Overview

Klinefelter syndrome (KS) is a common genetic disorder characterised by the presence of an extra X chromosome (the ‘female’ sex chromosome). Despite being the most common chromosomal abnormality in humans, there is a current lack of understanding of this disorder amongst healthcare professionals and is therefore hugely underdiagnosed. Most people with Klinefelter syndrome never receive a diagnosis.

Whilst those with Klinefelter syndrome typically develop as male, gender identity is an important issue. Studies have shown that the incidence of gender identity disorder, or gender dysphoria, is higher in individuals with Klinefelter syndrome than in the general population.

What is klinefelter syndrome?

Named after Dr. Harry Klinefelter, Klinefelter syndrome (KS) is the most common sex chromosomal disorder in males, affecting approximately 1 in 650 individuals assigned male at birth^1,2.

We inherit DNA from our parents, generally packaged into 46 chromosomes - 23 from each parent (23 pairs). The 23^rd pair, sex chromosomes (the X or Y chromosomes) determine whether a person develops into a male or female. Typically, cis-gendered females inherit two copies of the X chromosome (XX), one from each parent, and cis-gendered males inherit one X chromosome from the mother and one Y chromosome from the father (XY). The usual karyotype (chromosome pattern) of a healthy person is 46, XY.

In KS, a mistake in DNA replication occurs during the development of the egg or sperm, resulting in the egg or sperm carrying an extra chromosome. In Klinefelter syndrome, people typically inherit an extra X chromosome and have a karyotype of 47, XXY. Therefore, KS is also known as “XXY syndrome” or “47, XXY.” Individuals with Klinefelter syndrome almost always develop as male, despite the extra x chromosome.³

Diagnosis

KS is a significantly underdiagnosed condition, with only 25% of the expected patients to be diagnosed, and of these, most are only in adulthood.^{3, 4 5 6} Diagnosis is usually made during a fertility assessment.⁶

Signs and symptoms

Despite having two copies of the X chromosome, individuals with KS usually develop as males due to the presence of the Y chromosome.

The clinical features of people with KS vary, but common symptoms include:^1,6

• Testicular failure and small testicles
• Infertility or low sperm count
• Gynaecomastia (enlarged breasts in males)
• Broad hips
• Sparse male-pattern body hair
• Features of eunuchoidism (lack of fully developed reproductive organs and the presence of certain female sex characteristics)
• Low testosterone levels, coupled with elevated gonadotropins
• Emotional and psychological problems

The cognitive or psychological symptoms that often accompany these physical traits include:

• Cognitive problems and a reduction in overall IQ⁷
• Language and reading disabilities and other psychological impairment⁷
• Difficulties in communication and social skills
• Emotional and behavioural dysregulation
• Insufficient emotional arousal ⁸
• Depression and psychosis⁸
• Autistic traits/autism spectrum disorder⁹

Regardless, there is significant variability in the severity of symptoms among individuals with KS.⁹

Gender identity disorder in klinefelter syndrome

Gender identity is defined as “A person’s deeply felt, inherent sense of being a boy, a man, or a male; a girl, a woman, or a female; or an alternative gender (e.g., genderqueer, gender non-conforming, gender neutral), that may or may not correspond to a person’s sex assigned at birth or to a person’s primary or secondary sex characteristics.”¹⁰

A complex set of factors determines a person’s gender identity since it is influenced in part by innate factors, including genes. Studies indicate a high prevalence of gender dysphoria is significantly higher in people with Klinefelter syndrome than in the general population.⁶ Gender dysphoria is defined as “discomfort or distress that is associated with a discrepancy between a person’s gender identity and that person’s sex assigned at birth (and the associated gender role and/or primary and secondary sex characteristics).” Individuals with gender dysphoria experience a different gender from what they were assigned at birth and cannot correlate to their gender expression when identifying themselves within the traditional binary male or female gender roles, which may cause cultural stigmatisation. 

It can result in relationship difficulties with family, friends, and peers and lead to interpersonal conflicts, rejection from society, depression and anxiety, substance abuse, low self-esteem, a negative sense of well-being, and an increased risk of self-harm and suicide. Psychiatric support should be provided, and depending on the individual’s needs, possibly also hormonal therapy and surgery¹¹ Professional help is important but can be difficult as Klinefelter syndrome is so underdiagnosed.

Reasons behind gender identity disorder in klinefelter syndrome

The underlying causes of the higher incidence of gender dysphoria in KS are still unknown. Genetic factors (namely, the presence of an extra X chromosome in Klinefelter syndrome) have been thought to be the main cause of gender dysphoria, but it is still not well understood.

Current research suggests two explanations behind the higher incidence of gender dysphoria in Klinefelter syndrome:

1. Hormonal factors: reduced exposure to androgens (sex hormones), contributing to a different gender identity development.¹²
2. Physical characteristics: e.g. gynecomastia (enlarged breasts in men) and less body hair, can be perceived as feminine. This could lead to decreased masculine behaviours and the individual doubting their masculinity.¹³

It is reported that boys with Klinefelter syndrome feel more negatively about their male gender role and are judged less masculine by their peers. This could be due to lower testosterone levels during puberty.^14,15 There are studies supporting this that show gender dysphoria improved after treatment with testosterone.^3,16 However, results can vary. However association between gender identity disorder and Klinefelter syndrome is still incompletely understood, and more research is required. Not all gender clinics report chromosome disorders, and since Klinefelter syndrome is significantly underdiagnosed in the general male population,⁵ increasing detection rates must increase to improve our understanding of the association with gender identity.

Recent studies have linked the high prevalence of gender dysphoria in Klinefelter syndrome to autistic traits. It has been suggested that the increase in dysphoria symptoms in people with Klinefelter syndrome is mediated by the presence of autistic traits.

Autism and klinefelter syndrome

It has been suggested that autism explains some of the clinical features of individuals with Klinefelter syndrome. Studies have demonstrated autism spectrum disorder¹⁷ are more prevalent in individuals with KS, contributing to gender dysphoria

It has been hypothesised that the rigid thinking typical of autism spectrum disorder causes distress related to gender identity in individuals who do not identify as traditionally male.

The presence of such autistic traits in people with Klinefelter syndrome has been extensively described in various studies.^18,19,20

Testosterone replacement therapy in klinefelter syndrome

The clinical features of Klinefelter syndrome differ for each patient, so each treatment plan should be individualised, but hormone replacement therapy with testosterone is usually involved.²¹ Testosterone replacement therapy (TRT) can have numerous medical and psychosocial benefits, with studies showing that gender dysphoria improves after treatment with testosterone.^13,16 It has been suggested that testosterone treatment should be offered to these patients from early puberty to secure proper masculine development.

However, since Klinefelter syndrome is a complex disorder with diverse clinical features for each individual, TRT is not a one-size-fits-all solution. For some people with Klinefelter syndrome, especially those who have not yet fully developed in puberty, treatment can be life-changing. However, it may not work for everyone. Some patients question their gender identity when diagnosed and throughout treatment.²¹ TRT will not help those who may not consider themselves female but do not wish to be more ’male’ either.³

A recent study in 2023 investigated these issues, finding that a third of individuals receiving treatment were satisfied with the physical changes they saw. Some patients were unhappy with the behavioural changes they experienced on testosterone replacement treatment, and one-tenth of patients stopped their treatment altogether.²¹

Choosing not to have testosterone replacement may have many negative long-term medical consequences,⁵ but this may not be the priority for those who do not wish to be medicated to change them into a person they do not want to identify as.³ Gender-affirming treatment must be appropriately adjusted according to the risks and medical implications of Klinefelter syndrome. Individuals should be informed and counselled about the risks and options for hormone therapy before initiating treatment⁽⁶⁾.

Summary

Klinefelter syndrome is the most common sex chromosome disorder in humans, affecting approximately 1 in 650 males. Despite its prevalence, it is significantly underdiagnosed, with most diagnoses occurring in adulthood. 

Individuals with KS have a higher incidence of gender dysphoria compared to the general population. While testosterone replacement can improve symptoms, this does not work for everyone. More research is required to understand this complex disease and gender identity disorder in individuals with Klinefelter syndrome. Individuals display varying clinical features and symptoms, so there is currently no gold-standard treatment option available. Improving awareness and understanding among healthcare professionals is crucial to help raise awareness and improve detection rates. This would then improve understanding of the disorder and subsequently its treatment options.