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Page 78 Schmidt et al. J Transl Genet Genom 2024;8:77-84 https://dx.doi.org/10.20517/jtgg.2023.43

differences were observed in the birth to 12 months group for HT between the T group and No-T group. There
were only significant differences in WT in the birth to 12-month age range between the T group and the No-T
group, as well as in the 12-24-month age range.

Conclusion: EHT is not associated with reducing or advancing growth in children with 47,XXY over 2 years old.
After 24 months of age there is no discernible difference between boys with 47,XXY with EHT and without EHT.

Keywords: 47XXY, Klinefelter Syndrome, early hormonal treatment, growth, height, weight, head circumference

INTRODUCTION
Klinefelter Syndrome, or 47,XXY, is the most common Sex Chromosomal Aneuploidy (SCA), with an
[1]
incidence rate of about 1 in 500 male births . This variation is caused by the presence of an additional X
chromosome in males and is highly underdiagnosed, with only 10% to 25% of males receiving a diagnosis
[1]
throughout their lifetime . A diagnosis of Klinefelter Syndrome often occurs for several reasons: via
prenatal testing or genital abnormalities identified at birth, in adolescence in association with delays in
pubertal development, or in adulthood while being tested for infertility . Underdiagnosis occurs partially
[2]
because of a highly variable phenotype. The neurodevelopmental presentation of 47,XXY often includes
executive dysfunction, language-based learning disorders, and increased anxiety. Physically, 47,XXY
typically presents with characteristic androgen deficiency, reduced fertility, gynecomastia,
hypergonadotropic hypogonadism, hypotonia, and increased height .
[3]

Individuals with 47,XXY typically reach the 30th percentile in height before age 2, and ultimately reach the
75th to 90th percentile by age 18. Mean weight and head circumference measurements are typically at the
50th percentile . A study on the clinical presentation of Klinefelter Syndrome by Pacenza et al. found that
[2]
the average height of 94 males with 47,XXY was above the 50th percentile at 178.8 ± 9.0 cm . Regardless of
[4]
hormonal replacement therapy status, it is rare for post-pubertal males with 47,XXY to remain below the
25th percentile in height . One study found that body weight and body mass index did not significantly
[5,6]
[7]
differ between individuals with 47,XXY and individuals with a normal karyotype . However, this
population often outwardly presents as less athletic in appearance secondary to hypogonadotropic
hypogonadism. Their BMI levels tend to fall within a typical range due to the commensurate muscle-to-fat
ratio, with decreased muscle mass and increased body fat .
[6]
The cause for these characteristic growth patterns and body proportions is unclear due to a lack of research;
however, there are some working hypotheses. Tanner et al. proposed that an unequal growth rate caused by
possible incomplete activation of the extra X chromosome may account for these characteristics . This
[8]
[9]
hypothesis has been reaffirmed in later publications . However, it has also been hypothesized that these
proportional differences are caused by hormonal deficiency, as prepubertal hypoandrogenism typically
presents as increased long bone growth and eunuchoid proportions, a feature commonly associated with
47,XXY .
[10]

Hormonal replacement therapy (HRT) is the suggested treatment for 47,XXY because of the androgen
deficiency associated with the disorder. There are currently three types of HRT that exist in literature: Early
Hormonal Treatment (EHT), which is typically given during “minipuberty” in infancy, Hormonal Booster
Treatment (HBT), which is typically given at or around 5 years of age, and Testosterone Replacement
Therapy (TRT), typically administered regularly beginning at puberty and into adulthood.