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List of terms related to Klinefelter's syndrome

	Klinefelter's syndrome;
ICD-10	Q98.0-Q98.4
ICD-9	758.7
DiseasesDB	7189
MedlinePlus	000382
MeSH	D007713

VisualWikitext

Revision as of 14:19, 14 August 2012

For patient information click here

Not to be confused with XYY syndrome or XXX syndrome.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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 effects are development of small testicles 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. The condition exists in roughly 1 out of every 500 males.^[1] Because of the extra chromosome, individuals with the condition are usually referred to as "XXY Males", or "47, XXY Males".^[2]

Historical Perspective

It is named after Dr. Harry Klinefelter, an endocrinologist at Massachusetts General Hospital, Boston, Massachusetts, who first described it in 1942.^[3]

Pathophysiology

Genetics

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.^[4]

Associated Conditions

Causes

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 live male births.^[1]

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.^[5] A few genes located in the pseudoautosomal regions, however, have corresponding genes on the Y chromosome and are capable of being expressed.^[6] These triploid genes in XXY males may be responsible for symptoms associated with Klinefelter's syndrome.

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.^[7] 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.^[8]

Differentiating Klinefelter's syndrome from other Diseases

Epidemiology and Demographics

Natural History, Complications and Prognosis

Complications

Patients with Klinefelter syndrome have a 50 times greater risk of germ cell tumors (GSTs).^[9] In these patients, GSTs usually contain nonseminomatous elements, present at an earlier age, and seldom are testicular in location.

Diagnosis

History

Symptoms

Affected males are almost always effectively sterile, although advanced reproductive assistance is sometimes possible.^[10] Some degree of language learning impairment may be present,^[11] and neuropsychological testing often reveals deficits in executive functions^[12]. 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).^[13] Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population, but only about 10% of XXY males' gynecomastia is noticeable enough to require surgery.^[14]

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.^[15] Despite this misunderstanding of the term, however, it is true that XXY men often also have "microorchidism" (i.e. small testicles).^[15]

The more severe end of the spectrum of symptom expression is also associated with an increased risk of germ cell tumors, breast cancer,^[16] and osteoporosis,^[1] risks shared to varying degrees^[17] with females. Additionally, 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 possible correlations 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 or not someone has 47,XXY. The only reliable method of identification is karyotype testing.

Physical Examination

Appearance of the Patient

Vital Signs

Skin

Head

Eyes

Ear

Nose

Throat

Heart

Lungs

Abdomen

Extremities

Neurologic

Genitals

Other

Laboratory Findings

A karyotype is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. White blood cells are then separated from the sample, mixed with tissue culture medium, incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.

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.

Testosterone therapy may be prescribed. This can help:

Grow body hair
Improve appearance of muscles
Improve concentration
Improve mood and self esteem
Increase energy and sex drive
Increase strength

Most men with this syndrome are not able to father children. However, some men have been able to have children. An infertility specialist may be able to help.

Inadequately treated hypogonadism in Klinefelter syndrome increases recognized psychosocial morbidity.^[18] 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.^[18]

References

↑ ^1.0 ^1.1 ^1.2 "Klinefelter Syndrome" (HTML). Health Information. National Institute of Health and Human Development. 2007-02-19. Retrieved 2007-03-24. Check date values in: |date= (help) and "Klinefelter syndrome" (HTML). Genetics Home Reference. National Library of Medicine. 2006. Retrieved 2007-03-24. both provide statistical estimates.
↑ Bock, Robert (1993 Aug). "Understanding Klinefelter Syndrome: A Guide for XXY Males and Their Families" (HTML). NIH Pub. No. 93-3202. Office of Research Reporting, NICHD. Retrieved 2007-04-07. Unknown parameter |month= ignored (help); Check date values in: |date= (help)CS1 maint: Date and year (link)
↑ 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 ''too early to be indexed'' Check |pmid= value (help)CS1 maint: Date and year (link) . Klinefelter, HF (1986), "Klinefelter's syndrome: historical background and development.", South Med J, 79 (45): 1089–1093, PMID 3529433CS1 maint: Date and year (link) talks about the history of the development of the literature.
↑ 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
↑ 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
↑ Blaschke RJ, Rappold G (2006). The pseudoautosomal regions, SHOX and disease. Curr Opin Genet Dev. Jun; 16:233-9. PMID 16650979
↑ Jacobs PA, Strong JA (1959). "A case of human intersexuality having a possible XXY sex-determining mechanism". Nature. 183 (4657): 302–3. doi:10.1038/183302a0. PMID 13632697. Unknown parameter |month= ignored (help)
↑ Jacobs PA (1982). "The William Allan Memorial Award address: human population cytogenetics: the first twenty-five years". Am J Hum Genet. 34 (5): 689–98. PMID 6751075. Unknown parameter |month= ignored (help)
↑ 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}
↑ 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.2003.09.085CS1 maint: Date and year (link)
↑ 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 3368277CS1 maint: Date and year (link)
↑ Boone et al: (2001), "Neuropsychological profiles of adults with Klinefelter syndrome" in Journal of International Neuropsychological Society, #7, p 446-456.
↑ Abstract of Klinefelter, HF (1986), "Klinefelter's syndrome: historical background and development.", South Med J, 79 (9): 1089–1093, PMID 3529433CS1 maint: Date and year (link) provides information on microorchidism (small testes), hypogonadism (infertility/sterility and androgen hormone function) and gynecomastia. Bock, Robert (1993 Aug). "Understanding Klinefelter Syndrome: A Guide for XXY Males and Their Families" (HTML). NIH Pub. No. 93-3202. Office of Research Reporting, NICHD. Retrieved 2007-03-28. Unknown parameter |month= ignored (help); Check date values in: |date= (help)CS1 maint: Date and year (link) offers substantive information about body type and appearance until a more rigorous source is found/supplied.
↑ Bock, Robert (1993 Aug). "Understanding Klinefelter Syndrome: A Guide for XXY Males and Their Families, Adolescence section" (HTML). NIH Pub. No. 93-3202. Office of Research Reporting, NICHD. Retrieved 2007-03-29. Unknown parameter |month= ignored (help); Check date values in: |date= (help)CS1 maint: Date and year (link) describes statistical occurrence of gynecomastia and surgical treatment.
↑ ^15.0 ^15.1 Leask, Kathryn (October 2005). "Klinefelter syndrome" (HTML). National Library for Health, Specialist Libraries, Clinical Genetics. National Library for Health. Retrieved 2007-04-07.
↑ 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 Check date values in: |date= (help)CS1 maint: Date and year (link)
↑ 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 Check date values in: |date= (help)CS1 maint: Date and year (link) 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.
↑ ^18.0 ^18.1 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

@@ Line 27: / Line 27: @@
 It is named after Dr. Harry Klinefelter, an [[endocrinologist]] at [[Massachusetts General Hospital]], Boston, Massachusetts, who first described it in 1942.<ref name="kline1942">{{Citation| last = Klinefelter | first = HF Jr | last2 = Reifenstein | first2 = EC Jr | last3 = Albright | title = Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism and increased excretion of follicle-stimulating hormone. | journal = J Clin Endocrinol Metab | volume = 2 | pages = 615–624 | date = 1942 | year = 1942 | pmid = ''too early to be indexed''}}. {{Citation| last = Klinefelter | first = HF | title = Klinefelter's syndrome: historical background and development. | journal = South Med J | volume = 79 | issue = 45| pages = 1089–1093 | date = 1986 | year =1986 | pmid =  3529433}} talks about the history of the development of the literature.</ref>
-==Etiology==
+==Pathophysiology==
+===Genetics===
+====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 (genetics)|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.<ref name="eurjmedgenet2006">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</ref>
+===Associated Conditions===
+==Causes==
 The extra X chromosome is retained because of a [[Meiosis#Nondisjunction|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 live male births.<ref name="nihhd2007" />
@@ Line 34: / Line 44: @@
 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.<ref name="nature1959">{{cite journal |author=Jacobs PA, Strong JA |month=January 31, |year=1959 |title=A case of human intersexuality having a possible XXY sex-determining mechanism |journal=[[Nature (journal)|Nature]] |volume=183 |issue=4657 |pages=302–3 |pmid=13632697 |doi= 10.1038/183302a0}}</ref> 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.<ref name="amjhumgenet1982">{{cite journal |author=Jacobs PA |month=September |year=1982 |title=The William Allan Memorial Award address: human population cytogenetics: the first twenty-five years |journal=[[American Journal of Human Genetics|Am J Hum Genet]] |volume=34 |issue=5 |pages=689–98 |pmid=6751075 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1685430&blobtype=pdf}}</ref>
-==Variations==
+==Differentiating Klinefelter's syndrome from other Diseases==
-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.
+==Epidemiology and Demographics==
+==Natural History, Complications and Prognosis==
+===Complications===
+Patients with Klinefelter syndrome have a 50 times greater risk of [[germ cell tumors]] (GSTs).<ref>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}</ref>  In these patients, GSTs usually contain nonseminomatous elements, present at an earlier age, and seldom are testicular in location.
+==Diagnosis==
-Males with Klinefelter syndrome may have a [[Mosaic (genetics)|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.<ref name="eurjmedgenet2006">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</ref>
+===History===
-==Signs and symptoms==
+===Symptoms===
 Affected males are almost always effectively [[infertility|sterile]], although advanced reproductive assistance is sometimes possible.<ref name="fertstert2004">{{Citation|last = Denschlag|first = Dominik, MD|last2 = Clemens|first2 = Tempfer, MD|last3 = Kunze|first3 = Myriam, MD|last4 = Wolff|first4 = Gerhard, MD|last5 = Keck|first5 = Christoph, MD|title = Assisted reproductive techniques in patients with Klinefelter syndrome: A critical review|journal = Fertility and Sterility|volume = 82|issue = 4|pages = 775–779|date = October 2004|year = 2004|doi = 10.1016/j.fertnstert.2003.09.085}}</ref> Some degree of language learning impairment may be present,<ref name="ped1988">{{Citation|last = Graham |first = JM Jr|last2 = Bashir |first2 = AS|last3 = Stark |first3 = RE|last4 = Silbert |first4 = A|last5 = Walzer |first5 = S|title = Oral and written language abilities of XXY boys: implications for anticipatory guidance.|journal = Pediatrics|volume = 81|issue = 6|pages = 795–806|date = June 1988|year = 1988|pmid = 3368277 }}</ref> and neuropsychological testing often reveals deficits in [[executive functions]]<ref>Boone et al: (2001), "Neuropsychological profiles of adults with Klinefelter syndrome" in Journal of International Neuropsychological Society, #7, p 446-456.</ref>.  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).<ref name="smedj1986">Abstract of {{Citation|last = Klinefelter |first = HF |title = Klinefelter's syndrome: historical background and development.|journal = South Med J |volume = 79 |issue = 9|pages = 1089–1093 |date = 1986 |year = 1986 |pmid =  3529433}} provides information on microorchidism (small testes), hypogonadism (infertility/sterility and androgen hormone function) and gynecomastia. {{cite web |url=http://www.nichd.nih.gov/publications/pubs/klinefelter.cfm |title=Understanding Klinefelter Syndrome: A Guide for XXY Males and Their Families |last=Bock |first=Robert  |accessdate=2007-03-28 |date = 1993 Aug |year = 1993 | month = August |format=HTML |work=NIH Pub. No. 93-3202|publisher=Office of Research Reporting, NICHD}} offers substantive information about body type and appearance until a more rigorous source is found/supplied.</ref> Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population, but only about 10% of XXY males' gynecomastia is noticeable enough to require surgery.<ref name="orr-nichd1993">{{cite web |url=http://www.nichd.nih.gov/publications/pubs/klinefelter.cfm#xadol|title=Understanding Klinefelter Syndrome: A Guide for XXY Males and Their Families, Adolescence section |last=Bock |first=Robert  |accessdate=2007-03-29 |date = 1993 Aug |year = 1993 | month = August |format=HTML |work=NIH Pub. No. 93-3202|publisher=Office of Research Reporting, NICHD}} describes statistical occurrence of gynecomastia and surgical treatment.</ref>
@@ Line 50: / Line 68: @@
 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 or not someone has 47,XXY. The only reliable method of identification is [[karyotype]] testing.
-== Diagnosis==
+===Physical Examination===
+==== Appearance of the Patient ====
+====Vital Signs====
+====Skin====
+====Head====
+==== Eyes ====
+==== Ear ====
+====Nose====
+====Throat ====
+==== Heart ====
+==== Lungs ====
+==== Abdomen ====
+==== Extremities ====
+==== Neurologic ====
+====Genitals====
+==== Other ====
+===Laboratory Findings===
 A [[karyotype]] is used to confirm the diagnosis. In this procedure, a small blood sample is drawn. [[White blood cell]]s are then separated from the sample, mixed with [[Growth medium|tissue culture medium]], incubated, and checked for chromosomal abnormalities, such as an extra X chromosome.
@@ Line 67: / Line 117: @@
 Inadequately treated [[hypogonadism]] in Klinefelter syndrome increases recognized psychosocial morbidity.<ref name="jpediatrendo2006">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</ref> 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.<ref name="jpediatrendo2006" />
-==Complications==
-Patients with Klinefelter syndrome have a 50 times greater risk of [[germ cell tumors]] (GSTs).<ref>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}</ref>  In these patients, GSTs usually contain nonseminomatous elements, present at an earlier age, and seldom are testicular in location.
 ==References==