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Klinefelter Syndrome Clinical Presentation

  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Luis O Rohena, MD  more...
Updated: Jun 08, 2016


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.



Most frequently associated medical disorders

These include the following.[9]

Motor, cognitive, and behavioral dysfunction

Reduction in gross and fine motor skills, coordination, dexterity, running ability, poor muscle tone and strength, synkinetic movements, and tremor are usually identified in early childhood and may persist into adulthood.[10, 11]

Cognitive phenotype is manifested as deficits in the specific domains of language and executive functions.

Schizophrenia, psychosis, and bipolar disorder have been reported in Klinefelter syndrome patients.[12]


Mediastinal tumors may be present. Clinically, younger patients tend to present with precocious puberty; histologically, their tumors are mixed germ cell tumors. Older children present with thorax-associated symptoms, mainly chest pain, dyspnea, and cough; mixed germ cell tumors are more common, but teratomas and other mixed tumors occur.[13]

Breast cancer and testicular cancer are reported, although based on current literature, a relationship between Klinefelter syndrome and testicular cancer is not 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

These may include hypogonadism (pathognomonic) and associated osteoporosis. Additionally, an increased incidence of diabetes mellitus, obesity, metabolic syndrome, hypothyroidism, Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus have been reported in men with Klinefelter syndrome.

Other observations that have been noted


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 (see the image below).

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 general cognitive ability of patients with Klinefelter syndrome is not typically in the intellectual disability range.[14]

Most males with the 47,XXY karyotype have normal intelligence. Family background influences intelligence quotient (IQ) score. Intellectual disability 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.

Evidence for more general impairments in language has been consistent, with the most widely observed deficits reported in encoding of verbal information, auditory processing, comprehension, and processing speed. Expressive speech and verbal fluency are also affected.[15]

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.


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.[16]

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.[17] 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[18]

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 in Klinefelter syndrome to be 6.43, although the ratio decreased with age, being 12.10 in persons younger than age 30 years and 2.07 in persons aged 70 years or older.[19]

Klinefelter variants

Variants of Klinefelter syndrome are as follows[20] :

  • 48,XXYY variant: Patients typically have mild intellectual disability; 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 intellectual disability, 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 intellectual disability, 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 intellectual disability, radioulnar synostosis, and hypergonadotropic hypogonadism. Other clinical features include severely impaired language, behavioral problems, low birth weight, 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.


In 1959, Klinefelter syndrome was found to be caused by a supernumerary X chromosome in a male.[21]

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).[22] 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.[23]

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. [24, 25] 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.
Contributor Information and Disclosures

Harold Chen, MD, MS, FAAP, FACMG Professor, Department of Pediatrics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

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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.
G-banded 47,XXY karyotype.
Adolescent male with Klinefelter syndrome who has female-type distribution of pubic hair and testicular dysgenesis.
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