Endocrine: Reproductive

Klinefelter Syndrome (47 XXY)

Background

1. Definition
   • Congenital hypergonadotropic (primary) hypogonadism due to at least one additional X chromosome added to normal male karyotype of 46, XY
   • Most commonly 47 XXY
   • Most common genetic cause of human male infertility
   • Most common sex chromosomal disorder in males
   • Other names
     • XXY syndrome
     • XXY trisomy
2. General Information
   • Vastly underdiagnosed, estimated that only 25% are diagnosed during their lifetime
   • Only 10% diagnosed before puberty
     • No symptoms reliably indicate Klinefelter Syndrome (KS) in pre-pubescence
     • Most pass through puberty with only mild symptoms
3. Epidemiology
   • Incidence/Prevalence
     • ~ 1-2/1000 (0.1-0.2%) males
     • <200,000 U.S. cases per yr
     • Maybe underdiagnosed d/t mild signs and symptoms and the fact that symptoms overlap significantly w/ other conditions
   • Morbidity/Mortality
     • Life expectancy decreased (estimates range from 1.5-11.5 yrs) w/ significantly higher morbidity and mortality seen in all organ systems
     • Increased rate of hospitalization by ~ 70%
     • Endocrine
       • Central obesity and impaired glucose tolerance lead to increased frequency of metabolic syndrome (50% prevalence vs 10% in general population3, 5) and type 2 diabetes
       • Increased incidence of hypothyroidism
     • Osteoporosis, and related femoral fractures, associated w/ high mortality rate
     • Cardiovascular
       • LV dysfunction, impaired exercise performance, chronotropic incompetence, and increased carotid intima-media thickness
     • Vascular disease
       • Varicose veins, venous stasis syndrome with ulceration, thromboembolic events (most commonly pulmonary embolisms), increased intima thickness of carotids
     • Malignancy
       • Breast cancer ~ 20-50 times more common (incidence is ~ 3.7-7.5%); risk of death from breast cancer increased 60-fold
       • Increased risk of germ cell tumors, which mostly appear between ages 15-30 y/o
       • Possibly increased risk of non-Hodgkin’s lymphoma and lung cancer
     • Neurological disorders, including epilepsy

Pathophysiology

1. Pathogenesis
   • Nondisjunction event in maternal oogenesis (50% of cases) or paternal spermatogenesis leads to supernumerary X chromosome
   • Pathophysiology: Increased gene dosage of X-chromosome material
   • Most symptoms result from testosterone deficiency and gonadal dysfunction
2. Etiology/Risk Factors
   • Maternal or paternal age effect on likelihood of X chromosome non-disjunction event not clearly established
   • Generalized arterial diameter reduction, leading to chronic decreased organ perfusion, may be important risk factor for increased mortality
   • Low socioeconomic status may play role in increased mortality

Diagnostics

1. History/Symptoms
   • Infant presentation
     • Undescended testicles
     • Inability to sit up, crawl, and walk
     • Not starting to talk until later than average age
     • Low muscle power
     • Being quiet and passive
   • Childhood presentation
     • Neurocognitive, behavioral and psychiatric problems widely seen
     • Karyotyping should be considered in working up these cases, especially if absence of similar family history
     • In most cases, the physical appearance of hypogonadal/KS child does not differ from that of normal child
   • Adolescent presentation
     • Common complaints
       • Incomplete or arrested puberty
       • Chronic fatigue
       • Low aptitude for physical fitness
       • Learning or language problems, such as dyspraxia or dyslexia
       • Difficulty socializing or expressing feelings
   • Adult presentation (common complaints)
     • Bone fractures
     • Sexual dysfunction and/or decreased sexual interest
     • Infertility
   • General
     • Infertility is hallmark
       • Severe impairment of spermatogenesis leads to azoospermia in 91-99%
     • Low verbal and global intelligent quotient
       • Wide range of IQ’s have been reported, ranging from well below to well above average
   • Associated disorders include
     • Varicose veins
     • Thromboembolic disease
     • Diabetes mellitus
     • Osteopenia/Osteoporosis
     • Epilepsy
     • Psychiatric disorders
2. Physical Examination/Signs
   • Gynecomastia
     • Clinical breast and axilla exam indicated at each visit
   • Testicles are small, soft and atrophic
     • Small testicle size only consistent physical feature in KS
     • If noted, should suspect Klinefelter syndrome (and screen)
     • Testicular mal-descent seen in 25%
   • Micropenis
   • Reduced muscle tone
   • Narrower shoulders and wider hips
   • Weaker bones
   • Chronic fatigue
   • Tall stature with long legs and short trunk
     • Increase in height most significant between ages 5 and 8 (not reliable feature in deciding whom to screen in childhood)
     • Arm span does not exceed height
   • Other possible signs of testosterone deficiency
     • Decreased facial/body hair
     • Eunuchoid body habitus
3. Diagnostic Testing
   • Laboratory evaluations
     • Karyotype of peripheral blood (or via amniocentesis) is gold standard
       • Majority (80%) have characteristic 47, XXY
       • Other chromosomal abnormalities also seen: (>2 supra-numerous X chromosomes (i.e. 48 XXXY) or mosaicisms (47, XXY/46, XY)
       • Mosaics less severely affected
       • Higher aneuploidy associated with more severe pathology
     • Azoospermia diagnosed with semen analysis
     • Elevated gonadotropins (LH/FSH) and estradiol
     • Testosterone low to low-normal
     • Evaluation of comorbidities
       • DEXA scan to evaluate bone mineral density at time of diagnosis or by end of puberty
4. Diagnostic Imaging
   • Testicular sonography to evaluate testicle volume
     • Normal: between 30-60 mL
     • Affected patients have average volume between 2-10 mL

Differential Diagnosis

1. Developmental/language/behavior delays
   • Autism spectrum disorders
   • Depression
   • Anxiety
   • Endocrine dysfunction
   • Abuse
   • Fragile X syndrome
2. Infertility
   • Coital dysfunction; other genetic abnormalities (translocations, microdeletions)
3. Body habitus
   • Kallman syndrome
   • Marfan syndrome

Treatment/Management

1. Acute Treatment
   • Testosterone enanthate in oil 200 mg IM every 2-3 wks
     • Can alleviate long-term consequences of hypogonadism regarding bone development and glucose/lipid abnormalities
     • Little to no benefit in men with normal or normal-low testosterone levels
     • Has shown improved energy, endurance, mood and scholastic performance in adolescents; thus, androgen replacement should begin at puberty
     • Testosterone IM depot injections every 3 months most commonly used
     • Alternative routes: gels, implantable depot pellets
     • No specific dosage guidelines exist, endocrinology consultation is recommended
     • Treatment goal
       • Normalize LH and testosterone levels to mid-normal range
     • Testosterone can be used in conjunction with aromatase inhibitors to maintain normal testosterone-to-estradiol ratio
   • Anti-estrogens (tamoxifen)
     • Can be used to treat gynecomastia, especially if associated with pain
2. Further Management
   • Establishing a multidisciplinary team
   • Psychological support should be considered standard of care
   • Speech therapy particularly essential
   • Physical and occupational therapy should be considered
   • Fertility preservation
   • Advancing age negatively correlated with semen retrieval success rates, thus early referral important
   • Possible negative association between success rates and previous testosterone therapy
   • Can retrieve spermatozoa in semen samples from adolescents after onset of puberty
   • Semen cryopreservation can be offered to every adolescent with KS
   • Testicular sperm extraction via testicular biopsy and micro dissection may be considered in order to obtain viable testicular spermatozoa
   • Sperm retrieval rate in adult non-mosaic males: 50%
   • Testicular sperm extraction with intra-cytoplasmic sperm injection (ICSI) has resulted in successful 47, XXY male reproduction
   • Careful counseling on fertility impact of KS and options for future family building should be discussed with adolescent patient and his parents
   • Unsuccessful sperm recovery may have important emotional impact, and entire procedure remains somewhat experimental
   • Addressing comorbidities
   • Avoidance of smoking, dietary guidance/weight loss and testosterone treatment may prevent/alleviate impact of comorbidities
   • Early initiation of metformin may be appropriate for overweight adolescents with impaired fasting glucose
   • Preventive bone health measures should be initiated where appropriate (calcium and vitamin D supplementation)
3. Long-term Care
   • Genetic counseling
     • Recurrence risk in families of affected individuals not elevated
       • Syndrome results from random non-disjunction event occurring during meiosis
     • No evidence to suggest chromosomal non-disjunction event would recur in particular family
   • Annual lab studies should include
     • Serum testosterone, estrogen, SHBG, and FSH/LH levels from age 14 onward
     • Hgb/Hct, lipids, fasting glucose, HgbA1c, TSH
   • Monitoring for complications
     • Avoid elevated hematocrit levels due to increased risk of thromboembolic disease
4. Pharmacologic Side Effects
   • Testosterone enanthate
     • Acne
     • Anxiety
     • Altered libido
     • Breast soreness
     • Depression
     • Dizziness
     • Gynecomastia
     • Headache
     • Hirsutism
     • Injected site reactions
     • Male pattern baldness
     • Nausea
     • Priapism
     • Suppression of clotting factors II, VI, VII, X
   • Tamoxifen
     • Hot flashes
     • Abdominal cramps
     • Anorexia
     • Bone pain
     • Cough
     • Depression
     • Edema
     • Fatigue
     • Musculoskeletal pain
     • Nausea

Follow-Up

1. Return to Office
   • Regular follow-up at 3 months initially, then at least annually
2. Refer to Specialist
   • Consultation with developmental-behavioral pediatrician
   • Endocrinology should be involved, especially during puberty when natural testosterone levels are declining and supplemental testosterone may need close titration
   • Increased risk of dental carries requires early referral for dental care and regular dental follow-up

References

1. Bojesen A, Gravholt CH. Morbidity and mortality in Klinefelter syndrome (47, XXY). Acta Paediatrica. 2011; 100: 807-813
2. Bojeson A, Stochholm K, et al. Socioeconomic trajectories affect mortality in Klinefelter syndrome. J Clin Endocrinol Metab. 2011; 96(7): 2098-2104
3. Elfateh F, Wang R, Zhang Z, et al. Influence of genetic abnormalities on semen quality and male fertility: A four-year prospective study. Iran J Reprod Med. 2014; 12(2): 95-102
4. Foresta C, Caretta N, Palego P, et al. Reduced artery diameters in Klinefelter syndrome. Int J of Andrology. 2012; 35: 720-725
5. Gies I, et al. Management of Klinefelter syndrome during transition. European J of Endocrinology. 2014; 171(2): 67-77
6. Groth KA, Skakkebaek A, et al. Klinefelter syndrome—A clinical update. J Clin Endocrinol Metab. 2013; 98(1): 20-30
7. Hong DS, Hoeft F, Marzelli MJ, et al. Influence of the X-chromosome on neuroanatomy: Evidence from Turner and Klinefelter syndromes. Journal of Neuroscience 2014; 34(10): 3509-3516
8. Mehta A, et al. Safety and efficacy of testosterone replacement therapy in adolescents with Klinefelter syndrome. Am Urological Assoc Education and Research, Inc. 2014; 191(5): 1527-1531
9. Messina MF, Sgro DL, et al. A characteristic cognitive and behavioral pattern as a clue to suspect Klinefelter syndrome in prepubertal age. J Am Board Fam Med. 2012; 25(5): 745-749
10. Nahata L, Rosoklija I, et al. Klinefelter syndrome: Are we missing opportunities for early detection? Clin Pediatrics. 2013; 52(10): 936-994
11. Nieschlag E. Klinefelter syndrome: The commonest form of hypogonadism, but often overlooked. Dtsch Arztebl Int. 2013; 110(20): 347-353
12. Pasquali D, Arcopinto M, Renzullo A, et al. Cardiovascular abnormalities in Klinefelter syndrome. Int J Cardiol. 2013; 168(2): 754-759
13. Radicioni AF, De Marco E, Gianfrilli D, et al. Strategies and advantages of early diagnosis in Klinefelter syndrome. Molecular Human Reproduction. 2010; 16(6): 434-440
14. Rives N, Milazzo JP, Perdix A, et al. The feasibility of fertility preservation in adolescents with Klinefelter syndrome. Human Reproduction. 2013; 28(6): 468-479
15. Skakkebaek A, Bojesen A, Kristensen MK, et al. Neuropsychology and brain morphology in Klinefelter syndrome-the impact of genetics. Andrology 2014; 2: 632-640
16. Visootsak J, McGraham J. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J of Rare Disease. 2006; 1(42)

Contributor(s)

1. Anderson, Halley, DO
2. Marshall, Robert, MD MPH MISM
3. Miller, Thomas, MD
4. Scott, Carol, MD
5. Sowards, Clint, DO
6. Ausi, Michael, MD, MPH
7. Nagra, Avneet, PharmD Candidate

Updated/Reviewed: April 2024