Klinefelter syndrome

Definition

Klinefelter syndrome (KS) is a chromosomal disorder in males characterized by the presence of one or more extra X chromosomes, most commonly 47,XXY. It results in hypogonadism, infertility, and varying degrees of physical, endocrine, and cognitive abnormalities.

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Genetics and Etiology

• Karyotype: Most common is 47,XXY; other variants include mosaic forms (46,XY/47,XXY) and higher-grade aneuploidies (48,XXXY; 48,XXYY).

• Cause: Nondisjunction of sex chromosomes during meiosis in either parent.

• Not inherited in a typical Mendelian pattern; usually occurs as a random chromosomal event.

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Epidemiology

• Prevalence: Approximately 1 in 600 live male births.

• Often underdiagnosed due to variable presentation and mild symptoms in some cases.

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Pathophysiology

• The presence of an extra X chromosome disrupts normal testicular development.

• Leads to degeneration of seminiferous tubules and Leydig cell dysfunction.

• Results in reduced testosterone production, increased gonadotropins (LH, FSH), and infertility.

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Clinical Features

Infancy and Childhood

• Usually subtle signs or absent symptoms.

• May have cryptorchidism, micropenis, or developmental delays (especially speech).

Adolescence

• Tall stature with disproportionately long legs and arms.

• Delayed or incomplete puberty.

• Gynecomastia.

• Sparse facial and body hair.

• Small, firm testes.

Adulthood

• Infertility (azoospermia in most cases).

• Decreased muscle mass.

• Reduced libido and erectile dysfunction.

• Increased risk of osteoporosis.

• Possible learning difficulties and psychosocial issues.

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Associated Health Risks

• Endocrine: Hypogonadism, metabolic syndrome, type 2 diabetes.

• Bone health: Osteopenia/osteoporosis.

• Cancer: Higher risk of breast cancer, germ cell tumors.

• Autoimmune: Higher risk of autoimmune disorders (e.g., systemic lupus erythematosus).

• Psychiatric: Increased incidence of anxiety, depression.

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Diagnosis

1. Physical Examination

• Tall stature, eunuchoid body proportions.

• Gynecomastia.

• Small testes (<4 mL volume).

2. Laboratory Tests

• Low serum testosterone.

• Elevated LH and FSH (hypergonadotropic hypogonadism).

3. Genetic Testing

• Karyotyping is the gold standard to confirm extra X chromosome(s).

4. Imaging (as needed)

• Bone density scan (DXA) to assess osteoporosis risk.

• Testicular ultrasound to evaluate testicular volume and exclude masses.

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Management

1. Endocrine Therapy

Testosterone Replacement Therapy (TRT):

• Indicated to induce and maintain secondary sexual characteristics, improve muscle mass, bone density, mood, and energy levels.

• Preparations and typical doses:

  • Testosterone enanthate or cypionate: 50–100 mg intramuscularly every week, or 100–200 mg every 2 weeks.

  • Testosterone undecanoate: 1,000 mg intramuscularly initially, at 6 weeks, then every 12 weeks.

  • Transdermal testosterone gel: 50–100 mg applied once daily to shoulders/upper arms.

  • Transdermal patch: 4–6 mg applied nightly.

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2. Fertility Management

• Most men are azoospermic, but some (especially mosaic cases) may have residual spermatogenesis.

• Options:

  • Testicular sperm extraction (TESE) with intracytoplasmic sperm injection (ICSI).

  • Early fertility counseling is advised.

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3. Management of Comorbidities

• Monitor and treat metabolic syndrome, diabetes, and cardiovascular risk factors.

• Bone health monitoring with calcium and vitamin D supplementation as needed.

• Breast cancer screening if gynecomastia is significant or family history is present.

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4. Psychological and Educational Support

• Speech therapy for language delays in childhood.

• Educational support for learning difficulties.

• Counseling for psychosocial and emotional issues.

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Prognosis

• Life expectancy is slightly reduced, mainly due to comorbidities such as cardiovascular disease and cancer.

• With early diagnosis and management, most patients can lead healthy, productive lives.