eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Klinefelter Syndrome

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Contributor Information and Disclosures

Updated: Jun 10, 2009

Introduction

Background

• In 1942, Klinefelter et al published a report on 9 men who had enlarged breasts, sparse facial and body hair, small testes, and an inability to produce sperm.¹
• In 1959, these men with Klinefelter syndrome were discovered to have an extra sex chromosome (genotype XXY) instead of the usual male sex complement (genotype XY).
• Klinefelter syndrome is the most common chromosomal disorder associated with male hypogonadism and infertility. It is defined classically by a 47,XXY karyotype with variants that demonstrate additional X and Y chromosomes.
• The syndrome is characterized by hypogonadism (small testes, azoospermia, oligospermia), gynecomastia in late puberty, psychosocial problems, hyalinization and fibrosis of the seminiferous tubules, and elevated urinary gonadotropin levels.
• 
  

  

  Adolescent male with gynecomastia and Klinefelter syndrome.

  [ CLOSE WINDOW ]

  

  Adolescent male with gynecomastia and Klinefelter syndrome.

• 
  

  

  Child with Klinefelter syndrome. Other than a thin build and disproportionately long arms and legs, the phenotype is normal.

  [ CLOSE WINDOW ]

  

  Child with Klinefelter syndrome. Other than a thin build and disproportionately long arms and legs, the phenotype is normal.

• 
  

  

  Adolescent male with Klinefelter syndrome who has female-type distribution of pubic hair and testicular dysgenesis.

  [ CLOSE WINDOW ]

  

  Adolescent male with Klinefelter syndrome who has female-type distribution of pubic hair and testicular dysgenesis.

Pathophysiology

• The X chromosome carries genes that play roles in many body systems, including testis function, brain development, and growth.² The addition of more than one extra X or Y chromosome to a male karyotype results in variable physical and cognitive abnormalities. In general, the extent of phenotypic abnormalities, including mental retardation, is directly related to the number of supernumerary X chromosomes. As the number of X chromosomes increases, somatic and cognitive development are more likely to be affected.
• Skeletal and cardiovascular abnormalities can become increasingly severe. Gonadal development is particularly susceptible to each additional X chromosome, resulting in seminiferous tubule dysgenesis and infertility, as well as hypoplastic and malformed genitalia in polysomy X males. Moreover, mental capacity diminishes with additional X chromosomes. The intelligence quotient (IQ) score is reduced by approximately 15 points for each supernumerary X chromosome, but conclusions about reduced mental capacity must be drawn cautiously. All major areas of development, including expressive and receptive language and coordination, are affected by extra X chromosome material.
• The major consequences of the extra sex chromosome, usually acquired through an error of nondisjunction during parental gametogenesis, include hypogonadism, gynecomastia, and psychosocial problems.
• Klinefelter syndrome is a form of primary testicular failure, with elevated gonadotropin levels due to lack of feedback inhibition by the pituitary gland. Androgen deficiency causes eunuchoid body proportions; sparse or absent facial, axillary, pubic, or body hair; decreased muscle mass and strength; feminine distribution of adipose tissue; gynecomastia; small testes and penis; diminished libido; decreased physical endurance; and osteoporosis. The loss of functional seminiferous tubules and Sertoli cells results in a marked decrease in inhibin B levels, which is presumably the hormone regulator of the follicle-stimulating hormone (FSH) level. The hypothalamic-pituitary-gonadal axis is altered in pubertal patients with Klinefelter syndrome.
• A typical patient with Klinefelter syndrome presents with low serum testosterone levels, high luteinizing hormone (LH) and FSH levels, and, often, elevated estradiol levels; however, the decline in testosterone production is progressive over the life span, and not all men suffer from hypogonadism.³
• Men with Klinefelter syndrome are at a higher risk of autoimmune diseases, diabetes mellitus, leg ulcers, osteopenia and osteoporosis, tumors (breast and germ cells), systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome and historically have increased mortality.^4,5
• Whether the morbidity associated with Klinefelter syndrome is a result of hypogonadism and hyperestrogenism or due to abnormal function of X chromosome linked genes is unclear.⁶

Frequency

United States

• Klinefelter syndrome is the most common genetic form of male hypogonadism.
• Approximately 1 in 500-1,000 males is born with an extra sex chromosome; more than 3,000 affected males are born yearly.
• The prevalence rate is 5-20 times higher in individuals with mental retardation than in the general newborn population.
• Approximately 250,000 men in the United States have Klinefelter syndrome.⁷

Mortality/Morbidity

• About 40% of concepti with Klinefelter syndrome survive the fetal period.
• In general, the severity of somatic malformations in Klinefelter syndrome is proportional to the number of additional X chromosomes; mental retardation and hypogonadism are more severe in patients with 49,XXXXY than in those with 48,XXXY.
• The mortality rate is not significantly higher than in healthy individuals.

Race

• Klinefelter syndrome does not have any racial predilection.

Sex

• Because the syndrome is caused by an additional X chromosome on an XY background, this condition affects only males.

Age

• Klinefelter syndrome goes undiagnosed in most affected males; among males with known Klinefelter syndrome, many do not receive the diagnosis until they are adults. The most common indications for karyotyping are hypogonadism and infertility.

Clinical

History

• Infertility and gynecomastia are the 2 most common symptoms that lead to diagnosis in patients with Klinefelter syndrome.
• Other symptoms include fatigue, weakness, erectile dysfunction, osteoporosis, language impairment, academic difficulty, subnormal libido, poor self-esteem, and behavioral problems.

Physical

• Growth
  • Infants and children achieve normal height, weight, and head circumference. About 25% have clinodactyly. Height velocity increases by age 5 years, and adults with Klinefelter syndrome are usually taller than adults who do not have the syndrome. Affected individuals also have disproportionately long arms and legs.
  • Some individuals with Klinefelter variant 49,XXXXY have short stature.
  • 
    

    

    G-banded 47,XXY karyotype.

    [ CLOSE WINDOW ]

    

    G-banded 47,XXY karyotype.

• CNS
  • Most males with the 47,XXY karyotype have normal intelligence. Family background influences intelligence quotient (IQ) score. Subnormal intelligence or mental retardation may be associated with the presence of a higher number of X chromosomes.
  • About 70% of patients have minor developmental and learning disabilities. These may include academic difficulties, delayed speech and language acquisition, diminished short-term memory, decreased data-retrieval skills, reading difficulties, dyslexia, and attention deficit disorder.
  • Patients may exhibit behavioral problems and psychological distress. This may be due to poor self-esteem and psychosocial development or a decreased ability to deal with stress.
  • Psychiatric disorders involving anxiety, depression, neurosis, and psychosis are more common in this group than in the general population.
• Dental: About 40% of patients have taurodontism, which is characterized by enlargement of the molar teeth by an extension of the pulp. The incidence rate is about 1% in healthy XY individuals.
• Sexual characteristics
  • Patients may lack secondary sexual characteristics because of a decrease in androgen production. This results in sparse facial, body, or sexual hair; a high-pitched voice; and fat distribution as is observed in females.
  • By late puberty, 30-50% of boys with Klinefelter syndrome present with gynecomastia, which is secondary to elevated estradiol levels and an increased estradiol-to-testosterone ratio. The risk of developing breast carcinoma is at least 20 times higher than in healthy individuals.
  • Postpubertal patients may have testicular dysgenesis (small firm testis; testis size, <10 mL).
  • Infertility, azoospermia, or both may result from atrophy of the seminiferous tubules. Practically all individuals with a 47,XXY karyotype are infertile. Patients with Klinefelter syndrome mosaicism (46,XY/47,XXY) can be fertile. Guidelines for the assessment and treatment of people with fertility problems have been established.⁸
  • Patients may have an increased frequency of extragonadal germ cell tumors such as embryonal carcinoma, teratoma, and primary mediastinal germ cell tumor.
  • Although genital abnormalities are not commonly observed in patients with Klinefelter syndrome, the association is important to note because Klinefelter syndrome is one of the causes of genital abnormality or ambiguity.⁹ The phenotype include complete sex reversal, true hermaphroditism (eg, ovotestes), testicular feminization, ambiguous genitalia/undervirilization (eg, hypospadias, micropenis, epispadias, female external genitalia), and mild genital abnormalities.
• Cardiac and circulatory problems
  • Mitral valve prolapse occurs in 55% of patients.
  • Varicose veins occur in 20-40% of patients.
  • The prevalence of venous ulcers is 10-20 times higher than in healthy individuals, and the risk of deep vein thrombosis and pulmonary embolism is increased.
• Klinefelter variants
  • 48,XXYY variant: Patients typically have mild mental retardation; tall stature; eunuchoid body habitus; sparse body hair; gynecomastia; long, thin legs; hypergonadotropic hypogonadism; and small testes.
  • 48,XXXY variant: Patients typically have mild-to-moderate mental retardation, speech delay, slow motor development, poor coordination, immature behavior, normal or tall stature, abnormal face (epicanthal folds, hypertelorism, protruding lips), hypogonadism, gynecomastia (33-50%), hypoplastic penis, infertility, clinodactyly, and radioulnar synostosis and benefit from testosterone therapy.
  • 49,XXXYY: Patients typically have moderate-to-severe mental retardation, passive but occasionally aggressive behavior and temper tantrums, tall stature, dysmorphic facial features, gynecomastia, and hypogonadism.
  • 49,XXXXY variant: The classic triad is mild-to-moderate mental retardation, radioulnar synostosis, and hypergonadotropic hypogonadism. Other clinical features include severely impaired language, behavioral problems, low birthweight, short stature in some individuals, abnormal face (round face in infancy, coarse features in older age, hypertelorism, epicanthal folds, prognathism), short or broad neck, gynecomastia (rare), congenital heart defects (patent ductus arteriosus is most common), skeletal anomalies (genu valgus, pes cavus, fifth finger clinodactyly), muscular hypotonia, hyperextensible joints, hypoplastic genitalia, and cryptorchidism. Pea-sized testes, micropenis, and infantile secondary sex characteristics are characteristic in patients with 49,XXXXY, whereas patients with 48,XXXY exhibit milder hypogonadism similar to that found in patients with 47,XXY.

Causes

• In 1959, Klinefelter syndrome was found to be caused by a supernumerary X chromosome in a male.¹⁰
• The 47,XXY karyotype of Klinefelter syndrome spontaneously arises when paired X chromosomes fail to separate (nondisjunction in stage I or II of meiosis, during oogenesis or spermatogenesis).¹¹  Maternal and paternal meiotic nondisjunction each account for approximately 50% of Klinefelter syndrome cases. Seventy-five percent of maternal nondisjunction cases are caused by meiosis I errors, which are associated with increased maternal age. Increased paternal age has been linked to a possible increased risk of Klinefelter syndrome.¹²
• Postfertilization nondisjunction is responsible for mosaicism, which is seen in approximately 10% of Klinefelter syndrome patients. Men with mosaicism are less affected and are often not diagnosed.⁶
• The androgen receptor (AR) gene encodes the androgen receptor, which is located on the X chromosome.
  • The AR gene contains a highly polymorphic trinucleotide (CAG) repeat sequence in exon 1, and the length of this CAG repeat is inversely correlated with the functional response of the androgen receptor to androgens. Thus, a short AR CAG repeat sequence correlates with a marked effect of androgens.
  • In individuals with Klinefelter syndrome, the X chromosome with the shortest AR CAG repeat has been demonstrated to be preferentially inactivated; this process is called skewed or nonrandom X-chromosome inactivation.
  • Individuals with short AR CAG repeats have been found to respond better to androgen therapy, to form more stable partnerships, and to achieve a higher level of education compared with individuals with long CAG repeats.^13,14 Conversely, long AR CAG repeat lengths are associated with increased body height and arm span, decreased bone density, decreased testicular volume, and gynecomastia.
  • Nonrandom X-chromosome inactivation, which preferentially leaves the allele with the longest AR CAG repeat active, may actually contribute to the hypogonadal phenotype found in Klinefelter syndrome and may also explain some of the diverse physical appearances observed in affected individuals.
  • In boys with Klinefelter syndrome, the paternal origin of the supernumerary X chromosome is associated with later onset of puberty and longer CAG repeats of the androgen receptor, with later pubertal reactivation of the pituitary-testicular axis.
• The most common karyotype is 47,XXY, which accounts for 80-90% of all cases. Mosaicism (46,XY/47,XXY) is observed in about 10% of cases. Other variant karyotypes, including 48,XXYY; 48,XXXY; 49,XXXYY; and 49,XXXXY, are rare.
  • The mosaic forms of Klinefelter syndrome are due to mitotic nondisjunction after fertilization of the zygote. These forms can arise from a 46,XY zygote or a 47,XXY zygote.
  • Variant forms of Klinefelter syndrome include 48,XXXY; 49,XXXXY; 48,XXYY; and 49,XXXYY.

• Search for CME/CE on This Topic »

• Extragonadal Germ Cell Tumors (Oncology)
• Gynecomastia (Plastic Surgery)
• Hypothyroidism (Pediatrics: General Medicine)
• Hypogonadism (Pediatrics: General Medicine)

• Male Breast Cancer Presenting as an Axillary Mass: A Case Report and Literature Review
• Why Treat the Male in the Era of Assisted Reproduction?
• Physical Activity Levels of Children with Intellectual Disabilities during School