapy outside the study protocol

- Use of medications known to affect body composition, such as growth hormone or insulin

- Known allergy to the testosterone cypionate solution components including benzyl
benzoate, benzyl alcohol, or cottonseed oil