Klinefelter's syndrome: a brief overview and clinical example

Additional Information

Source of financing.

The search and analytical work was carried out with the support of the KAF Philanthropy Support and Development Fund as part of the Alfa-Endo charity program.

Conflict of interest.

The authors declare that there are no obvious or potential conflicts of interest related to the publication of this article that need to be disclosed.

Authors' participation.

Both authors made equal contributions to the search and analytical work and preparation of the final version of the article.

Information about authors

*Bespalyuk Daria Alekseevna

; address: Russia, 117036, Moscow, st. Dm.Ulyanova, 11 [address: 11 Dm. Ulyanova str., Moscow, 117036, Russia]; ORCID: https://orcid.org/0000-0002-4900-6652; eLibrary SPIN: 7129-8794; e-mail

Chugunov
Igor Sergeevich
, Ph.D. ; ORCID: https://orcid.org/0000-0003-4915-1267; eLibrary SPIN: 1514-5005; e-mail

Klinefelter syndrome - symptoms and treatment

Patients with Klinefelter syndrome initially turn to specialists such as pediatricians, endocrinologists, and urologists with complaints of delayed sexual development, obesity, enlarged mammary glands, small testicles and penis, undescended testicles into the scrotum [5].

An assessment of puberty using the Tanner scale [6]. At the same time, hair growth, the size of the penis, testicles, and the color of the scrotum are assessed. In patients with Klinefelter's syndrome, developmental delays and developmental arrest in the initial stages will be detected, which is manifested by a reduced size of the penis, testicles, scanty hair growth, and weak pigmentation of the scrotum.

When examining hormonal status, an increase in follicle-stimulating and luteinizing hormone is noted, with a sharp decrease in testosterone. There is also an increase in estradiol (one of the female sex hormones), which is caused by excess deposition of adipose tissue [6]. Sex hormone binding globulin increases, which leads to an even greater decrease in testosterone [5].

The main and most accurate method for confirming Klinefelter syndrome is karyotyping . In this case, the number of chromosomes in cells is counted, their structure is determined, which makes it possible to identify various chromosomal abnormalities. With this diagnostic method, it is also possible to determine mosaic forms of the disease. Sometimes a blood test reveals a normal chromosome set, but in the presence of characteristic clinical manifestations, a chromosomal analysis of cells obtained from testicular tissue biopsy and other cell cultures is indicated to exclude tissue mosaicism.

It is possible to determine sex chromatin (the substance of chromosomes) in the buccal (cheek) epithelium of patients, which allows you to quickly determine the presence of an excess X chromosome. This method is used for rapid diagnosis of Klinefelter syndrome. With this disease, sex chromatin will be detected in epithelial cells. For the study, the epithelium from the inner surface of the cheek is scraped, stained with a special method and examined under a microscope. The result can be obtained in just a few minutes.

Other diagnostic methods are auxiliary.

When conducting an ultrasound examination of the scrotal organs, the small size and compaction of testicular tissue are determined, sometimes the absence of testicles in the scrotum, and their visualization in the inguinal canal. Ultrasound examination of the mammary glands reveals the proliferation of breast tissue, which indicates true gynecomastia [6].

X-ray examination reveals a decrease in bone tissue density and a lag in bone age from the calendar age. Using this study, it is possible to determine various deformations of bones and joints.

When examined by a neurologist, mental retardation and autism spectrum disorders are noted.

Such patients are often observed by immunologists and rheumatologists due to the increased risk of autoimmune diseases [4].

When analyzing carbohydrate metabolism, impaired glucose tolerance and diabetes mellitus are detected. Hypofunction of the thyroid gland is common, which can be detected by an increase in the content of thyroid-stimulating hormone in the blood.

Establishing a diagnosis before the birth of a child is possible using a non-invasive prenatal genetic test that determines the number of sex chromosomes. This test is based on the analysis of fetal DNA found in the mother's blood./> As an invasive diagnostic method, ultrasound-guided chorionic villus biopsy is recommended.

When carrying out hormone replacement therapy with testosterone preparations, regular monitoring of the patient is necessary: ​​densitometry (bone density testing), general, biochemical, hormonal blood tests, including a study of testosterone and luteinizing hormone levels. Such studies should be carried out at least once a year [4].

It is necessary to differentiate Klinefelter syndrome from other diseases and conditions in which testosterone production is reduced. Such diseases include:

• orchitis (testicular inflammation);
• acquired anorchia (absence of testicles);
• undescended and dystopic testicles;
• testicular injuries;
• Noonan syndrome is a genetic defect that causes certain physical abnormalities, including short stature, heart defects, and abnormal appearance.
• Prader-Willi syndrome is a genetic disease characterized by the loss of the paternal chromosome 15 [4].

Diagnostic features

A violation of the number of sex chromosomes as part of Klinefelter syndrome does not lead to miscarriage or stillbirth, that is, the anomaly is not fatal. In this case, the disease begins to manifest itself relatively late, only after the onset of puberty, when there is a lag in the time of manifestation and severity of secondary sexual characteristics.

However, certain features of a boy’s development, the so-called “minor signs,” may alert a specialist to the risk of Klinefelter syndrome and direct them to carry out the necessary list of clarifying examinations.

These signs are considered to be a combination of the following signs:

• Excessive leg length;
• High waist;
• Tall – on average 7-10 cm taller than peers;
• Peak child growth between 5 and 8 years of age
• By puberty - taller than peers, more than half of which is due to the length of the legs;
• Some subtle difficulties in studying and expressing your thoughts;
• A decrease in the overall IQ level, with each extra chromosome in the karyotype reducing the IQ value by 14-17 points from the average population values;
• Alienation, shyness, shyness.

With the onset of puberty and after its completion, the following are added to the above-described manifestations:

• Enlarged mammary glands – bilateral gynecomastia;
• Small, dense testicles;
• Sexual dysfunction – infertility, erectile dysfunction;
• Small penis size, low libido;
• Female-type pubic hair growth;
• Almost complete absence of body hair, insufficient development of facial hair;
• Osteoporosis combined with muscle weakness;
• Obesity;
• Autoimmune lesions of various organs and systems.

In situations with mosaic Klinefelter syndrome - a combination of cells with karyotypes (44XY/44XXY) - all the above-described manifestations become even less pronounced and are often not clinically detected at all, and the pathology is revealed only during genetic studies.

Based on the above, until a certain time - the beginning of puberty, no obvious signs of the disease can be established, and those that exist are not expressed and may be a simple variant of individual development. In any case, only an attentive specialist, having suspected this pathology, can prescribe the necessary clarifying examinations.

Our doctors

In the best private clinic in Israel, Elite Medical, leading world-renowned specialists treat Klinefelter syndrome.

• Dr. Shai Shefi is a leading andrologist, specialist in male infertility and sexual dysfunction, microsurgery, member of the American Associations of Andrology and Urology, etc.
• Prof. Naomi Vayntrub – director Division of Endocrinology and Metabolic Disorders in Children, leading specialist in general and pediatric endocrinology, author of over 60 scientific papers, member of the Israeli Association of Pediatric Endocrinology, American and International Societies of Sexual Differentiation, etc.

Etiology and causes of the disorder

Klinefelter syndrome is a genetic disease that is not inherited because patients, with rare exceptions, are infertile. Pathology, as a rule, occurs as a result of a violation of chromosome divergence in the early stages of the formation of eggs and sperm. At the same time, Klinefelter syndrome, which occurs due to a disorder in female reproductive cells, occurs three times more often. Mosaic forms are caused by pathology of cell division in the early stages of embryogenesis, therefore some of the cells in such patients have a normal karyotype. The reasons for nondisjunction of sex chromosomes and disruption of cell division at the earliest stages of embryogenesis are still poorly understood. Unlike other chromosomal diseases, the effect of parental age is absent or only slightly expressed.

Secretory, but secret - Klinefelter's syndrome and pregnancy

One of the groups of male infertility is called secretory, since it depends on a decrease in the production of male sex hormones. What spermogram indicators are characteristic of secretory infertility?

One of the groups of male infertility is called secretory, since it depends on a decrease in the production of male sex hormones. Hypogonadism is a decrease in the secretion of testosterone, due to which the formation and maturation of sperm is reduced or completely stopped.

With PRIMARY hypergonadotropic hypogonadism, the structure of the gonads themselves (i.e., the testes) is disrupted, and therefore both the production of hormones and the production of sperm are disrupted. This pathology is characterized by a decrease in sperm concentration, an increase in the number of immobile, dead, pathologically altered sperm, as well as a decrease in the concentration of fructose and citric acid. In the conclusion on sperm analysis, this is reflected in the terms: (oligozoospermia 1-2-3 degrees), necrozoospermia, teratozoospermia.

If hypogonadism is pronounced, then signs of a reduced concentration of male hormones are noticeable: female body type, poor hair growth, scrotal hypotension, weakened prostate tone, muscle weakness, asthenic type of nervous response, decreased libido. Congenital hypogonadism is associated with serious diseases - Klinefelter syndrome, hermaphroditism, bilateral cryptorchidism. Klinefelter syndrome and pregnancy are a very pressing problem today.

But acquired hypergonadotropic hypogonadism is a consequence of serious illnesses with prolonged high fever or poisoning - from alcoholism to inhalation of nitro dyes at work. In addition, some men are diagnosed with hypogonadism caused by diabetes mellitus, thyrotoxicosis, and Itsenko-Cushing's disease.

Finally, secretory infertility can occur with varicose veins of the spermatic cord, i.e. with varicocele. Deterioration of sperm parameters occurs due to the combined influence of various factors: increased testicular temperature, hypoxia of its tissues (oxygen starvation), hormonal disorders, autoimmune processes, disruption of the blood-testicular barrier. Because of this, sperm motility and motility are reduced in the ejaculate, and there are many pathological and dead sperm.

When examining men suffering from secretory infertility, the doctor, as a rule, notes decreased tone of the scrotum, soft or reduced testicles, decreased tone of the prostate, and in severe cases - a sickle symptom, i.e. a kind of reduction in the prostate gland.

Treatment of secretory infertility, as a rule, is a very complex task: it is necessary to equalize hormonal levels, restore atrophied testicular tissue, and create conditions for long-term rehabilitation processes, as a result of which it will become clear whether the efforts were effective. Unfortunately, in many cases, men seek help when the disease has progressed so far that there are no longer any tissues left that could become the basis for the production of sperm. In such cases, unfortunately, there is only one way out - to resort to donor insemination.

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Modern approaches to diagnosis

At the modern level of medicine, there are many options for planning a healthy pregnancy, diagnostic searches in the early and late stages of pregnancy. At the same time, diagnosis before birth, and ideally at short stages of pregnancy, is a priority and preferable, as it allows to avoid the birth of a child with chromosomal developmental abnormalities. The main stages of this process are as follows:

• Genetic counseling and healthy pregnancy planning. At the same time, it is possible, having identified the main risks, to plan a normal pregnancy with a significant degree of probability. The negative point is that the percentage of guaranteed success is not high enough.

• Traditional screening of the first trimester, combining the study of serum hormonal markers and ultrasound. Already at a short stage of pregnancy, it allows to identify some abnormalities in the number of chromosomes to a certain extent. Its leading disadvantage is the significant probability of error due to low reliability.

• Non-invasive prenatal testing - the Prenetix test - includes the collection of venous blood from the expectant mother and the study of fetal biomaterial, the DNA of which is present in the mother’s blood from the 10th week of pregnancy. Allows you to identify the main chromosomal abnormalities of the fetus in the early stages of pregnancy, including Klinefelter syndrome, among other diseases. Moreover, its use is possible during pregnancy resulting from IVF, surrogacy, as well as donation of reproductive material. In addition, accurate, reliable data is obtained in the case of a twin pregnancy - in case of twins.

• An invasive diagnostic study involves direct sampling of fetal biomaterial (chorionic villus biopsy, amniocentesis, cordocentesis) and its genetic analysis.

The non-invasive prenatal test Prenetix significantly complements the results of traditional screening, increasing its informativeness, including in identifying anomalies associated with a violation of the number of chromosomes, for example, Klinefelter syndrome.