Klinefelter Syndrome– Causes, Symptoms, Diagnosis, Treatment and Ongoing care
- Klinefelter syndrome is a common genetic abnormality that presents in males who have ≥1 additional X chromosomes in many or all body cells.
- Presentation is highly variable; many patients do not have the “textbook” features.
- It is a common cause of primary hypogonadism in males.
- It is usually undiagnosed before puberty and many present in adulthood with infertility.
- Affects approximately 1.72 per 1,000 males
- Significantly underdiagnosed:
- Only 25% diagnosed in their lifetime
- Only 4–10% diagnosed before puberty
- Accounts for 3% of male infertility
Risk increases with maternal age.
- Mutations are spontaneous and patients have no family history.
- It is usually a result of maternal meiotic nondisjunction.
- Primary hypogonadism with variable Leydig cell function
- Low or low-normal testosterone
- High or high-normal gonadotropins (LH and FSH)
- Unclear whether many aspects of syndrome are caused by hormonal abnormalities or extra X chromosome
- ∼90% have the XXY karyotype, which is caused by meiotic nondisjunction of the X chromosome during gametogenesis.
- ∼10% have a mosaic karyotype, caused by nondisjunction of the X chromosome during early mitosis of the zygote.
- Prenatal diagnosis is possible by karyotyping cells obtained from amniocentesis.
- Parents should be counseled about the highly variable phenotypic range of Klinefelter syndrome and the risks associated with amniocentesis.
Commonly Associated Conditions
- Azoospermia and infertility (>99%)
- Gynecomastia (common)
- Developmental abnormalities (common):
- Learning difficulties, especially with language development
- Gross motor delay
- Autism spectrum behavior
- Psychiatric illness (common)
- problems with regulation of emotion and behavior
- psychotic disorder
- Cardiovascular disorders (common):
- Thromboembolic disease
- Recurrent leg ulcers owing to venous insufficiency and postthrombotic syndrome
- Mitral and aortic valve disease
- Metabolic disorders (common):
- Metabolic syndrome and diabetes
- Essential tremor (common)
- Taurodontism (enlargement of the pulp and thinning of the surface of the teeth) (common)
- Autoimmune disease (uncommon)
- Malignancies (rare):
- Breast cancer
- Mediastinal germ cell tumors
- Fertility history (infertility nearly universal)
- Learning disabilities, poor school performance
- Psychosocial problems and psychiatric illness
- Cardiovascular disease and risk factors
- Reproductive goals
- Small, firm testes (3–8 mL) (95%)
- Sparse facial and body hair (88%), female pubic hair distribution (53%)
- Gynecomastia (27%)
- Tall, long legs, narrow shoulders, broad arm span, and abdominal adiposity
- Poor muscle tone (76%) and increased fat:muscle ratio
- Specific mild dysmorphic features (1)
- Clinodactyly (74%)
- Hypertelorism (69%)
- Mild elbow dysplasia (36%)
- High arched palate (37%)
- No pathognomonic features
- Increased incidence of congenital abnormalities of all types, undescended testes, and micropenis
- Increased BMI (on average) (1) and increased fat:muscle ratio
- Poor muscle tone
- Small penis and testicles
- Specific mild dysmorphic features (see above)
Diagnostic Tests & Interpretation
Initial lab tests
- Chromosomal analysis:
- Gold standard: Cytogenetic analysis (karyotype)
- Alternative: Barr body analysis (if diagnosis suspected, PPV = 0.86, NPV = 0.94) (2)
- Rapid polymerase chain reaction technique looking at the copy number of the androgen receptor (AR) gene, (located to Xq11.2–q12) has been described as a screen for Klinefelter syndrome and other X-chromosome aneuploidies (3).
- Hormonal testing (neither sensitive nor specific; become more pronounced at puberty):
- Blood testosterone levels are low.
- Blood FSH & LH levels are elevated.
- Urinary gonadotropin levels are increased.
Follow-Up & Special Considerations
- Semen analysis (if indicated): Azoospermia
- Consider diabetes evaluation.
- Consider hypercoagulability screening.
Follow-Up & Special Considerations
- Consider bone density screening.
- Consider echocardiogram to evaluate for valve disease.
- Consider dental radiographs for diagnosis of taurodontism.
- XXY karyotype (or variation)
- Testicular biopsy in an adult demonstrates hyalinization of the seminiferous tubules and hyperplasia of Leydig cells.
- Secondary hypogonadism (low FSH and LH)
- Acquired primary hypogonadism (exposure to toxins, specific medications, radiation, mumps, or chronic disease)
- XYY karyotype (normal testicles and hormone levels, usually fertile)
- 46,XY/XO karyotype (features of Turner syndrome)
- Congenital anorchia (severe hypogonadism)
- Myotonic dystrophy (muscle weakness and pain, family history)
- Idiopathic hypogonadism
- Increases body hair and penis length and improves libido
- Improves bone density (4)[C]
- May reduce gynecomastia and abdominal adiposity and increase muscle mass (4)[C] (not replicated in all studies)
- May improve mood, energy level, cognition, and social functioning and decrease aggression (4)[B]
- May lower serum total cholesterol (4) and improve metabolic syndrome (5)[C]
- May possibly reduce hypercoagulability (6), improve autoimmune disease (7)[C]
- Risks and side effects:
- Lowering of HDL
- Worsening of aggression
- Peliosis hepatitis, hepatic adenomas, and hepatocellular carcinoma
- Worsening of subclinical prostate cancer
- May accelerate infertility in adolescents and young men; cryopreservation of existing sperm should be considered before starting therapy.
- Prostate cancer
- Liver disease
- Dosage and administration:
- Oral: Initial: 60–80 mg b.i.d.; maintenance: 20–60 mg b.i.d. (not available in US)
- Buccal: 30 mg b.i.d.
- Transdermal patch: 2.5–7.5 mg daily
- Transdermal gel: 5 g daily
- Intramuscular injection: 50–400 mg every 2–4 weeks
- Subcutaneous pellets: 150–450 mg every 3–6 months
- Titrate to symptoms and to maintain testosterone levels in middle of normal range. Normalization of gonadotropins may not be possible.
- Monthly during initial therapy, less frequently when dosage stabilized: CBC, liver enzymes, testosterone, FSH, LH, PSA (if appropriate)
- Serial prostate exams in older men
- Consider annual or semiannual lipid panel.
- Aggression and irritability levels
- Testosterone therapy, beginning at age 11–13, recommended by experts (8)[C]; consider semen cryopreservation before starting therapy.
- In addition to parameters listed above, monitor bone age.
- Micropenis in infants and children has been treated with topical or IM testosterone (8)[C].
- Consider pediatric endocrinology consultation.
- Preventive dental care
- Calcium and vitamin D supplementation
- Breast self-exams
Issues for Referral
- Adolescents and young men wishing to preserve fertility should be referred for cryopreservation of existing sperm if sperm are present on semen analysis.
- Fertility treatment may be offered using testicular fine-needle aspiration (TEFNA) or testicular sperm extraction (TESE) followed by in vitro fertilization. Embryos are at a modestly increased risk of cytogenetic abnormalities, but most of the resulting pregnancies are healthy.
Individual or family counseling, if indicated
- Infertility progresses rapidly during adolescence and early adulthood; therefore, adolescents should be referred for cryopreservation of sperm.
- Consider referrals for speech therapy, occupational therapy, physical therapy, and educational support.
Mastectomy can be performed to correct gynecomastia, which can be a cause of psychological strain and increase the risk of breast cancer.
- If patient is treated with testosterone, consider semiannual visits when the dosage is stabilized: Review interval history, symptoms, side effects, and therapy risks–benefits.
- If testosterone therapy is declined, annual review of interval history, physical exam, and therapy options
- Annual diabetes screening
- Annual clinical breast exam
- Periodic bone density testing
- Presentation is variable, with most patients appearing physically normal.
- Patients are likely infertile, but there are options for reproductive therapy.
- There is high incidence of learning disabilities and psychiatric illness. Appropriate therapy should be utilized.
- Risk of diabetes and importance of:
- Regular screening
- Healthy diet, exercise, and maintaining a healthy weight
- Risk of osteoporosis and importance of:
- Calcium, vitamin D, and weight-bearing exercise
- Periodic bone density testing
- Regular dental care
- Testosterone therapy risks–benefits
- American Association for Klinefelter Syndrome Information and Support, http://www.aaksis.org
- Klinefelter Syndrome Support Group, http://klinefeltersyndrome.org
- Infertility is nearly universal.
- Physical findings are generally subtle.
- Behavioral characteristics are highly variable.
- On average, adults have modestly reduced intelligence, verbal reasoning, language skills, and motor dexterity.
- Increased number of X chromosomes is correlated with increased phenotypic severity.
- Developmental and behavioral problems are common:
- 77% of children have difficulty learning to read.
- 42% of children have delayed speech.
- Motor delay
- Difficulty with social interaction (autism-like behavior)
- Sensory avoidance, gaze avoidance, and a passive demeanor
- Children are at risk of poor school performance and school failure.
- Children are more likely to require psychiatric care.
1. Zeger MP, Zinn AR, Lahlou N, et al. Effect of ascertainment and genetic features on the phenotype of Klinefelter syndrome. J Pediatr. 2008;152:716–22.
2. Kamischke A, Baumgardt A, Horst J, et al. Clinical and diagnostic features of patients with suspected Klinefelter syndrome. J Androl. 2003;24:41–8.
3. Ottesen AM, Garn ID, Aksglaede L, Juul A, Rajpert-De Meyts E et al. A simple screening method for detection of Klinefelter syndrome and other X-chromosome aneuploidies based on copy number of the androgen receptor gene. Mol Hum Reprod. 2007;13:745–50.
4. Wang C, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endo Metab. 2004;85(9):2085–98.
5. Spark RF. Testosterone, diabetes mellitus, and the metabolic syndrome. Curr Urol Rep. 2007;8:467–71.
6. Zitzmann M, Junker R, Kamischke A, et al. Contraceptive steroids influence the hemostatic activation state in healthy men. J Androl. 2002;23:503–11.
7. Koçar IH, Yesilova Z, Ozata M, Turan M, Sengül A, Ozdemir I et al. The effect of testosterone replacement treatment on immunological features of patients with Klinefelter’s syndrome. Clin Exp Immunol.2000;121:448–52.
8. Bojesen A, et al. Klinefelter syndrome in clinical practice. Nat Clin Prac. 2007;4(4):192–201.
Bruining H, Swaab H, Kas M, van Engeland H et al. Psychiatric characteristics in a self-selected sample of boys with Klinefelter syndrome. Pediatrics. 2009;123:e865–70.
Wattendorf DJ, Muenke M. Klinefelter syndrome. Am Fam Physician. 2005;72:2259–62.
758.7 Klinefelter’s syndrome
405769009 klinefelter’s syndrome, XXY (disorder)
- Klinefelter syndrome males have ≥1 additional X chromosomes in many or all body cells (XXY karyotype).
- Most men do not have the “textbook” features.
- Accounts for 3% of male infertility
- Frequently undiagnosed until adulthood
- Testosterone therapy, beginning in adolescence, has many benefits.