Continuing Education Activity

Klinefelter syndrome (KS) results from 2 or more X chromosomes in a phenotypic male. The clinical phenotype of KS was first described in males with tall stature, small testes, gynecomastia, and azoospermia, with the genetic etiology of supernumerary X chromosomes identified in 1959. Extra X chromosomes lead to testicular hyalinization, fibrosis, and testicular hypofunction, resulting in genital abnormalities, usually hypogonadism, and infertility. Neurocognitive differences associated with KS began to be recognized in the middle and latter of the 20th century. Often, androgen replacement and neuropsychological and adaptive therapies are beneficial in the medical management of KS. However, deficits in clinical care do exist as there are gaps or delays in diagnosis, lack of standardization of care, and access to treatment is not always available or affordable. This activity reviews the evaluation and treatment of Klinefelter syndrome and the role of the interprofessional team in managing this condition.

Objectives:

• Identify the cause of Klinefelter syndrome.

• Screen individuals at risk of Klinefelter syndrome, especially during early childhood and puberty.

• Implement evidence-based interventions and treatment plans tailored to the specific needs of individuals with Klinefelter syndrome, focusing on hormonal therapies, speech and language therapies, and psychosocial support.

• Collaborate with an interprofessional healthcare team to provide comprehensive care for individuals with Klinefelter syndrome.

Introduction

Klinefelter syndrome (KS) results from 2 or more X chromosomes in a phenotypic male. The clinical phenotype of KS was first described by American physician Dr. Harry Klinefelter in 1942.[1] The syndrome describes males with tall stature, small testes, gynecomastia, and azoospermia. The precise genetic etiology of supernumerary X chromosomes (47,XXY) was identified in 1959.[1][2] Extra X chromosomes lead to testicular hyalinization, fibrosis, and hypofunction, resulting in genital abnormalities, usually hypogonadism, and infertility.[3]

Neurocognitive differences associated with KS began to be recognized in the middle and latter of the 20th century.[4] Often, androgen replacement and neuropsychological and adaptive therapies are beneficial in the medical management of KS.[5][6] However, deficits in clinical care do exist as there are gaps in diagnosis, lack of standardization of care, and access to treatments can be limited or unaffordable.

A similar but much less common condition, Jacobs syndrome, has the genotype 47,XYY.[2]  Affected individuals are phenotypically male. The syndrome is associated with antisocial tendencies, asthma, autism, seizures, some infertility, tall stature, macrocephaly, and hypertelorism.[2][7] See our companion StatPearls reference article on "Jacobs Syndrome."[7]

Etiology

The most common KS karyotype is 47,XXY (greater than 90%). Mosaic karyotypes such as 46,XY/47,XXY, and other aneuploidies such as 48,XXXY, and 49,XXXXY have been described. The acquisition of the extra X-chromosome is random and usually due to meiotic nondisjunction or post-zygotic nondisjunction.[5] KS is not an inherited or inheritable disorder.[1]

The overall severity of the phenotype appears to be correlated with the amount of additional X chromosome material present.[1][5]

Epidemiology

KS is the most common form of aneuploidy, which occurs when an individual has an abnormal number of chromosomes in a cell. KS has an estimated prevalence of between 1:500 to 1:1000 males.[8] KS is not commonly recognized before adulthood; most diagnosed cases are not identified until later.[1] Recognizing and diagnosing KS typically occurs after 1 or more of the items listed below come to clinical attention: [1] 

• By prenatal testing or because of genital abnormalities seen at birth in a child with hypotonia 
• In an adolescent with learning or behavioral difficulties 
• In an adolescent evaluated for tall stature, small testicular size, or incomplete puberty
• In adult men evaluated for infertility (3% of all men evaluated for infertility have KS) or hypogonadism

Up to two-thirds of cases of KS may go undiagnosed.[1][9] Comparative studies suggest that KS may occur more often in the setting of increasing parental age, environmentally-derived errors in meiosis I, or decreased elective termination for prenatally diagnosed cases. Underdiagnosis is likely due to variable phenotype, with many cases having only subtle findings.[1]

It is estimated that approximately a quarter of individuals with KS have no discernable diagnostic features by history or exam. With the increased use of noninvasive prenatal testing (NIPT), the frequency of prenatal diagnosis is expected to increase, resulting in early diagnosis management by healthcare professionals who care for children.[5]

Less than 10% of cases are diagnosed before puberty, and only 26% to 37% of cases overall, with most patients going undiagnosed.[10][11][12] The average age of diagnosis of KS is 30 years, and their median lifespan is reduced by 5 or 6 years compared to the general male population.[13][14]

Pathophysiology

The molecular mechanisms underlying primary testicular failure and the phenotypic heterogeneity of physical and neurocognitive features in KS are not well-characterized. Studies are ongoing to determine the influence of genetic polymorphism, skewed X-inactivation, the parental origin of the extra X chromosome, and gene dosage.

Extra X-chromosome material is responsible for testicular hyalinization and fibrosis, leading to primary gonadal failure that often evolves through adolescence and young adulthood.[1] The prevalence of hypogonadism in adults with KS is between 65% to 85%.[15]

The condition may manifest in newborns as microphallus, hypospadias, cryptorchidism, and tiny testes. Later, evolving hypogonadism leads to incomplete puberty and gynecomastia. In adults, long-term hypogonadism and infertility are typical clinical manifestations.[5]

Decreased bone density is more common in men with KS. Osteoporosis is found in 6% to 15% and osteopenia in 25% to 48%.[16] This presentation tends to start in adolescence and is due to a higher rate of bone resorption with decreased bone formation. While hypogonadism partly explains this, other factors, such as decreased Vitamin D levels, are also involved.[16][17]

The additional gene dosage of the SHOX gene in the pseudoautosomal region of the X chromosome leads to tall stature, long limbs, and a reduced upper/lower segment ratio. 

The pathophysiology of neuropsychological differences observed in KS is not well-understood.[1][5]

Histopathology

The seminiferous tubules demonstrate hyalinization and fibrosis in the setting of gonadotropin excess, leading to firm, often undersized, testes. Limited studies of testicular biopsies from patients with KS demonstrate reduced germ cell number across the lifespan with a progressive deficit, especially following puberty, and only infrequent pockets of spermatogonia in adulthood.[5][18][19]

History and Physical

Most patients with KS will present with tall stature and long limbs, reflected in a low upper/lower segment ratio. Mean height is at the 75th percentile, with weight and head circumference at the 50th percentile.

In childhood, the phallus and testes may be relatively small (<1.9 cm). During adolescence, there is discordant puberty with fairly normal phallus and pubic hair development, although the testes rarely exceed 4 mL and are characteristically firm due to hyalinization and fibrosis. Testosterone levels are usually in the low to low-normal range. Gynecomastia is common, and those affected have a higher risk of developing subsequent male breast cancer.[20]

A wide range of intelligence quotients (IQs) have been described; however, the mean full-scale IQ is between 85 and 90, with an average decrease of 15 IQ points.[21] Verbal difficulties are due to problems with expressive language and auditory processing.[22] Behavioral difficulties, including immaturity, insecurity, shyness, anxiety, poor judgment, attention deficit hyperactivity disorder (ADHD), depression, and impaired formation of meaningful peer relationships, may be noted.[15][23][24][25][26]

Between 20% to 50% of individuals with KS will have intention tremors.[1][5] About ten percent of males with KS are estimated to have an autism spectrum disorder. This high association suggests that KS patients be screened for an autism spectrum disorder.[27] 

About two-thirds of KS patients will require remedial speech therapy for language deficiencies. Therefore, all male patients requiring remedial speech and language therapy should be considered for KS screening.[28]

Problems seen more commonly in men with KS include:

• Autism spectrum disorder
• Autoimmune disorders
• Behavioral disorders (anxiety, depression, ADHD, immaturity, relationship issues)
• Breast cancer (50 times more common than unaffected individuals)
• Cardiovascular disease
• Deep vein thrombosis
• Diabetes
• Germ cell tumors
• Gynecomastia
• Hypercholesterolemia
• Hyperlipidemia
• Hypertension
• Hypogonadism
• Increased belly fat
• Infertility
• Long leg bones
• Low libido
• Low muscular development compared to peers
• Lower IQ
• Metabolic syndrome
• Nodular thyroid disease
• Osteopenia and osteoporosis
• Pulmonary embolism
• Rheumatoid arthritis
• Small, firm testes
• Small penis size (<8 cm)
• Sparse facial and body hair
• Systemic lupus erythematosus
• Tall stature
• Tremors
• Varicose veins
• Verbal and language difficulties
• Venous stasis ulcers

Evaluation

The initial evaluation of KS may include a workup for hypogonadism or infertility. In KS, gonadotropins (FSH and LH) are usually elevated when testicular hyalinization and fibrosis are present, though this may evolve over adolescence. The finding of hypergonadotropic hypogonadism indicates primary gonadal failure.[29]

FSH elevation typically predominates over LH, though both are elevated above normal. Testosterone concentrations are usually low or low-normal in both adolescents and adults. Sex hormone-binding globulin (SHBG) tends to be elevated, which causes the free testosterone in the serum to be disproportionately low compared to the total testosterone. The majority of adults with KS will have hypogonadism, but not all. Serum estradiol is high-normal or elevated, but the estradiol/testosterone ratio is consistently elevated, which may explain the gynecomastia.[1][15][30]

In adults with KS, inhibin B is usually undetectable, and antimullerian hormone (AMH) is typically low due to abnormal Sertoli cell function.[31][32][33] These levels are typically normal during childhood and only become abnormal after puberty.[1][5] 

Noninvasive prenatal testing for cell-free DNA can identify sex chromosome abnormalities. Published positive predictive values in detecting KS via noninvasive prenatal testing (NIPT) are 67% to 78%.[5][34] NIPT analyzes small fetal DNA fragments free-floating in the mother's serum.[35] Additional prenatal or postnatal testing is suggested to confirm any suspected case. 

A definitive diagnosis of KS is typically made by prenatal or postnatal karyotype analysis or chromosomal microarray testing. A reference laboratory that performs these examinations frequently is recommended. At least 20 cultured metaphase lymphocytes should be examined to confirm the diagnosis by karyotyping.[36] Adding fluorescence in situ hybridization (FISH) technology improves accuracy.[37]

A baseline DEXA scan is recommended for all KS patients as these men typically have a lower bone mineral density and a higher risk of osteoporosis than unaffected males due to hypogonadism, low vitamin D levels, and other factors.[16][17] 

Treatment / Management

Earlier diagnosis of KS (often in utero) has permitted earlier developmental evaluation and intervention services to assist with neuropsychological development. Speech-language and motor skills delays are present in 50% to 75% of cases; therefore, proactive measures are recommended to screen for and address these delays.[28] Speech delays that are not addressed may limit self-expression, impact tolerance for frustration, and contribute to behavioral issues. In addition, hypotonia with hypermobility, pes planus, and genu valgum can affect motor development, including handwriting and self-care; therefore, physical and occupational therapy and adaptive treatments such as orthotics may be needed.[1][28]

Supplemental testosterone treatment under the supervision of a pediatric endocrinologist may prevent some of the physical manifestations of the "classic KS phenotype." Hypogonadism in KS may start early in the fetus. It plays a role in underdeveloped genitalia, cryptorchidism, reduced germ-cell number, small testicular size, and blunted "mini-puberty" of infancy. Some providers give supplemental testosterone during the first few months of life for treatment of microphallus, and because limited retrospective data suggests possible cognitive and behavioral benefits, although this is still unproven and prospective studies are ongoing.[38][39]

If cryptorchidism or an inguinal hernia is present, the infant should have appropriate surgery. The American Urological Association guidelines do not recommend hormonal treatment of cryptorchidism due to its low response rate and lack of evidence of long-term benefit.[40] However, others disagree and argue that there is little harm to hormonal therapy, that it may improve future fertility, and that it will work in a minority of individuals who would benefit by avoiding surgery.[41][42][43]

Patients with KS should be screened for autistic spectrum disorder. They are also more likely to have bone mineralization problems, significantly deficient language skills, diabetes, hypogonadism, and infertility.[5][16] For example, 44% of KS patients will likely have metabolic syndrome due to hypogonadism and obesity.[12]

In adolescence, most boys with KS will enter puberty normally, and endogenous testosterone usually supports virilization with normal penile enlargement and pubic hair development. However, these individuals may not have as much facial or body hair as expected. Supplemental testosterone may help minimize gynecomastia that often develops during adolescence. Other treatments for gynecomastia either have not been effective (aromatase inhibitors), have limited published data in KS (tamoxifen), or are invasive (surgery) and risk recurrence.[44] 

It is well known that testosterone is critical for bone growth and maintaining skeletal health in men, so early hormonal therapy may help prevent bone loss and decreased bone mineral density.[45] KS patients with osteopenia or osteoporosis will respond positively to testosterone, calcium, and vitamin D supplementation therapy and increase their bone mineral density on treatment if it is maintained long enough.[46][47] Those with more severe demineralization will need a bisphosphonate or rank ligand inhibitor.[16][48]  They should be treated and will respond like any other patient with osteopenia or osteoporosis. See our companion StatPearls reference article on "Osteoporosis in Males."[16][48]

To be properly educated about these issues, to build rapport, and to outline future monitoring and treatment plans, boys and their parents should establish care with a pediatric endocrinologist around the onset of puberty. The age to start androgen replacement is not standard and should be individualized. It may start at the time of pubertal onset or be delayed until there is clear evidence of hypogonadism, which may be in late adolescence or early adulthood. Guidelines for hormone replacement for men with hypogonadism are available from the Endocrine Society and the American Urological Association.[49][50] See our companion StatPearls reference article on "Male Hypogonadism."[29]

Advanced reproductive technology such as testicular sperm extraction (micro-TESE) has been successful in allowing up to half of the men with KS deemed "infertile" to have an opportunity to produce a biological child.[51][52] Small pockets of gonadal tissue producing sperm may be identified, extracted, and injected by intracytoplasmic sperm injection into an ovum for fertilization.[18][19]

Long-term, men with KS are more likely to develop disorders related to insulin resistance, such as type-2 diabetes, dyslipidemia, fatty liver disease, peripheral vascular disease, and thromboembolic disease. Careful screening and aggressive preventive measures are recommended. Bone mineral density may also be negatively affected, likely related to hypogonadism, so attention to bone health is essential. Some studies have documented higher rates of autoimmune disorders.[5]

Finally, the risk for certain malignancies is increased in KS patients. These malignancies include breast cancer, extragonadal germ cell tumors, and non-Hodgkin lymphoma.[53] Although the overall frequencies in KS individuals are still very low, and no routine screening is warranted, suspicious symptoms should be investigated.

Differential Diagnosis

The differential diagnosis for KS includes the following:

• Acromegaly
• Adrenogenital and gonadal-secreting tumors
• Azoospermia
• Beckwith-Weidemann syndrome
• Constitutional gigantism
• Diabetes
• Fragile X syndrome
• Hyperprolactinemia
• Hypogonadism
• Male infertility
• Marfan syndrome
• Mosaicism
• Neurofibromatosis
• Primary testicular failure
• San Filippo syndrome
• Simpson-Rosan-Golabi syndrome

Prognosis

While KS cannot be cured, early diagnosis and appropriate testosterone replacement can minimize many of the adverse effects and complications of the disorder. Even fertility can be restored in some patients with assisted reproductive technologies. Still, the average patient will see a shortened overall survival by about 5 to 6 years.[14]

Complications

Patients with KS have an increased risk of the following disorders: [1][5][12][16][27][28][54]

• Autism spectrum disorder
• Autoimmune disorders
• Azoospermia
• Behavioral disorders (anxiety, depression, ADHD, immaturity, relationship issues)
• Breast cancer 
• Cardiovascular disease
• Deep vein thrombosis
• Diabetes
• Germ cell tumors
• Gynecomastia
• Hypercholesterolemia
• Hyperlipidemia
• Hypertension
• Hypogonadism
• Increased belly fat
• Infertility
• Long leg bones
• Low libido
• Low muscular development compared to peers
• Lower IQ
• Metabolic syndrome
• Nodular thyroid disease
• Osteopenia and osteoporosis
• Pulmonary embolism
• Rheumatoid arthritis
• Small, firm testes
• Small penis size (<8 cm)
• Sparse facial and body hair
• Systemic lupus erythematosus
• Tall stature
• Tremors
• Varicose veins
• Venous stasis ulcers
• Verbal and language deficiencies

Deterrence and Patient Education

Once the diagnosis is confirmed, patients and families must be educated about the condition. It should be emphasized that KS is a genetic accident and is not inheritable. It could not have been prevented; it is nobody's "fault," and treatment is readily available. It is a genetic condition and not a disease and, therefore, cannot be "cured," but it can be treated and its negative effects minimalized.

Even fertility can now be restored in many cases using assisted reproductive techniques.[51][52][55][56] See our companion StatPearls reference articles on "Male Infertility," "Assisted Reproductive Technology (ART) Techniques," and "In Vitro Fertilization."[51][55][56]

Pearls and Other Issues

It is now much easier to diagnose KS early, which allows for improved treatment and outcomes.[1]

Pediatricians should be suspicious when there are developmental issues or small genitalia in phenotypic males.[1] Also, male patients with autism spectrum disorder and those with speech or language difficulties should be suspected of KS.[16]

Early diagnosis allows for the optional limited use of testosterone in neonates and infants less than 1 year of age. This will allow for improved growth of the associated micropenis.[57][58][59]

Hypogonadism, infertility, and small, firm testes are the clinical hallmarks of KS in adults. Definitive testing with karyotyping is indicated whenever KS is suspected.[1]

Early testosterone replacement is the mainstay of therapy.[1]

Fertility can be successfully restored in many KS patients but requires advanced assisted reproductive technologies.[52]

Enhancing Healthcare Team Outcomes

Individuals with KS require comprehensive care from an interprofessional team comprising an endocrinologist, urologist, neurologist, psychiatrist, geneticist, internist, pediatrician, psychologist, speech therapist, and physical therapist. This team collaboratively educates patients and caregivers on potential testosterone-related adverse effects, ensuring proper administration, follow-up testing, and monitoring. Reproductive endocrinologists and urologists skilled in male infertility may join the healthcare team.

As patients age, vigilance is essential for managing potential risks, including type 2 diabetes, fatty liver, breast cancer susceptibility, bone mineral density loss, and dyslipidemia. Primary care providers, including nurse practitioners, play a critical role in frequent evaluations due to increased cancer and health risks compared to the general population.

The prognosis for individuals with KS is generally guarded, with a slightly reduced lifespan and varying impacts on quality of life influenced by mental health. An interprofessional team approach remains pivotal for achieving the best possible outcomes for these patients.[60]