Overview

Chromosomes are those vital, thread-like materials that carry our DNA. Persons assigned male (AMAB) or female (AFAB) at birth typically have two sets of chromosomes. Persons AMAB inherit X and Y chromosomes from their mother and father respectively while persons AFAB inherit 2 X chromosomes from each parent. But sometimes, things don’t always go as smoothly. That is to say, a chromosomal condition can occur in people who are assigned male at birth which can affect their growth, development and fertility.

Klinefelter syndrome is a rare chromosomal condition that affects 1 in every 500 baby boys.¹ Many cases are not diagnosed until adulthood when the symptoms become more evident. 

This article is aimed at giving a basic understanding of Klinefelter Syndrome, Metabolic Syndrome and an enlightening link between the two. 

What is klinefelter syndrome?

According to the American Academy of Pediatrics, Klinefelter syndrome (47, XXY) occurs due to the presence of an extra X chromosome in people assigned to males at birth. The main signs of this condition are abnormal or impaired development of secondary male characteristics and infertility. This implies that this condition might not be recognised until a boy reaches puberty. 

There is a high risk of developing breast carcinoma in 47, XXY. The cause may be due to the estradiol to testosterone ratio being several-fold higher than that of a normal man or also due to increased conversion of testosterone to estradiol in men with Klinefelter syndrome.³ 

Additionally, autoimmune diseases such as systemic lupus erythematosus, Sjogren syndrome, and rheumatoid arthritis, are more commonly seen in men with Klinefelter syndrome. There can also be the development of varicose veins and leg ulcers which may result from venous stasis.³ 

How does klinefelter syndrome occur?

A biological error called nondisjunction can occur during meiosis I and meiosis II of maternal oogenesis or during meiosis I of paternal spermatogenesis causing a boy to have 47 XXY or XXX chromosomes. The only evidence-based risk factor of Klinefelter syndrome is increased maternal age, in particular women that are 40 years and above.³ 

Normally before meiosis is completed, chromosomes come together and exchange genetic materials.  At times, the two X chromosomes and the X and Y chromosomes from the mother and father respectively fail to pair and exchange genetic material. Thus, when aneuploid sperm with X and Y chromosome fertilises an egg that has a single X chromosome, or when a sperm that has only Y chromosome fertilises an egg with two X chromosomes, this results in the conception of an XXY male.¹  

Typical features of klinefelter syndrome

Although Klinefelter syndrome can be diagnosed at any age, the psychological features might not be present during the post-natal period.³ 

Klinefelter syndrome can be diagnosed during one of the four stages of life:⁴ 

• During the prenatal period at amniocentesis 
• In male children with developmental and learning difficulties, 
• In young adult men with deficient virilisation after puberty and 
• In men with fertility issues such as azoospermia  

The following are the features associated with this condition: 

The burden associated with Klinefelter syndrome is vast. It is associated with comorbidities leading to frequent hospitalization and a mortality rate of approximately 50%.⁵ 

Comorbidities include:⁶

• Various types of cancer: This includes breast cancer, prostate cancer, etc. 
• Type 2 diabetes and insulin resistance
• Obesity and hypogonadism
• Pulmonary embolism
• Metabolic syndrome
• Osteoporosis
• Venous thromboembolic disease
• Endocrine disorders
• Cardiovascular diseases
• Fatty liver disease
• Hyperinsulinemia and hyperlipidemia  

People with Klinefelter syndrome also have a higher risk of developing psychiatric disorders such as schizophrenia. Additionally, imaging studies showed reduced brain volume located in the insula, temporal gyri and amygdala, and enlargement of the ventricles. These changes are consistent with language problems observed in patients with 47 XXY syndrome.⁷ 

The overexpressed genes on the X chromosome are associated with higher occurrences of delayed speech development and the noticeable difference between performance IQ and verbal IQ, with verbal IQ below normal and delayed emotional development and problems at school. ⁸ 

It has to be emphasised that this description of Klinefelter syndrome is mostly based on patients seeking medical attention or showing severe symptoms of the condition. Not all patients will have these typical features as it depends on the severity. 

What is metabolic syndrome?

Metabolic syndrome (Syndrome X) is a term that encompasses the most dangerous risk factors of cardiovascular diseases, particularly heart attack. These risk factors include type 2 diabetes,
abdominal obesity, high blood pressure and hyperglycemia.⁹ Although each of these is a risk factor for cardiovascular disease, when someone has three or more and is diagnosed with metabolic syndrome, the probability of developing a chronic cardiovascular condition increases.

For instance, high blood pressure is an important risk factor for cardiovascular disease. However, when combined with hyperglycemia and abdominal obesity, the chance of developing cardiovascular disease is augmented. The most important causative factors of metabolic syndrome are truncal obesity and insulin resistance. Other causes include a sedentary lifestyle, adiposity, genetic factors and increasing age.

The link between klinefelter syndrome and metabolic syndrome

Hypogonadism, a condition where men are not able to produce enough sperm or enough testosterone for the body’s needs, has been established as the link between Klinefelter syndrome and metabolic syndrome. This is because hypogonadism is involved in the pathogenesis of the changes in body composition, leading to the onset of abdominal obesity and hence insulin resistance and metabolic syndrome. However, it is also plausible that increased visceral fat precedes hypogonadism. Thus, metabolic syndrome may be a specific feature of Klinefelter syndrome that is independent of hypogonadism, probably arising from the genetic predisposition of the syndrome.¹⁰

Therefore, the role of hypogonadism or testosterone deficiency is crucial as it can perpetuate a vicious circle of insulin resistance, dyslipidemia and obesity. This, in turn, is responsible for a progression of hypogonadism and other features of Klinefelter syndrome seen in adulthood. In other words, Klinefelter syndrome is the most common cause of hypogonadism. 

Testosterone is an essential sex hormone in men. It is needed for normal reproductive and sexual function. Invariably, testosterone performs other crucial functions in the body. These include the development of the penis and testes and the appearance of facial and body hair. It also helps the growth of bones and muscles, and it affects mood, libido and some aspects of mental capability. Testosterone deficiency in men with Klinefelter syndrome can affect the development of male characteristics and trigger the onset of other conditions including psychiatric disorders.

Summary

Men living with Klinefelter syndrome are not only subjected to higher cardiovascular risk and developing different health conditions but also experience devastating effects on their quality of life. Especially notable is the presence of discrimination, less social activities, language or speech problems and mental health issues. Early diagnosis and healthy lifestyle choices are recommended for adequate treatment options to be explored for men living with 47, XXY. 

Additionally, Klinefelter syndrome has a direct link with the development of cardiovascular diseases later on in life. Subsequently, the management of children with 47, XXY warrants the collaboration of a multidisciplinary team including pediatric endocrinologists and developmental and behavioural specialists, to ameliorate the developmental defects of early life. In addition, an initial echocardiographic study should be offered to reveal congenital cardiovascular abnormalities.¹¹ 

FAQs

What hormones are increased in klinefelter syndrome?

Plasma oestradiol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are elevated and there was increased peripheral conversion of testosterone to oestradiol.

Does klinefelter syndrome occur in women?

Klinefelter syndrome typically doesn’t occur in women. It only happens in people assigned male at birth only. 

Can klinefelter syndrome be treated? 

Klinefelter syndrome cannot be completely cured. However, If testosterone levels are abnormally low, treatment with testosterone replacement therapy (TRT) during and after adolescence may help ameliorate many of the psychological symptoms. It can also increase secondary sex characteristics and should be coupled with healthy lifestyle choices. 

Does the extra X chromosome cause a female appearance? 

No. The extra X chromosome causes damage to the normal function of the testis. However, low testosterone at puberty can cause a boy with KS to have less well-developed muscles in the upper body and a relatively narrow shoulder, wider hips and abdominal fat. Low testosterone level is also associated with the development of gynecomastia.