Klinefelter Syndrome Treatment Options

Owing to the wide spectrum of symptoms observed in boys or men with Klinefelter syndrome (KS), a multi-disciplinary approach is required while treating these patients. KS is a difficult-to-diagnose condition not only because the symptoms are non-specific and rarely obvious but also due to a lack of awareness of the markers of KS among physicians. However, once diagnosed, various treatment options are available depending on the symptoms to ensure these patients can lead fulfilling lives. This article provides an overview of KS, its symptoms and the treatment options that will help alleviate the symptoms.

What is KS?

Of the 46 chromosomes in humans, the sex of a baby is determined by the sex chromosomes, namely the X and Y chromosomes. A female possesses two X chromosomes (XX), whereas a male possesses an X and a Y chromosome (XY). As we know ‘excess of anything is not good’, in the same way, KS is a congenital condition in males wherein they possess an extra X chromosome (XXY). It occurs in approximately 1 in every 500–1000 male newborn babies. The presence of the extra X chromosome is owing to an error either during the sperm or egg formation. The risk of a baby being born with KS increases in women aged >35 years.¹

Symptoms of KS

The individuals with KS are genetically male, and they are unaware that they possess the extra X chromosome owing to the mild and non-specific symptoms. The symptoms of KS are as follows:²

• Increased levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
• Babies experience delays in sitting, crawling, walking and talking, in addition to muscle weakness
• Children struggle with reading and writing, have difficulty paying attention and exhibit behavioural problems such as lack of communication and social skills
• Adolescents have small and firm testes, a small penis, and enlarged breasts and are extremely tall compared with the height of their peers. The decreased production of testosterone (male sex hormone) causes an absence or reduction in the appearance of secondary sexual characteristics such as facial and body hair
• The low testosterone levels and absence of sperm production owing to the additional X chromosome causes infertility, poor sex drive and erection issues in adults. Approximately 5–15% of infertility issues in men are attributed to KS
• Individuals with KS are at high risk of developing additional health conditions, such as type 2 diabetes, cardiovascular diseases, autoimmune diseases, breast cancer, osteoporosis (weak bones) and hypothyroidism (underactive thyroid)

Diagnosis of KS

Despite the description of KS by Harry Klinefelter more than 80 years ago, KS continues to be under-diagnosed or hampered by diagnostic delays due to a lack of specific or obvious symptoms, with 64% of patients going undiagnosed, and only 10% and 26% being diagnosed prenatally and during adulthood, respectively. Most individuals are diagnosed with KS in adulthood under the pretext of infertility issues or low testosterone levels.³

A suspected case of KS is diagnosed via karyotyping, using a blood sample to check for the presence of an additional X chromosome.⁴ This is followed by determining the levels of FSH and LH.

Treatment for KS

The treatment of KS varies depending on the symptoms and usually, a multi-disciplinary approach is considered for these patients that involves specialists, such as urologists, endocrinologists, radiologists, psychologists, genetic counsellors and fertility specialists. The treatment options for KS are discussed below:

Testosterone replacement therapy

More than 50% of males have low testosterone levels. Supplemental testosterone is administered either via injections every 2–3 weeks, pills, or using a testosterone patch on the skin. The treatment benefits are as follows:

• Improved muscle mass
• Growth of facial and body hair, giving a masculine appearance, thereby reducing their self-consciousness
• Maturation of reproductive organs
• Enhanced focus and attention span

Testosterone therapy should be monitored by an endocrinologist who specialises in hormones and their functions to ensure favourable outcomes. The side effects include pimples, skin rashes due to testosterone patch use and breathing problems during sleep.⁵

Breast reduction surgery

Surgery is the mainstay for the treatment of enlarged breasts. The reduction of breasts by removing excess breast tissue reduces the risk of breast cancer, improves self-confidence and reduces the stress and anxiety caused by the feminine appearance. Liposuction is preferred to surgery in adolescents, and it eliminates the need for surgical removal of breast tissue.⁵

Fertility treatment

Infertility is common in the KS patient population as they cannot produce enough sperm to naturally fertilise the egg. Assisted reproduction technology, such as testicular sperm extraction with intracytoplasmic sperm injection (TESE-ICSI) has improved the chances of men with KS to have children. In this procedure, the sperms are surgically removed from the testes, and a sperm is injected into an egg. Some risks involved are as follows:

• The offspring may possess the XXY condition
• There is no assurance of the procedure’s success
• Costly procedure not covered by health insurance

Some studies indicate freezing the sperm collected during adolescence and using them later for fertility treatments as the sperm produced during adolescence are healthier compared with that produced in adulthood.⁶

Physiotherapy

Physiotherapy includes exercises and activities such as low-level karate, tennis and swimming to enhance muscle strength and motor skills for improving coordination and posture.⁷

Psychological support

Language and learning delays

If boys exhibit speech delays or reading and writing difficulties, visiting a speech and occupational/behavioural therapist would be beneficial. Occupational therapy will help develop skills for daily conversations at school or at work. Parents should also inform the school teachers on this aspect so that the children can receive the help they need to cope with school work. Parents can enquire from school officials whether their child is eligible for the Early Intervention Program for Infants and Toddlers with Disabilities or the Individualised Education Plan (IEP) where programs are specifically designed to improve communication, learning, social, and motor skills.^7,5

Emotional challenges

As boys or men with KS exhibit the absence of reduced facial or body hair, they may feel shy or frustrated in school or social settings. Consultations with a behavioural therapist will help them constructively cope with these emotions by improving their social skills and also encouraging other kids to play or initiate conversations with them. Mental health therapists can counsel patients and their families on handling depression, low self-esteem, and self-doubt.^7,5

Genetic Counselling

Genetic counselling should be considered as soon as KS is diagnosed in newborns or children to chart a treatment course that will benefit their physical, mental and social well-being. Adults who have been diagnosed with KS and are unable to conceive naturally can benefit from a genetic counsellor who can explain the cause of the condition and advise on choices for family planning.⁸

Lifestyle Modifications

Considering that these patients are susceptible to secondary health conditions, implementing a lifestyle that includes regular exercise and a healthy diet will reduce the risk of osteoporosis, diabetes, cardiovascular diseases, anxiety, and depression. Smoking should be avoided and alcohol consumption should be limited to 14 units per week. Regular health check-ups should be conducted to evaluate the physical, behavioural, social and intellectual development.⁹

Importance of early diagnosis of KS

Although treatment at any age is beneficial, the earlier the KS symptoms are identified and treated, the higher the chances of successfully reducing or eliminating them. Patients can be provided with the necessary support, including lifestyle changes to reduce the risk of co-morbidities, speech therapy, testosterone therapy and fertility preservation. 

Karyotype analysis in newborns with cryptorchidism (undescended testicles) and observation of a small penis is the best way to improve KS diagnostic rates. Early diagnosis can also adequately resolve speech and learning difficulties in childhood. The best age to begin treatment is during puberty due to the rapid occurrence of physical and psychological changes. Early diagnosis in adolescents who fail to demonstrate normal physical growth should be tested so that appropriate measures can be initiated to prevent the long-term consequences related to low sperm count and infertility. Physicians should consider testes examination as a part of their routine check-up to determine any abnormalities.²

Summary

The treatment of patients with KS varies according to the symptoms, thereby requiring a coordinated effort between the patient, their families and a multi-disciplinary team of specialists who can effectively address the symptoms. Currently, testosterone therapy, fertility treatment, physiotherapy, breast reduction surgery, mental and behavioural therapy, occupational therapy and speech therapy are the treatment options available to address the various symptoms associated with KS.

Future directions in KS management include educating patients and physicians and increasing awareness about the markers associated with the condition. This can be done by increasing the screening in the first year of life to adequately eliminate or reduce symptoms for these patients to lead a normal, healthy and long life.