What is Kleinfelter syndrome?

What is Klinefelter Syndrome

Klinefelter syndrome is a sex chromosome disorder in which males carry at least one extra X chromosome, most commonly resulting in a 47,XXY karyotype, and is the most common chromosomal disorder affecting males with a prevalence of 1 in 500 to 1 in 600 male births. 1, 2

Genetic Basis

• The classic karyotype is 47,XXY, caused by a supernumerary X chromosome, though variants exist including 48,XXXY, 48,XXYY, 49,XXXXY, and mosaic patterns 1, 3
• Less common variants include 46,XX males (caused by translocation of the sex-determining region Y [SRY] to the X chromosome) and males with isochromosome Xq 1, 3
• Each additional X chromosome beyond the first extra X is associated with an IQ decrease of approximately 15-16 points, with expressive language skills most affected 1

Clinical Features by Age

Infancy and Early Childhood

• May present with hypospadias, small phallus, or cryptorchidism 1
• Developmental delay can be an early presenting feature 1

School-Age Children

• Language delay, particularly affecting expressive language skills 1
• Learning disabilities and behavioral problems 1

Adolescence and Adulthood

• Small, firm testes (hallmark physical finding on examination) 2
• Delayed or incomplete pubertal development with eunuchoid body habitus 1
• Gynecomastia (breast tissue development) 1, 2
• Tall stature with narrow shoulders and broad hips 2, 3
• Sparse body and facial hair 2, 3
• Infertility due to azoospermia (present in >90% of cases) 4, 3

Hormonal Profile

• Elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels 4, 1
• Low to normal testosterone levels (androgen deficiency) 1, 2
• Normal to moderately reduced Leydig cell function 3

Associated Health Conditions

• Osteoporosis due to androgen deficiency 2, 3
• Increased risk of diabetes mellitus 3
• Thromboembolic disease and varicose veins 3
• Increased risk of breast cancer compared to the general male population 4
• Cardiovascular complications 5

Diagnosis

• Definitive diagnosis requires formal cytogenetic karyotype analysis 1
• Clinical suspicion based on small, firm testes on physical examination combined with characteristic hormonal profile (elevated FSH/LH, low testosterone) 2
• Karyotype analysis is recommended for males with azoospermia or severe oligospermia (sperm concentration <5 million/mL) 6, 7
• Increasingly diagnosed prenatally or in early infancy 5

Management Considerations

Hormonal Treatment

• Androgen replacement therapy should begin at puberty (around age 12 years) in increasing dosages to maintain age-appropriate testosterone, estradiol, FSH, and LH levels 1
• Testosterone therapy has positive effects on virilization, mood, self-esteem, and bone health but does not reverse infertility 4, 2

Fertility Preservation

• Testicular sperm extraction (TESE) can retrieve sperm in 20-50% of men with Klinefelter syndrome 4
• Fertility preservation should be discussed early, as sperm retrieval rates may be higher in younger patients 4
• Testosterone therapy does not improve fertility and may further suppress spermatogenesis 4

Important Clinical Pitfalls

• Many affected males have subtle or weakly pronounced features, leading to delayed diagnosis often not made until adulthood when presenting with infertility 3
• Klinefelter syndrome accounts for approximately 4% of male infertility cases, making it the most common genetic cause 3
• The phenotype varies significantly with different karyotypes—patients with additional isochromosome Xq are typically shorter than average height with normal intelligence, unlike classic 47,XXY patients who are tall 3, 8
• More obvious physical differences and greater developmental impact occur with increasing numbers of sex chromosomes 1, 3