What is Klinefelter syndrome?

What is Klinefelter Syndrome

Klinefelter syndrome is a chromosomal disorder in males characterized by the presence of at least one extra X chromosome (most commonly 47,XXY karyotype), making it the most common sex chromosomal abnormality in males with a prevalence of approximately 1 in 500 to 1 in 600 male births. 1, 2, 3

Genetic Basis

• The condition results from chromosomal nondisjunction during parental gametogenesis, leading to an additional X chromosome in males who would normally have a 46,XY karyotype 4
• The classic karyotype is 47,XXY, though variants exist including 48,XXYY (1 per 17,000-50,000 births), 48,XXXY, and 49,XXXXY (1 per 85,000-100,000 births) 2
• Mosaic forms can occur where some cells have the normal 46,XY karyotype while others have 47,XXY 2
• A rare variant is 46,XX males caused by translocation of the sex-determining region (SRY) from the Y chromosome to an X chromosome during paternal meiosis 2

Clinical Features by Age

Infancy and Early Childhood

• Small phallus, cryptorchidism (undescended testes), or hypospadias may prompt chromosomal evaluation 2
• Developmental delays can be an early presenting sign 2

School-Age Children

• Language delays, particularly affecting expressive language skills 2
• Learning disabilities and behavioral problems 2
• Tall stature or eunuchoid body habitus (long legs, short trunk) 2, 5

Adolescence and Adulthood

• Small, firm testes (typically <10 cc) with testicular atrophy are the hallmark physical finding 1, 5
• Delayed or incomplete pubertal development 2
• Gynecomastia (breast development) occurs in a significant proportion of patients 2, 5
• Sparse facial, axillary, and pubic hair due to low testosterone 5
• Azoospermia (complete absence of sperm) in >90% of cases 1
• Infertility is nearly universal without assisted reproductive technology 1, 3
• Increased risk of breast cancer compared to the general male population 1

Hormonal Profile

• Low or low-normal testosterone levels 2, 5
• Elevated follicle-stimulating hormone (FSH), typically >7.6 IU/L 1, 5
• Elevated luteinizing hormone (LH) 2, 5
• Elevated estradiol levels 5
• This pattern represents primary testicular failure (hypergonadotropic hypogonadism) 5

Pathophysiology of Infertility

• The extra X chromosome causes hyalinization and fibrosis of the seminiferous tubules where sperm are normally produced 5
• Increased susceptibility to meiotic errors during spermatogenesis results in aneuploid or polyploid gametes 4
• Dysregulation of interstitial and Sertoli cell function impairs normal sperm development 4
• Aberrant DNA methylation and other epigenetic modifications contribute to spermatogenic failure 4

Cognitive and Developmental Impact

• Each additional X chromosome is associated with an IQ decrease of approximately 15-16 points 2
• Language skills are most affected, particularly expressive language 2
• More severe physical and cognitive manifestations occur with increasing numbers of extra X chromosomes 2

Diagnosis

• Karyotype analysis is the definitive diagnostic test and should be performed in males with azoospermia, severe oligospermia, or clinical features suggestive of the syndrome 1, 6
• Barr body testing (chromatin test) can suggest the presence of extra X chromosomes but is not definitive 5
• Hormonal evaluation showing elevated FSH and LH with low testosterone supports the diagnosis but requires karyotype confirmation 1, 6

Associated Comorbidities

• Poor bone health and increased fracture risk 7
• Increased risk of type 2 diabetes 7
• Cardiovascular complications 7
• Increased risk of certain malignancies, particularly breast cancer 1, 7
• Higher rates of psychiatric and neurodevelopmental conditions 8

Management Considerations

Hormonal Therapy

• Testosterone replacement therapy should begin at puberty (around age 12 years) in increasing dosages to maintain age-appropriate serum concentrations of testosterone, estradiol, FSH, and LH 2
• Testosterone therapy improves masculinization, muscle mass, hair growth, and libido but does not increase testicular size, reduce gynecomastia, or restore fertility 5
• Exogenous testosterone must be avoided in men desiring fertility as it suppresses spermatogenesis through negative feedback 1

Fertility Preservation

• Testicular sperm extraction (TESE) can successfully retrieve sperm in 20-50% of men with Klinefelter syndrome 1, 3
• Sperm retrieval rates may be higher in younger patients, making early discussion of fertility preservation critical 1
• Microdissection TESE (mTESE) is 1.5 times more successful than conventional TESE 9
• Fertility counseling should be offered early, ideally before or shortly after initiating testosterone therapy 1

Genetic Counseling

• Genetic counseling should be offered to patients and their families given the hereditary implications and reproductive considerations 1

Important Clinical Pitfalls

• The diagnosis is frequently missed or delayed because clinical features can be subtle, particularly in childhood 2, 7
• Testosterone replacement, while beneficial for virilization and quality of life, permanently eliminates any chance of natural fertility and may reduce sperm retrieval success with TESE 1
• Klinefelter syndrome may be discovered incidentally during pharmacogenomic testing or prenatal screening 1
• The condition is increasingly diagnosed prenatally or in early infancy, requiring age-appropriate counseling and management strategies 7