NORD gratefully acknowledges Dr. Carole Samango-Sprouse, Associate Clinical Professor in the Department of Pediatrics at George Washington University and Adjunct Associate Professor in the Department of Human and Molecular Genetics at Florida International University, for assistance in the preparation of this report.
Klinefelter Syndrome (47, XXY) is a chromosomal variation in males in which one extra X chromosome is present, resulting in a 47,XXY karyotype. The extra X chromosome typically affects physical, neurodevelopmental, behavioral, and neurocognitive functioning. Common physical features may include tall stature, reduced muscle tone, small testes (hypogonadism), delayed pubertal development and lack of secondary male sex characteristics such as decreased facial and body hair. Increased breast growth (gynecomastia) may occur later in puberty without appropriate biological care. With proper treatment, the incidence of gynecomastia typically occurs in less than 10% of boys with 47,XXY (KS).
There is great variability to the neurodevelopmental profile or phenotype in boys with 47,XXY (KS). Common cognitive and behavioral features may include speech and language delays, ADHD and emotional and social functioning challenges. The features of 47, XXY (KS) are typically associated with decreased testosterone level and elevated gonadotropin levels. Early hormonal treatment (EHT) with three monthly injections of 25 mg. of testosterone enanthate, typically given between 4-12 months of age, may optimize brain development and neurodevelopmental outcomes. Testosterone should be administered based upon an evaluation with a pediatrician and pediatric endocrinologist familiar with 47,XXY (KS).
At birth, most neonates with 47, XXY (KS) have no significant dysmorphic or unusual features. Most individuals with 47, XXY (KS) are identified though prenatal diagnosis or when the child does not progress through puberty completely or adequately. Infants and young children with 47, XXY (KS) are sometimes initially identified because of an abnormality in the location of the urinary opening in the penis (hypospadias), small penis or testes, or developmental delay (e.g. speech delay). Older children and teenagers are sometimes diagnosed with 47, XXY (KS) if secondary sexual characteristics do not develop completely, puberty is delayed, testes are small, or breast development occurs. Many males with 47, XXY (KS) are not identified until they have low fertility problems as adults. Men with 47, XXY (KS) may have a relatively increased risk to develop breast cancer but not until after 60 years of age. Most males with 47, XXY (KS) have normal intelligence but there is an increased risk of language based learning disorders, dyslexia and mild social and executive functioning challenges. Often, boys and men with 47, XXY (KS) will present with verbal communication delays due to language-based learning disorders and subtle motor planning deficits. Research has shown, however, that nonverbal capacities in males with 47, XXY (KS), such as perceptual reasoning and receptive language skills, may be intact or even advanced. Thus, PIQ (nonverbal IQ) is often higher than VIQ (verbal IQ) on neurodevelopmental testing. Socially, males with 47, XXY (KS) may have difficulty perceiving social cues and regulating their emotions in stressful situations.
Men with 47, XXY (KS) may have an increased risk for endocrine conditions such as diabetes mellitus, hypothyroidism and hypoparathyroidism and autoimmune diseases such as systemic lupus erythematosus, Sjogren syndrome and rheumatoid arthritis. Many of these conditions can be treated with medications and lifestyle changes.
47, XXY (KS) is not inherited. Males with 47, XXY (KS) have one extra X chromosome because of a nondisjunction error that randomly occurs during the division of the sex chromosomes in the egg or sperm. Some males with 47, XXY (KS) are mosaic, meaning that some cells have an extra X chromosome and other cells do not. Mosaic 47, XXY (KS) occurs because of an error in the division of the sex chromosomes in the zygote after fertilization. The extra X chromosome typically results in primary testicular failure leading to androgen deficiency.
47, XXY (KS) is the most common human sex chromosome disorder and occurs in approximately 1 in 500-1,000 males. It is estimated that 3,000 affected boys are born each year in the United States.
Males with 47, XXY (KS) are most commonly identified before birth (e.g. through prenatal screenings for chromosomal disorders), at puberty or later in life because of low fertility. 47, XXY (KS) is diagnosed by a chromosome karyotype analysis on a blood sample or by a chromosomal microarray (CMA) test. CMA consists of an oral cheek (buccal) swab and is an easy and painless way to detect abnormalities of chromosome numbers and provide a definitive diagnosis. 47, XXY (KS) can also be diagnosed prenatally on chorionic villous or amniotic fluid cells.
One of the hallmarks of Klinefelter syndrome is hypergonadotropic hypogonadism, a condition that results in testosterone deficiency. Treatment involves the targeted administration of male hormones (androgens), such as testosterone enanthate, cypionate, or androgel. Early hormonal treatment (EHT), three monthly injections of 25 mg of testosterone enanthate, is typically administered between 4-12 months of age. These hormones are given to promote the development of secondary male sexual characteristics (virilization) and alleviate feminization effects that have occurred due to insufficient testosterone levels. Hormone replacement therapy is effective when initiated during early infancy or around pubertal development or even later in life. Some men with 47, XXY (KS) who have gynecomastia may elect to have surgical breast reduction for cosmetic purposes. This procedure often may be avoided if proper and timely dosage of testosterone as well as estrogen inhibitor is administered to an individual, although it varies with each individual.
As infants, these boys need to be monitored for positional torticollis which can be treated with pediatric physical therapy. Speech and language therapy, physical therapy and occupational therapy are often helpful for boys with 47, XXY (KS). These interventions are shown to significantly improve academic, physical, cognitive, and social outcomes in boys with 47, XXY (KS). A comprehensive psychoeducational evaluation is recommended to determine what resources may be helpful in the classroom. Social skills training classes can also be beneficial.
Men with 47, XXY (KS) have low fertility, and with novel assistive and reproductive techniques, more men with 47, XXY (KS) have the opportunity to reproduce a child. Men with mosaic 47, XXY (KS) have higher likelihood of fewer complications with reproduction. Surgical extraction of sperm from the testes and intracytoplasmic sperm injection (ICSI) directly into an ovum is a medical technology available to assist men with 47, XXY (KS) father children.
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