Klinefelter Syndrome

para>Prenatal diagnosis is incidental by karyotyping cells obtained from amniocentesis or chorion villus sampling.

COMMONLY ASSOCIATED CONDITIONS

Clinical manifestations of hypogonadism
- Infertility (>99%)
- Azoospermia (>95%)
- Osteopenia/osteoporosis (50%)
- Erectile dysfunction
Neurodevelopmental sequelae
- Gross motor delay or dysfunction
- Learning disabilities: speech, language, and reading difficulties (most common)
- Autism spectrum behavior
- ADHD, attention deficits
- Emotional and behavior problem
Cardiovascular and metabolic disorders
- Thromboembolic disease
- Mitral valve prolapse and aortic valve disease
- Metabolic syndrome and diabetes
Autoimmune diseases (5)[B]
- Addison disease
- Diabetes mellitus type 1
- Multiple sclerosis
- Acquired hypothyroidism
- Rheumatoid arthritis
- Sj ¶gren syndrome
Systemic lupus erythematosus malignancies (rare)
- Breast cancer (>50 times risk than the general population)
- Extragonadal germ cell tumors, mainly mediastinal (>65 times risk than the general population)

DIAGNOSIS

HISTORY

Adolescence: delayed or absent puberty or persistent gynecomastia; learning disabilities, psychosocial problems, psychiatric illness
Middle age: erectile dysfunction, infertility, decreased libido
Older age: metabolic syndrome, osteoporosis

PHYSICAL EXAM

Presentation is variable, with most patients appearing physically normal (1)[C].
Small, firm testes (4 to 6 mL) (95%)
Eunuchoid body habitus (long legs, short torso, narrow shoulders, broad hips)
Decreased facial hair (60 " 80%)
Gynecomastia (38 " 75%)
Decreased muscle strength (70%)
Decreased pubic hair (30 " 60%)
Varicose veins (40%)
Sparse facial and body hair (88%); female pubic hair distribution (53%)
Increased fat-to-muscle ratio; abdominal adiposity
Mitral valve prolapse
Specific mild dysmorphic features (6)[C]
- Clinodactyly (74%)
- Hypertelorism (69%)
- Mild elbow dysplasia (36%)
- High-arched palate (37%)

Pediatric Considerations

<10% diagnosed before puberty
Cryptorchidism in a prepubescent child with behavioral problems, learning disabilities, and tall stature may indicate the diagnosis (7).

DIFFERENTIAL DIAGNOSIS

Primary hypogonadism (elevated follicle-stimulating hormone [FSH] and luteinizing hormone [LH])
- Congenital
  - Pure gonadal dysgenesis
  - Congenital anorchia
  - Hemochromatosis
Acquired
- Mumps orchitis
- Injury to the testicles
- Chemotherapy or radiation therapy
Secondary hypogonadism (low FSH/LH)
- Kallmann syndrome
Other
- Marfan syndrome
- Fragile X syndrome
- Pituitary tumor
- Inflammatory disorders: sarcoidosis, TB, histiocytosis
- HIV/AIDS
- Medications: steroids, opiate pain medication
- Obesity
- Old age

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Confirm diagnosis of primary hypogonadism (more apparent after puberty)
- Testosterone levels can be normal or low.
- Elevated gonadotropins: FSH, LH
- Low insulin-like factor 3, Inhibin B, antim ¼llerian hormone (1)
Karyotype analysis to confirm genetic abnormality
- Cytogenetic analysis (karyotype)

Follow-Up Tests & Special Considerations

Fertility
- Semen analysis
- Most men are infertile; although rare, fertility is possible in mosaics.
Screening for associated conditions
- Look for metabolic abnormalities; fasting glucose, lipids, thyroid function.
- Vitamin D levels
Adequacy of androgen replacement
- Testosterone levels
Chest x-ray to rule out mediastinal tumor
Bone density screening
Echocardiogram to evaluate for valve disease
Testes and breast ultrasound

Test Interpretation
Testicular biopsy in an adult demonstrates hyalinization of the seminiferous tubules and hyperplasia of Leydig cells.

TREATMENT

GENERAL MEASURES

Preventive dental care
Calcium and vitamin D supplementation

MEDICATION

First Line
Testosterone therapy

Benefits
- Develops secondary male sex characteristics
  - Increases body hair and penis length and improves libido
  - May reduce gynecomastia and abdominal adiposity and increase muscle mass (8)[C] (not replicated in all studies)
- Improves libido/decreases erectile dysfunction
- Metabolic
  - Improves bone density (8)[C]
  - May lower serum total cholesterol (8) and improve metabolic syndrome (9)[C]
- Other
  - May improve mood, energy level, cognition, and social functioning and decrease aggression (8)[B]
  - May possibly reduce hypercoagulability (10)
Risks and side effects
- Erythrocytosis
- Acne
- 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
Contraindications
- Prostate cancer
- Liver disease
Medicine vehicle (11)[C]
- IM injection (most convenient)
- Transdermal gel (most effective adult)
- Transdermal patch
- Subcutaneous implant
- Buccal adhesive

Pediatric Considerations

Testosterone therapy, beginning at start of puberty. Watch for dosage changes. Consider starting with an oral or transdermal agent (11)[C]. Consider postponing testosterone therapy in adolescents wishing to pursue sperm cryopreservation or testicular sperm extraction (TESE) because long-term depot testosterone administration decreases spermatogenesis (6)[C].
Monitor bone age every 2 to 3 years (1)[C].
Perform DXA scan 1 to 2 times in childhood (1)[C].
Micropenis in infants and children has been treated with topical or IM testosterone (12)[C].

ISSUES FOR REFERRAL

Most men have azoospermia at time of diagnosis. Adolescents and young men wishing to preserve fertility should be referred for cryopreservation of existing sperm if sperm are present on semen analysis.
If viable sperm are noted on semen analysis, fertility treatment may be offered using TESE or micro-TESE followed by intracytoplasmic sperm injection (ICSI).
Sperm recovery rate = 66% and live birth success= 45% (7)[C]; embryos fertilized using TESE with ICSI are at a modestly increased risk of cytogenetic abnormalities, but most of the resulting pregnancies are healthy.
Boys born to fathers with KS do not have a higher incidence of KS (7)[C].
Optimum age at which to attempt TESE is unknown, but success rates decrease with increasing age (7)[C].

ADDITIONAL THERAPIES

Multidisciplinary team is vital: physical, occupational, and speech therapists, along with infertility specialists, endocrinologists, geneticists, and physiotherapists (1),(11)[C].

SURGERY/OTHER PROCEDURES

Mastectomy can be performed to correct gynecomastia and reduce the risk of breast cancer, which can be a cause of psychological strain.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

Every 3 months then annual metabolic screening: lipid, glucose, and thyroid function (11,13)[C]
Annual clinical breast exam ± breast imaging
Bone density testing every 2 to 10 years
Testosterone levels every 3 months once on treatment until normalized then annually (11,13)[C]

PATIENT EDUCATION

Presentation is variable, with most patients appearing physically normal (1). Patients are likely infertile, but there may be options for reproductive therapy.
There should be careful thought and discussion between the patient and the provider about the risks and benefits of androgen replacement. Patients should know that testosterone can induce puberty and increase libido.
There is high incidence of learning disabilities and psychiatric illness. Appropriate therapy should be used.
Risk of diabetes and importance of regular screening and maintaining a healthy weight
Risk of osteoporosis and importance of calcium, vitamin D, and weight-bearing exercise
Regular dental care due to taurodontism.American Association for Klinefelter Syndrome Information and Support: www.aaksis.org
Klinefelter Syndrome Support Group: http://klinefeltersyndrome.org

PROGNOSIS

Hypogonadism is permanent.
There is an increased risk for comorbidities associated with KS.
On average, adults have modestly reduced, verbal reasoning, language skills, and motor dexterity.
Increased number of X chromosomes is correlated with increased phenotypic severity.
50% increase in mortality risk and a 70% increase in risk of being admitted to the hospital (3).

REFERENCES

11 Aksglaede L, Link K, Giwercman A, et al. 47,XXY Klinefelter syndrome: clinical characteristics and age-specific recommendations for medical management. Am J Med Genet C Semin Med Genet. 2013;163C(1):55 " 63.22 Verri A, Cremante A, Clerici F, et al. Klinefelter 's syndrome and psychoneurologic function. Mol Hum Reprod. 2010;16(6):425 " 433.33 Bojesen A, Gravholt CH. Morbidity and mortality in Klinefelter syndrome (47,XXY). Acta Paediatr. 2011;100(6):807 " 813.44 Ottesen AM, Aksglaede L, Garn I, et al. Increased number of sex chromosomes affects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy. Am J Med Genet A. 2010;152A(5):1206 " 1212.55 Seminog OO, Semiong AB, Yeates D, et al. Associations between Klinefelter 's syndrome and autoimmune diseases: English national record linkage studies. Autoimmunity. 2015;48(2):125 " 128.66 Zeger MP, Zinn AR, Lahlou N, et al. Effect of ascertainment and genetic features on the phenotype of Klinefelter syndrome. J Pediatr. 2008;152(5):716 " 722.77 Gies I, Unuane D, Velkeniers B, et al. Management of Klinefelter syndrome during transition. Eur J Endocrinol. 2014;171(2):R67 " R77.88 Wang C, Cunningham G, Dobs A, 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 Endocrinol Metab. 2004;89(5):2085 " 2098.99 Gravholt CH, Jensen AS, H ¸st C, et al. Body composition, metabolic syndrome and type 2 diabetes in Klinefelter syndrome. Acta Paediatr. 2011;100(6):871 " 877.1010 Zitzmann M, Junker R, Kamischke A, et al. Contraceptive steroids influence the hemostatic activation state in healthy men. J Androl. 2002;23(4):503 " 511.1111 Groth KA, Skakkeb ¦k A, H ¸st C, et al. Clinical review: Klinefelter syndrome " a clinical update. J Clin Endocinol Metab. 2013;98(1):20 " 30.1212 Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol. 2007;4(4):192 " 204.1313 H ¸st C, Skakkeb ¦k A, Groth KA, et al. The role of hypogonadism in Klinefelter syndrome. Asian J Androl. 2014;16(2):185 " 191.

ADDITIONAL READING

Radicioni AF, Ferlin A, Balercia G, et al. Consensus statement on diagnosis and clinical management of Klinefelter syndrome. J Endocrinol Invest. 2010;33(11):839 " 850.
Wistuba J. Animal models for Klinefelter 's syndrome and their relevance for the clinic. Mol Hum Reprod. 2010;16(6):375 " 85.

CODES

ICD10

Q98.4 Klinefelter syndrome, unspecified
Q98.1 Klinefelter syndrome, male with more than two X chromosomes
Q98.0 Klinefelter syndrome karyotype 47, XXY
Q98.5 Karyotype 47, XYY
Q98.3 Other male with 46, XX karyotype

ICD9

758.7 Klinefelters syndrome

SNOMED

Klinefelter syndrome (disorder)
Klinefelters syndrome, XXY
Klinefelter's syndrome XXXY (disorder)
Klinefelter's syndrome, XXYY (disorder)
Klinefelter's syndrome - male with 46 XX karyotype (disorder)

CLINICAL PEARLS

Klinefelter syndrome males have ≥1 additional X chromosome (XXY karyotype) with associated features of hypergonadotropic hypogonadism.
Accounts for 3% of male infertility
Most men do not have "textbook features " and therefore, frequently remain undiagnosed until adulthood.
Testosterone therapy, beginning in adolescence, has many benefits.
Semen cryopreservation or TESE followed by ICSI are current options to achieve fertility.
More research is needed especially on a follow-up protocol.
Affected men have an increased risk for germ cell tumors.

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