Klinefelter Syndrome

Mr. Arvind Kumar

Introduction

  1. Klinefelter Syndrome (KS) is a chromosomal disorder affecting males, caused by the presence of one or more extra X chromosomes in their cells — the most common form being 47, XXY.

  2. The condition leads to testicular underdevelopment (hypogonadism), infertility, and hormonal imbalance due to reduced testosterone levels.

  3. It was first described by Dr. Harry Klinefelter in 1942 at Massachusetts General Hospital, when he studied a group of men with gynecomastia, small testes, and infertility.

  4. It is a major genetic cause of male infertility and one of the most common chromosomal abnormalities in humans.

  5. Most affected individuals are unaware of their condition until adulthood or evaluation for infertility.

Genetic Basis and Mechanism

 

Aspect Description
Chromosomal pattern 47, XXY (most common)
Variants 48, XXXY; 48, XXYY; Mosaic 46,XY/47,XXY
Sex affected Males only
Type of genetic error Nondisjunction (failure of chromosomes to separate during meiosis)
Inheritance pattern Usually sporadic (not inherited)
Incidence 1 in 500–1,000 male births worldwide

🔹 How it Happens

  • During meiosis, sex chromosomes (X and Y) fail to separate properly → sperm or egg carries an extra X chromosome.

  • When such a gamete combines with a normal gamete at fertilization, the resulting zygote has 47 chromosomes (XXY) instead of 46 (XY).

  • The presence of the extra X chromosome causes overexpression of certain X-linked genes that interfere with testicular development and hormone production.

 

Pathophysiology

1. Testicular Changes

  • Seminiferous tubules undergo fibrosis and hyalinization → leading to small, firm testes.

  • Leydig cell dysfunction → decreased testosterone synthesis.

  • Impaired spermatogenesis → azoospermia (absence of sperm).

2. Hormonal Feedback

  • ↓ Testosterone → loss of negative feedback to the hypothalamus → ↑ release of GnRH → ↑ FSH and LH (hypergonadotropic hypogonadism).

3. Developmental Effects

  • Low testosterone levels during puberty cause incomplete masculinization, poor secondary sexual characteristics, and gynecomastia.

 

Epidemiology

 

Feature Details
Prevalence 1 in every 700 male births
Age at diagnosis Often during puberty or adulthood (when fertility issues appear)
Maternal age factor Risk increases slightly in older mothers (>35 years)
Inheritance Usually new mutation; very rarely inherited

 

Clinical Features

Klinefelter’s Syndrome presents a spectrum of symptoms, from mild to severe, depending on the number of extra X chromosomes and mosaicism.

A. Physical Characteristics

System / Feature Findings
Height Tall with long arms and legs (eunuchoid body habitus)
Shoulders and hips Narrow shoulders, broad hips (feminine body shape)
Facial and body hair Sparse beard, reduced chest and pubic hair
Muscles Weak muscles, low tone (hypotonia in infancy)
Breasts Gynecomastia in 30–50% (risk of breast cancer ↑ 20-fold compared to normal men)
Testes Small, firm, nonfunctional (testicular atrophy)
Penis Normal or slightly small
Voice High-pitched voice
Bones Osteopenia and osteoporosis due to low testosterone

B. Reproductive and Hormonal Features

Aspect Effect
Testosterone ↓ Low (hypogonadism)
FSH, LH ↑ Increased (due to loss of negative feedback)
Sperm count Azoospermia or severe oligospermia
Fertility Usually infertile, but rare fertility possible in mosaic types
Sexual characteristics Poorly developed secondary sexual traits
Libido Decreased sexual drive

 

C. Cognitive and Behavioural Features

Domain Observation
Intelligence Usually normal, but slightly reduced (IQ 85–90)
Language skills Delayed speech and language learning
School performance Poor reading and writing skills (dyslexia common)
Personality Shy, quiet, introverted, low confidence
Behavioral problems Depression, anxiety, low self-esteem in adolescence

 

D. Associated Medical Conditions

System Complication
Endocrine Type 2 diabetes mellitus, metabolic syndrome
Cardiovascular Venous ulcers, varicose veins, thrombosis risk
Skeletal Osteoporosis due to long-term hypogonadism
Neoplastic Breast cancer, extragonadal germ cell tumors
Dental Taurodontism (large pulp chambers)
Musculoskeletal Flat feet, scoliosis

 

Diagnosis

1. Clinical Clues

  • Small, firm testes

  • Gynecomastia

  • Tall stature

  • Delayed puberty or infertility

2. Laboratory Investigations

Test Finding
Karyotyping Confirms extra X chromosome (47, XXY)
Serum testosterone ↓ Decreased
Serum LH and FSH ↑ Increased
Semen analysis Azoospermia or very low sperm count
Chromatin study Barr body present (one per cell in males)
Bone density (DEXA scan) Reduced
Hormonal profile Low testosterone, high estrogen:testosterone ratio

 

3. Imaging

  • Testicular ultrasound: small, fibrotic testes.

  • Mammography: for gynecomastia or suspected breast cancer.

  • Bone density scan: evaluates osteoporosis risk.

Differential Diagnosis

 

Condition Main Difference
Turner’s Syndrome (45,X) Affects females; short stature, streak ovaries
Kallmann Syndrome Hypogonadism with anosmia, normal karyotype (46,XY)
Androgen Insensitivity Syndrome Phenotypically female with XY genotype
Primary testicular failure Chromosome number normal (46,XY)

 

Management and Treatment

Although there is no cure, proper hormonal therapy and multidisciplinary support can ensure a normal life.

1. Hormone Replacement Therapy

Therapy Purpose
Testosterone replacement Initiated at puberty to develop secondary sexual traits
Benefits Increases muscle mass, facial hair, libido, bone density, and self-esteem
Forms available Injections, skin patches, gels, or oral forms
Monitoring Regular check of testosterone, lipid profile, liver function, and bone density

 

2. Fertility Support

  • Though infertility is common, testicular sperm extraction (TESE) combined with intracytoplasmic sperm injection (ICSI) may help some mosaic-type men become fathers.

  • Sperm banking (if possible early in life) is recommended.

3. Surgical and Medical Care

Condition Treatment
Gynecomastia Cosmetic surgery or anti-estrogen drugs (tamoxifen)
Osteoporosis Calcium and vitamin D, bisphosphonates if needed
Metabolic problems Weight control, diet, regular exercise
Psychological issues Counseling, therapy, and support groups

 

4. Educational and Psychological Support

  • Speech therapy: improves communication and vocabulary

  • Special education: helps overcome learning difficulties

  • Behavioural therapy: boosts self-esteem and confidence

  • Vocational training: helps adapt to social and work environments

5. Genetic Counselling

Purpose Details
Family awareness Explains genetic cause and reproductive risk
Recurrence risk Usually low (sporadic cases)
Prenatal diagnosis Amniocentesis or chorionic villus sampling (CVS) can detect XXY karyotype
Future family planning Informed decisions and emotional preparation

 

Prognosis

 

Aspect Outcome
Life expectancy Normal with treatment
Fertility Most remain infertile, but ART may help
Physical health Improves significantly with testosterone therapy
Cognitive function Stable with educational help
Mental health Good with counseling and support

 

Prevention

  1. No known prevention, as it is a random chromosomal error.

  2. Prenatal testing can identify cases early in pregnancy.

  3. Genetic counseling helps families understand and prepare for management.

 

MCQs

  1. Klinefelter’s Syndrome occurs in:
    A. Females
    B. Males
    C. Both males and females
    D. Only in newborns

  2. Klinefelter’s Syndrome is a result of:
    A. Monosomy
    B. Trisomy of sex chromosomes
    C. Deletion
    D. Translocation

  3. The karyotype of classical Klinefelter’s Syndrome is:
    A. 45, X
    B. 47, XXY
    C. 47, XYY
    D. 46, XY

  4. Klinefelter’s Syndrome is caused by:
    A. Nondisjunction of sex chromosomes
    B. Gene mutation
    C. Translocation
    D. Chromosomal deletion

  5. Which of the following is true about Klinefelter’s Syndrome?
    A. It affects only females
    B. It affects only males
    C. It affects both sexes equally
    D. It affects children only

  6. The presence of a Barr body in a male cell indicates:
    A. Normal male
    B. Klinefelter’s Syndrome
    C. Turner’s Syndrome
    D. Down’s Syndrome

  7. The extra chromosome in Klinefelter’s Syndrome is:
    A. X chromosome
    B. Y chromosome
    C. Chromosome 21
    D. Chromosome 13

  8. Klinefelter’s Syndrome was first described by:
    A. Watson and Crick
    B. Jerome Lejeune
    C. Harry Klinefelter
    D. Turner

  9. The most common cause of male hypogonadism is:
    A. Klinefelter’s Syndrome
    B. Turner’s Syndrome
    C. Down’s Syndrome
    D. Fragile X Syndrome

  10. Which of the following is not a feature of Klinefelter’s Syndrome?
    A. Tall stature
    B. Gynecomastia
    C. Small testes
    D. Short stature

  11. Which hormone is decreased in Klinefelter’s Syndrome?
    A. FSH
    B. LH
    C. Testosterone
    D. Estrogen

  12. Which hormones are increased in Klinefelter’s Syndrome?
    A. FSH and LH
    B. Testosterone and LH
    C. Estrogen and testosterone
    D. Progesterone and LH

  13. Which of the following features is seen in Klinefelter’s Syndrome?
    A. Short stature
    B. Sparse body hair
    C. Deep voice
    D. Large testes

  14. What is the typical voice characteristic in Klinefelter’s males?
    A. Deep and masculine
    B. Normal
    C. High-pitched voice
    D. Very loud voice

  15. Which of the following best describes the body build of a Klinefelter male?
    A. Obese with short limbs
    B. Tall with long legs and narrow shoulders
    C. Muscular and broad-shouldered
    D. Short and stocky

  16. Which of the following statements about fertility is true in Klinefelter’s Syndrome?
    A. Normal fertility
    B. Reduced fertility
    C. Complete infertility (usually)
    D. Increased fertility

  17. Klinefelter’s Syndrome represents:
    A. Female with Y chromosome
    B. Male with extra X chromosome
    C. Female with extra chromosome 21
    D. Male with chromosome 21 trisomy

  18. Which of the following is a common reproductive finding?
    A. Azoospermia
    B. Polycystic testes
    C. Increased sperm motility
    D. Hyperfunctioning Leydig cells

  19. The testes in Klinefelter’s Syndrome are:
    A. Normal-sized
    B. Small and firm
    C. Large and soft
    D. Absent

  20. Klinefelter’s Syndrome results in:
    A. Hypogonadotropic hypogonadism
    B. Hypergonadotropic hypogonadism
    C. Normal gonadal function
    D. Hypergonadism

  21. The presence of one Barr body in a male indicates:
    A. 46,XY
    B. 47,XXY
    C. 48,XXXY
    D. 45,X

  22. Which of the following is a hallmark clinical finding?
    A. Small, hard testes
    B. Large testes
    C. Undescended testes
    D. Painful testes

  23. Which of the following is increased in serum of Klinefelter’s patients?
    A. Testosterone
    B. FSH
    C. Cortisol
    D. Insulin

  24. Which of the following is decreased in Klinefelter’s Syndrome?
    A. Estrogen
    B. Testosterone
    C. LH
    D. FSH

  25. The commonest chromosomal abnormality leading to male infertility is:
    A. Turner’s Syndrome
    B. Klinefelter’s Syndrome
    C. Down’s Syndrome
    D. Edward’s Syndrome

  26. The voice of Klinefelter’s males is:
    A. Low-pitched
    B. High-pitched
    C. Normal
    D. Absent

  27. Klinefelter’s Syndrome is detected by:
    A. FISH test
    B. Karyotyping
    C. Blood sugar test
    D. CT scan

  28. Which of the following is a typical mental feature?
    A. Hyperactivity
    B. Learning difficulty, especially in language
    C. Very high IQ
    D. Aggressive behavior

  29. Which of the following is a common dental feature?
    A. Taurodontism
    B. Hypodontia
    C. Supernumerary teeth
    D. Microdontia

  30. What is the typical body hair pattern in Klinefelter’s males?
    A. Thick body hair
    B. Sparse facial and body hair
    C. Dense beard
    D. Normal hair distribution

  31. Which of the following is a long-term complication?
    A. Osteoporosis
    B. Hypercalcemia
    C. Polycythemia
    D. Hyperthyroidism

  32. What is the risk of breast cancer in Klinefelter’s males compared to normal males?
    A. No risk
    B. Equal risk
    C. Increased 20-fold
    D. Decreased

  33. Testosterone therapy in Klinefelter’s Syndrome improves all except:
    A. Muscle mass
    B. Libido
    C. Height
    D. Bone density

  34. Which type of nondisjunction causes Klinefelter’s Syndrome?
    A. Meiotic
    B. Mitotic
    C. Both meiotic and mitotic
    D. Postzygotic deletion

  35. The definitive diagnostic test for Klinefelter’s Syndrome is:
    A. Blood test for testosterone
    B. FSH estimation
    C. Karyotype analysis
    D. Ultrasound of testes

Answer Key

  1. B — Males

  2. B — Trisomy of sex chromosomes

  3. B — 47, XXY

  4. A — Nondisjunction of sex chromosomes

  5. B — It affects only males

  6. B — Klinefelter’s Syndrome

  7. A — X chromosome

  8. C — Harry Klinefelter

  9. A — Klinefelter’s Syndrome

  10. D — Short stature

  11. C — Testosterone

  12. A — FSH and LH

  13. B — Sparse body hair

  14. C — High-pitched voice

  15. B — Tall with long legs and narrow shoulders

  16. C — Complete infertility (usually)

  17. B — Male with extra X chromosome

  18. A — Azoospermia

  19. B — Small and firm

  20. B — Hypergonadotropic hypogonadism

  21. B — 47, XXY

  22. A — Small, hard testes

  23. B — FSH

  24. B — Testosterone

  25. B — Klinefelter’s Syndrome

  26. B — High-pitched

  27. B — Karyotyping

  28. B — Learning difficulty, especially in language

  29. A — Taurodontism

  30. B — Sparse facial and body hair

  31. A — Osteoporosis

  32. C — Increased 20-fold

  33. C — Height

  34. C — Both meiotic and mitotic

  35. C — Karyotype analysis