KLINEFELTER SYNDROME

Overview

• Definition: Klinefelter syndrome is the most common genetic cause of primary hypogonadism in phenotypic males.
• Incidence: ~1 in 1000 live-born phenotypic male births.
• Typical Karyotypes:
  • 47,XXY (most common)
  • Variants: 48,XXXY, mosaicism (46,XY/47,XXY), or even 46,XX (phenotypic male).
• Genetic Mechanism:
  • 47,XXY usually results from nondisjunction of sex chromosomes during parental gametogenesis.
  • Mosaicism arises from mitotic errors after fertilization.

Pathophysiology and Clinical Features

1. Testicular Pathology
   • Becomes apparent at/after adolescence.
   • Small, firm testes with hyalinized seminiferous tubules; disrupted Leydig cell function.
   • Azoospermia, testicular failure → decreased testosterone, infertility.
   • May have a small phallus, gynecomastia, and some degree of eunuchoid proportions (due to delayed epiphyseal fusion).
2. Hormonal Changes
   • ↑ LH and ↑ FSH (due to primary testicular failure).
   • ↓ Testosterone, variable increases in estradiol → risk of gynecomastia.
3. Spectrum of Masculinization
   • Ranges from moderate eunuchoidism to near-normal male phenotype.
   • Gynecomastia severity is highly variable.
4. Histology
   • Seminiferous tubules show thickened basement membranes, sclerosis, and hyalin deposits.
   • Leydig cells may be clumped or increased in number; can form adenoma-like nests.
   • Before adolescence, testes may appear near-normal pathologically.
5. Other Clinical Issues
   • Typically no multiple congenital anomalies (unlike Turner syndrome).
   • Mild mental impairment or learning disabilities (especially verbal) can occur.
   • Increased psychosocial and behavioral difficulties (anxiety, depression, poor judgment).
   • Higher risk for pulmonary disorders (emphysema, bronchiectasis), certain cancers (mediastinal germ cell tumors, breast cancer), diabetes mellitus, and varicose veins.
6. 46,XX Male Variant
   • Similar phenotype to Klinefelter but often with hypospadias and shorter stature.
   • Arises from translocation of SRY to the X chromosome.
7. 47,XYY Karyotype**
   • Phenotypically normal males, usually fertile, typically normal testicular function.
   • May have increased risk of speech/language developmental delays and learning disabilities.

Diagnosis

1. Clinical Suspicion
   • Tall adolescent/adult male with small firm testicles, gynecomastia, infertility.
   • Often presents with delayed or incomplete puberty.
2. Laboratory Findings
   • Karyotype of peripheral leukocytes confirms extra X material (e.g., 47,XXY).
   • Serum LH, FSH: Elevated.
   • Testosterone: Low or low-normal.
   • Inhibin-B: Decreased.
   • Semen analysis: Typically azoospermia.

Management

• Testosterone Replacement
  • Addresses hypogonadism: improves virilization, muscle mass, bone density.
  • Dosage titrated to maintain mid-normal male testosterone levels.
• Fertility Considerations
  • Most men with Klinefelter syndrome are infertile (azoospermia).
  • Rarely, mosaic patients (46,XY/47,XXY) may have some spermatogenesis.
• Counseling and Support
  • Address learning disabilities, psychosocial issues, risk of breast cancer and other comorbidities.
  • Genetic counseling recommended, especially for variant karyotypes.