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Klinefelter's syndrome

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Klinefelter's syndrome
ICD-10 Q980-Q984
ICD-9 758.7
OMIM [1]
DiseasesDB 7189
MedlinePlus [2]
eMedicine ped/1252
MeSH {{{MeshNumber}}}


Not to be confused with XYY syndrome or XXX syndrome.

Klinefelter's syndrome, 47, XXY or XXY syndrome is a condition caused by a chromosome aneuploidy. Affected males have an extra X sex chromosome. The principal effect is abnormal testicular development and reduced fertility. A variety of other physical and behavioral differences and problems are common, though severity varies and many boys and men with the condition have few detectable symptoms. It is the second most common extra chromosome condition, and is named after Dr. Harry Klinefelter, an endocrinologist at Massachusetts General Hospital, Boston, Massachusetts, who first described it in 1942.[1] The condition exists in roughly 1 out of every 500 to 1,000 males.[2]

Signs and symptoms

Affected males are almost always effectively sterile, although advanced reproductive assistance is sometimes possible[3] and some degree of language learning impairment may be present.[4] In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue).[5] Gynecomastia to some extent is present in about a third of individuals affected, a slightly higher percentage than in the normal XY population, but only about 10% of XXY males' gynecomastia is noticeable enough to require surgery.[6]

The term "hypogonadism" in XXY symptoms is often misinterpreted to mean "small testicles" or "small penis". In fact, it means decreased testicular hormone/endocrine function. Because of this hypogonadism, patients will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.[7] Despite this misunderstanding of the term, however, it is true that XXY men often also have "microorchidism" (i.e. small testicles).[7]

The more severe end of the spectrum of symptom expression is also associated with an increased risk of breast cancer,[8] and osteoporosis[2], risks shared to varying degrees[9] with females. Additionally, extant medical literature shows some individual case studies of Klinefelter's syndrome coexisting with other disorders, such as pulmonary disease, varicose veins, diabetes mellitus, and rheumatoid arthritis, but the etiologies (understanding of any potential causation relationship) between Klinefelter's and these other conditions are not well characterized or understood.

In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions occur even less frequently in XXY males than in normal XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.

There are many variances within the XXY population, just as in the most common 46,XY population. While it is possible to characterise 47,XXY males with certain body types, that in itself should not be the method of identification as to whether someone has 47,XXY or not. The only reliable method of identification is karyotype testing.

Cause

The extra X chromosome is retained because of a nondisjunction event during meiosis (sex cell division). The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about 1 in 500 to 1,000 live male births.[2] Because of the extra chromosome, individuals with the condition are usually referred to as "XXY Males", or "47,XXY Males".[10] In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males as well as normal XX females.[11] A few genes, however, have corresponding genes on the Y chromosome and are capable of being expressed, these are located in the pseudoautosomal regions.[12] These triploid genes in XXY males may be responsible for symptoms associated with Klinefelter's syndrome.[How to reference and link to summary or text]

The first published report of a man with a 47,XXY karyotype was by Patricia A. Jacobs and Dr. J.A. Strong at Western General Hospital in Edinburgh, Scotland in 1959.[13] This karyotype was found in a 24-year-old man who had signs of Klinefelter's syndrome. Dr. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address.[14]

Treatment

The genetic variation is irreversible, but its symptoms can be altered or treated in a number of ways, including testosterone treatment and other therapies.[How to reference and link to summary or text]

Inadequately treated hypogonadism in Klinefelter syndrome increases recognized psychosocial morbidity.[15] At least one study indicates that planned and timed support should be provided for young men with Klinefelter syndrome, to ameliorate current poor psychosocial outcomes.[15]

Variations

The 48, XXYY (male) syndrome occurs 1 in 17,000 births and has traditionally been considered to be a variation of Klinefelter's syndrome. XXYY is no longer generally considered a variation of KS, although it has not yet been assigned an ICD-9 code.

Males with Klinefelter syndrome may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Mosaicism 47,XXY/46,XX with clinical features suggestive of Klinefelter syndrome is very rare. Thus far, only about 10 cases have been described in literature.[16]

Complications

Patients with Klinefelter syndrome have a 50 times greater risk of germ cell tumors (GSTs)[17]. In these patients, GSTs usually contain nonseminomatous elements, present at an earlier age, and seldom are testicular in location.

References

  1. Klinefelter, HF Jr; Reifenstein, EC Jr; Albright (1942), "Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone.", J Clin Endocrinol Metab 2: 615-624, PMID: too early to be indexed . Klinefelter, HF (1986), "Klinefelter's syndrome: historical background and development.", South Med J 79 (9): 1089-1093, PMID: 3529433  talks about the history of the development of the literature.
  2. 2.0 2.1 2.2 Klinefelter Syndrome. (HTML) Health Information. National Institute of Health and Human Development. URL accessed on 2007-03-24. and (2006). Klinefelter syndrome. (HTML) Genetics Home Reference. National Library of Medicine. URL accessed on 2007-03-24. both provide statistical estimates.
  3. Denschlag, Dominik, MD; Clemens, Tempfer, MD; Kunze, Myriam, MD; Wolff, Gerhard, MD; Keck, Christoph, MD (October 2004), "Assisted reproductive techniques in patients with Klinefelter syndrome: A critical review", Fertility and Sterility 82 (4): 775-779, doi:10.1016/j.fertnstert.2003.09.085  describes assisted reproduction techniques for Klinefelter patients.
  4. Graham, JM Jr; Bashir, AS; Stark, RE; Silbert, A; Walzer, S (June 1988), "Oral and written language abilities of XXY boys: implications for anticipatory guidance.", Pediatrics 81 (6): 795-806, PMID: 3368277 
  5. Abstract of Klinefelter, HF (1986), "Klinefelter's syndrome: historical background and development.", South Med J 79 (9): 1089-1093, PMID: 3529433  provides information on microorchidism (small testes), hypogonadism (infertility/sterility and androgen hormone function) and gynecomastia. Bock, Robert (1993). Understanding Klinefelter Syndrome: A Guide for XXY Males and Their Families. (HTML) NIH Pub. No. 93-3202. Office of Research Reporting, NICHD. URL accessed on 2007-03-28. offers substantive information about body type and appearance until a more rigorous source is found/supplied.
  6. Bock, Robert (1993). Understanding Klinefelter Syndrome: A Guide for XXY Males and Their Families, Adolescence section. (HTML) NIH Pub. No. 93-3202. Office of Research Reporting, NICHD. URL accessed on 2007-03-29. describes statistical occurrence of gynecomastia and surgical treatment.
  7. 7.0 7.1 Leask, Kathryn Klinefelter syndrome. (HTML) National Library for Health, Specialist Libraries, Clinical Genetics. National Library for Health. URL accessed on 2007-04-07.
  8. Hultborn, R; Hanson, C; Kopf, I; Verbiene, I; Warnhammar, E; Weimarck, A (1997 Nov-Dec), "Prevalence of Klinefelter's syndrome in male breast cancer patients.", Anticancer Res. 17 (6D): 4293-4297, PMID: 9494523 
  9. For instance, while Hultborn, R; Hanson, C; Kopf, I; Verbiene, I; Warnhammar, E; Weimarck, A (1997 Nov-Dec), "Prevalence of Klinefelter's syndrome in male breast cancer patients.", Anticancer Res. 17 (6D): 4293-4297, PMID: 9494523  shows a 50-fold increased risk of developing breast cancer versus normal males, study of the SEER Cancer Statistics Review (CSR) databases available at the National Cancer Institute reveal that female relative risk of breast cancer incidence compared to normal males is around a 100 to 200-fold increase, which indicates XXY males may not be as much at risk statistically as normal females are.
  10. Bock, Robert (1993). Understanding Klinefelter Syndrome: A Guide for XXY Males and Their Families. (HTML) NIH Pub. No. 93-3202. Office of Research Reporting, NICHD. URL accessed on 2007-04-07.
  11. Chow J, Yen Z, Ziesche S, Brown C (2005). "Silencing of the mammalian X chromosome". Annu Rev Genomics Hum Genet 6: 69-92. PMID 16124854
  12. Blaschke RJ, Rappold G (2006). The pseudoautosomal regions, SHOX and disease. Curr Opin Genet Dev. Jun; 16:233-9. PMID 16650979
  13. Jacobs PA, Strong JA. "A case of human intersexuality having a possible XXY sex-determining mechanism". Nature 1959 Jan 31;183(4657):302-3. PMID 13632697
  14. Jacobs PA. "The William Allan Memorial Award address: human population cytogenetics: the first twenty-five years". Am J Hum Genet. 1982 Sep;34(5):689-98. PMID 6751075
  15. 15.0 15.1 Simm PJ, Zacharin MR. "The psychosocial impact of Klinefelter syndrome--a 10 year review". J Pediatr Endocrinol Metab 2006 Apr;19(4):499-505. PMID 16759035
  16. Velissariou V, Christopoulou S, Karadimas C, Pihos I, Kanaka-Gantenbein C, Kapranos N, Kallipolitis G, Hatzaki A. "Rare XXY/XX mosaicism in a phenotypic male with Klinefelter syndrome: case report". Eur J Med Genet 2006 July - August;49(4):331-337. PMID 16829354
  17. Mediastinal germ cell tumor in a child with precocious puberty and Klinefelter syndrome. Gregory G. Bebb, Frederic W. Grannis, Jr, Isaac B. Paz, Marilyn L. Slovak, Robert Chilcote. Ann Thorac Surg 1998;66:547-548. [http://ats.ctsnetjournals.org/cgi/content/abstract/66/2/547 Online}

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