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This chapter should be cited as follows:
Elias, S, Shulman, L, Glob. libr. women's med.,
(ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10358
Update due

Males with Polysomy Y and Females with Polysomy X



Both polysomy Y in males (47,XYY; 48,XYYY; 48,XXYY; 49,XXYYY) and polysomy X in females (47,XXX; 48,XXXX; 49,XXXXX) may be encountered by obstetricians-gynecologists as (1) an abnormal fetal chromosome complement detected by chorionic villus sampling, amniocentesis, or percutaneous umbilical blood sampling or (2) part of an evaluation for infertility, abnormal sexual development, other congenital malformations, or mental aberrations. Polysomic sex chromosome complements may also provide valuable information concerning sex chromosome function and abnormalities of meiosis or mitosis. In this chapter epidemiologic data and clinical features of polysomy X and polysomy Y will be reviewed as well as recommendations for counseling both affected individuals and women carrying affected fetuses. The reader is referred to a previous publication for additional information.1




The first individual with a 47,XYY chromosomal complement (Fig. 1) was described by Sandberg and co-workers in 1961.2 For several years thereafter, relatively few cases were reported, but in 1965-1966, several investigators reported that among mentally retarded criminals the prevalence of 47,XYY was higher than expected by chance, creating a resurgence of interest in this disorder.3,4,5,6 Jacobs7 summarized the data collected from eight chromosome surveys of unselected infants.8,9,10,11,12,13,14,15 Among 39,557 males studied, 38 (0.1%) were found to have 47,XYY complements. These data correspond closely to those of two large sex chromatin surveys of newborns16,17 as well as recent data reported by Hecht and Hecht18 demonstrating the frequency of XYY in newborn males to be 1 in 975.

Fig. 1. Karyotype of a lymphocyte of a 47,XYY individual. Trypsin-giemsa banding.

Among a total of 13,406 male infants studies, 9 (0.07%) were determined to have two Y-bodies. Subsequently, 47,XYY karyotypes were confirmed in these 9 infants. There has been some suggestion that the incidence of 47,XYY males may be lower among blacks than among whites.19


The most likely origin of 47,XYY is paternal nondisjunction at meiosis II, resulting in 24,YY spermatozoa, followed by syngamy with a normal 23,X ovum. A 24,YY spermatozoon would also be a normal product of meiosis in a male with a 47,XYY chromosomal constitution; however, this phenomenon probably accounts for relatively few 47,XYY men.20 Alternatively, postzygotic nondisjunction in a 46,XY zygote could give rise to 45,X/47,XYY mosaicism. Either exclusion of the 45,X line or selection in favor of the 47,XYY line could result in an apparently “pure” 47,XYY zygote. The occurrence of double aneuploidy, for example, 48,XYY,+21, raises the possibility that genetic factors could be important in the etiology of polysomy Y.21 Finally, parental age appears to play no important part in the genesis of 47,XYY.22


Psychologic and Intellectual Function.

The first psychologic studies of 47,XYY males were those of Price and co-workers,23,24 who studied inmates at a Scottish maximum security prison. Compared with 18 46,XY inmates, 9 47,XYY inmates (1) incurred their first conviction at a younger age (mean age 13.1 years for 47,XYY; 18 years for 46,XY, (2) less often had a sibling who had received a conviction (1/31 siblings of 47,XYY inmates; 13/63 sibs of 46,XY inmates), and (3) committed crimes against property more often than crimes against persons. These observations suggested that 47,XYY inmates are incarcerated for different reasons than are other inmates. Probably the most objective study was from Denmark, conducted by Witkin and co-workers,25 in which a 42% (5/12) rate of criminality was found among 47,XYY males compared with 9.3% in 4096 46,XY controls. The difference is about 4.5-fold and is significant at the 0.05 level. Hook26 suggested that despite the observation that intelligence quotients of 47,XYY males are lower than 46,XY controls in exclusively penal settings, it is not the lower intelligence per se that is exclusively responsible for the higher frequency of incarceration but rather the significant increase in risk of social maldevelopment associated with the 47,XYY genotype.

On the other hand, some investigators object to these conclusions regarding the increased frequency of social maldevelopment and predisposition to “criminality.”27 Accurate assessment of the intellectual and psychologic problems in 47,XYY individuals therefore awaits the results of larger prospective surveys of neonates or randomly ascertained adults. Robinson and associates28 summarized the findings of 43 47,XYY infants prospectively ascertained through various chromosome surveys of unselected neonates. About a third of the children showed delayed speech or language development (7 of 18), an increased frequency over their siblings and controls. IQ scores ranged from 78 to 145; however, there was a slight skew to the left in IQ distribution, with 14 of 37 children being in the 70 to 89 IQ range. Gross motor development was generally found to be normal, although there was a suggestion of fine motor problems. There currently appears to be insufficient information to make any conclusions regarding the frequency or magnitude of the increased risk for social pathology28,29 in 47,XYY individuals.

Somatic Abnormalities.

In summarizing the data concerning the 43 47,XYY neonates who were prospectively ascertained through newborn surveys, Robinson and associates28 found that birthweights, length, head circumference, and course during the first year of life were within normal ranges. There was no clear “XYY syndrome” identifiable at birth, with the majority of neonates being completely normal in appearance. There was only one major anomaly, that is, congenital hip dislocation. Eight neonates had one or more minor anomalies, including clinodactyly (2 cases) with a single crease of the fifth finger in one, inguinal hernia (2 cases), abnormal ears (2 cases), pectus carniatum, borderline large head, asymmetric head, strabismus, epicanthic folds, micrognathia, acne, philosis, simian crease, and an undefined heart murmur.

In addition to the aforementioned clinical manifestations, 47,XYY individuals are sometimes quite tall. In the Scottish prison surveys, 47,XYY inmates30 had a mean height of 71.3 inches (181.2 cm) compared with 67.2 inches (170.7 cm) for 46,XY inmates. Some investigators believe that electrocardiographic abnormalities are present31,32; however, others have not been able to confirm such abnormalities.33,34 Dermatoglyphic analyses have shown decreased total digital ridge counts consistent with the general observation of an inverse relationship between sex chromosome polysomy and total ridge count.35,36 The sizes of deciduous teeth of 47,XXY individuals have been found to be larger than controls, suggesting that the Y chromosome regulates quantitative variation of dental growth.37 Finally, abnormal electroencephalograms have been reported in 47,XYY men in psychiatric hospitals and prisons38; however, persons resident in institutions are more likely to exhibit abnormal electroencephalograms compared with normal individuals.

The evidence of fertility of 47,XYY males is limited; however, the sons of 47,XYY males usually show normal 46,XY complements.20,37,38,39,40,41 Seminiferous tubules characterized by spermatogenic arrest are detected in about 50% of 47,XYY males, and about 30% of tubules consist solely of Sertoli cells.42 Sperm counts may be low, even if testes are normal in size.42 Although somewhat controversial, the consensus is that testosterone levels are within normal ranges in most 47,XYY males. Migeon and associates43 investigated the plasma testosterone levels in 15 47,XYY males from the United States and 15 such individuals from England, whose ages ranged from 20 to 50 years. Seventeen of these 30 individuals showed a normal range of testosterone. Seven showed a level over 2 standard deviations above the mean and 6 showed a level under 2 standard deviations below the mean (normal range, 460 1 mμg/100 ml; SD, ± 125 mμg/100 ml).


Theoretically, meiosis in 47,XYY males should lead to 50% normal gametes with a single X or Y and to 50% gametes with 24,YY or 24,XY complements; hence, 50% of the offspring should be trisomic, either 47,XYY or 47,XXY. However, offspring of 47,XYY males have usually been reported to be chromosomally normal. Some 47,XYY men have purportedly had offspring with trisomy 21,44 which raises the possibility that the abnormal sex chromosome constitution affects segregation of autosomal chromosomes as well. Further investigations are needed to understand gametogenesis in 47,XYY individuals. Until such data become available, it seems warranted to offer prenatal diagnosis in this situation.

If fetal cytogenetic studies reveal a 47,XYY complement, the couple must be fully informed regarding potential psychiatric, social, and somatic abnormalities of 47,XYY individuals. As in all cases of prenatal diagnosis, the couple must make the ultimate decision of whether to continue the pregnancy. Their decision must be supported by the physician and the entire genetic counseling team.

47,XYY and Female Phenotype

Individuals with 47,XYY cells may occasionally have female or ambiguous external genitalia and may be categorized into three groups:

  1. 45,X/47,XYY mosaicism. These individuals might be expected to display a wide clinical spectrum, that is, (1) almost normal male development,45 (2) ambiguous external genitalia associated either with two dysgenetic testes or with a unilateral streak gonad and a contralateral testis (mixed gonadal dysgenesis), or (3) female external genitalia and bilateral streak gonads.46 Mosaicism of the 45,X/47,XYY type has been detected in two and possibly three siblings whose parents were consanguineous47,48; therefore, in some cases this mosaicism may be influenced by genetic factors.
  2. Suspected 45,X/47,XYY mosaicism, 47,XYY cells may be the only demonstrable cells in individuals who have both müllerian derivatives and genital ambiguity. The presence of müllerian derivatives suggests mosaicism.
  3. 47,XYY individuals with female or ambiguous external genitalia but no uterus. The absence of a uterus suggests a disorder other than undetected mosaicism because a uterus is usually present in 45,X/47,XYY individuals. Some cases may represent the coincidental association of testicular feminization and 47,XYY; others are more difficult to explain and could be teratogenic in etiology.


Relatively few cases of 48,XYYY have been reported.49,50,51,52,53 Presumably 48,XYYY arises from Y nondisjunction in mitosis of spermatocyte formation followed by a Y nondisjunction during meiosis I and subsequent chromatid nondisjunction of one Y during meiosis II, resulting in a sperm bearing three Y chromosomes.

Clinical features which appear similar in some 48,XYYY males include low normal intelligence quotient, behavioral problems with aggressive outbursts, repeated pulmonary infections during childhood, sparse body hair, clinodactyly of fifth fingers, acne, and hypotrophic testes.50,52 However, Hunter and Quaife51 described a patient exhibiting no stigmata other than sterility.

48,XXYY and 49,XXXYY

48,XXYY and 49,XXXYY are associated with Klinefelter's syndrome phenotype (see related chapter in this volume).




Jacobs and co-workers54 first reported an individual with a 47,XXX chromosomal complement (Fig. 2) in 1959, and since that time such trisomic females have been determined to be relatively common. Jacobs7 tabulated the frequency of 47,XXX to be about 1 per 1,000 female births in reviewing seven chromosome surveys of unselected newborn infants (20 of 20,790 neonates). Hecht and Hecht18 recently confirmed this finding by reporting the frequency of XXX complement to occur in 1 of 975 female newborns. Two X-chromatin masses are detected in approximately 1 per 232 females in institutions for psychotic or neurotic individuals.55 47,XXX is rarely detected among spontaneous abortuses.7

Fig. 2. Karyotype of a lymphocyte of a 47,XXX individual. Trypsin-giemsa banding.


47,XXX can be the result of a nondisjunction of the two X chromosomes during meiosis I of the primary oocyte. It can also be the result of X chromatid nondisjunction during meiosis II, either of the secondary oocyte or of the secondary spermatocyte carrying an X chromosome. 48,XXXX and 49,XXXXX are due to double nondisjunction of the female germ cell. A 48,XXXX could originate from sequential nondisjunction of (1) the oogonial XX bivalents during meiosis I and (2) chromatids of one X chromosome during meiosis II, resulting in a 25,XXX ovum and, after fertilization with an X-carrying sperm, in a 48,XXXX zygote. The mechanism leading to 49,XXXXX is somewhat similar, except that chromatid nondisjunction of both X chromosomes during meiosis II has to take place to produce an ovum with four X chromosomes.

The origin of the extra X chromosome in 47,XXX patients is usually nondisjunction occurring during maternal meiosis I. Study of Xg blood group* alleles provided initial data concerning origin of the extra X chromosome56; however, Morton and associates57 found the Xg locus to be virtually uninformative about the origin of the extra X chromosome in 47,XXX women because of the long distance between the Xg locus and the centromere. This long distance makes distinction between meiosis I and meiosis II unreliable; as the distance between a gene locus and centromere increases, the chance of crossing-over between the two increases, leading to potential diagnostic discrepancies.

More recently, May and colleagues58 used X-linked DNA polymorphisms, located relatively close to the X chromosome centromere, to study parental origin of the extra X chromosome in 28 47,XXX women. Maternal nondisjunction accounted for the extra X chromosome in 26 of the 28 women; of these 26 women, the extra X chromosome was definitely shown to be an error at meiosis I in 15 women, and to an error at meiosis II in 6 women. In the remaining 5 women, the origin of the extra maternal X chromosome could not be determined.

In addition, this study revealed an association between advanced maternal age and 47,XXX offspring59 resulting from errors at maternal meiosis I but failed to reveal an association between advanced maternal age and nondisjunction occurring at maternal meiosis II. This may explain findings of Barr and colleagues,55 who found advanced maternal age to be associated with 47,XXX offspring but not as strongly as is seen in autosomal trisomies involving acrocentric chromosomes.


Several studies have suggested that there is an increased likelihood that 47,XXX women will exhibit developmental delay or mental illness. The magnitude of the increased risk is difficult to estimate because most 47,XXX patients have been ascertained in surveys of the mentally retarded. However, the prevalence of 47,XXX is higher among the mentally retarded than among consecutively born neonates; these observations support the apparent relationship between mental retardation and 47,XXX. Tennes and colleagues60 are prospectively studying 11 females whose 47,XXX was identified at birth. About a third have shown delayed motor and speech development. Robinson28 summarized the clinical findings from 49 children with 47,XXX complements who were studied prospectively at six different medical centers. Nineteen of 41 children studied showed delays in both receptive and expressive language development. Full-scale IQ levels were significantly lower than for siblings and controls. Five of 34 probands had IQ levels below 70. Salbenblatt and co-workers61 found 47,XXX women to exhibit both gross and fine motor dysfunction as well as abnormal sensory-motor integration. These difficulties resulted in language delays that inevitably led to poor classroom performance. In addition, 47,XXX children exhibited a delay in the age of independent walking, thereby confirming the consistency of motor dysfunction throughout development. These data must be considered as tentative because of the spectrum of ages among probands, siblings, and controls and the variety of tests used.

In addition to neurologic deficits, 47,XXX individuals exhibit dermatoglyphic abnormalities; however, it is difficult to determine whether 47,XXX individuals exhibit other somatic abnormalities more often than expected by chance. Dermatoglyphic abnormalities include decreased mean digital ridge count, increased radial loops and arches, absence of patterns in the first and second interdigital areas, wide ridges in the a-b interval, and complex patterns of the soles.62 It has been estimated that about 20% of 47,XXX women may experience delayed menarche, premature ovarian failure, and underdevelopment of secondary sexual characteristics.63,64,65 Varrela and Alvesalo66 have demonstrated taurodontism in four 47,XXX women. In addition, Lenoble and Kaplan67 described a 47,XXX woman who developed systemic lupus erythematosus (SLE), remarkable for numerous visceral localizations, multiple antinuclear antibodies, and high serum levels of IgG and IgA. However, the majority of 47,XXX individuals are normal and may be fertile.


Theoretically, one would expect that 47,XXX women would have a 50% risk of having aneuploid offspring (i.e., 25% 46,XX; 25% 46,XY; 25% 47,XXX; 25% 47,XXY); however, most progeny are chromosomally normal. These empiric observations may reflect (1) selection against abnormal embryos, (2) preferential segregation of 24,XX into a polar body, or (3) decreased fertilizability of 24,XX oocytes. Nonetheless, various reports have suggested that 47,XXX and 46,XX/47,XXX women show some increased risk of producing chromosomally abnormal offspring. For example, in 1969, Barr and co-workers tabulated that 1 of 20 reported 47,XXX women had a 47,XXY son; 3 of 8 46,XX/47,XXX women had 47,XXY or 46,XY/47,XXY sons; and 1 of the 8 had a 46,XX/47,XXX daughter. Although controversial, there is also a suggestion that maternal trisomy X may affect the disjunction of the autosomes as well. At least two 47,XXX women have had trisomy 21 offspring.68,69 However, biases of ascertainment and reporting make the significance of the above findings uncertain. Nonetheless, it still seems prudent to offer prenatal diagnosis to 47,XXX and 46,XX/47,XXX women.

48,XXXX and 49,XXXXX

About 30 48,XXXX individuals have been reported.70,71,72,73,74,75,76 A “typical” phenotype has not yet been delineated. A few 48,XXXX have had normal appearances, whereas others have shown dysmorphic features such as simian crease, facies reminiscent of Down's syndrome, esotropia myopia, strabismus, nystagmus, and dermatoglyphic abnormalities.62,70,71,77,78,79 Alvaro-Gracia and colleagues80 described a 48,XXXX woman who developed SLE, indicating a possible association of autoimmune disorders and sex chromosome polysomy. Almost all 48,XXXX have been subnormal in intelligence; thus, 48,XXXX individuals are more likely to be retarded than are 47,XXX individuals. Hara and co-workers76 reported a pregnancy in a 48,XXXX woman which ended in the delivery of a macerated male weighing 700 gm with an omphalocele.

About a dozen cases of 49,XXXXX have been reported.81,82,83,84,85,86 Mental retardation is invariably associated with 49,XXXXX; however, major malformations are relatively uncommon, albeit higher than in 47,XXX or 48,XXXX. The anomalies most commonly present in 49,XXXXX are hypertelorism, slanting palpebral fissures, a broad nasal bridge, everted lips, esotropia, small hands and feet, abnormal teeth, clinodactyly V, a short neck, and a decreased total digital ridge count84; some of these anomalies also occur in 48,XXXX.

Although few cases of pregnancy have been reported in either 48,XXXX or 49,XXXXX women, prenatal cytogenetic diagnosis seems warranted.


Mosaicism may also be associated with polysomy X. The most common mosaic complement is 46,XX/47,XXX; 47,XXX/48,XXXX and 48,XXXX/49,XXXXX have also been described.87,88

Diagnosis of Sex Chromosome Polysomy

Newborns, children, or adults suspected of having abnormal chromosome complements, including sex chromosome polysomic states, can be evaluated by cytogenetic analysis of peripheral blood lymphocytes. Women at increased risk for fetal chromosome abnormalities can now be offered several invasive prenatal diagnostic techniques for fetal cytogenetic evaluation. Chorionic villus sampling (CVS) is performed in the first-trimester (i.e., 9 to 12 weeks gestation) and can provide both rapid (2 to 4 days) results from direct analysis of uncultured cytotrophoblasts and standard culture analysis of mesenchymal core cells.89 Amniocentesis is routinely performed in the second trimester (14 to 20 weeks gestation) and provides fetal karyotypic information by analysis of cultured amniotic fluid cells. Amniocentesis can also be performed in the third trimester, and its use in the first trimester is currently being investigated.90 Percutaneous umbilical blood sampling (PUBS) can be used to obtain fetal blood samples in the second and third trimesters; analysis of fetal lymphocytes and nucleated erythrocytes can provide rapid cytogenetic results.91 However, the safety of PUBS remains to be elucidated.92

Until recently, confirmation of abnormal complements has been made by standard cytogenetic analysis (e.g., G-banded karyotyping) of cells. However, recent advancements in molecular biology techniques, specifically in situ hybridization, provides a new method for the diagnosis of polysomic states. In situ hybridization involves the hybridization of a radiolabelled probe, representing a unique sequence within the genome, to a specific chromosome in a cell during either interphase or metaphase.93 Autoradiographs show the specific area of the chromosome to which the probe was hybridized (Fig. 3). The number of chromosomes present in the cell will therefore be equal to the number of signals (discrete domains of probe hybridization) visualized. For example, a unique X-chromosome probe will exhibit three signals in a 47,XXX woman and a unique Y-chromosome probe will reveal two signals in a 47,XYY man.

Fig. 3. In situ hybridization of metaphase spread using a unique Y-specific probe. The single signal reflects a 46,XY complement.

In situ hybridization has been primarily applied to analysis of cultured cells. Recently, such technology has been applied to uncultured cells, thereby allowing for rapid screening of a large number of cells for aneuploidy.94 This could prove particularly useful to evaluate suspected mosaicism. Nonetheless, for diagnostic purposes, standard cytogenetic studies should be performed whenever chromosome abnormalities, including sex chromosome polysomy, are suspected. In situ hybridization might not, for example, permit detection of structural chromosome abnormalities that can result in phenotypes similar to those resulting from numerical chromosome abnormalities.



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