Klinefelter Syndrome

• Klinefelter syndrome (KS) is a chromosomal disorder characterised by the presence of one or more extra X chromosomes in a phenotypic male. The most common karyotype is 47,XXY.
• Approximately 90% of affected individuals have the non-mosaic 47,XXY pattern, while the remaining 10% exhibit mosaic forms, such as 46,XY/47,XXY. Rarer aneuploidies include 48,XXXY and 49,XXXXY.
• KS is not inherited but arises due to nondisjunction during meiosis, leading to an extra X chromosome from either maternal or paternal origin.
  
  

Introduction

• KS was first described in 1942 by Dr. Harry Klinefelter in males exhibiting tall stature, small testes, gynaecomastia, and azoospermia.
• The chromosomal basis was elucidated in 1959, confirming the 47,XXY karyotype as the most frequent form.
• KS represents the most common sex chromosome aneuploidy in males, with an estimated prevalence of 1 in 500 to 1 in 660 live male births.
• Despite this, underdiagnosis is common, with up to two-thirds of cases remaining undiagnosed. Most diagnoses occur during evaluation for male infertility or delayed puberty.

Chromosomal Origin

• Klinefelter syndrome (KS) results from the presence of one or more extra X chromosomes in a phenotypic male, most commonly presenting with a 47,XXY karyotype.
• Over 90% of individuals with KS have the non-mosaic 47,XXY karyotype. Mosaic forms (e.g., 46,XY/47,XXY) account for a smaller proportion and tend to result in milder phenotypes.
• Rarer aneuploidies include 48,XXXY and 49,XXXXY, which are associated with more severe manifestations.

Mechanism of Chromosomal Abnormality

• The extra X chromosome arises due to meiotic nondisjunction, occurring during either meiosis I or II in gametogenesis—affecting either maternal oogenesis or paternal spermatogenesis.
• The contribution from maternal and paternal nondisjunction is approximately equal (roughly 50/50).
• Advanced maternal age has been identified as a weak risk factor, primarily linked to an increased rate of maternal meiosis I errors.
• In mosaic KS, the chromosomal error arises post-zygotically, during early embryonic cell division, leading to a mixture of normal (46,XY) and aneuploid (47,XXY) cells.
  
  
  

Genotype–Phenotype Correlation

• The severity of the clinical phenotype tends to correlate with the quantity of supernumerary X chromosome material.
• Individuals with higher-order aneuploidies (e.g., 48,XXXY; 49,XXXXY) often present with more pronounced developmental delays, physical abnormalities, and intellectual disabilities compared to those with a single extra X chromosome.
• Conversely, those with mosaic karyotypes often exhibit subtler symptoms and may remain undiagnosed until adulthood.

Inheritance Considerations

• KS is not a hereditary condition and does not typically recur within families. It arises as a sporadic chromosomal event.
• There is no known increased transmission risk from an affected male to offspring since most affected men are infertile.
  
  
  
  

Overview of Chromosomal Abnormality and Testicular Dysfunction

• Klinefelter syndrome (KS) arises due to the presence of one or more supernumerary X chromosomes in a phenotypic male.
• In approximately 80–90% of cases, the karyotype is 47,XXY, while mosaicism (e.g., 46,XY/47,XXY) is seen in around 10%, leading to milder phenotypes.
• Rare variants such as 48,XXXY and 49,XXXXY result in more severe clinical manifestations.
• These chromosomal anomalies stem from meiotic nondisjunction during gametogenesis. When nondisjunction occurs post-fertilisation during mitosis, mosaic patterns emerge.
  
  

Testicular Pathology

• KS leads to progressive testicular degeneration, beginning in childhood and accelerating at puberty.
• There is early destruction of seminiferous tubules, followed by fibrosis and hyalinisation, primarily affecting Sertoli and Leydig cells.
• The result is hypergonadotrophic hypogonadism due to impaired testosterone production and severely reduced spermatogenesis.
• Despite extensive damage, focal spermatogenesis and residual normal tubules may exist, allowing potential for assisted reproductive techniques.
  
  
  

Hormonal Profile and Hypogonadism

• Individuals with KS typically have:
  • Low to low-normal serum testosterone.
  • Elevated luteinising hormone (LH) and follicle-stimulating hormone (FSH).
  • Frequently increased oestradiol due to peripheral aromatisation of androgens.
• Androgen deficiency contributes to characteristic features such as:
  • Small testes and penis.
  • Gynaecomastia.
  • Sparse facial and body hair.
  • Reduced muscle mass and physical endurance.
  • Increased abdominal adiposity.
    
    

Androgen Receptor Sensitivity and Genetic Modifiers

• Phenotypic variability in KS is partly attributed to differences in androgen receptor (AR) gene sensitivity.
• The AR gene includes CAG trinucleotide repeats; a longer CAG tract is associated with reduced androgen receptor activity and more pronounced symptoms.
• Androgen responsiveness may thus modulate the degree of hypogonadism and secondary sexual characteristics.
  
  

Epigenetic and Molecular Mechanisms

• The extra X chromosome triggers widespread DNA methylation and transcriptomic dysregulation across both sex chromosomes and autosomes.
• Organ-specific gene expression changes may account for diverse clinical features of KS, beyond endocrine dysfunction.
• Emerging evidence highlights disrupted testicular microvasculature, with impaired vascular maturation and function, further limiting testosterone release into circulation.
  
  

Effects on Growth and Development

• The presence of an additional SHOX gene in the pseudoautosomal region of the X chromosome accelerates linear growth, especially limb length, leading to disproportionately long legs.
• This growth effect is not mediated by growth hormone but attributed to direct genetic influence on growth plate activity.
  
  

Neurocognitive and Psychosocial Effects

• Brain development is variably affected, with cognitive and behavioural difficulties prevalent.
• Common challenges include:
  • Language delay (especially expressive skills).
  • Impaired executive functioning and attention regulation.
  • Social withdrawal or difficulty interpreting social cues and emotional expression.
• The extent of cognitive impairment correlates with the number of supernumerary X chromosomes. Each additional X chromosome is associated with an approximate 15-point reduction in IQ.
  
  

Systemic Comorbidities

• KS is linked to an increased risk of:
  • Type 2 diabetes and metabolic syndrome.
  • Osteopenia and osteoporosis.
  • Autoimmune conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome).
  • Breast cancer and germ cell tumours.
• These risks reflect both hormonal imbalances and aberrant X chromosome gene expression. Inflammatory and vascular mechanisms may also play a role.
  
  

Impact on Quality of Life

• Quality of life in individuals with KS is influenced by both the physical phenotype and psychosocial outcomes.
• Reduced income, physical activity, and sexual function contribute to diminished well-being.
• Studies suggest a significant correlation between phenotypic severity and reduced quality of life in affected boys and men.
  
  

Prevalence and Incidence

• Klinefelter syndrome (KS) is the most common male sex chromosome aneuploidy, with an estimated prevalence of approximately 1 in 500 to 1 in 660 live male births.
• Reported frequencies vary slightly across sources:
  • General prevalence: 1 in 500 to 1,000 males.
  • Based on newborn screening studies: around 1 in 660 males.
  • Among men undergoing infertility assessment: 3% have KS; prevalence rises to 10–15% in those with non-obstructive azoospermia.
• The overall population prevalence is higher than clinical diagnosis rates suggest, due to substantial under-recognition.
  
  
  

Diagnostic Rates and Age at Diagnosis

• Despite being common, KS remains underdiagnosed. Only 25–50% of affected individuals are identified during their lifetime.
• Diagnosis most often occurs during:
  • Evaluation of adult males for infertility or hypogonadism.
  • Adolescent assessment for tall stature, delayed puberty, or small testes.
  • Childhood evaluation for developmental delays, especially speech or motor difficulties.
  • Prenatal testing, particularly with increasing use of non-invasive prenatal testing (NIPT).
• According to the 2021 European Academy of Andrology:
  • 21% of diagnoses occur antenatally.
  • 10–12% in pre-pubertal childhood.
  • 16% during puberty.
  • 51% in adulthood.
• The average age at diagnosis is around 30 years.
  
  
  

Reasons for Underdiagnosis

• Many individuals with KS exhibit subtle or non-specific features, such as mild hypogonadism or behavioural issues, which may not prompt genetic testing.
• A significant proportion—up to two-thirds—may never receive a diagnosis.
• Approximately 25% of those with KS have no overt clinical signs on examination or history.
• Clinical inexperience with assessing testicular volume and the variable phenotypic presentation contribute to missed diagnoses.
  
  

Influence of Parental Age and Prenatal Detection

• While most KS cases arise from random nondisjunction events, a weak association exists with increased maternal age, likely due to more frequent meiotic I errors.
• There is no consistent evidence of increased risk associated with paternal age.
• The frequency of antenatal detection is rising due to:
  • Greater use of NIPT.
  • Expanded fetal anomaly screening protocols.
  • Reduced elective termination rates following prenatal diagnosis.
    
    

Global Diagnostic Variability

• Diagnostic rates vary geographically:
  • Denmark and the UK: Only about 25% of expected cases are diagnosed.
  • Australia: Detection rates may reach 50%, possibly due to broader access to screening and greater clinical awareness.
• Ethnic differences in prevalence are not well established, though one US study reported a higher frequency among Asian males compared with White males.
  
  

Associated Morbidity and Mortality

• KS is associated with a modest reduction in life expectancy, with affected individuals living, on average, 5 to 6 years less than the general male population.
• Increased risks of comorbidities—such as diabetes, cardiovascular disease, and certain cancers—contribute to this reduction.
• However, the overall mortality rate is not significantly elevated when compared with non-KS individuals, especially when appropriately treated.

• Infertility
  • Most common presenting complaint (>99% of affected men).
  • Over 90% of men with KS are azoospermic.
  • KS accounts for:
    • 3–4% of all cases of male infertility.
    • 6% in men with sperm counts <10 million/ejaculate.
    • Up to 15% in cases of non-obstructive azoospermia.
  • Karyotyping is recommended for any man with severe oligozoospermia or non-obstructive azoospermia.
    
    
• Delayed or Incomplete Pubertal Progression
  • Pubertal onset is typically on time, but progression often stalls after 1–2 years.
  • Hypogonadism typically develops from late puberty (Tanner stage 5, ~age 14).
  • Features may include reduced virilisation, sparse body/facial hair, and gynaecomastia.
    
    
• Developmental and Learning Delays
  • Expressive language delay is reported in ~40% of boys.
  • General learning difficulties (especially verbal IQ) affect >75% of individuals.
  • Some cases present with early motor delay (e.g., delayed walking).
  • Special educational needs and support are common in childhood.
    
    
• Behavioural and Social Concerns
  • Passive temperament in infancy; later behavioural dysregulation and frustration.
  • Difficulties with attention, executive functioning, and emotional regulation.
  • Increased risk of ADHD and autism spectrum disorder.
  • Social withdrawal or difficulty with peer interactions is common.
    
    
• Tall Stature
  • Affects ~30% of KS males due to SHOX gene overexpression.
  • Childhood height often shifts to a higher centile compared to siblings or mid-parental height.
  • Disproportionately long legs and eunuchoid body habitus may be noted.
    
    
• Sexual Dysfunction and Reduced Libido
  • Typically presents in adulthood; not common in adolescents.
  • May include erectile dysfunction, decreased libido, or difficulty maintaining arousal.
    
    
• History of Delayed or Absent Secondary Sexual Characteristics
  • Sparse pubic, facial, and body hair.
  • Decreased muscle mass and strength.
  • Female fat distribution with central obesity from childhood or adolescence.
    
    
• Fatigue and Lethargy
  • Common in untreated hypogonadism; often vague and underreported.
    
    
    

Less Common Historical Features

• Micropenis
  • Rare; may be present at birth in severe phenotypes due to intrauterine hypogonadism.
  • More typically, penile size is low-normal or slightly reduced.
    
    
• Cryptorchidism
  • Occasionally present at birth; contributes to differential diagnosis in neonates.
    
    
• Family History and Maternal Age
  • KS is not inherited.
  • Weak association with increasing maternal age due to higher rates of meiosis I errors.
    
    
• Psychiatric and Neurocognitive Issues
  • Higher prevalence of mood disorders (anxiety, depression), autism, schizophrenia, and substance misuse.
  • Poor self-esteem and social anxiety may be reported.
  • Difficulties with emotional expression and recognition of social cues.
    
    
• Comorbid Medical History (often revealed through review of systems)
  • Early-onset osteopenia/osteoporosis.
  • History of fractures or bone pain.
  • Type 2 diabetes or metabolic syndrome.
  • Personal or family history of autoimmune diseases (e.g., lupus, rheumatoid arthritis, thyroiditis).
  • History of breast changes or concerns (male breast cancer risk is elevated).
    
    
    

Neonatal and Prepubertal Examination

• Micropenis: Present in severe phenotypes; defined as stretched penile length ≥2.5 SD below the mean.
• Hypospadias or Cryptorchidism: Occasionally present; should prompt consideration of KS in the differential.
• Clinodactyly and Hypertelorism: Observed in some neonates, particularly in syndromic variants.
• Developmental Delay Features: May include hypotonia and poor motor coordination detectable in infancy.
• Testes: Typically normal size in early childhood; no distinguishing features until puberty.
  
  
  

Pubertal Examination

• Small Testes:
  • Hallmark clinical sign.
  • Despite initial testicular growth at puberty onset, regression typically follows with final volume <6 mL in over 95% of affected adults.
  • Testes may be firm or soft.
    
    
• Delayed or Incomplete Pubertal Development:
  • Sparse facial, axillary, and pubic hair.
  • Failure to achieve full virilisation.
    
    
• Gynaecomastia:
  • Common in late puberty (30–50%), due to altered oestradiol:testosterone ratio.
    
    
• Tall Stature with Disproportionate Limb Length:
  • Especially long legs relative to trunk and arms.
  • SHOX gene overexpression contributes to accelerated growth during childhood.
    
    
• Body Habitus:
  • Eunuchoid appearance with broad hips and narrow shoulders.
  • Increased adiposity in the lower abdomen and hips.
    
    
    

Adult Examination

• Genitalia:
  • Small, firm testes ≤4 cc in classic KS.
  • Penis typically normal in size, though may appear small in context of tall stature.
  • Sexual hair distribution remains sparse.
    
    
• Musculoskeletal:
  • Decreased muscle mass and tone, particularly in upper limbs.
  • Osteopenia or osteoporosis common; often not clinically evident until fracture occurs.
    
    
• Breast Tissue:
  • Gynaecomastia visible in up to 75% of adults.
  • Risk of breast carcinoma markedly elevated, although absolute risk remains low.
    
    
• Fat Distribution:
  • Increased central adiposity and high fat-to-muscle ratio.
    
    
• Neurological:
  • Essential tremor or Parkinsonian features observed in ~25%.
  • Coordination and fine motor skills may be impaired from childhood.
    
    
• Dentofacial Features:
  • Taurodontism in ~40%.
  • Prognathism, missing permanent teeth in some cases.
    
    
    

Examination in Syndromic Variants

• 48,XXYY / 48,XXXY / 49,XXXYY / 49,XXXXY:
  • Increasing dysmorphism, intellectual impairment, and congenital anomalies with more X chromosomes.
  • Common features include:
    • Epicanthal folds.
    • Ocular hypertelorism.
    • Radioulnar synostosis.
    • Fifth-finger clinodactyly.
    • Microcephaly and cleft palate (in 49,XXXXY).
    • Cardiac anomalies such as patent ductus arteriosus.
    • Muscular hypotonia and joint hyperextensibility.
      
      

Associated Medical Findings on Examination

• Cardiovascular:
  • Mitral valve prolapse (~55%).
  • Varicose veins (20–40%); venous ulcers more frequent.
  • Signs of venous thromboembolism or chronic venous insufficiency.
    
    
• Pulmonary:
  • Signs of recurrent chest infections or chronic lung disease in some cases.
    
    
• Endocrine/Metabolic:
  • Truncal obesity, signs of insulin resistance, or type 2 diabetes.
    
    
• Autoimmune Manifestations:
  • May include thyroid enlargement (Hashimoto's thyroiditis) or arthritic joint changes (rheumatoid arthritis).
    
    
• Behavioural/Cognitive Clues:
  • Lack of eye contact or social disengagement.
  • Speech deficits during interaction, particularly expressive language.
  • Difficulty with sequencing or verbal fluency tasks (informally noted during consultation).
    
    
    
    

Initial Diagnostic Approach

• Karyotype Analysis
  • Gold standard for confirming Klinefelter syndrome (KS).
  • Performed on peripheral blood lymphocytes.
  • Confirms presence of supernumerary X chromosome, usually 47,XXY.
  • Mosaicism (e.g., 46,XY/47,XXY) or rarer variants (48,XXXY; 49,XXXXY) detected in ~10% of cases.
  • Indicated in:
    • Non-obstructive azoospermia or severe oligozoospermia (<10 million sperm/ejaculate).
    • Primary hypogonadism with elevated LH/FSH and small testes (<5 mL).
    • Cryptorchidism, particularly if bilateral and persistent beyond 1 year.
    • Developmental delay with speech/language difficulties in toddlers (>2 years).
  • Counselling is advised before testing.
    
    
    
• Prenatal Testing
  • May identify KS via:
    • Chorionic villus sampling.
    • Amniocentesis.
    • Non-invasive prenatal testing (NIPT) from cell-free fetal DNA in maternal blood.
  • Requires confirmatory karyotyping.
  • Diagnosis does not routinely lead to termination, given generally mild phenotype compared to other trisomies.
    
    
    

Hormonal Evaluation

• Serum Total Testosterone
  • Collected early-morning (8–9 a.m.), fasting.
  • Repeat on two separate occasions.
  • Typically normal in childhood and early puberty.
  • Low or low-normal levels emerge in late puberty and persist into adulthood.
  • A level <10.4 nmol/L (<300 ng/dL) in adults is consistent with hypogonadism.
    
    
    
• Serum LH and FSH
  • Normal in childhood.
  • Begin to rise at puberty, often markedly elevated in adulthood.
  • Elevated gonadotrophins with low testosterone indicate primary testicular failure (hypergonadotropic hypogonadism).
    
    
    
• Inhibin B
  • Normal until puberty, then progressively declines.
  • Often undetectable in adults, reflecting Sertoli cell dysfunction.
  • May be useful in assessing fertility potential.
    
    
    
• Anti-Müllerian Hormone (AMH)
  • Falls before testosterone levels decline.
  • Typically not used in routine assessment due to variability in laboratory standards.
    
    
    
• Extended Hormonal Panel (select cases)
  • Estradiol, prolactin, and IGF-1 may be assessed in pubertal males.
  • Some studies note elevated estradiol and adrenal insufficiency in up to 47% of KS males.
    
    

Specialised and Ancillary Investigations

• Androgen Receptor (AR) Gene qPCR
  • Measures copy number of the AR gene on Xq11.2–q12.
  • Emerging diagnostic tool for suspected X chromosome aneuploidy.
    
    
• Histology (Testicular Biopsy)
  • Not routine; may be performed in fertility assessments.
  • Prepubertal testes: preserved seminiferous tubules with reduced germ cells.
  • Adult testes: extensive fibrosis, hyalinisation, absent spermatogenesis, and Leydig cell hyperplasia.
  • Focal spermatogenesis may exist in mosaic or less severe cases.

Imaging and Screening

• Bone Mineral Density Scan (DEXA)
  • Recommended due to increased risk of osteopenia and osteoporosis secondary to androgen deficiency.
    
    
• Echocardiography
  • To screen for mitral valve prolapse, present in over 50% of KS patients.
    
    
• Skeletal Radiography
  • May reveal radioulnar synostosis, taurodontism, and other congenital anomalies.
    
    
• Hypercoagulability Screening
  • Consider in those with thrombosis history or strong family history.
  • Justified by elevated risk of deep vein thrombosis and pulmonary embolism.
    
    
    

Diagnostic Strategy by Age

• Neonates and Infants
  • Perform karyotyping in presence of:
    • Micropenis.
    • Hypospadias.
    • Cryptorchidism.
  • Consider hormonal testing (testosterone, LH) in early postnatal months.
    
    
• Children (Toddlers to School Age)
  • Evaluate speech delay, hypotonia, or behavioural issues.
  • Developmental concerns may prompt karyotyping.
    
    
• Adolescents
  • Initiate investigation for:
    • Tall stature with small testes.
    • Pubertal delay or arrest.
    • Gynaecomastia.
    • Sparse sexual hair.
      
      
• Adults
  • Karyotyping in:
    • Primary infertility.
    • Primary hypogonadism with small testes.
    • Classic KS features (e.g., eunuchoid habitus).
    • Can be presumed in classic cases not seeking fertility, though confirmation is advised when pursuing assisted reproduction.
      
      

Other Male Sex Chromosome Aneuploidies

• 48,XXXY / 48,XXYY / 49,XXXXY
  • Tend to exhibit more severe phenotypes than classic Klinefelter syndrome (KS), with marked intellectual disability, developmental delay, and dysmorphic skeletal features.
  • Common anomalies include radioulnar synostosis, clinodactyly, and craniofacial dysmorphisms.
  • Testicular dysfunction is often more severe, with earlier onset of androgen deficiency and infertility.
  • Diagnosis is confirmed via chromosomal karyotype.
    
    
• 47,XYY Syndrome
  • Typically presents with normal testicular size and less pronounced hypogonadism.
  • Behavioural traits may include impulsivity or learning challenges, but physical stigmata are minimal.
  • Fertility is generally preserved.
  • Diagnosis by karyotype analysis distinguishes it from KS.
    
    
    

Central (Secondary) Hypogonadism

• Caused by hypothalamic or pituitary disorders such as:
  • Pituitary macroadenomas
  • Craniopharyngiomas
  • Infiltrative disorders (e.g., sarcoidosis, haemochromatosis)
• Unlike KS, patients do not typically have small testes or tall stature.
• Laboratory findings show:
  • Low serum testosterone
  • Inappropriately normal or low LH and FSH
• Imaging (e.g., MRI of the pituitary) is often necessary.
• No associated developmental or behavioural abnormalities.
  
  
  

Marfan Syndrome

• A connective tissue disorder with phenotypic overlap, especially tall stature and long limbs.
• Distinguishing features include:
  • Arachnodactyly, pectus excavatum, scoliosis
  • Lens dislocation and aortic root dilation
• Family history may be suggestive.
• Diagnostic tools include:
  • Echocardiography (aortic dilation)
  • Slit-lamp eye examination (lens abnormalities)
  • Genetic testing for FBN1 mutations
    
    

Fragile X Syndrome

• Leading cause of inherited intellectual disability.
• Presents with:
  • Macroorchidism, especially post-puberty
  • Prominent ears, long face, hyperactivity, autism spectrum behaviours
• Unlike KS, testosterone levels are normal, and there is no testicular fibrosis.
• Confirmed via FMR1 gene analysis.
  
  

Mosaicism

• Males with 46,XY/47,XXY mosaicism may present with:
  • Milder phenotypes
  • Larger testicular size
  • Higher chance of fertility
• Karyotype analysis may miss low-percentage mosaics; thus, skin fibroblast or buccal cell analysis may be needed in suspected cases.
  
  

Other Causes of Developmental Delay

• Broader differential includes:
  • Autism spectrum disorder
  • Attention deficit hyperactivity disorder (ADHD)
  • Dyslexia
• In contrast to KS, many of these conditions involve global developmental delay including receptive comprehension, while KS typically affects expressive language.
• Investigation involves:
  • Educational psychology assessment
  • Speech and language evaluation
  • Karyotype in suspected genetic syndromes
    
    

Genetic and Syndromic Mimics

• Sanfilippo Syndrome: progressive neurodegeneration and coarse facial features.
• Simpson-Golabi-Behmel Syndrome: pre- and postnatal overgrowth, intellectual disability.
• Beckwith-Wiedemann Syndrome: macroglossia, organomegaly, hemihypertrophy.
• Neurofibromatosis Type 1: café-au-lait spots, neurofibromas, optic gliomas.
• Constitutional Gigantism / Acromegaly:
  • Increased growth hormone (GH) production; may show coarse facial features and soft tissue overgrowth.
  • Confirmed by measuring IGF-1, GH suppression test.
• Hyperprolactinaemia:
  • May cause secondary hypogonadism and infertility.
  • Detected by elevated serum prolactin, often with galactorrhoea.
• Primary Testicular Failure (non-KS):
  • May be due to orchitis, chemotherapy, radiation, or torsion.
  • Distinguished from KS by history of insult and absence of chromosomal abnormality.
    
    

General Principles

• Management should be tailored to the age at diagnosis, clinical phenotype, and individual needs.
• A multidisciplinary team approach involving endocrinologists, paediatricians, fertility specialists, speech therapists, psychologists, and primary care physicians is ideal, especially for patients with complex needs.
• Key goals include:
  • Testosterone replacement
  • Fertility planning
  • Neurodevelopmental support
  • Monitoring and prevention of comorbidities
    
    
    

Early-Life Management (Antenatal and Childhood)

• Early diagnosis provides an opportunity for targeted support but may not improve long-term outcomes.
• Paediatric assessment is essential to guide individualised interventions for:
  • Speech and language delay
  • Learning difficulties
  • Psychosocial development
• Speech therapy, special education plans, and psychological counselling are often beneficial.
• Ongoing developmental monitoring should continue into adolescence.
• Testosterone therapy is not routinely indicated in childhood, but short-term low-dose treatment may be considered for micropenis or early signs of hypogonadism under specialist guidance.
  
  
  

Testosterone Therapy

• Initiation is based on either:
  • Biochemical hypogonadism: Low early-morning testosterone from Tanner stage 5 onward.
  • Clinical hypogonadism: Delayed/stalled puberty, gynaecomastia, persistent high BMI, or micropenis.
• Rising LH/FSH alone is not an indication for treatment.
• Therapy should be initiated by a paediatric endocrinologist, and families should receive counselling regarding fertility before treatment begins.
  
  

• Testosterone therapy should be offered to all men with KS and clinical/biochemical hypogonadism unless there is an immediate plan for fertility treatment.
• Delay treatment if TESE/mTESE for sperm retrieval is being considered.
• Lifelong testosterone therapy helps prevent:
  • Osteoporosis
  • Metabolic syndrome
  • Mood disturbances
    
    

• Transdermal gels are preferred during puberty for gradual titration.
• Long-acting intramuscular injections (e.g. testosterone undecanoate) are useful in adults.
• Monitoring includes serum testosterone, LH/FSH, and haematocrit every 3–6 months initially, then annually.
  
  
  

Fertility Management

• Over 90% of men with KS are azoospermic, but up to 44% may have focal spermatogenesis amenable to sperm retrieval via:
  • Testicular sperm extraction (TESE)
  • Microsurgical TESE (mTESE)
• Cryopreservation of viable sperm for intracytoplasmic sperm injection (ICSI) is possible in some.
• Donor sperm or adoption remain primary reproductive options for many.
• Sperm retrieval success is highest in young adults, and retrieval in those <16 years is not recommended due to low yield.
• Thorough pre-procedural counselling is vital to manage expectations and emotional responses, especially given the potential psychological distress of infertility.
  
  
  

Prevention and Monitoring of Comorbidities

• KS is associated with increased risk of:
  • Type 2 diabetes (prevalence: 10–39%)
  • Metabolic syndrome
  • Hypertension
  • Dyslipidaemia
• Risk is only partially reduced by testosterone; lifestyle advice, annual screening (weight, waist circumference, BP, fasting glucose, HbA1c, lipids), and standard therapies are essential.
  
  

• Testosterone deficiency contributes to poor peak bone mass.
• DXA scan:
  • Recommended every 2 years if vitamin D deficiency or risk factors are identified during adolescence.
  • Baseline DXA in adults, with repeat scans depending on risk.
• Ensure adequate vitamin D and calcium.
• Treat osteoporosis according to standard guidelines if diagnosed.
  
  
  

• KS increases the risk of male breast cancer, although lifetime risk remains low.
• Clinical breast exam at diagnosis and periodically thereafter is advised.
  
  

• Cognitive, behavioural, and executive function impairments can persist into adulthood.
• Referral to neuropsychology is often required to manage:
  • Social functioning
  • Emotional regulation
  • Executive dysfunction
• Support with employment, independent living, and mental health is important, particularly for those with severe phenotypes.
  
  

Life Expectancy and Mortality

• Individuals with KS have a slightly reduced life expectancy, with an estimated shortening of lifespan by 1.5 to 6 years.
• This increased mortality is primarily due to:
  • Type 2 diabetes mellitus
  • Cerebrovascular disease
  • Breast cancer
  • Osteoporosis-related fractures
• The risk of mortality is not solely attributable to untreated hypogonadism; some risk appears intrinsic to the underlying chromosomal aneuploidy.
  
  

Morbidity Patterns

• Morbidity is increased in KS across a broad spectrum of conditions, including:
  • Endocrine and metabolic diseases (e.g., diabetes, obesity)
  • Cardiovascular disease
  • Skeletal complications, such as osteopenia and osteoporosis, leading to higher fracture rates
  • Malignancies, particularly male breast cancer
• Morbidity tends to be more pronounced in individuals with severe phenotypes, which are also more likely to be diagnosed and reported.
  
  

Impact of Testosterone Therapy

• Testosterone replacement therapy can reduce morbidity related to:
  • Hypogonadism
  • Osteoporosis
  • Metabolic syndrome
• However, it does not eliminate all risks, particularly those directly linked to the presence of an extra X chromosome.
  
  

Socioeconomic and Psychosocial Factors

• Individuals with KS often face socioeconomic disadvantages, which may contribute to poorer health outcomes:
  • Lower levels of educational attainment
  • Higher unemployment rates
  • Lower income levels
  • Earlier retirement age
• These factors may partly explain increased comorbidities and decreased longevity independent of biological risk.
  
  
  

Diagnosis and Disease Burden

• Many individuals with KS remain undiagnosed, particularly those with milder phenotypes.
• As a result, existing epidemiological data may be skewed towards more severe cases, potentially overestimating average morbidity and mortality.
• Early diagnosis and timely intervention can significantly reduce the burden of disease, improve quality of life, and support better psychosocial outcomes.
• Fertility is not always lost—assisted reproductive technologies can offer biological paternity to some men with KS.
  
  

Endocrine and Reproductive Complications

• Hypogonadism: A hallmark of KS, manifesting as low testosterone levels, poor virilisation, and small firm testes.
• Azoospermia and Infertility: Present in over 90% of affected males due to impaired spermatogenesis.
• Gynecomastia: Occurs in up to three-quarters of adult men, driven by altered oestrogen:testosterone ratio.
• Small genitalia: Includes a small penis (<8 cm) and reduced testicular volume, especially after mid-puberty.
• Low libido: Secondary to testosterone deficiency.
• Delayed or incomplete pubertal development: Due to inadequate androgen production.
  
  

Metabolic and Cardiovascular Complications

• Metabolic Syndrome: Nearly half of KS adults meet diagnostic criteria; features include central obesity, insulin resistance, and dyslipidaemia.
• Type 2 Diabetes Mellitus: Prevalence ranges from 10% to 39%, partly driven by androgen deficiency and possible epigenetic mechanisms.
• Hypercholesterolaemia and Hyperlipidaemia: Common findings, contributing to increased cardiovascular risk.
• Hypertension: Frequently observed in adulthood.
• Increased visceral fat: Central adiposity is a common phenotypic feature beginning in childhood.
• Low muscle mass: Present even after testosterone therapy, partly due to early hypogonadism.
  
  
  

Thromboembolic and Vascular Complications

• Deep Vein Thrombosis and Pulmonary Embolism: Significantly increased risk; studies suggest a hypercoagulable state in KS.
• Varicose Veins and Venous Stasis Ulcers: Particularly in the lower limbs.
• Mitral Valve Prolapse: Seen in over 50% of patients in some cohorts.
• Atherosclerosis and Ischaemic Heart Disease: Elevated risk compared with the general population.
  
  

Oncological Risks

• Male Breast Cancer: Up to 50-fold increased risk; although lifetime risk remains below 1%.
• Extragonadal Germ Cell Tumours: Especially mediastinal tumours in adolescence or early adulthood.
• Non-Hodgkin Lymphoma and Testicular Tumours: Observed at slightly increased frequencies.
  
  

Neurodevelopmental and Cognitive Issues

• Language and Verbal Deficiencies: Particularly in expressive language, with deficits in fluency, comprehension, and verbal encoding.
• Learning Disabilities: Reported in more than 70% of KS individuals, including reading difficulties and dyslexia.
• Lower IQ: Although most have normal intelligence, average IQ tends to be 10-15 points lower than peers.
• Motor Coordination Deficits: Including fine and gross motor delays, hypotonia, and persistent tremors.
  
  

Neuropsychiatric and Behavioural Complications

• Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD): Risk is increased relative to the general population.
• Anxiety, Depression, and Low Self-esteem: Common, often exacerbated by social difficulties and neurocognitive limitations.
• Emotional Immaturity and Poor Relationship Skills: Related to deficits in executive function and emotional regulation.
  
  

Autoimmune Disorders

• KS is associated with higher prevalence of autoimmune conditions, such as:
  • Systemic Lupus Erythematosus
  • Rheumatoid Arthritis
  • Hashimoto's Thyroiditis
  • Type 1 Diabetes Mellitus
  • Sjögren Syndrome
• These are likely influenced by the additional X chromosome and altered immune regulation.
  
  

Skeletal and Musculoskeletal Complications

• Osteopenia and Osteoporosis: Affecting up to 40% of KS males; low bone mineral density begins in mid-puberty due to insufficient androgenisation.
• Taller-than-average stature: Usually due to SHOX gene overexpression; patients often have disproportionately long limbs.
• Tremors: Including essential tremor and Parkinson-like syndromes.
• Scoliosis and other skeletal anomalies: May be present in variant karyotypes.

Other Complications

• Nodular Thyroid Disease
• Sparse Facial and Body Hair
• Clinodactyly
• Speech and Occupational Difficulties
• Social Isolation and Difficulties with Peer Interaction
  
  

1. Abramsky L, Chapple J. 47,XXY (Klinefelter syndrome) and 47,XYY: Estimated rates of aneuploidy and associated morbidity and mortality. J Med Genet. 1997;34(8):597–604.
2. American College of Medical Genetics and Genomics. Noninvasive prenatal screening for fetal aneuploidy. ACMG Practice Resource. 2016.
3. American College of Obstetricians and Gynecologists. Screening for fetal chromosomal abnormalities. Practice Bulletin No. 226. 2020.
4. Belling K, Russo F, Jensen AB, et al. Klinefelter syndrome comorbidities linked to increased X chromosome gene dosage and altered protein interactome activity. Hum Mol Genet. 2017;26(7):1219–1229.
5. Bojesen A, Juul S, Gravholt CH. Morbidity and mortality in KS: A Danish registry study. J Clin Endocrinol Metab. 2004;89(9):4232–4238.
6. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2003;88(2):622–626.
7. Bojesen A, Kristensen K, Birkebaek NH, et al. The metabolic syndrome is frequent in Klinefelter's syndrome and is associated with abdominal obesity and hypogonadism. Diabetes Care. 2006;29(7):1591–1598.
8. Bonomi M, Rochira V, Pasquali D, et al. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. J Endocrinol Invest. 2017;40(2):123–134.
9. British Society for Paediatric Endocrinology and Diabetes. Clinical guidelines: Androgen therapy in paediatric patients. BSPED. 2020.
10. Butler G, Srirangalingam U, Faithfull J, et al. Klinefelter syndrome: going beyond the diagnosis. Arch Dis Child. 2023;108(3):166–171.
11. Carlomagno G, et al. Contrast-enhanced ultrasonography reveals microvascular impairment in testes of men with Klinefelter syndrome. Andrology. 2022;10(1):164–171.
12. Chang S, et al. Risk of thromboembolism in Klinefelter syndrome: A population-based study. Thromb Res. 2019;179:91–96.
13. Close S, et al. Phenotype and quality of life in Klinefelter syndrome: a linear regression analysis. J Pediatr. 2015;167(3):650–656.
14. Daly RF. Mental illness and patterns of behavior in 10 XXY males. J Nerv Ment Dis. 1969;149(4):318–327.
15. Davis S, Howell S, Wilson R, et al. Advances in the interdisciplinary care of children with Klinefelter syndrome. Adv Pediatr. 2016;63(1):15–46.
16. Deebel NA, et al. Spermatogonial presence across life stages in Klinefelter syndrome. Fertil Steril. 2020;114(6):1209–1218.
17. Ferlin A, Selice R, Di Mambro A, et al. Role of vitamin D levels and vitamin D supplementation on bone mineral density in Klinefelter syndrome. Osteoporos Int. 2015;26(8):2193–2202.
18. Gravholt CH, Chang S, Wallentin M, et al. Klinefelter Syndrome: Integrating genetics, neuropsychology, and endocrinology. Endocr Rev. 2018;39(4):389–423.
19. Groth KA, Skakkebæk A, Høst C, et al. Clinical review: Klinefelter syndrome—a clinical update. J Clin Endocrinol Metab. 2013;98(1):20–30.
20. Herlihy AS, Halliday JL, Cock ML, McLachlan RI. The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison. Med J Aust. 2011.
21. Herlihy AS, McLachlan RI, Gillam L, et al. The psychosocial challenges of Klinefelter syndrome. J Pediatr Endocrinol Metab. 2011;24(3–4):223–230.
22. Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex-determining mechanism. Nature. 1959;183(4657):302–303.
23. Jha P, Sheth D, Ghaziuddin M. Autism spectrum disorder and Klinefelter syndrome. Eur Child Adolesc Psychiatry. 2007;16(5):305–308.
24. Johannsen TH, et al. Testicular blood flow and vascular maturation in Klinefelter syndrome. J Clin Endocrinol Metab. 2020;105(8):e2940–e2949.
25. Lanfranco F, et al. Klinefelter's syndrome. Lancet. 2004;364(9430):273–283.
26. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male. Fertil Steril. 2021;116(1):36–47.
27. Ross JL, Kushner H, Kowal K, et al. Androgen treatment effects on motor function, cognition, and behavior in boys with Klinefelter syndrome. J Pediatr. 2017;185:193–199.e4.
28. Salbenblatt JA, et al. Klinefelter syndrome in adolescence and adulthood. Pediatrics. 1985;75(3):445–450.
29. Skakkebæk A, et al. Cardiometabolic and neurological morbidity in KS: A nationwide study. J Clin Endocrinol Metab. 2020;105(3):e139–e149.
30. Skakkebæk A, et al. Neurocognitive and psychiatric phenotype in Klinefelter syndrome. Am J Med Genet C Semin Med Genet. 2013;163C(1):27–38.
31. Skakkebæk A, et al. Quality of life in men with Klinefelter syndrome: a population-based study. J Clin Endocrinol Metab. 2018;103(2):639–647.
32. Swerdlow AJ, Higgins CD, Schoemaker MJ, et al. Mortality and cancer incidence in Klinefelter syndrome. J Clin Endocrinol Metab. 2005;90(12):6516–6522.
33. van Rijn S, Swaab H, Aleman A, Kahn RS. Social behaviour and autism traits in a sex chromosomal disorder: Klinefelter (47,XXY) syndrome. J Child Psychol Psychiatry. 2008;49(6):640–648.
34. Wikström AM, Dunkel L. Testicular function in Klinefelter syndrome. Horm Res. 2002;57(2):68–73.
35. Zitzmann M, et al. European Academy of Andrology guidelines on Klinefelter syndrome. Andrology. 2021;9(1):145–167.