Klinefelter syndrome, also known as seminiferous tubule dysgenesis, is a type of aneuploid chromosomal disorder. It represents the most common form of primary testicular hypofunction and the most frequent genetic cause of male infertility. The incidence of Klinefelter syndrome among newborns is approximately 1 in 660, with no differences observed across races or regions.
Etiology and Pathogenesis
The cause of Klinefelter syndrome is an abnormality in the sex chromosomes, where affected individuals possess two or more X chromosomes. This includes standard karyotypes and variant forms. Approximately 40% of individuals with the 47,XXY karyotype inherit the condition due to meiotic nondisjunction during spermatogenesis, while about 60% arise from meiotic nondisjunction during oogenesis. A mosaic karyotype (46,XY/47,XXY) results from nondisjunction of sex chromosomes during mitosis in the zygote, accounting for about 10% of cases in Klinefelter syndrome. Other karyotypic subtypes include 48,XXYY and 48,XXXY. Major risk factors contributing to sex chromosome abnormalities include advanced parental age and genetic factors.
Clinical Manifestations
The primary clinical features include small, firm testes, androgen deficiency, and infertility.
Small Testes
Before puberty, testicular volume may be slightly smaller than normal. During mid-to-late puberty, patients exhibit small, firm testes, with an average bilateral testicular volume of 4 mL as measured by ultrasound. Around one-third of patients experience poor testicular descent.
Incomplete Development of Secondary Sexual Characteristics
Puberty onset may be normal or delayed. Most patients display painless bilateral gynecomastia during puberty, along with a small penis, sparse facial hair, and scant pubic and axillary hair. By adulthood, approximately 70% of patients experience progressive declines in libido and sexual function.
Other Features
At birth, affected individuals may have a low birth weight and small head circumference, along with physical anomalies such as curved fingers or toes. During puberty, characteristic skeletal development begins, often resulting in average or above-average adult height. The disproportion in limb-to-trunk ratio becomes evident, with a lower body segment longer than the upper body segment and an arm span exceeding the upper body segment by half. Cognitive abnormalities are common but do not represent global intellectual impairments; deficits are particularly noted in areas such as language and executive functioning.
Associated Abnormalities
Androgen deficiency can lead to osteoporosis and reduced muscle strength. Additional comorbidities include obesity, impaired glucose tolerance, and diabetes, with a significantly increased risk of diabetes-related mortality. Patients are also susceptible to extragonadal malignant germ cell tumors (e.g., mediastinal non-seminomatous germ cell tumors and central nervous system germ cell tumors), as well as hematological malignancies such as leukemia and lymphoma.
Laboratory and Other Diagnostic Tests
Hormone Measurements
Before puberty, basal levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) are comparable to those of age-matched peers. Affected children undergo puberty similarly to normal boys, with an initial rise in LH, FSH, and testosterone levels to normal or low-normal ranges. However, by mid-puberty, hormonal abnormalities become evident, characterized by progressively elevated LH and FSH levels indicative of hypergonadotropic hypogonadism. The rise in FSH is particularly pronounced and rapid. Serum testosterone levels decline and remain low throughout puberty.
Karyotype Analysis
Chromosomal karyotyping of peripheral blood cells confirms the diagnosis.
Testicular Ultrasound
Testicular volume can be initially assessed via palpation and comparison to testicular measurement molds, with precise measurements obtained through testicular ultrasound.
Semen Analysis
Sperm count is typically zero.
Testicular Biopsy
With the onset of puberty, seminiferous tubules show progressive atrophy and hyaline degeneration. The testicular interstitium develops fibrosis, along with loss of spermatogonia, regression of Sertoli cells, and hyperplasia of Leydig cells.
Diagnosis
A diagnosis can be established in typical cases based on clinical manifestations such as small, firm testes; gynecomastia; eunuchoid body proportions; and underdeveloped secondary sexual characteristics, combined with the aforementioned laboratory findings. Chromosomal karyotype analysis plays a definitive diagnostic role and aids in distinguishing between typical and atypical forms of Klinefelter syndrome.
Differential Diagnosis
Differentiation from hypogonadotropic hypogonadism is necessary, as the latter also presents with small testes and significantly reduced serum testosterone. However, low levels of LH and FSH, as well as results from chromosomal karyotype analysis, offer distinguishing features. Differentiation from other causes of hypergonadotropic hypogonadism is also required.
Treatment
When serum testosterone levels fall below the normal range, androgen replacement therapy can begin. The treatment aims to achieve mid-normal testosterone levels and should be continued for life. The purpose of replacement therapy is to alleviate symptoms of androgen deficiency, promote the development of secondary sexual characteristics, improve sexual function and quality of life, and prevent complications and sequelae associated with androgen insufficiency.
Available formulations include intramuscular injections and oral preparations. Intramuscular testosterone enanthate or testosterone undecanoate is administered at a dose of 200–250 mg every 2–4 weeks. Oral formulations such as testosterone undecanoate are absorbed via the lymphatic system and are suitable for long-term use. The initial dose is 120–160 mg/day, which can be adjusted to a maintenance dose of 40–120 mg/day after 2–3 weeks of continuous usage, typically divided into two daily doses (morning and evening).
Androgen replacement therapy does not restore fertility in patients.