Klinefelter Syndrome Clinical Presentation

Updated: Jan 31, 2022
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Hypogonadism, gynecomastia, and infertility are common symptoms that lead to the diagnostic evaluation of males for Klinefelter syndrome.

Other symptoms include the following:

  • Tall height with long arms and legs
  • Delayed or incomplete pubertal development
  • Sparse facial, body, and sexual hair
  • Erectile dysfunction
  • Osteoporosis
  • Breast malignancy
  • Speech and language deficits (especially expressive language)
  • Learning disabilities (lower verbal IQ than performance IQ scores)
  • Poor self-esteem (increased incidence of anxiety, depression)
  • Behavioral problems (substance abuse)


Frequently associated medical disorders

These include the following. [18]

Motor, cognitive, and behavioral dysfunction

Poor muscle tone and strength, as well as impaired gross and fine motor skills, coordination, dexterity, and running ability, are observed. Synkinetic movements and tremor can be seen in early childhood and may persist into adulthood. [19, 20]

Cognitive phenotype is manifested as deficits in the specific domains of language and executive functions. Expressive language is affected more than comprehension or receptive language skills. Problems in understanding complex grammatical constructions, oral language production, word retrieval, and oral narrative construction are observed in these patients. [21]  A study by Skakkebæk et al suggested that in persons with KS, the level of social engagement has an impact on executive cognitive functioning and/or vice versa. The study indicated that while lower general intelligence seems to be the principal factor in memory deficits among these individuals, a combination of decreased intelligence and lower social skills produce deficits in executive function. [22]

Schizophrenia, psychosis, and bipolar disorder have been reported in males with Klinefelter syndrome. [23]


Mediastinal tumors may occur in young patients, presenting as precocious puberty; histologically, these neoplasms are classified as mixed germ cell tumors. Mediastinal tumors in older males present with thorax-associated symptoms, primarily chest pain, dyspnea, and cough; mixed germ cell tumors are more common, but teratomas and other mixed tumors occur. [24]

Breast cancer and testicular cancer are reported, although a clear relationship between Klinefelter syndrome and testicular cancer has not been documented.

Vascular disease

Vascular diseases associated with Klinefelter syndrome include hypostatic ulceration, deep vein thrombosis, pulmonary embolism, and ischemic heart disease.

Endocrine/metabolic and autoimmune diseases

Hypogonadism (pathognomonic) and associated osteoporosis occur. Bone density decreases in 25% of males with Klinefelter syndrome, with this most likely being related to decreased bone formation, increased bone resorption, and/or hypogonadism.

An increased incidence of diabetes mellitus, obesity, hypothyroidism, Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus have been reported in males with Klinefelter syndrome.

Other observations


Infants and children achieve normal height, weight, and head circumference. Height velocity shows a notable increase between ages 5 and 8 years. Adults with Klinefelter syndrome are usually taller than nonaffected adult males, reaching a mean final height of about 185 cm (73 in). XXY males (see the image below) also have disproportionately long arms and legs. About 25% of patients have fifth-finger clinodactyly. Some males with Klinefelter syndrome variant 49,XXXXY have short stature.

G-banded 47,XXY karyotype. G-banded 47,XXY karyotype.


Contrary to other genetic syndromes that arise from chromosomal trisomy (eg, Down syndrome, trisomy 18), the overall cognitive abilities of males with Klinefelter syndrome typically are within the range of average intellectual ability. [25]  Most males with the 47,XXY karyotype have normal intelligence. Intellectual disability occurs in males with Klinefelter syndrome variants, who have 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. Evidence for more general impairments in language has been consistent, with the most widely observed deficits having been reported in encoding of verbal information, auditory processing, comprehension, and processing speed. Expressive speech and verbal fluency are also affected. [26]

Behavioral problems and psychological distress are reported and may be due to poor self-esteem, compromised psychosocial development, or an inability to deal with stress. Psychiatric disorders with features of anxiety, depression, neurosis, and psychosis are more common than in the general population.


About 40% of patients have taurodontism, a dental finding characterized by enlargement of the molar teeth by an extension of the pulp. In comparison, the incidence of taurodontism is about 1% in XY males.

Sexual characteristics

Genital abnormalities are not commonly observed in 47,XXY males. This is an important observation because Klinefelter syndrome is considered a cause of genital abnormality or ambiguity. [27]  The genital phenotype can include complete sex reversal, true hermaphroditism (eg, ovotestes), testicular feminization, and ambiguous genitalia/undervirilization (eg, hypospadiasmicropenis, epispadias, female external genitalia).

Pubertal changes with lack of secondary sexual characteristics are due to decreased androgen production. This results in sparse facial, body, or sexual hair; a high-pitched voice; and body fat distribution as is observed in females. By late puberty, 30-50% of boys with Klinefelter syndrome present with gynecomastia, which is due to elevated estradiol levels and an increased estradiol:testosterone ratio. The risk of developing breast carcinoma in Klinefelter syndrome is at least 20 times higher than in healthy individuals. There is also an increased risk of extragonadal germ cell tumors such as embryonal carcinoma, teratoma, and primary mediastinal germ cell tumor.

Postpubertal males may have testicular dysgenesis (small firm testis; testis size < 10 mL). Infertility, azoospermia, or both may result from atrophy of the seminiferous tubules. Most males with a 47,XXY karyotype are infertile, but 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. [28]

A literature review by Deebel et al indicated that, while azoospermia is a characteristic of Klinefelter syndrome, patients are frequently positive for spermatogonia. Indeed, spermatogonial cells were found in 100% of fetal/infantile patients and in 83%, 42.7%, and 48.5% of prepubertal, peripubertal, and adult patients. In addition, positive spermatogonia results were found in 46.4% of peripubertal/adolescent patients and 24.3% of adult patients, who were negative for spermatozoa. [29]

Cardiac and circulatory problems [30]

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.

A Swedish study found the standardized incidence ratio for venous thromboembolism (VTE) in Klinefelter syndrome to be 6.43, with a ratio of 12.10 in persons younger than age 30 years and 2.07 in persons aged 70 years or older. Based on the study's findings, an association exists between Klinefelter syndrome and a high risk for VTE. The authors suggest that Klinefelter syndrome could be recognized as a genetic hypercoagulable state. [31]

A study by Chang et al also found the thrombosis risk to be higher in Klinefelter syndrome, with hazard ratios for VTE and total thrombotic death, as measured against a comparison cohort, being 3.95 and 1.76, respectively. The investigators also reported an insignificant decrease in venous thromboembolism and thrombotic deaths in patients who received testosterone treatment. [32]

Klinefelter syndrome variants/sex chromosome aneuploidies

Variants of Klinefelter syndrome are as follows [33]   [34] :

  • 48,XXYY variant: Patients typically have intellectual challenges (IQ range 60-80, delayed speech, learning disabilities); tall stature (adult height >6 feet); eunuchoid body habitus; sparse body hair; gynecomastia; long, thin legs; hypergonadotropic hypogonadism; and small testes and penis.

  • 48,XXXY variant: Patients typically have intellectual challenges (IQ range 40-60, marked speech delay, slow motor development, poor coordination), average or tall stature, abnormal face (epicanthal folds, ocular hypertelorism, flat nasal bridge), gynecomastia (33-50%), hypergonadotrophic hypogonadism, hypoplastic penis, small testes, fifth-finger clinodactyly, and radioulnar synostosis. 

  • 49,XXXYY: Patients typically have severe intellectual disabilities; passive, but occasionally aggressive, behavior and temper tantrums; tall stature; dysmorphic facial features; gynecomastia; and hypogonadism.

  • 49,XXXXY variant: Males are severely intellectually challenged (IQ range 20-60). Patients have short stature and are microcephalic with dysmorphic facial features (ocular hypertelorism, epicanthal folds, flat nasal bridge, prognathism), and a short or broad neck. Other clinical features include severely impaired language, behavioral problems, low birth weight, cleft palate, gynecomastia (rare), congenital heart defects (patent ductus arteriosus is most common), skeletal anomalies (radioulnar synostosis, genu valgus, pes cavus, fifth-finger clinodactyly), muscular hypotonia, hyperextensible joints, hypergonadotropic hypogonadism, hypoplastic genitalia, and cryptorchidism



In 1959, Klinefelter syndrome was found to be caused by a supernumerary X chromosome in a male. [35]

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). [36] 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. [37]

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. [38, 39] 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.