Klinefelter syndrome

The signs and symptoms of Klinefelter syndrome (KS) are not consistent and vary from individual to individual.

In Children

• Small testis
• Longer legs
• Tall stature
• Increased fat/lean mass proportion
• Delay in learning to talk
• Difficulty using language to express thoughts and needs
• Difficulty in processing auditory information
• Reading difficulties (poor reading comprehension or slower reading)

In Adolescents

• Reduced testicular growth
• Longer legs
• Tall stature
• Broader hips
• Impaired erectile function
• Impaired sexual desire
• Decrease in muscle mass
• Loss of bone mass (osteoporosis)
• Behavioral, social, and psychosocial difficulties
• Mood disturbances

In Adults

• Oligospermia (low sperm count)
• Azoospermia (absence of sperm in semen)
• Infertility
• Decreased facial hair
• Decreased pubic hair
• Decreased beard growth
• Abdominal obesity
• Longer legs
• Tall stature
• Broader hips

Find out 8 common causes of low sperm count or oligospermia! Read Now

Klinefelter syndrome is a genetic disorder that occurs due to an abnormal number of chromosomes. Chromosomes are thread-like structures composed of protein and DNA, carrying genetic information from cell to cell. Each cell normally contains 46 chromosomes (23 pairs). Males have one X and one Y chromosome, while females have two X chromosomes.

In 80-90% of cases, KS men have 47 chromosomes with an extra X chromosome, denoted as 47,XXY. However, some individuals with KS may have two extra chromosomes, denoted as 48,XXXY or 48,XXYY. In rare cases, a structurally abnormal X chromosome can also be a cause of KS.

The extra X chromosome results from the non-separation of sex chromosomes during cell division. This can occur during the multiplication of eggs or sperm and, less frequently (in <3% of cases), during the early division of the fertilized egg.

Did you know?

• The effects on physical and mental development increase with the number of extra X chromosomes.
• Each extra X is associated with a decrease in IQ by approximately 15-16 points.
• It primarily affects language processing in children, particularly expressive skills.

Klinefelter syndrome is a genetic disorder. There are no known factors that increase the risk of Klinefelter syndrome. The error that produces the extra X chromosome occurs randomly and can affect anyone.

However, studies have shown that the risk of delivering a son with Klinefelter syndrome increases with the age of the mother.

Additionally, babies conceived through artificial reproductive techniques, such as:

• ICSI (intracytoplasmic sperm injection)
• IVF (in vitro fertilization)

also have an increased chance of chromosomal anomalies.

Did you know? Klinefelter syndrome is also observed in domestic and wild animals.

Most men with Klinefelter syndrome (KS) remain undiagnosed or are diagnosed very late. Poor awareness and the absence of specific signs in all patients lead to delays in diagnosis. The diagnosis of chromosomal abnormalities in newborns with altered testicles is the best way to increase the diagnostic rate. The various diagnostic approaches used to predict KS are:

• Hormonal assays: Individuals with KS exhibit fluctuations in the concentration of several hormones. While hormonal assays do not confirm the disease, they help guide the treatment plan. Recommended hormonal assays in KS include follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and gonadotropins.
• Karyotyping (chromosome analysis): This is the gold standard and the only definitive method to confirm KS. In this process, chromosomes are examined under a microscope using a blood sample. A karyotype test yields consistent results throughout a person's life.
• Testicular biopsy (TESE): This procedure involves removing a piece of tissue from the testicles for examination. Individuals with KS have altered structure and function of the testes. The procedure is expensive and invasive, and is only recommended for patients with negative chromosomal karyotyping who exhibit related symptoms.
• Prenatal testing: Klinefelter syndrome can be diagnosed before the birth of the baby. These tests are typically performed between the 11th and 14th weeks of pregnancy and include:
  • Amniocentesis: Examination of amniotic fluid, which surrounds the baby during pregnancy.
  • Chorionic villus sampling: Removal and testing of a small sample of cells from the placenta, the organ that connects the mother's blood supply with the growing baby.
  • Cell-free DNA testing: Analysis of chromosomal abnormalities through the mother's blood, which contains some DNA from the unborn baby.

These prenatal tests carry a small risk of miscarriage; therefore, they are not recommended for routine use. Prenatal testing for chromosomal abnormalities is performed in the following cases:

• If the woman is 35 years of age or older.
• If the woman has had another baby with a chromosomal abnormality.
• If the fetal ultrasound appears abnormal.
• If other prenatal tests show abnormal results.

To ensure a healthy pregnancy, it is imperative to have regular health check-ups. Book pregnancy tests to detect health problems in the growing fetus.

Testing of associated symptoms:

• Routine bone density screening: Recommended for all confirmed KS individuals, as androgen deficiency increases the risk of osteoporosis.
• Hypercoagulability screening: Hypercoagulability refers to an increased tendency of the blood to form clots, which can lead to conditions such as deep vein thrombosis and pulmonary embolism. Screening for hypercoagulability is recommended for KS individuals due to their increased risk for these disorders.

Klinefelter syndrome cannot be prevented as it is a genetic condition. The changes in the chromosomes occur before birth.

However, the risk can be reduced by:

• Conceiving early, as the chances of delivering a Klinefelter syndrome baby increase if the mother is above 35 years of age.

The early identification plays a very important role in the management of Klinefelter syndrome. Various treatment modalities for the management of symptoms include:

• Testosterone Replacement Therapy: This therapy improves the hormonal status of KS patients through the administration of testosterone. The two forms that are widely used include testosterone enanthate and testosterone cypionate, which are injected intramuscularly. The dose of testosterone depends upon the age of the patient. Once initiated, the therapy should continue throughout the life of the patients.
• Speech Therapy: This is used in children to develop skills that aid in comprehension and learning. It involves several treatment sessions either one-on-one or in a group. The treatment approach includes:
  • Exercises to differentiate and produce sounds
  • Exercises to improve fluency of speech
  • Exercises to improve breathing and swallowing
  • Sessions to improve communication using sign language, communication boards, and computer-assisted speech
• Physical Therapy (Physiotherapy): It is recommended for boys who have reduced muscle mass and delayed motor skills. This therapy helps in improving muscle tone, balance, and coordination. It includes guided movements and massages by the therapist on the patient’s body. The treatment also involves stimuli such as heat, cold, and electrical currents.
• Occupational Therapy: This therapy is recommended for boys who have trouble coordinating normal physical movements such as walking up or down stairs, kicking balls, or jumping. It also helps infants who have difficulty in feeding from a bottle or latching.
• Treatment for Infertility: KS is the most common cause of infertility in males. However, assisted reproductive technologies (ART) have enabled over 50% of men with Klinefelter syndrome to have their own children.
  • Testicular Sperm Extraction - Intracytoplasmic Sperm Injection (TESE-ICSI): This involves extracting viable sperm from a small portion of testicular tissue. The sperm is then injected into the egg through a technique called intracytoplasmic sperm injection (ICSI).
• Surgery: The enlarged breast puts a psychological strain on the patient and increases the chances of breast cancer. Surgical removal of the breasts (mastectomy) is indicated in such patients.

Klinefelter syndrome increases the risk of several health conditions:

• Autoimmune disorders: These disorders occur when the immune system attacks healthy cells in one’s own organs and tissues. The decreased testosterone in individuals with Klinefelter syndrome (KS) increases the chances of autoimmune disorders such as:
  • Systemic lupus erythematosus
  • Rheumatoid arthritis
  • Sjogren syndrome
• Osteoporosis: Testosterone prevents bone breakdown. A significant reduction in testosterone increases the risk of bone-related disorders such as osteoporosis in KS.
• Endocrine disorders: Individuals with KS have an increased risk of developing diabetes over time. The risk of hypothyroidism and hypoparathyroidism also increases in KS.
• Venous diseases: KS predisposes patients to several venous diseases such as varicose veins, venous ulcers, and pulmonary embolism.
• Taurodontism: This condition refers to changes in tooth shape characterized by reduced root size and an enlarged body of the tooth. KS individuals have a higher chance of developing this disorder.
• Intellectual and psychiatric disorders:
  • Children with Klinefelter syndrome exhibit neurocognitive abnormalities such as low IQ, difficulties in speech and learning, and language issues.
  • Such children are at an increased risk of developing dyslexia (a learning disorder that involves difficulty in reading) and attention-deficit disorder.
  • Symptoms such as feminine physical features, poor motor coordination, and difficulties in speech and memory can impact the self-esteem of the individual.
  • Disfigurement and infertility can also lead to several psychiatric disorders such as anxiety and depression.
• Breast cancer: Individuals with KS have 20 times the likelihood of developing breast cancer compared to normal men. Studies suggest that this risk is higher in men with gynecomastia.
• Extragonadal germ cell tumors: These tumors form in parts of the body other than the gonads (testicles or ovaries). KS increases the risk of developing these tumors, especially in the mediastinum (the space in the chest that holds the heart).

KS impacts males psychologically due to differences in physical features. They often have concerns about sexuality, masculinity, and fertility following a diagnosis. Here are a few steps that can help in living with this condition:

• Be informed: Many individuals lack knowledge regarding KS. Parents of KS individuals should seek professional support to care for their children.
• Ensure periodic screening: Individuals with KS should regularly undergo screenings for associated complications such as osteoporosis, diabetes, breast cancer, anxiety, or depression.
• Go for fertility preservation: Sperm retrieval at prepubertal and adolescent ages proves to be more successful. The preservation of sperm at a younger age also avoids more invasive surgical procedures in the future.
• Get psychological support: Men diagnosed with KS may experience psychological conditions that significantly impact their overall quality of life. Concerns vary by age; adolescents and young adults may struggle with body image, while couples may face the heartbreak of infertility. It is important to seek psychological support from experts to maintain a healthy state of mind.