INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1942, Klinefelter et al published a report on 9 men who had enlarged breasts, sparse facial and body hair, small testes, and an inability to produce sperm.¹ In 1959, these men with Klinefelter syndrome were discovered to have an extra sex chromosome (genotype XXY) instead of the usual male sex complement (genotype XY).

Klinefelter syndrome is the most common chromosomal disorder associated with male hypogonadism and infertility. It is defined classically by a 47,XXY karyotype with variants that demonstrate additional X and Y chromosomes. The syndrome is characterized by hypogonadism (small testes, azoospermia/oligospermia), gynecomastia in late puberty, psychosocial problems, hyalinization and fibrosis of the seminiferous tubules, and elevated urinary gonadotropin levels.

Pathophysiology

The addition of more than one extra X or Y chromosome to a male karyotype results in variable physical and cognitive abnormalities. In general, the extent of phenotypic abnormalities, including mental retardation, is directly related to the number of supernumerary X chromosomes. As the number of X chromosomes increases, somatic and cognitive development are more likely to be affected.

Skeletal and cardiovascular abnormalities can become increasingly severe. Gonadal development is particularly susceptible to each additional X chromosome, resulting in seminiferous tubule dysgenesis and infertility, as well as hypoplastic and malformed genitalia in polysomy X males. Moreover, mental capacity diminishes with additional X chromosomes. The intelligence quotient (IQ) score is reduced by approximately 15 points for each supernumerary X chromosome, but conclusions about reduced mental capacity must be drawn cautiously. All major areas of development, including expressive and receptive language and coordination, are affected by extra X chromosome material.

The major consequences of the extra sex chromosome, usually acquired through an error of nondisjunction during parental gametogenesis, include hypogonadism, gynecomastia, and psychosocial problems. Klinefelter syndrome is a form of primary testicular failure, with elevated gonadotropin levels due to lack of feedback inhibition by the pituitary gland. Androgen deficiency causes eunuchoid body proportions; sparse or absent facial, axillary, pubic, or body hair; decreased muscle mass and strength; feminine distribution of adipose tissue; gynecomastia; small testes and penis; diminished libido; decreased physical endurance; and osteoporosis. The loss of functional seminiferous tubules and Sertoli cells results in a marked decrease in inhibin B levels, which is presumably the hormone regulator of the follicle-stimulating hormone (FSH) level. The hypothalamic-pituitary-gonadal axis is altered in pubertal patients with Klinefelter syndrome.

An increased incidence of autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome, has been reported in persons with Klinefelter syndrome. This may be due to lower testosterone and higher estrogen levels because androgen may protect against (and estrogen promote) autoimmunity.

Frequency

United States

Approximately 1 in 500-1,000 males is born with an extra sex chromosome; more than 3,000 affected males are born yearly. The prevalence rate is 5-20 times higher in individuals with mental retardation than in the general newborn population.

Mortality/Morbidity

• About 40% of concepti with Klinefelter syndrome survive the fetal period.
• In general, the severity of somatic malformations in Klinefelter syndrome is proportional to the number of additional X chromosomes; mental retardation and hypogonadism are more severe in patients with 49,XXXXY than in those with 48,XXXY.
• The mortality rate is not significantly higher than in healthy individuals.

Race

Klinefelter syndrome does not have any racial predilection.

Sex

Because the syndrome is caused by an additional X chromosome on an XY background, this condition affects only males.

Age

• Klinefelter syndrome goes undiagnosed in most affected males; among males with known Klinefelter syndrome, many do not receive the diagnosis until they are adults. The most common indications for karyotyping are hypogonadism and infertility.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Infertility and gynecomastia are the 2 most common symptoms that lead to diagnosis.
• Other symptoms include fatigue, weakness, erectile dysfunction, osteoporosis, language impairment, academic difficulty, subnormal libido, poor self-esteem, and behavioral problems.

Physical

• Growth
  
  
  • Infants and children achieve normal height, weight, and head circumference. About 25% have clinodactyly. Height velocity increases by age 5 years, and adults with Klinefelter syndrome are usually taller than adults who do not have the syndrome. Affected individuals also have disproportionately long arms and legs.
  • Some individuals with Klinefelter variant 49,XXXXY have short stature.
• CNS
  
  
  • Most males with the 47,XXY karyotype have normal intelligence. Family background influences IQ score. Subnormal intelligence or mental retardation may be associated with the presence of a higher number of X chromosomes.
  • About 70% of patients have minor developmental and learning disabilities. These may include academic difficulties, delayed speech and language acquisition, diminished short-term memory, decreased data-retrieval skills, reading difficulties, dyslexia, and attention deficit disorder.
  • Patients may exhibit behavioral problems and psychological distress. This may be due to poor self-esteem and psychosocial development or a decreased ability to deal with stress.
  • Psychiatric disorders involving anxiety, depression, neurosis, and psychosis are more common in this group than in the general population.
• Dental:  About 40% of patients have taurodontism, which is characterized by enlargement of the molar teeth by an extension of the pulp. The incidence rate is about 1% in healthy XY individuals.
• Sexual characteristics
  
  
  • Patients may lack secondary sexual characteristics because of a decrease in androgen production. This results in sparse facial, body, or sexual hair; a high-pitched voice; and fat distribution as is observed in females.
  • By late puberty, 30-50% of boys with Klinefelter syndrome present with gynecomastia, which is secondary to elevated estradiol levels and an increased estradiol-to-testosterone ratio. The risk of developing breast carcinoma is at least 20 times higher than in healthy individuals.
  •  Postpubertal patients may have testicular dysgenesis (small firm testis; testis size, <10 mL).
  • Infertility, azoospermia, or both may result from atrophy of the seminiferous tubules. Practically all individuals with a 47,XXY karyotype are infertile. Patients with Klinefelter syndrome mosaicism (46,XY/47,XXY) can be fertile.
  • Patients may have an increased frequency of extragonadal germ cell tumors such as embryonal carcinoma, teratoma, and primary mediastinal germ cell tumor.
• Cardiac and circulatory problems
  
  
  • Mitral valve prolapse occurs in 55% of patients.
  • Varicose veins occur in 20-40% of patients.
  • The prevalence of venous ulcers is 10-20 times higher than in healthy individuals, and the risk of deep vein thrombosis and pulmonary embolism is increased.
• Klinefelter variants
  
  
  • 48,XXYY variant: Patients typically have mild mental retardation; tall stature; eunuchoid body habitus; sparse body hair; gynecomastia; long, thin legs; hypergonadotropic hypogonadism; and small testes.
  • 48,XXXY variant: Patients typically have mild-to-moderate mental retardation, speech delay, slow motor development, poor coordination, immature behavior, normal or tall stature, abnormal face (epicanthal folds, hypertelorism, protruding lips), hypogonadism, gynecomastia (33-50%), hypoplastic penis, infertility, clinodactyly, and radioulnar synostosis and benefit from testosterone therapy.
  • 49,XXXYY: Patients typically have moderate-to-severe mental retardation, passive but occasionally aggressive behavior and temper tantrums, tall stature, dysmorphic facial features, gynecomastia, and hypogonadism.
  • 49,XXXXY variant: The classic triad is mild-to-moderate mental retardation, radioulnar synostosis, and hypergonadotropic hypogonadism. Other clinical features include severely impaired language, behavioral problems, low birthweight, short stature in some individuals, abnormal face (round face in infancy, coarse features in older age, hypertelorism, epicanthal folds, prognathism), short or broad neck, gynecomastia (rare), congenital heart defects (patent ductus arteriosus is most common), skeletal anomalies (genu valgus, pes cavus, fifth finger clinodactyly), muscular hypotonia, hyperextensible joints, hypoplastic genitalia, and cryptorchidism. Pea-sized testes, micropenis, and infantile secondary sex characteristics are characteristic in patients with 49,XXXXY, whereas patients with 48,XXXY exhibit milder hypogonadism similar to that found in patients with 47,XXY.

Causes

• Klinefelter syndrome is caused by the presence of an additional X chromosome in a male.
• The genetic cause of Klinefelter syndrome is meiotic nondisjunction. Maternal and paternal meiotic nondisjunction each account for approximately 50% of Klinefelter syndrome cases. Seventy-five percent of maternal nondisjunction cases are caused by meiosis I errors, which are associated with increased maternal age.
• Androgen receptor gene
• • The androgen receptor (AR) gene encodes the androgen receptor, which is located on the X chromosome. 
  • The AR gene contains a highly polymorphic trinucleotide (CAG) repeat sequence in exon 1, and the length of this CAG repeat is inversely correlated with the functional response of the androgen receptor to androgens. Thus, a short AR CAG repeat sequence correlates with a marked effect of androgens.
  • In individuals with Klinefelter syndrome, the X chromosome with the shortest AR CAG repeat has been demonstrated to be preferentially inactivated; this process is called skewed or nonrandom X-chromosome inactivation.
  • Individuals with short AR CAG repeats have been found to respond better to androgen therapy, to form more stable partnerships, and to achieve a higher level of education compared with individuals with long CAG repeats.^{33, 6} Conversely, long AR CAG repeat lengths are associated with increased body height and arm span, decreased bone density, decreased testicular volume, and gynecomastia. 
  • Nonrandom X-chromosome inactivation, which preferentially leaves the allele with the longest AR CAG repeat active, may actually contribute to the hypogonadal phenotype found in Klinefelter syndrome and may also explain some of the diverse physical appearances observed in affected individuals.
  • In boys with Klinefelter syndrome, the paternal origin of the supernumerary X chromosome is associated with later onset of puberty and longer CAG repeats of the androgen receptor, with later pubertal reactivation of the pituitary-testicular axis.

• The most common karyotype is 47,XXY, which accounts for 80-90% of all cases. Mosaicism (46,XY/47,XXY) is observed in about 10% of cases. Other variant karyotypes, including 48,XXYY; 48,XXXY; 49,XXXYY; and 49,XXXXY, are rare.
• • The mosaic forms of Klinefelter syndrome are due to mitotic nondisjunction after fertilization of the zygote. These forms can arise from a 46,XY zygote or a 47,XXY zygote.
  • Variant forms of Klinefelter syndrome include 48,XXXY; 49,XXXXY; 48,XXYY; and 49,XXXYY

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Kallmann syndrome
46,XX karyotype (in males)
Infertility

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Cytogenetic studies
• • Klinefelter syndrome may be diagnosed prenatally based on cytogenetic analysis of a fetus. 
  • If Klinefelter syndrome is not diagnosed prenatally, the 47,XXY karyotype may manifest as various subtle age-related clinical signs that may prompt chromosomal evaluation. 
  • • Infants - Hypospadias, small phallus, cryptorchidism, or developmental delay
    • Kindergarten- and elementary school–aged boys - Language delay, learning disabilities, or behavioral problems
    • Older boys and adolescent males -  Eunuchoid body habitus, gynecomastia, or small testes
  
  
  • The 47,XXY variant is found in 80-90% of patients.
  • About 10% of patients have mosaicism; karyotypes include 46,XY/47,XXY; 46,XY/48,XXXY; and 47,XXY/48,XXXY.
  • Remaining cases include variants such as the 48,XXYY; 48,XXXY; 49,XXXYY; and 49,XXXXY karyotypes.
  • About 1% of cases are due to a structurally abnormal X in addition to a normal X and Y, such as 47,X,i(Xq)Y and 47,X,del(X)Y.
• Hormone testing
  
  
  • Patients aged 12-14 years have high plasma FSH, luteinizing hormone (LH), and estradiol levels and low plasma testosterone levels.
  • In response to administration of human chorionic gonadotropin (hCG), the increase in testosterone levels in patients with Klinefelter syndrome is diminished compared with in the general population.  
  • Urinary gonadotropin levels are increased because of abnormal Leydig cell function.
  • Serum osteocalcin levels are decreased and the hydroxyl-proline–to-creatinine ratio is increased, reflecting decreased bone formation and increased bone resorption.

Imaging Studies

• Echocardiography is performed to assess for mitral valve prolapse.
• Radiography is performed to assess for lower bone mineral density, radioulnar synostosis, and taurodontism.

Histologic Findings

Findings may include small, firm testes with seminiferous tubular hyalinization; sclerosis; and atrophy with focal hyperplasia of mostly degenerated Leydig cells. Germ cells are markedly deficient or absent. Spermatogenesis is rare. In patients with mosaicism, progressive degeneration and hyalinization of seminiferous tubules take place after puberty despite the presence of normal-sized testes and spermatogenesis at puberty. Histology of gynecomastic breasts shows hyperplasia of interductal tissue.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Early identification and anticipatory guidance are extremely helpful, although the syndrome is rarely diagnosed in prepubertal males.
• Treatment should address 3 major facets of the disease: hypogonadism, gynecomastia, and psychosocial problems.
• Androgen therapy 
• • Androgen therapy is the most important aspect of treatment. Testosterone replacement should begin at puberty, around age 12 years, and the dose should increase until it is sufficient to maintain age-appropriate serum concentrations of testosterone, estradiol, FSH, and LH. 
  • Androgen therapy is used to correct androgen deficiency, to provide appropriate virilization, and to improve psychosocial status. Regular testosterone injections can promote strength and facial hair growth; build a more muscular body type; increase sexual desire; enlarge the testes; improve mood, self-image, and behavior; and protect against precocious osteoporosis.
• A multidisciplinary team approach can assist in improving speech impairments, academic difficulties, and other psychosocial and behavioral problems.
• In children, early speech and language therapy is particularly helpful in developing skills in the understanding and production of more complex language. 
• Physical therapy should be recommended in boys with hypotonia or delayed gross motor skills that may affect muscle tone, balance, and coordination. 
• Occupational therapy is advised in boys with motor dyspraxia. 
• Males with Klinefelter syndrome should receive a comprehensive psychoeducational evaluation to assess their areas of strengths and weaknesses. The information obtained from these evaluations may be helpful in planning appropriate resources and classroom placement.
• Treatment for infertility 
• • Men with Klinefelter syndrome were considered infertile until 1996. With the development of testicular sperm extraction and intracytoplasmic sperm injection (ICSI), viable spermatozoa can now be extracted from the testes via surgical biopsy, and a spermatozoon can be injected directly into an ovum. 
  • More than 60 children have been born worldwide after successful ICSI in couples in which the male partner has Klinefelter syndrome. 
  • A minority of men with Klinefelter syndrome have viable sperm in their ejaculate and are able to provide sperm for cryopreservation for future pregnancies.
• Genetic counseling
  
  
  • The recurrence risk is not increased above that in the general population.
  • Physicians should provide parents with information from unbiased follow-up studies of children with Klinefelter syndrome.
  • The best time to reveal the condition to an affected male is probably mid-to-late adolescence, when he is old enough to understand his condition.

Surgical Care

Mastectomy may be indicated for gynecomastia, which places considerable psychological strain on the patient and increases the risk of breast cancer.

Consultations

• Clinical geneticist
• Endocrinologist
• Surgeon
• Psychologist
• Speech therapist

Diet

No special diet is needed.

Activity

No activity restrictions are required.

MEDICATION

Section 7 of 11  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Drug Category: Androgen

Exogenous androgen (testosterone) is the treatment of choice for many aspects of Klinefelter syndrome.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Admission for supportive care is not necessary.

Further Outpatient Care

• The patient should be monitored by an endocrinologist for testosterone replacement therapy.

In/Out Patient Meds

• Administer regular testosterone injections.

Complications

• The risk of breast carcinoma in men with the XXY variant may approach 20 times that of healthy men. Other types of neoplasia occur in 1.6% of patients and include acute leukemia, Hodgkin and non-Hodgkin lymphomas, chronic myelogenous leukemia, and other myeloproliferative diseases. Gonadal and extragonadal germ cell tumors (mediastinal germ cell tumors, teratoma, teratocarcinoma, choriocarcinoma) may also occur.
• Psychologic and psychiatric complications may occur in individuals with lower-than-average intelligence, hypogonadism, or impotence.
• Vertebral collapse may result from osteoporosis.
• Development of varicose veins and leg ulcers may result from venous stasis.
• Associated endocrine diseases include diabetes mellitus, hypothyroidism, empty sella syndrome, hypoparathyroidism, and precocious puberty in association with hCG-producing germ cell tumors.
• Benign prostatic hyperplasia may result from testosterone supplementation. Adults undergoing such therapy should be screened for prostatic enlargement starting at age 30 years.
• In males with polysomic X Klinefelter syndrome, the mortality rate due to cerebrovascular diseases such as aortic valvular disease and berry aneurysm rupture is more than 6 times that in healthy males aged 25-84 years. Enhanced platelet aggregation, thrombotic disease, and hypercoagulability have been demonstrated and may be related to increased estrogen levels.

Prognosis

• Early studies of men with XXY Klinefelter syndrome produced disturbing findings of an increased risk of psychiatric disturbance, criminality, and mental retardation. These results are considered highly questionable because of selection bias from institutionalized populations.
• Babies with the XXY form differ little from healthy children.
• Although boys with the 47,XXY karyotype may struggle through adolescence with limited academic success, many frustrations, and, in a few instances, serious emotional or behavioral difficulties, most move toward full independence from their families as they enter adulthood. Some have completed graduate education and have a normal level of functioning.
• Life span is presumably normal.
• Hypogonadism, low libido, and psychosocial problems can be helped by testosterone treatment.
• Gynecomastia can be corrected by mastectomy.

Patient Education

• Useful resources for patients and families include the following:
  • Klinefelter Syndrome and Associates
    PO Box 119
    Roseville, CA 95678
    Phone: 888-999-9428
    
  • The American Speech, Language, and Hearing Association
    10801 Rockville Pike
    Rockville, MD 20852
    Phone: 800-498-2071

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Underdiagnosis and delayed diagnosis of Klinefelter syndrome is a major problem. Early diagnosis permits identification of speech problems and scholastic difficulties that require speech therapy and educational support. -Early diagnosis facilitates prevention or remediation of the long-term consequences of gonadal insufficiency.
• Failure to inform patient of an increased risk of breast carcinoma associated with gynecomastia and increased risk of developing osteoporosis in later life is a pitfall.
• Patients should be referred to an endocrinologist for testosterone replacement.

Special Concerns

• Klinefelter syndrome can be detected prenatally with amniocentesis and cytogenetic analysis of amniotic fluid. This presents a dilemma for parents because prognosis is good but phenotypic abnormalities are possible.
• Few patients with 46,XY/47,XXY mosaicism are known to have fathered a child, which is associated with a risk of having an offspring with the 47,XXY form. All individuals with the 47,XXY form are infertile.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Adolescent male with gynecomastia and Klinefelter syndrome.
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Media file 2:  Child with Klinefelter syndrome. Other than a thin build and disproportionately long arms and legs, the phenotype is normal.
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Media file 3:  G-banded 47,XXY karyotype.
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Media file 4:  Adolescent male with Klinefelter syndrome who has female-type distribution of pubic hair and testicular dysgenesis.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Klinefelter HF Jr, Reifenstein EC Jr, Albright F. Syndrome characterized by gynecomastia aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone. J Clin Endocr Metabl. 1942;2:615-624.
2. Anawalt BD, Bebb RA, Matsumoto AM, et al. Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab. Sep 1996;81(9):3341-5. [Medline].
3. Bagatell CJ, Bremner WJ. Androgens in men--uses and abuses. N Engl J Med. Mar 14 1996;334(11):707-14. [Medline].
4. Bender BG, Harmon RJ, Linden MG, Robinson A. Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. Pediatrics. Aug 1995;96(2 Pt 1):302-8. [Medline].
5. Bhasin S, Ma K, Sinha I, et al. The genetic basis of male infertility. Endocrinol Metab Clin North Am. Dec 1998;27(4):783-805, viii. [Medline].
6. Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol. Apr 2007;4(4):192-204. [Medline].
7. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. Feb 2003;88(2):622-6. [Medline].
8. De la Chapelle A. Sex Chromosome Abnormalities. In: Emery AEH, Rimoin DL, eds. Principles and Practice of Medical Genetics. Vol 1. Edinburgh, England: Churchill Livingstone; 1990:273-299.
9. Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C. Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review. Fertil Steril. Oct 2004;82(4):775-9. [Medline].
10. Ferrier PE, Ferrier SA, Pescia G. The XXXY Klinefelter syndrome in childhood. Am J Dis Child. Jan 1974;127(1):104-5. [Medline].
11. Kamischke A, Baumgardt A, Horst J, Nieschlag E. Clinical and diagnostic features of patients with suspected klinefelter syndrome. J Androl. Jan-Feb 2003;24(1):41-8. [Medline]. [Full Text].
12. Kleczkowska A, Fryns JP, Van den Berghe H. X-chromosome polysomy in the male. The Leuven experience 1966-1987. Hum Genet. Sep 1988;80(1):16-22. [Medline].
13. Linden MG, Bender BG, Robinson A. Sex chromosome tetrasomy and pentasomy. Pediatrics. Oct 1995;96(4 Pt 1):672-82. [Medline].
14. Mandoki MW, Sumner GS, Hoffman RP, Riconda DL. A review of Klinefelter's syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry. Mar 1991;30(2):167-72. [Medline].
15. Meschede D, Louwen F, Nippert I. Low rates of pregnancy termination for prenatally diagnosed Klinefelter syndrome and other sex chromosome polysomies. Am J Med Genet. Dec 4 1998;80(4):330-4. [Medline].
16. Nielsen J, Pelsen B, Sorensen K. Follow-up of 30 Klinefelter males treated with testosterone. Clin Genet. Apr 1988;33(4):262-9. [Medline].
17. Peet J, Weaver DD, Vance GH. 49,XXXXY: a distinct phenotype. Three new cases and review. J Med Genet. May 1998;35(5):420-4. [Medline].
18. Ratcliffe SG, Bancroft J, Axworthy D, McLaren W. Klinefelter's syndrome in adolescence. Arch Dis Child. Jan 1982;57(1):6-12. [Medline].
19. Robinson A, Bender BG, Linden MG. Prognosis of prenatally diagnosed children with sex chromosome aneuploidy. Am J Med Genet. Oct 1 1992;44(3):365-8. [Medline].
20. Robinson A, Lubs HA, Nielsen J, Sorensen K. Summary of clinical findings: profiles of children with 47,XXY, 47,XXX and 47,XYY karyotypes. Birth Defects Orig Artic Ser. 1979;15(1):261-6. [Medline].
21. Schiff JD, Palermo GD, Veeck LL, et al. Success of testicular sperm injection and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab. Nov 2005;90(11):6263-7. [Medline].
22. Schulte-Beerbuhl M, Nieschlag E. Comparison of testosterone, dihydrotestosterone, luteinizing hormone, and follicle-stimulating hormone in serum after injection of testosterone enanthate of testosterone cypionate. Fertil Steril. Feb 1980;33(2):201-3. [Medline].
23. Schwartz ID, Root AW. The Klinefelter syndrome of testicular dysgenesis. Endocrinol Metab Clin North Am. Mar 1991;20(1):153-63. [Medline].
24. Smith S. Index of suspicion. Case 1. Diagnosis: Klinefelter syndrome. Pediatr Rev. Nov 1992;13(11):435-6. [Medline].
25. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med. Jun 22 1998;158(12):1309-14. [Medline].
26. Swerdlow AJ, Higgins CD, Schoemaker MJ, et al. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab. Dec 2005;90(12):6516-22. [Medline].
27. Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA,. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. Aug 17 2005;97(16):1204-10. [Medline].
28. Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006;1:42. [Medline].
29. Wattendorf DJ, Muenke M. Klinefelter syndrome. Am Fam Physician. Dec 1 2005;72(11):2259-62. [Medline].
30. Wikstrom AM, Painter JN, Raivio T, Aittomaki K, Dunkel L. Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome. Clin Endocrinol (Oxf). Jul 2006;65(1):92-7. [Medline].
31. Yoshida A, Miura K, Nagao K, et al. Sexual function and clinical features of patients with Klinefelter's syndrome with the chief complaint of male infertility. Int J Androl. Apr 1997;20(2):80-5. [Medline].
32. Zaleski WA, Houston CS, Pozsonyi J, Ying KL. The XXXXY chromosome anomaly: report of three new cases and review of 30 cases from the literature. Can Med Assoc J. May 28 1966;94(22):1143-54. [Medline].
33. Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients. J Clin Endocrinol Metab. Dec 2004;89(12):6208-17. [Medline].

Article Last Updated: Jul 31, 2007