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Klinefelter Syndrome Causes, Symptoms And Karyotype

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Klinefelter Syndrome Causes, Symptoms And Karyotype

Klinefelter syndrome is a heterogeneous group of abnormalities of the sex chromosomes, where there is at least one X chromosome in addition to the normal karyotype, 46XY, in males. Symptoms and etiology of Klinefelter syndrome are heterogeneous.

In 1942, Dr. Harry Klinefelter reported a group of nine men with increased urinary gonadotropins, microorchidism, azoospermia, and gynecomastia. In 1959, Jacobs admits Klinefelter syndrome etiology by the presence of 47XXY karyotype.

Klinefelter Syndrome

Klinefelter Syndrome

The incidence of Klinefelter syndrome is 1 to 500 in male newborns  for 47XXY and 1 to 300 in spontaneous abortions, 1 to 50.000 for karyotype 48XXXY and 1 to 85.000 for karyotype 49XXXXY.

Klinefelter syndrome is the most common cause for hypogonadism in males.


Molecular cytogenetic studies, by recent investigations with DNA markers showed that, in 50% of cases of Klinefelter syndrome, the error occurs in primary paternal meiosis, in the third of the cases the error occurs in primary maternal meiosis, and  in the rest of the cases of Klinefelter syndrome, error occurs in the secondary meiosis or are errors which are leading to postzygotes mosaicism.

Three quarters of cases of Klinefelter syndrome with maternal origin, come from errors in primary meiosis and thereby is incriminated the advanced age of the mother. It is assumed that maternal meiotic non-disjunction can be correlated with an increased frequency of recombination near the centromeres, suggesting an association between recombination and chromosome non-disjunction in these situations.

Klinefelter Syndrome

Klinefelter Syndrome

The clinical presentation of Klinefelter syndrome:

Before puberty, physical development is age-appropriate, the phenotype is normal, rarely can be suspected the existence of Klinefelter syndrome.

In childhood may occur: hypospadias, micropensi, cripotorhidis, signs suggestive for Klinefelter syndrome, which are leading to cytogenetic investigation to the child.

Patients are generally high, significant increase in height is between 5 years and 8 years, average height is 179.2 cm ±6.2 cm. Patients are asthenic, presenting upper limbs and legs longer than usual (growth occurs through large leg length). Muscle tissue distribution is ginoid and in obese patients can be seen a eunucoid type constitution. It can be seen a smaller bitrohanterian diameter than biacromial diameter.

Hypogonadism becomes apparent at puberty and is the cardinal sign of testicular hyplopazia, tests remain underdeveloped and secondary sexual characters are not installed. Facial hair growth, body hair growth and genital hair growth is reduced. Normal testosterone levels tend to decline with the end of adolescence and in young adult life.

As a general rule, Klinefelter syndrome is associated with sterility, due to oligospermia or azoospermia.

Gynecomastia is almost a constant clinical sign (56% of cases of Klinefelter syndrome, with variations up to 88%) achieved by hypertrophy of the mammary glands or extraglandular tissue overgrowth, considering that these patients have a risk of 20 times more likely to develop breast cancer compared with normal subjects.

Besides hypogonadism and absence of secondary sexual characters, which marks the phenotype of Klinefelter syndrome patients, the intellect is nearly normal developed (if exist mental retardation, this have a moderate intensity), only rarely are noted some difficulties in schooling training, intelligence coefficient can have lower values. Sometimes patients have dyslexia and a decrease psychosocial adaptability. Many of the behavioral and clinical characteristics of Klinefelter syndrome are modified by the treatment with testosterone.

Klinefelter Syndrome

Klinefelter Syndrome

Described karyotypes in Klinefelter syndrome:

Of all patients with Klinefelter syndrome, 80% – 85% have 47XXY karyotype. In Klinefelter syndrome, there may be other options of karyotype than the one presented, such as 48XXXY, 48XXYY and 49XXXXY. Addition of X chromosome causes more severe affections with major phenotypic abnormalities, abnormal sexual development and always serious intellectual disorders. Each additional X chromosome, reduces the coefficient of intelligence with 15-16 points, language being the most affected.

About 15% of cases of Klinefelter syndrome, presents mosaic karyotype and have variable phenotype, sometimes with near-normal development (and may even be fertile). Most often mosaicism is 46XY / 47XXY.

Tests for diagnosis of Klinefelter syndrome:

  • Standard karyotype;
  • Elevated levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol;
  • Low levels of testosterone (12 – 14 years or undiagnosed adults);
  • Very high urinary gonadotropins show that Leydig cell function is abnormal.


  • Risk of developing breast cancer is 20 times higher than in normal individuals, the frequency of breast cancer in patients with Klinefelter syndrome is 3.7%;
  • Endocrine complications: diabetes, hypothyroidism, hypoparathyroidism;
  • Autoimmune diseases: systemic lupus erythematosus, Sjogren syndrome, rheumatoid arthritis;
  • Varicose veins and varicose ulcers.

The medical management of Klinefelter syndrome:

Treatment with testosterone has to start at puberty around the age of 12 years, increasing levels of testosterone by therapy is maintaining normal levels of estradiol, FSH and LH. The treatment  can harmonize the physical development, the development of secondary sexual characters and can prevent gynecomastia. It also improves behavioral development, prevents depression, osteoporosis, autoimmune diseases and breast cancer.

Prenatal diagnosis:

Klinefelter syndrome can be detected by amniocentesis and fetal karyotype study, parents are advised on the clinical manifestations of this syndrome.

Klinefelter Syndrome

Klinefelter Syndrome

Cytogenetic variants of Klinefelter syndrome:


Patients may develop: hypertelorism, flattened nose, radioulnar synostosis, cliniodactyly of five finger, hypogonadism, IQ = 40 – 60. Generally these patients are taller, immature, passive, cooperative and are not aggressive.


These patients are more severely affected showing: microcephaly, short stature, hypertelorism hypogonadism, micropenis, cleft palate, heart defects, radio ulnar synostosis, hypotonia with joint laxity. Have an IQ = 20-60 and friendly behavior.


Clinically, these patients are characterized by taller stature, hypogonadism, micropenis. Have an IQ = 60-80, are more aggressive and have a impulsive behavior.