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.
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 48ХХХУ, 47ХХУ / 46ХХ, 47ХХУ / 45ХО 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 father's age 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 signs of the 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, the testicles have a dense consistency. 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, hypertension, 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.
Klinefelter syndrome - what is it
The chromosome set of a healthy person consists of 46 chromosomes (23 pairs), all pairs of which are called somatic, except for the last one - sex. On these chromosomes lies the task of determining whether a boy or a girl will be born. Women have XX chromosomes, men - XY. The normal male genotype is as follows: 46 XY, which means the presence of X, Y chromosomes in one copy. When the XXY chromosome genotype occurs, the patient has xxy syndrome.
Klinefelter syndrome - karyotype
Violation of puberty in people with extra chromosome can not manifest itself outwardly, as seen in the photo. The karyotype of a man with Klinefelter syndrome has a direct effect on the manifestation of symptoms of the disease. The level of physical and mental abnormality depends on how many extra X chromosomes are in the genotype. Among adult patients, a tendency to drugs and alcohol is found, it is difficult for adolescents to communicate with their peers. Types of polysomies in males for chromosomes X and Y:
|48XXYY||One additional chromosome X and Y||Dual X chromosomes||The frequency of manifestation - rare, in the form of three additional X-chromosomes|
|46 XY / 47XXU||The mosaic form may contain both normal sex cells and defective|
These diagnostic methods are physical and psychological discomfort for pregnant women. Approximately half of the patients feel pain cramping character. There is even a chance of miscarriage after these procedures, but it is extremely small - about 1%. Other possible complications include: infection, leakage of amniotic fluid, bleeding.
It is worth noting that these diagnostic methods, due to their insecurity, are prescribed by the doctor strictly if there are certain indications:
- The age of the future mother is over 35 years old,
- There was a high risk of chromosomal abnormalities in the fetus according to the results of screening during pregnancy,
- There was already a pregnancy with chromosomal abnormalities in the fetus, ending in miscarriage,
- In the family there is a child with chromosomal pathology,
- Future parents are related.
Consequently, the future mother’s desire to undergo a highly accurate examination for the presence of Klinefelter syndrome and other genetic pathologies in the fetus will not be enough.
Fortunately, methods for prenatal diagnosis are constantly being improved, and there is a safe way to detect a large number of fetal pathologies already in early pregnancy. An example of the successful development of prenatal technologies is the non-invasive DNA test Panorama, developed in the USA in 2012 and having proved its effectiveness in many countries around the world, including Russia.
The test identifies fetal chromosomal abnormalities such as Down syndrome, Edwards and Patau syndromes, microdeletion syndromes, and sex chromosome abnormalities, which include Klinefelter syndrome. Not only women who have indications for invasive diagnostics can pass the test, but also all who wish to receive the most complete information about the future health of the future baby.
To study a pregnant woman, you just need to donate blood from a vein. Further, with the help of molecular technologies, the cells of the fetus are extracted from the material obtained, which will be carefully studied for the presence of genetic variations. The low risk result obtained as a result of the analysis shows that the probability that the child has pathologies that the test can reveal is almost zero. High risk is not a sentence, but requires further diagnosis, namely, invasive studies to confirm or deny the diagnosis.
The study has high accuracy (more than 99%) since the 9th week of pregnancy. The test is absolutely safe for both the mother and the fetus, and allows parents to find out the sex of the child.
Summarizing the issue of diagnosis of this disease, it should be noted that its early detection is extremely important. This will help prevent possible complications in the form of physical and mental abnormalities in the patient.
Symptoms and forms of the disease
If you look at the photos of children with Klinefelter's syndrome, then you will notice that at an early age there are no characteristic external manifestations of this pathology. The disease should be suspected if the boy has a retarded mental development, learning difficulties and some behavioral anomalies. A child with Klinefelter syndrome may be aggressive, restless, or, conversely, too cheerful. Also, these children have difficulty in establishing psychosocial contacts.
The closer the boy comes to puberty, the clearer are the classic external signs of the disease. The most prominent symptoms of Klinefelter syndrome in children and adolescents:
Children with Klinefelter syndrome are noticeably superior in the growth of their peers. A sharp increase in their growth occurs, as a rule, from five to eight years.
Disproportions in the body structure are noted, first of all, this is a high waist and limbs that are too long.
Due to the lack of androgens (steroid male sex hormones), many patients are characterized by a female-built body mass with excessive fat. Accompanied by this feature wide hips and narrow shoulders, like women.
This phenomenon, characterized by a painless, symmetric enlargement of the mammary glands in men due to glandular and fatty tissues, is observed in 50-70% of healthy adolescents. In rare cases, the condition is accompanied by painful sensations when palpating. Pubertal gynecomastia regresses independently, and its signs disappear without a trace within two years. However, if a person has Klinefelter syndrome, the involution of enlarged glands to the former state does not occur.
Violation of the structure of the genital organs
The size of the testicles in patients with the syndrome is small and not age-appropriate. This becomes especially clear at a transitional age, when their growth slows down very much or stops at all. The penis is also distinguished by its small size. In some cases, there is cryptorchidism (absence of one or two testicles in the scrotum). These changes lead to infertility in adulthood.
People with Klinefelter syndrome have some typical facial features for this disease: a wide eyed and a small degree of Mongoloid, deformed auricles, a large parted mouth, a wide and flat nose, some have a squint.
40% of adolescent boys with Klinefelter's syndrome have hair that is too rare on their face. Many have little underarm hair and female pubic hair growth.
Anomalies of bone tissue
In addition to disorders associated with sexual development, carriers of extra X - chromosomes suffer from congenital anomalies of bone tissue. They may experience deformity of the sternum, congenital defects of the fingers (clinodactyly), abnormal development of the jaw and nasopharynx ("Gothic" sky and micrognathia).Some of these defects can be eliminated with surgery.
Teenager with Klinefelter Syndrome
Mental and mental development
Approximately every second patient who has Klinefelter syndrome, suffers from a moderate mental retardation. As a result of this factor, difficulties often arise in attempts to establish contact with peers and behavioral disorders.
Observations suggest that in children and adolescents with Klinefelter syndrome, there is often a delay in speech development, problems with the auditory perception of the material. Decrease in verbal intelligence, violation of information processing processes, difficulty in acquiring reading skills lead to the fact that maintaining normal school performance becomes a real problem. In a more mature age, this flows into the inability to clearly express one’s thoughts. Also, adult patients have a tendency to alcoholism and drug use.
The karyotype of a man with Klinefelter syndrome affects the severity of certain symptoms of the disease. In other words, the number of extra X chromosomes in the genotype has a direct effect on the formation of mental and physical abnormalities.
|Karyotype||Features of the patient|
It can be noted that an increase in the number of X chromosomes in the genotype contributes to an increase in the severity of developmental defects and abnormalities in mental development. For example, carriers of karyotype 43 XXXXY have such an impressive set of symptoms that it is possible to detect the presence of the syndrome at an early age.
Mosaicism is found only in 15% of cases of pathology. Most men with a karyotype 47 XXY, do not have any obvious defects of appearance and are characterized by normal development of intelligence.
Life with Klinefelter syndrome
The prevalence of the syndrome takes a rather impressive position - the third place among the whole range of endocrine diseases. Only diabetes mellitus and thyroid pathology are ahead of it.
The life expectancy of men affected by this gene mutation is, in total, the same as that of healthy people. However, it is worth noting that in many cases their life path is accompanied by health problems that can lead to early death.
Complications that may result from this disease:
- mental developmental problems that may develop to the debilityal stage,
- mental disorders leading to alcoholism, suicidal feelings, antisocial lifestyle,
- high risk of diabetes, obesity,
- aggravation of congenital heart defects,
- osteoporosis (bone fragility),
- the probability of occurrence of malignant tumors, for example, breast carcinoma, provoked by gynecomastia,
One of the main problems of Klinefelter syndrome is infertility. The loss of fertility is due to abnormalities of the genital organs and the absence of viable spermatozoa in the seminal fluid. Today, an active search is underway to find a solution to this problem, including through IVF (in vitro fertilization), but for these patients, this technique is under development and is not widely used.
In general, the prognosis for patients with Klinefelter syndrome is favorable. Patients are quite well adapted to life. The severity of complications caused by the syndrome depends on how early the chromosomal abnormality was diagnosed and how soon the treatment was started. The sooner this happens, the fewer the complications.
Treatment and Prevention
There are no special preventive measures for Klinefelter syndrome. A genetics consultation is worth taking if there are cases of hereditary diseases in previous generations or there are other risk factors.
It is impossible to completely cure the syndrome today, however, continuous therapy can greatly facilitate the lives of patients. The syndrome is treated by means of substitution therapy, which involves taking drugs that increase the concentration of testosterone. The therapeutic course helps to improve the appearance and well-being of the patient, as well as restores the ability of a man to lead a normal sex life. Competent therapy can prevent the development of osteoporosis and muscle weakness.
In order to prevent gynecomastia, treatment should begin at a young age, as soon as Klinefelter syndrome has been diagnosed. In adulthood, gynecomastia develops to such a state that it cannot be treated. Enlarged breasts are often the cause of psychological complexes in patients, in which case you can resort to the removal of the mammary glands (mastectomy).
Experts recommend that patients monitor their diet and do not gain excess weight, so as not to provoke obesity and type 2 diabetes.