Approach

Key Points

  • The presenting features of Klinefelter syndrome (KS) vary with age and developmental stage. Prepubertal clinical features are typically subtle and nonspecific. Many individuals never receive a diagnosis and most who do are not diagnosed until they are adults, although this may change over time with increasing rates of prenatal diagnosis.[1][2][3][4]

  • Symptoms and signs of testosterone deficiency are the most common feature, usually emerging when puberty begins normally but fails to complete.[2][3]​​[5][14][15]​ The only clinical examination feature reliably seen in individuals with KS is small testes from mid-puberty onward. Infertility is the most frequent presenting symptom in adults, affecting >99% of men with KS.[4]​ In childhood, there may be developmental and learning delays, particularly with expressive language.[2]​

  • Testosterone in postpubertal boys and adults with KS is typically in the low or low-normal range, with elevated gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) present in the vast majority.[1][2][3][4]

  • A definitive diagnosis of KS requires karyotype analysis confirming the presence of an extra X chromosome (47,XXY).[3]​

General principles

KS is a sex chromosome aneuploidy (abnormal chromosome number) in which an extra X chromosome is present, resulting in a genetic karyotype of 47,XXY.[1][2][3]

  • The extra X chromosome leads to testicular hypofunction and KS is the most frequent cause of primary hypogonadism.[2][3][4][16]

KS is the most common male sex chromosome disorder, affecting around 1 in 660 males.[1][2]

  • Around 90% of cases have the 47,XXY karyotype (47 chromosomes, with an extra X), with the remainder having mosaic karyotypes such as 46,XY/47,XXY (i.e., the extra X chromosome is present in some cells but other cells have the typical male karyotype of 46,XY).[4]

  • The mosaic form of KS has been reported to be associated with a milder symptom presentation, although further research is needed to confirm this.[4]

Definitive diagnosis requires confirmation of the extra X chromosome on karyotype analysis.[3]

History

The key clinical features of KS are symptoms and signs of testosterone deficiency, in some cases accompanied by language and developmental delay.[1][2][3][4]

  • However, the symptoms of KS are highly variable and sometimes subtle, with many boys and men functioning fairly normally.[2][3]

  • The combination of tall stature with small testes in an otherwise physically healthy male child may raise the possibility of KS.[7] Suspicion is heightened if this is accompanied by developmental delay, especially with expressive language most affected.[2][17][18] Puberty that starts on time but stalls after a year or two is another suggestive sign.[2][3][5][14][15]

  • In practice, the majority of diagnoses occur during evaluation for male infertility.[4]

The presenting features depend on the individual’s age at evaluation. Prepubertal clinical features are very nonspecific and very few individuals with KS are diagnosed during childhood.[3][4]

  • Most newborn boys with KS have no unusual features of note and major congenital abnormalities are unusual.[2] In rare cases, cryptorchidism (undescended testes) may be present.[3]

  • In infants and children, key symptoms that should prompt consideration of KS are:[2][3][12][17][19]

    • Speech or developmental delay. Learning and developmental delays are common in KS and most often noted between 1-5 years of age, but are often nonspecific and do not necessarily point to the diagnosis.[13][17][20] Some degree of learning disability has been reported in >75% of boys with KS, with delayed speech development in 40%.[1][4] Expressive verbal ability is most often affected; toddlers may be slow to start speaking but their receptive comprehension is usually normal.[2][21] Some boys with KS have problems with attention and executive cognitive function, which can lead to expressions of frustration.[2][3] In rare cases, a boy with KS may be very slow to start walking and KS will be identified on chromosomal testing.[22] Boys with KS will often be receiving special educational support, although a specific diagnosis is unlikely to have been made.[1][2][3]

    • Behavioral differences. Infants are sometimes reported as being easy to manage and not as demanding as their siblings.[2] Boys with KS may be quiet and passive but impulsivity may be present and difficulties with self-expression and executive tasks may lead to temper tantrums and anger outbursts.[2][23] One population-based study found an increased risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders among individuals with KS.[24]

    • Social and psychological issues, which can continue into adolescence and adulthood.[3] Social skills may take longer to develop and boys with KS sometimes feel isolated and/or prefer their own company.[2] KS has been reported to be associated with difficulties identifying and verbalizing emotions.[3]

    • Tall stature with disproportionately long legs, following a growth spurt in childhood.[3][4] Tall stature affects around 30% of individuals with KS and is believed to be due to the presence of three copies of the SHOX gene, but extreme tall stature is unusual.[1][2][4][23] Infant length is typically within age-related norms and the rate of height increase tends to accelerate throughout childhood, so that by school age, boys with KS may be on a higher centile than their siblings and that predicted by mid-parental height.[2]

    • A small penis and/or testes.[3] Decreased penile size is seen in 10% to 25% of boys with KS.[1] In rare cases, cryptorchidism may be present, but it is rare for boys with KS to fulfill the criteria for micropenis (stretched length ≥2.5 standard deviations [SD] below the mean for age).[3]

  • In adolescence, puberty begins on time but may not fully complete.[2][3][5][14][15]

    • Biochemical and clinical hypogonadism develops from late puberty, typically beginning at around 14 years of age at Tanner stage 5 of puberty.[2]

    • Testicular growth begins normally but is then followed by involution and a reduction in testes size.[2][4]

    • Gynecomastia is common, affecting around one third of adolescents and adults with KS.[2]

    • A high abdominal fat mass often becomes apparent during adolescence, together with decreased muscle mass and strength; this is in contrast to the typical male pattern of slimming down and becoming more muscular as puberty progresses. These features are present in around half of adolescents with KS and they persist into adulthood.[4] However, they are very nonspecific for KS.[2]

    • Deficits in expressive language skills are more common than in peers without KS.[3]

    • Note that there is no overall increase in gender dysphoria reported in individuals with KS.[25]

  • In adult men, infertility is the most common presenting symptom, affecting >99% of men with KS, and can be due to oligospermia or more commonly azoospermia.[4]

    • The prevalence of KS is 3% to 4% among all infertile men, 6% among those with a total sperm count <10 million/ejaculate, and 10% to 15% in those with nonobstructive azoospermia.[3]

    • More than 90% of individuals with KS are azoospermic.[2]

  • Other common symptoms of hypogonadism that may be present at the point of diagnosis in men with KS include:[1][3]

    • Small testes (bi-testicular volume <6 mL): present in >95%.[1][26]

    • Lack of facial and pubic hair: present in 60% to 80% and 30% to 60%, respectively.[1] It can be helpful to compare with the norm for the family.

    • Gynecomastia: affecting 38% to 75%.[1]

    • Psychosexual problems: in particular, low libido.[3]

    • Obesity, with a high fat:lean mass ratio, particularly around the abdomen and hips.[2][3]

    • Lethargy and fatigue, although this is a very nonspecific feature of hypogonadism.[2]

Diagnostic delay and nondiagnosis

Many individuals with KS never receive a diagnosis, likely because of lack of awareness among healthcare professionals together with the phenotypic variability and mild clinical features in many affected boys and men.[3][4][23]

  • Most diagnoses are made in adult men, with a reported average age at diagnosis in the mid-30s.[4]

  • The 2021 European Academy of Andrology guideline reports that among individuals who do receive a diagnosis of KS, 21% are diagnosed prenatally, 10% to 12% in prepubertal childhood, 16% at puberty, and 51% as adults.[3]

Prenatal diagnosis is becoming increasingly common.[3][4][8]

  • In the US, the American College of Obstetricians and Gynecologists (ACOG) recommends offering all pregnant women prenatal screening for fetal chromosome abnormalities including sex chromosome aneuploidies (SCAs) such as KS.[8] The American College of Medical Genetics (ACMG) strongly recommends noninvasive prenatal screening (NIPS) via analysis of cell-free fetal DNA in maternal blood as the most sensitive and specific screening test for SCAs in singleton pregnancies.[9][27] This can be done starting from around 10 weeks of gestation. Because of the risk of false positives, amniocentesis or chorionic villus sampling followed by karytopye analysis is needed to confirm a prenatal diagnosis of KS.[3][8][28]

Risk factors

The additional X chromosome in males with KS occurs randomly and KS is not a heritable disorder. The extra chromosome arises from nondisjunction errors during spermatogenesis or oogenesis and can be inherited from either parent, with a roughly 50/50 split between maternal and paternal disjunction.[1][3]

  • Advanced maternal age is a weak risk factor for having a son with KS and this is believed to be attributable to a higher rate of maternal meiosis I errors in older women.[3][5]

  • The effect of advanced paternal age is controversial, with studies finding conflicting results but no clear association confirmed.[29][30][31]

Physical exam

The only clinical examination feature reliably seen in individuals with KS is small testes from mid-puberty onward. The testes may be firm or soft.[2][4]​​[14][18]​ Testicular volume can be measured using the Prader orchidometer.

  • The testes are typically normal in size or only slightly small in prepubertal childhood. They begin to enlarge normally at the onset of puberty, typically around 11-12 years of age. However, they rarely progress beyond a bi-testicular volume of 10 mL and then usually shrink to around 3-5 mL (the size of an almond kernel) in older adolescents due to a stalling of puberty.[2][4]

  • Almost all adult men with KS have a bi-testicular volume <6 mL.[1][26]

[Figure caption and citation for the preceding image starts]: Prader orchidometerCreated by BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@132caf36

Gynecomastia may be seen on exam in around one third of adolescents with KS and up to three-quarters of adult men. However, this is very nonspecific for KS.[1][2]

Sparse facial, pubic, and axillary hair may be noted in postpubertal adolescents and adult men.[1]

A high abdominal fat mass may be seen, beginning in childhood and persisting into adulthood.

  • Central obesity (“pot belly” and wider hips) is common after the adiposity rebound at 6-7 years of age.[2]

Consider KS in the differential diagnosis if examination of a newborn identifies a micropenis (stretched length ≥2.5 SD below the mean for age, usually with a diminished circumference) or undescended testes, but bear in mind that infants with KS are usually phenotypically normal.[2][3]

Look for an upward shift in height centiles in childhood.

  • Boys with KS grow more quickly than the norm throughout childhood, often resulting in a height centile higher than predicted (based on mid-parental height). Tall boys with KS have disproportionately longer legs.[3][4]

  • However, extreme tall stature is unusual in individuals with KS.[2]

Initial investigations

Hypergonadotropic hypogonadism (i.e., primary hypogonadism) is a key feature of KS and is confirmed by elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), together with low testosterone levels.[1] It is seen in >75% of adult men with KS.[4]​

  • In KS, testosterone, LH, and FSH levels are typically normal until the start of puberty, after which FSH and LH begin to increase.[1]

  • Testosterone may be within the age- and pubertal stage-related range in early puberty but typically fails to rise in late puberty, leading to low levels compared with boys without KS.[1] This biochemical hypogonadism is generally detectable from around age 14 years (at Tanner stage 5 of puberty), when the usual accelerated nocturnal rise in testosterone becomes blunted.[2]​

  • Low testosterone levels are present in the majority of adult men with KS, and nearly all affected men have elevated LH levels, reflecting primary testicular (Leydig cell) damage.[3]​

  • Compensated hypergonadotropic hypogonadism (i.e., elevated LH levels but testosterone levels in the low end of the normal range) is seen in a substantial proportion of pubertal adolescents with KS. This compensatory mechanism allows pubertal development to proceed normally.[3]​

A definitive diagnosis of KS requires karyotype analysis of sex chromosomes.[3]​

The order in which hormone levels and genetic investigations are undertaken will depend on the age at which KS is suspected as a possible diagnosis and the presenting symptoms/signs that underlie that suspicion.

Testosterone levels

Investigation of testosterone levels may be indicated:

  • As part of the workup for an adult man who presents with infertility.[32]​ This is the most common scenario in which KS is diagnosed.[4]​

  • When evaluating a postpubertal adolescent or adult man who presents with symptoms/signs of testosterone deficiency (e.g., small testes, gynecomastia, lack of facial/pubic hair, sexual dysfunction).[23]​

  • For ongoing monitoring of an individual who has been diagnosed with KS in childhood. If KS has been diagnosed prenatally, the 2021 European Academy of Andrology guideline recommends checking testosterone levels in the first 2-3 months of life to aid in diagnosis of micropenis.[3]​ If KS is diagnosed in childhood, it is usual practice to start evaluating testosterone on a regular basis (e.g., annually) once puberty has started or when clinical signs of hypogonadism are seen.

Measure total serum testosterone with an early-morning fasting sample (8-9 a.m.). Check the level on two different days before confirming a diagnosis of hypogonadism.[32]​

  • An early-morning sample is important for accurate measurement as testosterone levels follow a diurnal pattern and this is when levels are at their highest. They also vary day to day, making it important to check the level on two separate mornings.​[2][32]

  • Testosterone levels can be suppressed by intake of food, hence the recommendation for a fasting level.[32]

Testosterone in postpubertal boys and adults with KS is typically in the low or low-normal range.[2]​​[14]​​​[18]

  • Be aware that a normal testosterone level therefore does not exclude KS. Some adolescents and adult men with KS have testosterone levels in the lower end of the normal range but this group often have symptoms/signs of testosterone deficiency.

  • A level less than 300 nanograms/dL (<10.4 nanomol/L) is generally accepted as being consistent with hypogonadism in a postpubertal adolescent or adult man, but reference ranges vary between laboratories so check your local protocol.

Gonadotropin levels

In KS, serum LH and FSH levels are typically normal until puberty, after which they become elevated.[2][14]​​​[18]​​[23]​​ Elevated gonadotropins have been reported in >95% of postpubertal individuals with KS.[1]

If hypogonadism is confirmed as part of evaluation for infertility or for symptoms/signs of testosterone deficiency, it is essential to measure serum LH and FSH to confirm the hypogonadism is primary (i.e., due to testicular failure).[23]​

  • KS is the most common cause of primary hypogonadism, in which low testosterone levels are accompanied by elevated gonadotropins.[1]

If KS is diagnosed in childhood, it may be helpful to monitor serum LH and FSH levels once clinical signs of puberty are seen and annually thereafter.

  • However, bear in mind that raised gonadotropins per se are not an indication to start testosterone therapy.[3]​

If KS has been diagnosed prenatally, the 2021 European Academy of Andrology guideline recommends checking LH levels in the first 2-3 months of life to aid in diagnosis of micropenis.[3]​

Chromosomal karyotype analysis

If suspicion for KS is high, request karyotype analysis of sex chromosomes (usually from a blood lymphocyte sample - check your local laboratory protocol). There is no clear consensus on the clinical symptoms/signs that warrant karyotype analysis for suspected KS.

  • The US Endocrine Society guideline on hypogonadism recommends karyotype analysis to diagnose KS in any individual who has primary hypogonadism confirmed based on low total serum testosterone (in two early-morning fasting samples) and high serum LH and FSH, especially if bi-testicular volume <6 mL.[32]​

  • The 2021 European Academy of Andrology KS guideline states that karyotype analysis is indicated in the following scenarios:[3]​

    • Men with nonobstructive azoospermia or severe oligozoospermia (total sperm count <10 x 10⁶/ejaculate or sperm concentration <5 x 10⁶/mL)

    • Men with primary hypogonadism (low serum testosterone level) and elevated serum gonadotropins (LH and FSH) combined with small testicular volume (<5 mL per testis)

    • Boys born with cryptorchidism, especially if bilateral, who do not experience spontaneous descent of the testes by 1 year of age.

Occasionally, KS may be identified unexpectedly when a karyotype analysis is performed to investigate developmental delay (e.g., in speech and/or walking) in a toddler over 2 years of age.[2]​

In KS, karyotype analysis will confirm the presence of an extra X chromosome.[1][2][3]​​

  • Around 90% of individuals with KS have the 47,XXY karyotype (47 chromosomes, with an extra X).

  • The remainder have mosaic karyotypes such as 46,XY/47,XXY (i.e., the extra X chromosome is present in some cells but other cells have the typical male karyotype of 46,XY).[4]​

Ensure counseling takes place prior to karyotype analysis.

  • Parental consent will be needed for a child and the boy himself must also consent if he has legal capacity (e.g., Gillick competence). Check your local legal guidelines around capacity.

Other investigations

Inhibin B levels are typically normal until puberty in males with KS, after which they decrease to a low-normal or subnormal level.[1][2][23]

  • Inhibin B is most often requested during investigation of fertility prospects in individuals with KS.

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