Klinefelter syndrome: a man with a female chromosome

Klinefelter syndrome is a genetic disease characterized by an additional female sex chromosome X (one or even several) in the male karyotype XY . At the same time, insufficient sex hormones are produced in the male gonads - the testicles.

As you know, the human genetic set has 46 chromosomes, of which 22 pairs are called somatic, and the 23rd pair is called sexual.
Women have a pair of sex chromosomes XX , and men have XY . Klinefelter syndrome requires the presence of a male Y chromosome, so despite the additional X chromosomes, patients are always male.

Classification: types of karyotypes in Klinefelter syndrome

Based on the number of additional X chromosomes, the following variants of Klinefelter syndrome are distinguished:

• 47,XXY - the most common
• 48,ХХХY
• 49,XXXXY

In addition, Klinefelter syndrome also includes male karyotypes that include, in addition to additional X chromosomes, an additional Y chromosome - 48,XXYY . And finally, among patients with this syndrome there are individuals with a mosaic karyotype 46,XY / 47,XXY (that is, some of the cells have a normal chromosome set).

History of the discovery of the syndrome

The syndrome got its name in honor of Harry Klinefelter, a doctor who first described the clinical picture of the disease in 1942. Klinefelter and colleagues published a study of 9 men with common symptoms such as low body hair, eunuchoid body type, tall stature, and small testicles. Later, in 1956, geneticists Plunkett and Barr (E.R. Plunkett, M.L. Barr) discovered sex chromatin bodies in the nuclei of cells of the oral mucosa in men with Klinefelter syndrome, and in 1959 Polanyi and Ford (P.E. Polanyi, SE Ford) and colleagues showed that patients have an extra X chromosome in their chromosome set.

Active research into this pathology was conducted in the 70s in the USA. Then all newborn boys were subjected to karyotyping, as a result of which it was possible to reliably identify the prevalence and genetic characteristics of Klinefelter syndrome.

Interestingly, mice can also have XXY sex chromosome trisomy, making them useful models for studying Klinefelter syndrome.

Diagnostic measures

Prenatal diagnosis

Invasive prenatal diagnosis and subsequent karyotyping allow the correct diagnosis to be made.

There are two methods by which you can obtain material for research:

• A chorionic villus biopsy is performed from 9.5 to 12 weeks of pregnancy.
• Amniocentesis - from 16 to 18 weeks.

Each of these methods can detect chromosomal abnormalities with up to 99% accuracy.

During diagnostic surgery, fetal tissue is obtained from which the DNA of the unborn child is extracted. In the laboratory, genetic material is examined for the presence of chromosomal pathologies.

1. During a biopsy, specialists pierce the anterior abdominal wall of a pregnant woman with a puncture needle and remove chorionic villi from the placenta. The procedure is controlled by an ultrasound machine.
2. Amniocentesis is the collection of amniotic fluid containing genetic information. A special needle is inserted into the uterine cavity under the control of an ultrasound machine sensor and amniotic fluid is collected.

Postnatal diagnosis

Diagnosis of genetic diseases in the postnatal period is carried out by endocrinologists, andrologists and geneticists.

Specialists begin their work by collecting complaints, life history and illness. They find out: the time of onset of symptoms, their changes, cases of genetic diseases in the family and in the next generation. Then they move on to a visual inspection, palpation, percussion and auscultation if necessary. The meager clinical picture of Klinefelter syndrome does not always allow timely diagnosis of the pathology and initiation of hormone replacement therapy. The diagnostic sign of the disease are Barr bodies, which are found in the cells of the oral mucosa.

Karyotype examination allows a definitive diagnosis to be made. Karyotyping is performed on all infertile men with gynecomastia and boys with mental retardation.

Additional diagnostic methods:

• Ultrasound examination of the scrotum allows you to determine the size and structure of the testicles.
• Ultrasound examination of the heart is performed to detect congenital defects.
• Densitometry is a method for detecting osteoporosis.
• Determination of sex hormones in the blood - testosterone, FSH and LH.
• Spermogram is an analysis of ejaculate carried out to determine a man’s fertility, the presence of sexual diseases, the number and activity of sperm. Individuals with Klinefelter syndrome experience a decrease in the number or complete absence of sperm in the ejaculate.
• Testicular biopsy reveals the state of spermatogenesis and has great diagnostic value.

Prevalence of the disease

Klinefelter syndrome is one of the most common genetic diseases: for every 500 newborn boys, there is 1 child with this pathology.

In addition, Klinefelter syndrome is the third most common endocrine pathology in men (after diabetes mellitus and thyroid pathology) and the most common cause of congenital reproductive dysfunction in men.

To date, about half of cases of Klinefelter syndrome remain unrecognized. Often such patients seek help for infertility, erectile dysfunction, gynecomastia, osteoporosis, anemia, etc. without a previously established diagnosis.

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.

Forecast

If the manifestations of Klinefelter syndrome are mild, there are no changes in the intellectual sphere, and there are no serious consequences, then the prognosis is favorable. With timely treatment and correction of possible complications, patients can live a full life.

If Klinefelter's symptoms are more pronounced and there are mental disorders and serious chronic conditions, then the prognosis noticeably worsens. In such patients, treatment should be comprehensive, including not only medication, but psychocorrection and rehabilitation.

Severe concomitant diseases of internal organs lead to early mortality and disability.

Lack of testosterone leads to spontaneous fractures and acute heart problems, such as myocardial infarction.

Early signs

Unlike most diseases associated with a violation of the number of chromosomes, the intrauterine development of children with Klinefelter syndrome proceeds normally, and there is no tendency to premature termination of pregnancy. So in infancy and early childhood it is almost impossible to suspect pathology. Moreover, clinical signs of classic Klinefelter syndrome usually appear only in adolescence. However, there are symptoms that suggest the presence of Klinefelter syndrome in the prepubertal period:

• high growth (peak height increase occurs between 5–8 years);
• long legs (disproportionate physique);
• high waist.

Some patients experience some delay in speech development.

In adolescence, the syndrome often manifests itself as gynecomastia, which with this pathology has the appearance of bilateral symmetrical painless enlargement of the mammary glands. Since this type of gynecomastia is often observed in completely healthy adolescents, this symptom often goes unnoticed. Normally, teenage gynecomastia disappears without a trace within several years, but in patients with Klinefelter syndrome, reverse involution of the mammary glands does not occur. In some cases, gynecomastia may not develop at all, and then the pathology manifests itself as signs of androgen deficiency already in the postpubertal period.

Prevention

There is no specific prevention for Klinefelter syndrome. There are only a few activities that reduce the risk of developing the disease.

Preventive actions:

• planning pregnancy before age 30;
• quitting smoking and alcohol during pregnancy;
• regular screening tests during pregnancy;
• genetic consultation for women aged 35 to 40 years.

If Klinefelter syndrome is detected during screening, the doctor may suggest termination of the pregnancy. But in this case, the decision remains with the woman.

Symptoms of androgen deficiency in Klinefelter syndrome

Androgen deficiency in Klinefelter syndrome is associated with gradual testicular atrophy, which leads to decreased testosterone synthesis. The degree of androgen deficiency varies dramatically.

First of all, the external signs of hypogonadism attract attention:

• scanty facial hair or its complete absence;
• female-pattern pubic hair growth;
• there is no hair on the chest or other parts of the body;
• small volume of the testicles (2–4 ml) and their dense consistency (pathognomonic sign).

Since degeneration of the gonads, as a rule, develops in the postpubertal period, in most patients the size of the male genital organs, with the exception of the testicles, corresponds to age norms.

Patients may complain of weakened libido and decreased potency. Many men with Klinefelter syndrome do not experience sexual desire at all, while some, on the contrary, start a family and live a normal sex life. The most constant sign of pathology is infertility; it is this that most often becomes the reason for such patients to consult a doctor. 10% of men with azoospemia have Klinefelter syndrome.

All patients with spermatogenesis disorders must have their karyotype determined to exclude or confirm the diagnosis of Klinefelter syndrome.

Androgen deficiency leads to the development of osteoporosis, anemia and skeletal muscle weakness. In a third of patients, varicose veins of the legs can be observed.

Androgens affect metabolism, so patients with Klinefelter syndrome are prone to obesity, impaired glucose tolerance and type 2 diabetes.

The predisposition of such patients to autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroid diseases and others) has been proven.

Psychological characteristics

The IQ of patients with classic Klinefelter syndrome varies from below average to well above average. However, in all cases there is a disproportion between the general level of intelligence and verbal abilities, so that patients with a fairly high IQ often experience difficulties in perceiving large volumes of material by ear, as well as in constructing phrases containing complex grammatical structures. Such features cause patients a lot of trouble during the training period and often continue to affect their professional activities.

Data on the psychological characteristics of patients with Klinefelter syndrome are quite contradictory, but most experts assess patients as modest, timid people with somewhat low self-esteem and increased sensitivity. There is evidence that patients with Klinefelter syndrome are prone to homosexuality, alcoholism and drug addiction. It is difficult to say whether the mental characteristics of such patients are caused by the direct influence of a chromosomal abnormality, or whether it is a reaction to problems in the sexual sphere.

With regard to different cytogenetic variants of Klinefelter syndrome, the rule is true that with an increase in the number of additional X chromosomes, the number and severity of pathological symptoms increases.

Classification

Normally, a human karyotype contains 46 chromosomes. It distinguishes between the sex chromosomes X - chromosome (female) and Y - chromosome (male).

In healthy men, the karyotype has both chromosomes. In Klinefelter syndrome, the karyotype contains additional female sex chromosomes.

Extra female sex chromosomes have a great impact on the condition of the body with Klinefelter syndrome. The mutation suppresses testosterone levels, reducing its concentration, leading to pathologies of the reproductive system.

Chromosome combinations vary in patients with Klinefelter syndrome. The karyotype can be of several types:

• 47 XXY;
• 48 XXYY;
• 48 XXXY;
• 49 XXXYY;
• 49 XXXXYY;
• 47 XXY (mosaicism).

Diagnosis of Klinefelter syndrome

In many countries, Klinefelter syndrome is often diagnosed before the birth of a child, since many women of late childbearing age, due to the high risk of genetic defects in future offspring, use prenatal genetic diagnosis of the fetus. Often, prenatal detection of Klinefelter syndrome is a reason for termination of pregnancy, including on the recommendation of doctors. In Russia, analysis of the karyotype of an unborn child is extremely rare.

If Klinefelter syndrome is suspected, a laboratory blood test is performed to determine the level of male sex hormones. Differential diagnosis with other diseases that occur with manifestations of androgen deficiency is necessary. An accurate diagnosis of Klinefelter syndrome is made based on studying the karyotype (set of chromosomes) of the patient.

Tests needed to confirm the diagnosis

In all men with sharply increased concentrations of gonadotropins, it is necessary to exclude Klinefelter syndrome, since often the first laboratory sign of this genetic pathology is an increase in the concentration of gonadotropins in the blood with normal levels of total testosterone.
Klinefelter syndrome must be differentiated from other forms of primary hypogonadism. In any case, if the level of FSH in the blood increases, it is necessary to determine the karyotype to exclude, first of all, Klinefelter syndrome.

Treatment

Treatment goals for Klinefelter syndrome:

• Restoring normal testosterone levels
• Restoration of sexual function
• Elimination of metabolic disorders

In case of clinically pronounced pathology, lifelong replacement therapy with testosterone preparations is necessary. Adequate therapy allows not only to improve the appearance and general well-being of the patient, but also to restore the ability to have a normal sexual life. In addition, replacement therapy prevents the development of osteoporosis and relieves muscle weakness. At a young age, treatment should begin immediately after diagnosis. For Klinefelter syndrome, it is better to use long-acting testosterone drugs:

• a mixture of testosterone esters in the form of an oil solution, injections of which must be done 2-3 times a month;
• testosterone undecanoate in the form of an oil solution - a depot preparation with a slow release of the active substance - injections once every 3 months.

Hormone treatment for the presence of the X chromosome in men should be permanent. The dose of the drug is selected individually under the control of testosterone and LH levels in the blood serum.

Already developed gynecomastia in Klinefelter syndrome does not undergo involution even with adequate treatment, so it is often necessary to resort to surgical correction (mastectomy).

To prevent concomitant diseases such as obesity and type 2 diabetes, patients are advised to adhere to a diet and monitor their own weight.

Patients with Klinefelter syndrome should be monitored at least once every 6–12 months. It should include the following studies:

• complete blood count to assess hemoglobin and hematocrit levels;
• hormonal blood test, including determination of testosterone and LH (carried out against the background of drug therapy 1–2 days before the next testosterone injection);
• densitometry (all patients who had osteopenia or osteoporosis at the time of diagnosis).

The introduction of intracytoplasmic sperm injection (ICSI) and data on the possibility of the presence of germ cells in the testes in patients with Klinefelter syndrome predetermined the use of artificial insemination for this category of patients, some attempts were successful.

Dispensary observation

Clinical observation is carried out throughout life by an endocrinologist and other specialists as necessary.

In childhood, observation is carried out by a pediatrician. In the first year of life, the frequency of examinations is 1 time per month (as in healthy children). Then the number is reduced to 1 time every 3 months.

As the child grows up, an endocrinologist joins the observation. Since such children develop endocrine problems.

In adults, if there are no complaints, examinations can be carried out once a year.

In addition, additional studies are prescribed:

• clinical blood test;
• blood biochemistry;
• Ultrasound of the abdominal organs;
• Ultrasound of the penis and testicles;
• general urine analysis;
• ECG or ultrasound of the heart.

Specialist consultations are carried out. And special attention is paid to consultations with a cardiologist, urologist, reproductive specialist, and psychotherapist.