What Istwhat Is the Likelihood That Klinefelther Syndrome Could Happen Again in a Future Pregnancy

Klinefelter syndrome (KS) describes the phenotype of the almost common sex chromosome abnormality in humans and occurs in one of every 600 newborn males. The typical symptoms are a tall stature, narrow shoulders, broad hips, thin body hair, gynecomastia, small testes, absent-minded spermatogenesis, normal to moderately reduced Leydig prison cell office, increased secretion of follicle-stimulating hormone, androgen deficiency, and normal to slightly decreased verbal intelligence. Apart from that, among others, osteoporosis, varicose veins, thromboembolic disease, or diabetes mellitus are observed. Some of the typical features can be very weakly pronounced so that the affected men often receive the diagnosis just at the adulthood by their infertility. With a frequency of four%, KS is described to be the most common genetic reason for male infertility. The most widespread karyotype in affected patients is 47,XXY. Apart from that, various other karyotypes have been described, including 46,XX in males, 47,XXY in females, 47,Xx,der(Y), 47,X,der(X),Y, or other numeric sex chromosome abnormalities (48,XXXY, 48,XXYY, and 49,XXXXY). The focus of this review was to abstruse the unlike phenotypes, which come about by the various karyotypes and to compare them to those with a 'normal' KS karyotype. For that the patients have been divided into vi different groups: Klinefelter patients with an additional isochromosome Xq, with boosted rearrangements on i of the 2 X chromosomes or appropriately on the Y chromosome, also equally Twenty males and true hermaphrodites, 47,XXY females and Klinefelter patients with other numeric sex chromosome abnormalities. In the latter, an most linear increment in top and developmental delay was observed. Men with an boosted isochromosome Xq testify infertility and other small-scale features of 'normal' KS but not an increased tiptop. Aside from the infertility, in male person patients with other der(X) besides as der(Y) rearrangements and in XXY women no specific phenotype is recognizable amid others due to the small number of cases. The phenotype of Twenty males depends on the presence of SRY (sex-determining region Y) and the level of X inactivation at which SRY-negative patients are generally rarely observed.

Introduction

Klinefelter syndrome (KS) was outset described past Harry F. Klinefelter in 1942 [Klinefelter et al., 1942]. He reported 9 men with testicular abnormalities who failed to produce sperm and had gynecomastia. In 1959, this was establish to exist the consequence of an additional 10 chromosome [Jacobs and Strong, 1959]. Virtually lxxx% of KS patients show a 47,XXY karyotype, 20% have other numeric sex chromosome abnormalities (48,XXXY, 48,XXYY, 49,XXXXY), 46,XY/47,XXY mosaicism, or structurally abnormal sex chromosomes [Lanfranco et al., 2004].

In approximately half of the Klinefelter cases the aberrant X chromosome is thought to be paternally derived, and recent testify suggests that it may be related to advancing paternal historic period, although this is controversial [Jacobs et al., 1988; Lowe et al., 2001]. With a frequency of i out of 600 newborn males KS is described to be the most mutual sexual practice chromosome abnormality [Bojesen and Gravholt, 2007]. Afflicted patients are characterized by an increment of the trunk acme of about 6.5 cm, narrow shoulders, wide hips, thin torso hair, gynecomastia, small testes, absent spermatogenesis, normal to moderately reduced Leydig cell function, increased secretion of follicle-stimulating hormone (FSH), androgen deficiency, and normal to slightly decreased verbal intelligence [Bojesen and Gravholt, 2007; Wikstrom and Dunkel, 2008]. Apart from that, amidst others, osteoporosis [van den Bergh et al., 2001], varicose veins, thromboembolic disease [Igawa and Nishioka, 2003], or diabetes mellitus [Ota et al., 2002] are observed. KS is the most frequent genetic cause of male infertility, and is found in eleven% of azoospermic men and 4% of infertile men [Wikstrom and Dunkel, 2008]. In most of the cases KS is not diagnosed before puberty and fifty-fifty in machismo information technology was estimated that only a fourth of afflicted males receive diagnosis, mostly past their infertility [Bojesen and Gravholt, 2007], because in many cases the phenotype is not as distinct as described higher up.

If somebody has an boosted X chromosome, there is an excess of X-chromosomal genes. Normally one of the 2 10 chromosomes in a female person is inactivated, merely it has been shown that in full, about 15% of Ten-linked genes escape inactivation [Carrel and Willard, 2005]. The aforementioned applies for KS patients and, therefore, it is very probable that these genes are responsible for nearly of the KS features.

Over the last virtually fifty years there have been reported many cases of KS patients with a different karyotype than 47,XXY. These variants show, amongst others, a 47,X,der(X),Y karyotype, a 47,Twenty,der(Y) karyotype, an additional isochromosome Xq, likewise every bit translocations or deletions involving one of the sex chromosomes. Apart from that there have been reported a lot of male cases with a 46,20 karyotype too as women with a 47,XXY chromosome complement. In addition to all these patients with variations on the sex activity chromosomes, male person KS patients with ii X and 1 Y chromosomes and an additional rearrangement on one or more autosomal chromosomes take been described.

Methods

In this review we focused on the different genetic variants of the sex chromosomes in KS patients. Therefore, nosotros attended to male patients with ii or more X chromosomes and women with a 47,XXY karyotype. The aim of the review is to summarize the diverse phenotypes of these different variants of KS and to compare them to that of the classical 47,XXY KS patients. For our search nosotros used 2 dissimilar databases: Get-go PubMed using the following search terms: 'Klinefelter' AND 'Syndrome'; 'Klinefelter' AND 'Isochromosome Ten'; '46 20' AND 'Male'; '47 XXY' AND 'Female'; '48 XXYY'; '48 XXXY' and '49 XXXXY' and second for the KS cases with derivative X or Y chromosomes the online database of the Jena University Hospital, Establish of Human Genetics, Jena (Germany). All searches were restricted to articles in English and German. We were looking exclusively for studies in which additional aberrations on the sexual practice chromosomes were described. Manufactures on additional autosomal chromosomes or 47,XXY/46,XY karyotypes were excluded. For 46,Twenty males and 47,X,der(X),Y patients nosotros included only SRY (sexual practice-determining region Y) and XIST- (10 (inactive)-specific transcript) positive patients or those where the breakpoints were plain distal to the XIST location.

In the end we found more than than 300 articles of KS variant patients at which nigh of the studies draw KS patients with other numeric sex chromosome abnormalities and XX males. Much of the literature was published betwixt the 60s and 80s of the terminal century. In these cases the used ISCN nomenclature differs from the current version. To forestall misinterpretation or fifty-fifty cariosity of the original karyotypes, we always took over the karyotypes as indicated in the original literature.

Klinefelter Patients with an Additional Isochromosome Xq

The prevalence of the Klinefelter variant with an additional isochromosome Xq is calculated to be betwixt 0.three–0.ix% in males with a KS phenotype [Arps et al., 1996]. The kickoff study of a 47,X,i(Xq),Y male was reported in 1969 [Zang et al., 1969]. Apart from that, to our cognition, 24 farther cases of isochromosome Xq have been reported then far [Demirhan et al., 2009]. Most of them described a monocentric isochromosome. The clinical and laboratory data on these cases are summarized in table 1. The patients show a almost similar phenotype with characteristic features such every bit infertility, elevated plasma luteinizing hormone (LH) and FSH levels, low or normal testosterone levels, sometimes gynecomastia, normal to reduced body tiptop, and a normal to slightly reduced intelligence level [Demirhan et al., 2009]. Most of the literature indicated that the normal superlative is due to the presence of only one Xp carrying the growth gene SHOX (short stature homeobox-containing gene) [Richer et al., 1989; Stemkens et al., 2007] and other putative Xp-specific growth genes [Rao et al., 1997]. The observation of increased body height in a KS patient with an isodicentric X (pter→q22::q22→pter), with 3 copies of Xp and ane distal part of Xq, is in understanding with this theory [Zelante et al., 1991].

Table i

Clinical features in 25 patients with KS and an additional isochromosome Xq sorted by the year of publication

Zang et al. [1969] described the origin of an additional isochromosome Xq as an unusual event, because it would crave a double error during meiosis. Arps et al. [1996] proposed that the well-nigh probable origin of an additional isochromosome Xq is a misdivision of the centromere or a sister-chromatid exchange of one 10 chromosome. Höckner et al. [2008] investigated a male patient with a 47,X,idic(X)(p11.i),Y karyotype and establish loss of heterozygosity for all informative Xq markers on the isochromosome and the presence of the other maternal allele on the normal homolog in each case of maternal heterozygosity. These results are in line with a maternal origin of a true dicentric isochromosome and non a maternal Xq/Xq translocation, and most likely postzygotic germination subsequent to a nondisjunction in maternal meiosis II [Höckner et al., 2008].

Klinefelter Patients with Boosted Aberrations on One of the Two X Chromosomes

In the literature, simply 5 cases with a 47,X,der(10),Y karyotype accept been described. All of the cases were reported before 1981. Therefore, there is only little information near these rearrangements. The clinical and laboratory data on these cases are summarized in table 2. The offset case showing such a karyotype was reported by Nielsen who described a male KS patient with final deleted X chromosome mosaic (10% normal 46,XY cells) [Nielsen, 1966]. At the age of 54 years, the man was just 160 cm tall and his whole torso hair was scanty. He did not testify gynecomastia, his penis was of normal size, and his testes were soft and measured x mm from pole to pole. His personality was described as childish and primitive and in comparison with 'normal' Klinefelter patients he showed more marked personality defects and his sexual activeness was more pronounced. The sex chromatin percentage in buccal smear was fourteen% which is less than usually found in patients with KS. The decreased body acme in the man, stands, because of his 2 Xp arms, in contrast to the hypothesis about the relevance of the number of SHOX gene copies, only it should be mentioned that Nielsen et al. published the case in 1966 and it is not possible to control the definiteness of the karyotype.

Tabular array 2

Clinical features in 5 male patients with KS and a 47,XY,der(X) karyotype sorted by the year of publication

Chandra et al. [1971] besides reported a male patient with a 47,XXq-Y karyotype. A niggling less than half of the long arm appears to take been deleted from ane of the 10 chromosomes. One sex activity chromatin body could be seen in xl–60% of the examined cells from pilus roots and buccal mucosa. The patient was described as a ho-hum-looking boy with rather a large build for his age and bilateral gynecomastia. His trunk hair had a feminine distribution and the testes were minor and soft. All these symptoms resemble to those of normal KS patients and are partly identical to those of Nielsen'southward case. The differences between these 2 cases are the gynecomastia and the torso pinnacle, which supports the assertion of the SHOX gene hypothesis. Nevertheless, it should be mentioned that Chandra et al. [1971] described a boy of unknown age and Nielsen [1966] a 54-twelvemonth-one-time man.

Patil et al. [1981] reported a case of a xix-year-old KS patient with gynecomastia, small testes, and azoospermia. The assay of the chromosomes showed a deletion of parts of the long arm of the Ten chromosome with the breakpoint in q22. The authors interpreted the karyotype as 47,X,del(Ten)(pter→q22:),Y. Growth, weight and intellectual development were normal. Just the FSH and LH levels were increased. These symptoms were consistent with those reported in the instance by Chandra et al. [1971]. Patil et al. [1981] suggested that the region q11→22 might be associated with the phenotype of the KS, but this was revised in the aforementioned year past Fryns. He described a case of a xxx-yr-old male with completely normal phenotype without gynecomastia and normal sexual evolution [Fryns, 1981]. Both testes were modest and sperm assay revealed azoospermia. Co-ordinate to the report, his testosterone and LH levels were normal but FSH levels were elevated. The karyotype was 47,XY,+del(Xp11). Buccal smear assay showed a pocket-sized Barr body in 20% of the cells.

In comparison, nosotros can say that a terminal deletion of the X chromosome shows a nearly similar phenotype to 'normal' KS. Just the body height differs from the typical KS phenotype and is normal to slightly reduced in the patients. The only reported case of a del(Xp) differs from all the other cases and did not even prove affinity to the cases with an additional isochromosome Xq.

Klinefelter Patients with Additional Aberrations on the Y Chromosome

Xi cases of KS patients with a 47,Twenty,der(Y) karyotype were found, but only 7 of them were described in detail (tabular array 3). Every bit the private cases differ greatly from each other, we must consider them separately.

Table 3

Clinical features in xi male patients with KS and a 47,Xx,der(Y) karyotype sorted by the year of publication

The virtually recent case we institute was reported in 2009. The group presented a case of an unborn boy with a 47,XX,mar(Y) karyotype [Sheth et al., 2009]. Using different FISH clones for the SRY gene and for the centromeric and the subtelomeric region of the Y chromosome they plant the presence of a neocentric inv dup (Y)(pter→Yp11.2::Yp11.2→pter). Spinner et al. [2008] presented a case of a newborn infant with ovotesticular disorder of sexual activity development and sexual activity chromosome mosaicism. The karyotype was divers as 46,XXr(Y)[10]/46,Twenty[40]. The patient showed ambiguous genitalia and a micropenis. Later an exploratory laparotomy the right gonad could be identified as an ovotestis and the left gonad equally an undescended dysgenetic testis and a uterus defective endothelial uterine glands. The r(Y) chromosome was transmitted via ICSI from the oligospermic but otherwise unremarkable father to the child. Apart from this commodity we constitute another one which described a instance of an additional r(Y) chromosome [Weimer et al., 2006]. The patient showed signs of KS including gynecomastia, decreased torso hair, hypergonadotropic hypogonadism, learning difficulties, an increased value of FSH, and a decreased value of testosterone. His sex evolution was male person, consistent with the presence of the SRY locus on the r(Y) chromosome. At the age of 15 years, the boy presented with a mild overgrowth (182 cm), obesity (121 kg), and a slight outsized head circumference (59 cm). The karyotype was described as 48,XX,r(Y),+r(8)[68]/ 47,Xx,+r(Y)[19]/47,XX,r(8)[6]/46,XX[8]. In 2006, a example of a 24-year-old man with a KS karyotype and an boosted microdeletion on the Y chromosome was presented [Samli et al., 2006]. The man was infertile and showed abnormally high LH and FSH levels only a lower testosterone level than usual. The grouping constitute a deletion in the AZFa region on the Y chromosome. The phenotype of the patient did not differ from those of KS patients without microdeletions in this region. Microdeletions in AZFa are frequently associated with Sertoli-cell-merely syndrome and azoospermia and with a frequency of 1–2% they are one of the near frequent reasons of spermatogenetic failure and infertility [Poongothai et al., 2009].

An interesting case about a 31-year-old male patient with an in part Klinefelter phenotype and an isodicentric Y-chromosome was reported past Heinritz et al. [2005]. The karyotype was indicated as 47,20,+idic(Y)(q12). The human showed a tall stature, unproportionally long slender legs, a normal male body hair patterning, just slightly reduced growth of his facial hair, gynecomastia, genitalia with hypoplastic, soft testes, and a modest penis. The behavior of the human being was described as ambitious with rapid alterations of the mood and a naive and inappropriate social functioning. The LH and FSH levels were increased, but testosterone levels were lower than normal [Heinritz et al., 2005]. Ordinarily, psychological and behavioral bug like violence, aggressiveness, and a depression IQ are the master features of males with 48,XXYY and are very untypical for KS patients [Heinritz et al., 2005]. In before studies, the presence of an boosted Y chromosome, as in men with 47,XYY, was discussed to be related to personality problems and mainly a choleric beliefs, but the molecular basis for the behavioral anomalies in patients with structural rearrangements of the sexual activity chromosomes is not fully understood [Heinritz et al., 2005].

Arnedo et al. [2005] reported a case of a transmitted SRY-positive band Y chromosome from the father to his KS son. The frequency of ring chromosomes in clinically detected conceptions is 1:25,000 and has been reported for all human chromosomes [Arnedo et al., 2005]. In most of the cases a mosaic is presented and simply ≤1% of all the band chromosomes are inherited. In the study of Arnedo et al. [2005], the boy had a 47,XX,r(Y)/46,20 karyotype and his father a 46,X,r(Y)/45,X karyotype. All men with a r(Y) studied so far were infertile and as well the father showed a moderate oligozoospermia (four.5 × 10⁶ sperm/ml) which could be explained by the arrest of the spermatocytes during meiosis [Arnedo et al., 2005]. All the same, his married woman became meaning by natural formulation. Both the begetter and his son showed no phenotype abnormalities and their intelligence level was reported as normal. Because of the normal trunk top of the begetter the group suggested that the loss of genetic material implicated in ring Y formation may not accept included the SHOX locus on Yp. Via microsatellite DNA markers the paternal origin of the additional X chromosome could also exist detected. Further information like the hormonal status was not provided in the study.

In conclusion, most of the patients show some typical phenotype features of KS similar small testes or increased FSH and LH levels. In 1 of the patients an increased ambitious and primitive behavior could be adamant, whereas all other patients presented with normal behavior and intelligence levels despite from their aberration on the Y chromosome. A comparison of the cases is not possible because the rearrangements are located on various parts of the Y chromosome.

Men with a 46,XX Karyotype Including Patients with Ambiguous Genitalia

Sex reversal syndrome (SRS) is a human being genetic disease, which is characterized by inconsistency between gonadal sexuality and chromosome sexuality and includes 46,XY females and 46,Xx males [Wang et al., 2009]. The XX male SRS, besides called de la Chapelle syndrome, was outset characterized in 1972 [de la Chapelle, 1972]. With an incidence of one:20,000–25,000 the syndrome is rare [Rajender et al., 2006]. About XX men result from an abnormal X-Y interchange while spermatogenesis. During meiosis the human X and Y chromosomes pair in homologous regions named pseudoautosomal region i (PAR1) on Xp22.iii and Yp11.3 and pseudoautosomal region two (PAR2) on Xq28 and Yq12. PAR1 spans about two.7 Mb and PAR2 about 0.33 Mb on each chromosome. A translocation of Y material, which includes the key sexual activity-determining region (SRY) that is located centromeric to PAR1, to the X chromosome during paternal meiosis results in 46,Xx males, with normal male sexual evolution [Ferguson-Smith, 1966; Rigola et al., 2002].

Individuals with 46,20 maleness can be classified every bit Y-positive or Y-negative according to the presence or absenteeism of the SRY gene [Valetto et al., 2005]. Approximately ninety% of the patients without ambiguous genitalia carry Y-derived fabric, particularly the SRY gene caused by an X/Y or Y/autosome rearrangement [Ramos et al., 1996]. In agreement nearly XX males with ambiguous genitalia are SRY negative [Ramos et al., 1996]. In XX individuals i of the 2 X chromosomes is inactivated in early on embryonic development as a mechanism of dosage bounty for sex-linked genes [Sharp et al., 2005]. A skewed X inactivation was establish in Twenty males with complete masculinization. As well, XX sex-reversed individuals with incomplete masculinization ordinarily bear witness non-random inactivation, preferentially of the SRY-conveying X chromosome [Bouayed Abdelmoula et al., 2003]. Sharp et al. [2005] suggested that incomplete masculinization in cases of X/Y translocations is a result of abnormal SRY cistron expression past a positional effect, rather than X chromosome inactivation.

While the clinical symptoms of 20 male person patients often show some degree of heterogeneity [Ergun-Longmire et al., 2005], usually, the development of genitalia is normal and masculinity signs are obvious in SRY cistron-positive patients [Wang et al., 2009]. Evolution of the genitals and sex psychology was described to be normal likewise as erection and ejaculation, and at that place are almost no significant signs except cryptorchidism before puberty in most of the patients [Wang et al., 2009]. In most of the cases the patients are found by chromosome analysis for the reason of infertility. The clinical and laboratory information on 20 male person patients are summarized in table 4.

Table four

Clinical features in 149 patients with KS and a 46,XX karyotype sorted past the year of publication

Only 3 cases accept been described in the literature about 46,20 men with SRY located on an autosomal chromosome [Dauwerse et al., 2006; Queralt et al., 2008; Chien et al., 2009]. It was postulated that the translocation between the SRY conveying Y chromosome and an autosomal chromosome was due to nonhomologous recombination between the autosomal chromosome and Ypter (containing SRY locus) during paternal meiosis [Queralt et al., 2008; Chien et al., 2009]. Regarding the phenotype at that place are no differences between the patients with the SRY gene on the X chromosome and the patients carrying the SRY gene on an autosomal chromosome.

On the contrary, SRY factor-negative patients can oftentimes be easily discriminated due to abnormality of genitalia shortly after nascence. Some patients even show genital ambiguity [Ergun-Longmire et al., 2005] and belong to the group of true hermaphrodites and in some cases the patients have normal male person genitalia in face of SRY-negative 46,Xx karyotype [Rajender et al., 2006; Mustafa and Mehmet, 2010]. In many cases masculinity signs are not clear in SRY-negative patients. Mainly in adult patients, breast development and female secondary sex activity characteristics were found. Domenice et al. [2004] proposed that ninety% of 46,XX males carried Y chromosome material including the SRY factor. At that place have been postulated 2 dissimilar theories for the remaining 10%: The first indicates that a structural gene that determines homo gender could be located on an autosomal chromosome which is regulated by X chromosome inactivation and the activation of Y chromosome [Wang et al., 2009]. Due to defects in the X inactivation, which result in spontaneous activation of a downstream gene in the absence of SRY, 46,20 males could develop [Wang et al., 2009]. In previous studies, other genes in mouse and goat take been identified that pb, in the example of a mutation, to SRS. The corresponding homologs in homo, FOXL2 (forkhead box L2) and WNT4 (wingless-blazon MMTV integration site family unit, fellow member 4) were likewise by and large analyzed since these findings [Temel et al., 2007]. In unlike studies information technology was postulated that NR0B1 (nuclear receptor subfamily 0, group B, member 1), likewise known as DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on the 10 chromosome, gene 1) acts every bit an anti-testis gene past antagonizing SRY function and that this genemay be necessary for testis development and its consequence seems to be dosage sensitive [Ergun-Longmire et al., 2005]. Domenice et al. [2004] analyzed mutations in the DAX1 and the WNT4 genes in sex-reversed patients and found out that the dosage of these genes was normal in their patients. With the assistance of these information, they proposed that the DAX1 and WNT4 are rarely involved in the etiology of male person gonadal development in sex-reversed patients. This fact suggests the presence of other genes in the sex determination cascade.

The second hypothesis is well-nigh a SOX9 gene (SRY box-related gene 9) overexpression. It was suggested that this cistron might role downstream to the SRY gene in the sexual practice-determination pathway. Therefore, an upregulation of SOX9 expression caused past chromosomal abnormalities or mediated by other bypass activation mutations could pb to female-to-male sexual activity reversal in 46,XX SRY-negative males [Dorsey et al., 2009; Wang et al., 2009].

Maciel-Guerra et al. [2008] identified in 2008 a case of XX maleness and Twenty true hermaphroditism in SRY-negative monozygotic twins, suggesting that these entities might correspond pleomorphic manifestations of the same disorder of gonadal development. Rajender et al. [2006] likewise described an SRY-negative man with 46,20 karyotype who presented with normal genitalia. The group did not find a mutation in the coding region of the SOX9 and the DAX1 cistron and no re-create number variant in the SOX9 gene. In general, the reported patients with SRY-negative 46,20 karyotype have modest or undescended testes [Valetto et al., 2005; Rajender et al., 2006; Temel et al., 2007; Dorsey et al., 2009] and in office additional ovarian tissue [Maciel-Guerra et al., 2008; Dorsey et al., 2009]. Nigh of the men have normal body hair and no gynecomastia. In that part they differ from the 'normal' KS patients. Nevertheless, the hormone condition shows the typically increased FSH and LH values and normal to decreased testosterone levels.

Women with a 47,XXY Karyotype

Searching in PubMed we found only xiii cases describing a female phenotype with a 47,XXY karyotype and one patient with a 47,Xx+der(Y) karyotype. 7 of these cases have been diagnosed as suffering from androgen insensitivity (testicular feminization) syndrome resulting from mutations in the androgen receptor (AR) gene [German and Vesell, 1966; Bartsch-Sandhoff et al., 1976; Gerli et al., 1979; Müller et al., 1990; Uehara et al., 1999; Saavedra-Castillo et al., 2005; Girardin et al., 2009]. Just iii cases are reported well-nigh women with an additional or at least parts of the Y chromosome. One report describes a mother and her daughter with a 47,XXY SRY-negative karyotype [Röttger et al., 2000] and the other a adult female with a 47,XX+mar karyotype where the extra chromosome contained centromeric Deoxyribonucleic acid derived from the Y chromosome [Causio et al., 2002]. In the other two 47,XXY female cases, the cause for their femaleness could not exist clarified [Schmid et al., 1992; Thangaraj et al., 1998]. The clinical and laboratory data of the reported 47,XXY women are summarized in table v.

Table v

Clinical features in 13 female person patients with KS and a 47,XXY karyotype sorted by the year of publication

The consummate androgen insensitivity syndrome (CAIS) describes an X-linked disorder in which affected people have normal female external ballocks, female breast evolution, absence of the müllerian structures and intestinal or inguinal testes, despite a normal male karyotype. At puberty, female secondary sex activity characteristics similar breasts develop, simply flow and fertility do not. The prevalence of CAIS is estimated between ane in 20,000–threescore,000 births [Girardin et al., 2009]. It is due to mutations in the AR gene, which is located on the X chromosome on Xq12 and may occur de novo or be inherited.

Normally, a defect resulting from a mutant AR allele on i X chromosome is masked by the effect of the normal allele on the other 10 chromosome [Uehara et al., 1999]. In 2009, ii different hypotheses were suggested that could explain a CAIS phenotype in a 47,XXY individual. The first is that the homozygosity for the mutated AR gene implies either complete or partial maternal molecular identical material. The second hypothesis involves two dissimilar X chromosomes with 2 dissimilar AR alleles but with skewed X inactivation of the nonmutated X chromosome [Girardin et al., 2009].

The external ballocks similar breast development or formation of the vagina differ in the reported cases. High german and Vesell [1966] described monozygotic female twins with a 47,XXY karyotype and normal female person external genitalia. Nevertheless, Saavedra-Castillo et al. [2005] reported a woman with the same karyotype simply hypoplasia of labial folds, clitoris, and vagina. Apart from that, the internal genitalia are nearly similar. All patients are characterized past the absence of the uterus and ovaries. Most of them have no wolffian and müllerian ducts but testes. Interestingly, in most of the described cases the testosterone levels were lower than expected in androgene insensitivity. This could be explained by testicular dysgenesis due to the 47,XXY karyotype. But one time the testosterone and LH levels were increased as expected in CAIS [Girardin et al., 2009]. The loftier FSH level likely reflects testicular dysgenesis in the context of the 47,XXY karyotype. Girardin et al. [2009] found a point mutation in the AR cistron on both X chromosomes and Uehara et al. [1999] found 2 mutations in the AR gene in a xxx-year-old adult female with severely increased hormone levels. This can explicate why CAIS occurred in this XXY patient. In the other cases the AR factor was not sequenced.

Röttger et al. [2000] reported the but 2 cases of women with an SRY-negative 47,XXY karyotype. They described these 47,XXY females resulting from an aberrant 10-Y interchange with transfer of Xp material onto Yp, with concomitant loss of the SRY cistron. The two patients are mother and daughter, which is very uncommon considering usually XXY women are sterile. The information of Röttger et al. [2000] indicated that the Y chromosome in the mother and, by inference, in the daughter prove a replacement of the Yp material that includes SRY and PRKY (poly peptide kinase, Y-linked) by Xp textile upwards to and including PRKX (protein kinase, X-linked). The absence of SRY explains the sex reversal in these two 47,XXY females. One X and the Y chromosome in the girl were inherited from the female parent. Her phenotype was non described. At her birth the daughter showed a female phenotype with normal external genitalia and bilateral clubbed feet. Two years later a patient was reported with a normal female person karyotype but an additional marking chromosome, resembling an Y chromosome in size and QFQ-staining pattern [Causio et al., 2002]. The woman presented an apparently normal female habitus, with normal secondary sexual development. The extra chromosome independent centromeric regions of the Y. By means of sequence-tagged-sites PCR the absence of the SRY gene and the presence of the AZF genes could exist defined. In none of two farther reports the reason of the femaleness could be determined [Schmid et al., 1992; Thangaraj et al., 1998].

A comparison between the symptoms of a Klinefelter patient and a 47,XXY female is hardly possible because about of the KS symptoms too chronicle to a more feminine expression of sure body parts (east.g. gynecomastia). Symptoms like a tall stature, sparse body and pubic hair development, and elevated FSH and LH levels occur in nearly but not all of the described women. These characteristics are similar to those of KS.

Other Numeric Sex Chromosome Abnormalities

Besides the 47,XXY karyotype, a less frequent group of KS patients have boosted Ten and/or Y chromosomes and evidence karyotypes similar 48,XXYY, 48,XXXY, or 49,XXXXY [Visootsak and Graham, 2009].

48,XXYY syndrome occurs in approximately 1:17,000–1:45,000 males [Borja-Santos et al., 2010]. The physical features accept been described to be similar to 47,XXY but with some more pronounced phenotypic abnormalities. These are mild craniofacial dysmorphism, skeletal anomalies such every bit radioulnar synostosis and clinodactyly, lower IQ (typically between seventy and 80), meaning developmental delays, and medical problems like neurological symptoms such as intention tremor, poor dentition, or reactive airway affliction [Lenroot et al., 2009; Visootsak and Graham, 2009]. The behavior of the patients is described to be shy and reserved. It can include hyperactivity, attention bug, impulsivity, aggression, mood instability, 'autistic-like' behaviors, and poor social function [Lenroot et al., 2009; Visootsak and Graham, 2009]. In comparison to 47,XXY patients, men with 48,XXYY karyotype show a greater impairment in cerebral, exact, and social performance [Visootsak and Graham, 2009] and also the physical height is increased [Lenroot et al., 2009]. Tartaglia et al. [2008] reported a cohort of 95 subjects ranging from ane to 55 years of age and having a 48,XXYY karyotype. 92% of the men showed speech/language delays and 100% received special didactics for learning disabilities. The group found common medical problems including allergies and asthma, built middle defects, radioulnar synostosis, inguinal hernia and/or cryptorchidism, and seizures in the patients [Tartaglia et al., 2008]. In the machismo, medical features like hypogonadism, deep vein thrombosis, intention tremor, and type II diabetes were institute [Tartaglia et al., 2008, 2009]. In the same yr, Zhang and Li [2009] reported a case with 48,XXYY karyotype. They proposed the origin of this karyotype in a successive nondisjunction during paternal meiosis I and Two. As the begetter of the patient was 56 years quondam, this case adds to the evidence that an age-related increase in sex activity chromosomal aneuploidies occurs in sperm.

The 48,XXXY karyotype is considered a variant of KS with features generally more than pronounced than 47,XXY only less severe than 49,XXXXY and with an incidence of 1:17,000 to one:50,000 in male births it is uncommon [Linden et al., 1995; Venkateshwari et al., 2010]. Affected males show a normal to tall stature with a decreased upper segment to lower segment ratio, hypertelorism and epicanthic folds, simplified ears and mild prognathism, skeletal anomalies including clinodactyly, abnormalities of the elbows and radioulnar synostosis, hypergonadotropic hypogonadism and testicular histology similar to 47,XXY and 48,XXYY, gynecomastia, and an abnormal glucose tolerance [Linden et al., 1995]. One quaternary of these patients has a hypoplastic penis and is infertile [Linden et al., 1995]. In accordance with Zhang and Li [2009], the IQs of the patients range between 40 and 60, and a greater arrears in daily living skills, communication, and socialization in comparison to 48,XXYY cases could be detected [Visootsak et al., 2007]. Behavioral characteristics are immaturity, passivity, and irritability with temper tantrums [Visootsak and Graham, 2009]. Similarities to the 48,XXYY males are the activity level, the helpfulness, the pain tolerance, the morality, and the rejection based on the Reiss Personality Contour [Visootsak et al., 2007].

The rarest of the described variants in this review is the 49,XXXXY that shows an incidence of 1:85,000 to 1:100,000, and is in improver described to be the most severe variant of KS [Linden et al., 1995]. The extra X chromosomes in this variant accrue during maternal meiosis I and 2 and are the production of a double nondisjunction consequence [Simsek et al., 2009]. A correlation between maternal age and 49,XXXXY syndrome could not be detected in previous studies [Celik et al., 1997]. Clinical features of the syndrome are a coarse face with microcephaly, ocular hypertelorism, flat nasal bridge, upslanting palpebral fissures, bifid uvula and/or crack palate, skeletal abnormalities including radioulnar synostosis, knee valgum, pes cavus, or clinodactyly, brusque stature with hypotonia, hyperextensible joints, and underdeveloped genitalia with hypergonadotropic hypogonadism [Visootsak et al., 2007]. The behavior of affected people is described as timid and shy to friendly, but the patients show a low frustration tolerance and and then irritability and tour of temper tin occur sometimes [Linden et al., 1995]. The IQs of the patients range between 20 to 60 points [Linden et al., 1995]. Therefore, mental retardation was long described to exist a feature feature for the syndrome. However, recent studies have reported that cognitive delays were not every bit meaning every bit described in the by and personalities and learning styles are similar to 47,XXY cases [Samango-Sprouse, 2001; Visootsak et al., 2001, 2007; Visootsak and Graham, 2006; Gropman et al., 2010]. Variability in clinical and cognitive performance may reverberate skewed X inactivation, mosaicism, or other factors that warrant farther investigation [Gropman et al., 2010]. Recently, Ottesen et al. [2010] reported a study about the increased top in patients with additional sexual practice chromosomes. In line with other reports [Bojesen and Gravholt, 2007; Tartaglia et al., 2008], they establish an increased stature in subjects with 47,XXY, 47,XYY, or 48,XXYY karyotypes. In patients with a 49,XXXXY karyotype the stature was reduced and for that the group suggests a nonlinear effect of the number of sex chromosomes on tiptop [Ottesen et al., 2010]. Altogether, the phenotypic features of 49,XXXXY patients share some characteristics with 47,XXY, but at that place are also other unique and distinctive traits.

In conclusion, the effects on physical and mental development increment with the number of extra 10 chromosomes, and each 10 reduces the overall IQ by 15–xvi points, with language most affected [Polani, 1969]. In add-on, it was found that height decreases and radioulnar synostosis becomes more frequent as the number of X chromosomes increases [Visootsak et al., 2007].

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