Handbook of Genetic Counseling/Klinefelter Syndrome

Klinefelter Syndrome


  • The most common sex chromosome abnormality
  • The most common cause of male hypogonadism and infertility
  • Characterized by the addition of at least one extra X chromosome to a 46,XY male karyotype
    • Most descriptions refer to 47,XXY karyotype
    • Over 50% of males with Klinefelter syndrome have 47,XXY karyotype
    • Those with mosaicism or other chromosome complements may have different prognosis
  • Presentation and prognosis are quite variable
  • In 1942, Dr. Klinefelter described testicular dysgenesis (defective development), elevated urinary gonadotropins (hormones that stimulate the gonads) microorchidism (small testes), eunuchoidism (deficient hormone production by the testes), azoospermia (no spermatozoa in the semen), and gynecomastia (enlargement of breast tissue)
  • The clinical features are not present until mid to late adolescence, so it is technically correct to refer to fetuses, newborns, and children as having 47,XXY
    • Reserve the term Klinefelter syndrome for affected adolescents and adults


  • Most are identified by a karyotype as part of a work-up for infertility or by prenatal diagnosis detected by amniocentesis performed for other indications


  • Estimated to be 1/500 to 1/1000 male births
  • But many are probably never diagnosed

Clinical ManifestationsEdit

  • Lifespan is normal
  • Development
    • By adolescence, most boys are at or above the 80th percentile for height
    • There is a tendency toward slightly delayed motor and language milestones
    • 2/3 of boys with 47,XXY are delayed in walking
    • Key language milestones may be delayed in up to 50% affected but are often within normal limits
    • Sensorimotor integration problems may arise by age 6-7 years
      • May include hypotonia, apraxia, primitive reflex tension, and problems with bilateral coordination and visual perceptual motor integration
    • On average, intellectual skills are slightly diminished and learning problems are increased, but this varies widely
    • Cognitive difficulties are largely limited to the area of verbal skills
    • Reading skills are the area of academic progress that can be most problematic for boys with 47,XXY
    • Often boys are unable to demonstrate success in physical achievements as compared to male peers
  • Behavior
    • Tend to be shy, nonassertive, and immature
    • Language difficulties contribute to the reluctance for interpersonal interactions
    • Aggressive behavior can occur due to prolonged frustration but are not characteristic of this group
    • Some investigators have reported an increased occurrence of ADHD but others have not
    • Adolescent males are often reluctant to speak freely and lack confidence
    • Some may experience serious psychological distress due to limited athletic and academic success and continued learning difficulties
    • There are few reports on the adult adaptation of men with 47,XXY
    • Sexual functioning is typically normal, although sexual drive is often low if supplemental testosterone therapy is not utilized
    • There is no evidence for increased aberrant sexual behavior
    • There is normal gender orientation
  • Endocrine
    • Sexual development is normal in infancy and during childhood
    • There is an adolescent elevation of testosterone that begins to plateau around age 14 years, then serum levels remain in the low to low normal adult range
    • By mid-puberty, boys have FSH and LH levels 5-10 times the normal range
    • Due to endocrine changes, testicular growth is arrested
      • Testicular volume and size is decreased
      • The number of Leydig cells (testosterone-secreting cells) is decreased
    • Gynecomastia is seen in about 15% of cases
      • Increased breast tissue is common in adolescent males, but it may not always regress in some adolescents with 47,XXY
      • Supplemental testosterone does not usually prevent or diminish gynecomastia but simple mastectomy can be performed
    • Facial hair, axillary hair, and pubic hair all increase during puberty, but this may occur to a lesser degree than in 46,XY males
      • Hair pattern is male
    • Older literature described fat distribution as being female, but this is not true
  • Infertility
    • Sexual function is normal, but ejaculate contains no sperm
    • A few cases of fertility have been reported in the literature, but it is thought that cryptic mosaicism may be present in some of the men
    • Men on testosterone therapy will not attain fertility
    • Intracytoplasmic sperm injection (ICSI)
      • Some men with 47,XXY have been shown to have a few sperm in their testes, even when no sperm are present in ejaculate
      • After testosterone therapy and testicular biopsy, sperm have been recovered and utilized in the ICSI procedure to achieve pregnancy and birth
      • Preimplantation/prenatal diagnosis is necessary to rule out chromosomal aneuploidy
      • The process of testicular sperm extraction, ICSI, and preimplantation diagnosis is not routinely offered at this time
      • For most 47,XXY males, the most realistic prospects for fatherhood are by utilization of artificial insemination by donor or adoption
  • Neoplasia
    • There is a 1% lifetime risk for developing extragonadal germ cell tumors, usually in the mediastinum
      • For unknown reasons, Klinefelter syndrome is a predisposing factor to the aberrant migration of primordial germ cells
      • Affected males may present with respiratory symptoms due to the mass size
      • Some cases of precocious puberty in boys with 47,XXY have been caused by germ cell tumors that secrete hCG.
      • The ages of susceptibility are early adolescence to age 30
    • Increased risk of breast cancer, probably up to 3% lifetime risk
      • This is a 20-fold increase over the normal male population
      • This risk does not warrant routine screening
  • Immunologic
    • Adults are at a slightly increased risk for certain autoimmune disorders
      • Such as systemic lupus erythematosis, diabetes mellitus, and thyroid disorders
    • It has been suggested that sex hormones may be involved in the pathogenesis of autoimmune diseases
  • Cardiovascular
    • Mitral valve prolapse has been reported but a baseline cardiac echo is NOT warranted
    • There is a risk for cardiovascular disease associated with elevated cholesterol levels
    • Chronic leg ulcers are seen in approximately 6-13% of patients


  • Adolescents and adults with Klinefelter syndrome are unable to produce normal quantities of testosterone, so supplemental testosterone can maintain levels in the normal range
    • This enables them to stimulate and maintain androgen-dependent processes
    • In many cases, it promotes increased sense of well-being
    • Helps to maintain secondary sex characteristics including facial and body hair
    • Can increase and maintain muscle mass and promote weight gain
    • Can increase energy and sex drive and lower cholesterol levels
    • Can stimulate bone mineralization and prevent loss of bone mass which can lead to osteoporosis
  • Testosterone therapy is usually considered in mid to late adolescence because serum testosterone levels do not plateau until about age 14 years in most affected males
    • Therapy can begin as early as age 12 however
  • Serum testosterone levels should be carefully monitored during the initiation process
    • Excess testosterone can lead to inappropriate sexual behavior
    • There are some reports of aggressiveness when higher concentrations are administered
  • Intramuscular injections of testosterone enanthate or cypionate have been the most common method of testosterone replacement
    • The standard adult dose is 200mg every 10-14 days
    • In an adolescent, the initial dose is considerable lower, usually 100mg every 4 weeks
    • Because this method does not mimic normal physiologic production, there may be fluctuations in mood and physical functioning
    • Usually injected into deep muscle in the thighs or buttocks
    • Because testosterone ether is dissolved in an oil base, the injections can be slow and painful
  • Transdermal testosterone patches can provide a more normal physiological availability of testosterone
    • Patches are replaced every 24 hours
    • Scrotal patch is effective in postpubertal males, but adolescents in one study were resistant to daily application to their genitalia
    • A nonscrotal patch can be worn on the thighs, abdomen, trunk, or upper arm
    • Side effects are rare but include: acne, leg edema, breast tenderness, and local skin reactions
  • Oral testosterone is not generally available in the U.S.
  • New formulations of testosterone currently being investigated include implantable pellets, sublingual tablets, and long-lasting injections

Differential DiagnosisEdit

  • Karyotype analysis may be indicated with the following features:
    • Learning disabilities, language difficulties, attention deficits, psychosocial problems, small testes, infertility
  • Kallman syndrome
    • Characterized by hypogonadotrophic hypogonadism and anosmia (loss of the sense of smell)


  • Nondisjunction of the sex chromosomes during the first or second meiotic division of gametogenesis in either parent causes chromosomal aneuploidy
  • The extra X chromosome is contributed only slightly more frequently by the mother than the father
    • There are no apparent differences in phenotype or imprinting effects
  • AMA is slightly associated with the extra X chromosome; there is no paternal age effect
  • There are no predisposing or preventative factors
    • This is important for parents to understand

Other Male X Chromosome AneuploidyEdit

  • Few cases of variants of 47,XXY have been followed prospectively so the natural history is not known
    • Most information is from case reports of abnormal individuals
    • This ascertainment bias could mean that individuals with a variation of the 47,XXY karyotype are actually more mildly affected than reported here
  • Mosaicism
    • 46,XY/47,XXY mosaicism is the most common form of 47,XXY mosaicism
    • The normal cell line modifies the risk for developmental delay
    • Fertility may be possible
    • Testosterone supplementation is probably not indicated
  • 48,XXYY
    • The most common variant of Klinefelter syndrome
    • Similar physical phenotype to 47,XXY, but males are taller and have disproportionately longer lower extremities
    • IQ is typically reduced and ranges from 60 to 80; however, at least 10% of reported cases had IQs ranging from 80 to 111
    • Speech and motor delays are common, and behavior may be shy or impulsive and aggressive
    • Hypergonadotrophic hypogonadism is similar to that in males with 47,XXY and testosterone treatment is the same
    • Genitalia may be small
  • 48,XXXY (3 X chromosomes)
    • Results from the addition of an extra X to a 47,XXY karyotype
    • A more abnormal phenotype including facial anomalies such as hypertelorism, epicanthic folds, simplified ears, and mild prognathism (projection of the jaw beyond the forehead)
    • Tall stature is common
    • May be skeletal anomalies such as clinodactyly, elbow abnormalities, and radioulnar synostosis
    • Generally, there is mild to moderate mental retardation (IQ=40-60)
    • Behavior is usually passive and cooperative
    • Genitalia may be small, and gynecomastia is frequently reported
  • 49,XXXXY (4 X chromosomes)
    • This is the most severe variant of Klinefelter syndrome
    • Abnormal facial features include hypertelorism, epicanthic folds, broad nasal bridge, low-set and malformed ears and prognathism
    • Cardiac defects, usually patent ductus arteriosus, are present in 15-20% of cases
    • Males have short stature, short, broad neck, narrow thorax, radioulnar synostosis, and hyperextensible joints
    • Genitalia are hypoplastic
    • Cryptorchidism (failure of testes to descend) is often present at birth
    • Range of mental retardation is broad (IQ is generally 20 to 70)
    • Speech and motor sills are severely impaired
    • Behavior ranges from placid to aggressive
  • 46,XX males
    • Males who have clinical features of Klinefelter syndrome but normal female karyotype
    • Occurs in about 1 in 20,000 male births
    • Clinical features
      • Shorter than males with 47,XXY, and extremities are not disproportionately long
      • Genitalia are usually normal male, but there is an increased risk for hypospadias or ambiguous genitalia
      • Testes are small and azoospermia is present
      • IQ is generally higher than with 47,XXY males, and the risk for learning disabilities and behavior problems is lower
    • Over 90% have a portion of Yp containing the SRY gene translocated to the paternally derived X chromosome
      • This material is no always cytogenetically visible, but can be detected by FISH
    • The remaining 10% are thought to be the result of an autosomal or X chromosome mutation
      • These males are more likely to have genital abnormalities


  • Understanding Klinefelter Syndrome, A Guide for XXY Males and Their Families, by Robert Bock (1993), National Institute of Health
Available free of charge by calling 301-496-5133
  • Klinefelter Syndrome, For Boys Only, A Supplement, by Diane Plumridge, Christine Barkost, and Stephen La Franchi (1982) :Oregon Health Sciences Center
Available for $1.25 at P.O. Box 574, Portland, OR 97207
  • Klinefelter Syndrome and Associates
Online at www.genetic.org
Mailing address: 11 Keats Court, Coto de Caza, CA 92679
Phone: (888)999-9428


  • Cassidy, Suzanne B., and Judith E. Allanson. Management of Genetic Syndromes. Chapter 12: Klinefelter Syndrome, by Arthur Robinson, Bruce G. Bender, and Mary G. Linden. Pages 195-206, 2001.
  • Geschwind, Daniel H., et al. Neurobehavioral Phenotype of Klinefelter Syndrome. Mental Retardation and Developmental Disabilities Research Reviews 6: 107-116, 2000.
  • Genetic Counseling Issues for Klinefelter Syndrome and Other Sex Chromosome Abnormalities. Lecture given on 02/04/02.


The information in this outline was last updated in 2002.