Klinefelter's syndrome: what is it, signs, treatment, prognosis

What is Klinefelter Syndrome?

Klinefelter's syndrome (SK) is a disease that occurs in men when they have an extra X chromosome. Some men with the disorder have no overt signs or symptoms, while others may have varying degrees of cognitive, social, behavioral, and cognitive impairment. Adults with Klinefelter syndrome may also have primary hypogonadism (decreased testosterone production), small and / or undescended testes (cryptorchidism), enlarged breasts (gynecomastia), high growth and / or inability to have children (infertility), as well as an abnormal opening of the penis (hypospadias) and small penis (micropenis). Klinefelter syndrome is not an inherited disorder, but usually occurs as an accidental event during formation reproductive cells (eggs and sperm), which leads to the presence in each cell of one additional copy of the X chromosome (47, XXY). Treatment for the condition is based on the signs and symptoms present in each patient. Life expectancy is generally normal, and many people with the disease have normal lives. There is very little risk of developing 

breast cancer and other conditions, such as a chronic inflammatory condition called systemic lupus erythematosus.

In some cases, each cell has more than one X chromosome (for example, 48, XXXY or 49, XXXXY). These conditions, often referred to as “variants of Klinefelter's syndrome,” are usually associated with more severe problems (mental retardation, skeletal problems and impaired coordination) than classic Klinefelter syndrome (47, XXY).

Signs and symptoms

The main signs are infertility and small, poorly functioning testes (testes). Symptoms are often subtle and many sufferers are unaware of the syndrome. Sometimes the symptoms are more severe (see. Photo) and may include decreased muscle tone, greater height, poor coordination, less body hair, breast growth, and less interest in sex. Often these symptoms are only noticed during puberty.

It has been estimated that 60% of infants with Klinefelter syndrome end in miscarriage.

The presence or absence of visible symptoms in a man with Klinefelter syndrome depends on many factors, including how much testosterone is produced by his body, whether it is mosaic (with cells XY and XXY) and his age when this condition is diagnosed and is being treated. Some people have a slightly increased risk of developing breast cancer, a rare extragonadal germ cell tumor, lung diseases, varicose veins and osteoporosisas well as some autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and Sjogren's syndrome.

Some patients with Klinefelter syndrome have more than one extra X chromosome in each cell (for example, 48, XXXY or 49, XXXXY). In these cases, known as “variants of Klinefelter's syndrome,” the signs and symptoms can be more severe and may include:

• intellectual disability;
• distinctive facial features;
• skeletal abnormalities;
• poor coordination;
• severe speech problems;
• behavioral problems;
• heart defects;
• dental problems.

Causes and risk factors

Klinefelter's syndrome is not inherited. Males have one extra X chromosome due to a nondisjunction error that occurs randomly during the division of sex chromosomes in an egg or sperm.

The most common karyotype of Klinefelter's syndrome is 47, XXY (more than 90%). Mosaic karyotypes such as 46, XY / 47, XXY, and other aneuploidies such as 48, XXXY and 49, XXXXY have been described. The acquisition of an additional X chromosome is accidental and is usually associated with meiotic nondisjunction or postzygotic nondisjunction. The overall severity of the phenotype appears to be correlated with the amount of additional X chromosome material present.

Epidemiology

Klinefelter's syndrome is the most common form of aneuploidy that occurs when a person has an abnormal number of chromosomes in a cell. The estimated prevalence of the disease is between 1: 500 and 1: 1000 in men. The 47 karyotype is not always recognized until adulthood and can be diagnosed later. However, the recognition and diagnosis of a disorder usually occurs after one or more of the items listed below become the subject of clinical attention.

• By prenatal diagnosis or due to genital abnormalities observed at birth in a child with hypotension.
• A teenager with learning or behavioral difficulties.
• In a teenager who is assessed to be tall, small testicles, or incomplete puberty.
• In adult men screened for infertility (3% of all men screened for infertility have the syndrome).

However, up to two-thirds of cases of Klinefelter's syndrome (KS) may go undetected. Comparative studies show that the disease can be more common in conditions of increasing age of parents, mistakes, related to the environment, in meiosis I or a decrease in selective abortion in cases diagnosed prenatally. Underdiagnosis is also likely due to a variable phenotype, with only minor signs found in many cases. It is estimated that about a quarter of people with the disorder do not show diagnostic signs by history or examination. With increasing use of non-invasive prenatal testing (NIPT), the frequency of prenatal diagnosis is expected to be will increase, allowing health professionals caring for children to diagnose early stages.

Pathophysiology

The molecular mechanisms underlying primary testicular failure and the phenotypic heterogeneity of physical and neurocognitive characteristics in SC are poorly understood. Research is ongoing to determine the effects of genetic polymorphism, distorted X inactivation, parental origin of the extra X chromosome, and gene dosage.

The extra X chromosome material is responsible for testicular hyalinization and fibrosis leading to primary gonadal insufficiency, which often develops during adolescence and adolescence. If there is early dysfunction, the affected newborn will develop microfallos, hypospadias, cryptorchidism, and unusually small testicles. Later, developing hypogonadism leads to incomplete puberty and gynecomastia. Prolonged hypogonadism and infertility are typical.

Additional gene dose SHOX in the pseudo-autosomal region of the X chromosome leads to high growth, long limbs and a decrease in the ratio of the upper and lower segments.

The pathophysiology of neuropsychological differences seen in KS is poorly understood.

Close Disorders

Kalman syndrome (Callman) is a rare hereditary disorder that primarily, but not exclusively, affects men. The main characteristics of Kallman syndrome in both men and women are lack of puberty and complete or partial loss of smell. Lack of puberty reflects hormonal imbalancecaused by the failure of a part of the brain known as the hypothalamus. Patients with Kalman syndrome show signs of small genitals, sterile gonads that cannot produce germ cells (hypogonadism), and loss of smell (anosmia). Disruption in the production of hormones, as well as sperm and eggs, causes delayed puberty, growth and infertility.

Diagnostics

The diagnosis of KS is usually based on prenatal or postnatal karyotyping and chromosomal microchip analysis. Non-invasive prenatal testing (NIPT) for extracellular DNA can detect sex chromosome abnormalities. The published positive predictive values ​​for the detection of Klinefelter syndrome with NIPT are 67%. Additional prenatal or postpartum testing is suggested to confirm any suspected case.

An initial assessment of the UK may include testing for hypogonadism or infertility. In KS, gonadotropins are usually elevated in the presence of testicular hyalinization and fibrosis, although this can develop during adolescence. Detection of hypergonadotropic hypogonadism indicates primary gonadal insufficiency. Level up follicle-stimulating hormone (FSH) usually predominates over luteinizing hormone (LH) levels, although both are above normal. Testosterone concentrations are usually low or below normal in both adolescents and adults. A minority of children may have low inhibin B levels and elevated anti-Müllerian hormone (AMH) levels, which indicates a dysfunction of Sertoli cells, but it is unclear whether the identification of these differences is a predictor of future gonadal failure.

Treatment

Earlier diagnosis of Klinefelter syndrome (often in utero) allows for earlier developmental evaluation and interventions to assist neuropsychological development. Delays in speech and motor skills are present in 50–75% of cases; therefore, proactive measures are recommended to identify and resolve these delays. Speech delays that are not resolved can limit self-expression, affect tolerance for frustration, and contribute to behavioral problems. Hypotension with hypermobility, flat feet and varus deformity may affect motor development, including handwriting and personal care; therefore physical therapy, occupational therapy and adaptive therapies such as orthopedic insoles may be required.

Supplemental testosterone treatment under the supervision of a pediatric endocrinologist may prevent some of the physical manifestations of the "classic Klinefelter syndrome phenotype." Hypogonadism in Klinefelter syndrome can begin early in the fetus and plays a role in genital underdevelopment. cryptorchidism, a decrease in the number of germ cells, a small size of the testicles and a dull "mini-puberty" in infancy. Some doctors give extra testosterone during the first few months of life for treatment micropenisalthough limited retrospective data suggest possible cognitive and behavioral benefits; prospective studies are ongoing. If present cryptorchidism or inguinal hernia, the infant should be referred to a pediatric urologist.

During adolescence, most boys with KS progress to puberty normally, and endogenous testosterone usually maintains virilization with penile enlargement and development pubic hair. However, these people may not have as much facial or body hair as expected. Supplemental testosterone can help minimize gynecomastia, which often develops during adolescence. Other treatments for gynecomastia are either ineffective (aromatase inhibitors) and have limited published data with Klinefelter syndrome (tamoxifen), or are invasive (surgery) and are at risk relapse. To gain proper knowledge of these issues, build rapport and outline plans for the future observation and treatment, the boy's parents should consult a pediatric endocrinologist during sexual intercourse ripening. The age at which to start androgen replacement therapy is not standard and should be individualized. It may start during the onset of puberty or delayed until puberty appears. clear evidence of hypogonadism, which can be late adolescence or early adulthood age. Recommendations for hormone replacement therapy for men with hypogonadism can be obtained from endocrinologists.

Advanced reproductive technologies such as microsurgical epididymal sperm aspiration (micro-TESE) proved to be successful and allowed nearly half of men with KS that were deemed "infertile" to have biological child. Small pockets of sperm-producing gonadal tissue can be identified, removed and then injected by intracytoplasmic sperm injection into the egg for fertilization.

In the long term, men with Klinefelter syndrome are more likely to develop disorders associated with insulin resistance, such as type 2 diabetes, dyslipidemia and fatty hepatosis (non-alcoholic fatty liver disease), as well as peripheral vascular disease and thromboembolic disease. A thorough examination and aggressive preventive measures are recommended. Bone mineral density can also be compromised, which is likely associated with hypogonadism, so it is important to pay attention to bone health. Several studies have documented a higher incidence of autoimmune diseases. Finally, the risk of some malignant neoplasms is increased. These include breast cancer, extragonadal germ cell tumors, and non-Hodgkin lymphoma. Although the overall incidence is still very low and routine screening is not required, suspicious symptoms should be investigated.

Forecast

Infants with the Klinefelter 47, XXY form differ little from healthy children. Results from one study of non-mosaic XXY children under 2 years of age showed that most XXY children had normal external genitals and facial features with height and weight within norms.

Boys with a 47, XXY karyotype may experience learning difficulties, various frustrations and, in some cases, severe emotional or behavioral difficulties during adolescence. However, most of them, entering adulthood, strive for complete independence from their families. Some have graduated from higher education and have a normal standard of living. Klinefelter's syndrome does not affect life expectancy.