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Klinefelter syndrome
Last reviewed: 23.04.2024
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Klinefelter syndrome, 47, XXY is a clinical example of sex chromosome lesions.
Klinefelter disease is characterized by the presence of at least one extra X chromosome in boys, which leads to impaired puberty in them. It was clinically described for the first time by Kleinfelter in 1942. The population frequency is 1: 1000 males. Klinefelter syndrome occurs in about 1/800 live-born boys. The child gets the extra X chromosome from the mother in 60% of cases.
[1],
What causes Klinefelter disease?
In most cases, the incorrect divergence of sex chromosomes occurs in the gametes of the parents. There are also mosaic variants, for example 47, XXY / 46, XY.
Klinefelter syndrome is caused by chromosomal abnormality, presented in the most typical form as 47XXU. Much less common mosaic forms - 46HU / 47HHU. As casuistic variants of the karyotype, forms 48XXXU, 47XXU / 46XX, 47XXU / 45XO are described. There is also the observation of a patient with a karyotype 47ХХУУ46ХХ / 45ХО. The reason for these chromosomal abnormalities — the extra X chromosome in the male karyotype — may be the non-divergence of the X chromosome during the first or second meiotic division or the disruption of the mitotic discrepancy of chromosomes during the development of zygotes (mosaic variants). The method of DNA analysis revealed that 53% of patients with Klinefelter syndrome had an additional chromosome of paternal origin, which was the result of nondisjunction during the first meiotic division. 43% of patients had an extra chromosome of maternal origin as a result of the pathology of the first and second meiotic division. Apparently, there are no differences in the phenotype in patients who have an additional maternal or paternal X chromosome. The frequency of birth of boys with Klinefelter syndrome increases with increasing age of the mother. No similar dependence on the age of the father has been identified. The presence of an extra X chromosome in the male karyotype does not affect the differentiation of the testicles and the formation of male genitalia. However, the vital activity of germinative cells is disturbed, spermatogenesis is absent. The reason for this is the activity of an extra X chromosome in germinative cells that normally have a haploid set of chromosomes. It was shown that in germinal cells of the ovary of the fetus in girls, before entering into meiosis, the second X chromosome is reactivated (normally only one is activated). In boys with the XXY karyotype, the pre-meiotic process of reactivation of the second X chromosome is also preserved; however, the discrepancy process is disrupted, and the germinative cell may contain two active X chromosomes, which leads to its death in the first days after the X chromosome is reactivated. In adult males with Klinefelter syndrome, when analyzing sperm cells, single, intact germinal cells had only a normal haploid chromosome set.
Symptoms of Klinefelter syndrome
At birth, Klinefelter syndrome is not clinically manifested. There are quite a lot of clinical options related to abnormalities of sexual status and somatic disorders in Klinefelter syndrome. The general regularity of the effect of the karyotype on the phenotype has not been identified, but patients with a mosaic karyotype with a normal male clone 47XXU / 46XU have less severe disorders.
The first distinct phenotypic symptoms. disease appear in the pre- and pubertal periods of ontogenesis. Before puberty, boys can detect cryptorchidism (usually bilateral) and small penis size. 50% of boys have moderate mental retardation, accompanied by behavioral disorders, difficulties in contact with peers. Boys usually have a body length above the average age. Characterized by relatively long limbs, excess fat deposition of the female type (eunuchoid body type).
Late secondary signs appear. The most characteristic symptom of Klinefelter syndrome is hypoplasia of the testes and the penis (hypogonadism and hypogenitalism). In 50% of patients in puberty, gynecomastia is detected. There is a shallow decline in intelligence, which affects school performance. Adult patients are prone to alcoholism, drug addiction, homosexuality and antisocial behavior, especially under stress.
Puberty usually begins at a normal age, but often hair growth on the face is low. Such children have a predisposition to learning disorders, many have reduced verbal intelligence, impaired auditory perception and information processing, as well as reading skills. Clinical variability is significant, many boys and men with karyotype 47, XXY have normal appearance and normal intelligence.
At pubertal age, secondary body hair appears in the usual periods, there is also an increase in the penis. However, the volume of the testicles increases slightly, not exceeding, as a rule, 8 ml; testicles have a dense texture. Pubertal gynecomastia, often quite early, is detected in 40-50% of boys. In the future, these patients are at increased risk of developing breast carcinoma. Bone maturation usually corresponds to the age at the time of pubertal initiation, but later the differentiation of the skeleton bones is delayed due to insufficient testosterone secretion. Linear growth of limbs lasts up to 18–20 years, which leads to the formation of eunuchoid body proportions, the final growth of patients, as a rule, is higher than the growth of parents. Post-pubertal involution of the testicles leads to hypogonadism and loss of fertility. Histological examination revealed hyalinosis of the seminiferous tubules and the absence of spermatogenesis. The number of Leydig cells may be normal, but with age they undergo atrophy.
In addition to the symptoms of impaired sexual development in patients with Klinefelter syndrome, a number of congenital anomalies of bone tissue can be detected: clinodactyly, sternum deformity, cubitus valgus, coxa valga, hypertonorism, micrognathia, “gothic” palate, etc. Often the disease is accompanied by congenital heart disease. System. In patients, malignant neoplasms are quite often detected, in particular, there is information about a high frequency of germ cell tumors.
Mosaicism is observed in 15% of cases. These men can have children. Some men can have 3,4 and even 5 X chromosomes together with one Y chromosome. With an increase in the number of X chromosomes, the severity of mental retardation and malformations increases.
Diagnosis of Klinefelter syndrome
Often, Klinefelter syndrome is detected during an examination for infertility (probably all 47, XXY men are sterile). Testicular development varies from hyalinized non-functioning tubular structures to some sperm production; increased excretion of follicle-stimulating hormone with urine is often noted.
In the presence of phenotypic signs of Klinefelter syndrome, sex chromatin is determined. If the test is positive, then karyotyping is indicated. In most cases, the karyotype 47, XXY or its mosaic version is detected. However, there are other cytogenetic variants of the syndrome, for example 48, XXXY; 48, XXYY.
[8], [9], [10], [11], [12], [13], [14]
Features of gonadotropic and gonadal functions
In the pre-pubertal age, LH, FSH and T values in boys with Klinefelter syndrome usually are normal. By the beginning of puberty, the level of FSH rises and by the age of 14–15 years already significantly exceeds the norm. The level of testosterone at the time of puberty usually increases, but its concentration does not reach the standard indicators. The level of LH during puberty is normal, but subsequently, as the level of testosterone decreases, the concentration of LH increases. The reaction of LH and FSH to the introduction of GnRH is usually hyper-ergic in the early stages of puberty.
The process of the formation of androgen deficiency, which is secondary to the primary damage to the germinal epithelium of the testicles, is currently not fully understood. The early death of spermatogenic epithelium leads to a deficiency of sertoli cells secreting inhibin, a natural regulator of FSH secretion in men. As a result, the level of FSH in patients is elevated from early puberty. However, testosterone production and LH secretion in the early years of puberty and post pubertal age are not impaired, only later there is a decrease in testosterone secretion and an increase in LH secretion - the development of hypergonadotropic hypogonadism. Obviously, the germinal epithelium and Sertoli cells have a definite trophic effect on the interstitial Leydig cells, and the absence of their trophic effect makes normal testosterone secretion impossible.
[15], [16], [17], [18], [19], [20], [21], [22]
Differential diagnosis of Klinefelter syndrome
In cases of signs of Klinefelter syndrome with a normal karyotype (46, XY), it is necessary to exclude other forms of hypogonadism.
Who to contact?
How is Klinefelter's disease treated?
At puberty, androgens conduct training that contributes to the formation of secondary sexual characteristics, but Infertility can not be cured.
Adolescents with Klinefelter syndrome, despite partial androgen deficiency, therapy with testosterone esters according to the standard scheme should be prescribed from 13-14 years. Androgen preparations significantly improve adolescent adaptation and intelligence, prevent the development of eunuchoidism. Long-term observation of adolescents with Klinefelter syndrome showed that early therapy with testosterone significantly improves the intelligence of adult patients, their ability to work and social adaptation.
[25]
Evaluation of the effectiveness of treatment
The criterion for the effectiveness of treatment is the development of secondary sexual characteristics.
Complications and side effects of treatment
The introduction of testosterone esters can cause fluid retention, agitation in the first days after injection.
Clinical observation is carried out by an endocrinologist.
What is the prognosis of Klinefelter syndrome?
Klinefelter syndrome has a different prognosis and depends on the form of the disease, combined hormonal and somatic disorders. Replacement therapy with sex hormones for life.