The etiology of maleness in XX men

Summary Information relating to the etiology of human XX males is reviewed. The lesser body height and smaller tooth size in comparison with control males and first-degree male relatives could imply that the patients never had any Y chromosome. Neither reports of occasional mitoses with a Y chromosome, nor of the occurrence of Y chromatin in Sertoli cells are convincing enough to support the idea that low-grade or circumscribed mosaicism is a common etiologic factor. Reports of an increase in length of one of the X chromosomes in XX males are few and some are conflicting. Nor is there any evidence to support the idea of loss of material. However, absence of visible cytogenetic alteration does not rule out the possibility of translocations, exchanges or deletions.A few familial cases are known. Mendelian gene mutations may account for a number of instances of XX males, similar genes being well known in several animal species. The existing geographical differences in the prevalence of human XX males could be explained by differences in gene frequency. But if gene mutation were a common cause of XX maleness there would be more familial cases.Any hypothesis explaining the etiology of XX males should take into account the following facts. There are at least 4 examples of XX males who have inherited the Xg allele carried by their fathers, and at least 9 of such males who have not. The frequency of the Xg phenotype among XX males is far closer to that of males than to that of females, while the absence of any color-blind XX males (among 40 tested) resembles the distribution in females. Furthermore, H-Y antigen is present in XX males, often at a strength intermediate between that in normal males and females. Finally, in a pedigree comprising three independently ascertained XX males, the mothers of all three are H-Y antigen-positive, and the pattern of inheritance of the antigen in two of them precludes X-chromosomal transmission.Many of the data are consistent with the hypothesis that XX males arise through interchange of the testic-determining gene on the Y chromosome and a portion of the X chromosome containing the Xg gene. However, actual evidence in favor of this hypothesis is still lacking, and the H-Y antigen data are not easy to explain. In contrast, if recent hypotheses on the mechanisms controlling the expression of H-Y antigen are confirmed, a gene exerting negative control on testis determination would be located near the end of of the short arm of the X chromosome. This putative gene is believed not to be inactivated in normal females, for at least two other genes located in the same region, i.e. Xg and steroid sulfatase, are not. Deletion or inactivation of these loci would explain how XX males arise and would be consistent with most, but not all, the facts.There is yet no single hypothesis that by itself can explain all the facts accumulated about XX males. While mosaicism appears very unlikely in most cases, Mendelian gene mutation, translocation, X-Y interchange, a minute deletion or preferential inactivation of an X chromosome, or part thereof, remain possible. The etiology of XX maleness may well be heterogeneous.     

Patterns and trends in the incidence of paediatric and adult germ cell tumours in Australia, 1982–2011

PurposeGerm cell tumour (GCT) aetiology is uncertain and comprehensive epidemiological studies of GCT incidence are few.MethodsNationwide data on all malignant GCTs notified to Australian population-based cancer registries during 1982–2011 were obtained. Age- and sex-specific, and World age-standardised incidence rates were calculated for paediatric (0–14) and adult (15+) cases using the latest WHO subtype classification scheme. Temporal trends were examined using Joinpoint regression.ResultsThere were 17,279 GCTs (552 paediatric, 16,727 adult). Age-specific incidence in males (all histologies combined) was bimodal, with peaks during infancy for most sites, and second, larger, peaks during young adulthood. Incidence of ovarian tumours peaked at age 15–19. Around half of paediatric tumours were extragonadal, whereas adult tumours were mostly gonadal. Yolk sac tumours and teratomas predominated in infants, whereas germinomas became more frequent towards adulthood. Increasing incidence trends for some adult gonadal tumours have stabilised; the trend for male extragonadal tumours is also declining.ConclusionBroad similarities in the shape of age-specific incidence curves, particularly for gonadal, central nervous system, and mediastinal tumours provide epidemiological support for commonalities in aetiology among clinically disparate GCT subtypes. Differences in peak ages reflect underlying subtype-specific biological differences. Declining incidence trends for some adult gonadal tumours accords with the global transition in GCT incidence, and supports the possibility of a reduction in prevalence of shared aetiological exposures.     

Heteromorphic X chromosomes in 46,XX males: Evidence for the involvement of X-Y interchange

Summary G- and R-banded chromosome preparations from eight of twelve 46,XX males, with no evidence of mosaicism or a free Y chromosome, were distinguished in blind trials from preparations from normal 46,XX females by virtue of heteromorphism of the short arm of one X chromosome. Photographic measurements on X chromosomes and on chromosome pair 7 in cells from twelve 46,XX males, eight 46,XX females, and four 46,XY males revealed a significant increase in the size of the p arm of one X chromosome in the group of XX males, independently characterised as being heteromorphic for Xp. No such differences were observed between X chromosomes of normal males and females or between homologues of chromosome pair 7 in all groups. The heteromorphism in XX males is a consequence of an alteration in shape (banding profile) and length of the tip of the short arm of one X chromosome, and the difference in size of the two Xp arms in these 46,XXp+ males ranged from 0.4% to 22.9%. From various considerations, including the demonstration of a Y-specific DNA fragment in DNA digests from nuclei of one of three XX males tested, it is concluded that the Xp+ chromosome is a product of Xp-Yp exchange. These exchanges are assumed to originate at meiosis in the male parent and may involve an exchange of different amounts of material. The consequences of such unequal exchange are considered in terms of the inheritance of genes located on Yp and distal Xp. No obvious phenotypic difference was associated with the presence or absence of Xp+. Thus, some males diagnosed as 46,XX are mosaic for a cryptic Y-containing cell line, and there is now excellent evidence that maleness in others may be a consequence of an autosomal recessive gene. The present data imply that in around 70% of 46,XX males, maleness is a consequence of the inheritance of a paternal X-Y interchange product.     

Genes that escape from X inactivation

To achieve a balanced gene expression dosage between males (XY) and females (XX), mammals have evolved a compensatory mechanism to randomly inactivate one of the female X chromosomes. Despite this chromosome-wide silencing, a number of genes escape X inactivation: in women about 15% of X-linked genes are bi-allelically expressed and in mice, about 3%. Expression from the inactive X allele varies from a few percent of that from the active allele to near equal expression. While most genes have a stable inactivation pattern, a subset of genes exhibit tissue-specific differences in escape from X inactivation. Escape genes appear to be protected from the repressive chromatin modifications associated with X inactivation. Differences in the identity and distribution of escape genes between species and tissues suggest a role for these genes in the evolution of sex differences in specific phenotypes. The higher expression of escape genes in females than in males implies that they may have female-specific roles and may be responsible for some of the phenotypes observed in X aneuploidy.     

Incidence patterns and trends of malignant gonadal and extragonadal germ cell tumors in Germany, 1998–2008

BackgroundMalignant gonadal (GGCT) and extragonal germ cell tumors [GCT (EGCT)] are thought to originate from primordial germ cells. In contrast to well reported population-based data of GGCTs in males, analyses of GGCTs in females and EGCTs in both sexes remain limited.MethodsIn a pooling project of nine population-based cancer registries in Germany for the years 1998–2008, 16,883 malignant GCTs and their topographical sites were identified using ICD-O morphology and topography for persons aged 15 years and older. We estimated age-specific and age-standardized incidence rates.ResultsAmong males, the incidence of testicular GCTs increased over time. In contrast, there was no increase in the incidence of EGCTs. Among females, rates of ovarian GCTs were stable, while rates of EGCTs declined over time. The most frequent extragonadal sites were mediastinum among males and placenta among females.ConclusionsOur results underline different incidence trends and distinct age-specific incidence patterns of malignant GGCTs and EGCTs, as reported recently by several population-based registries. The differences suggest that GGCT and EGCT may have different etiologies.     

Genetics and biology of human ovarian teratomas. I. Cytogenetic analysis and mechanism of origin.

One hundred and two benign, mature ovarian teratomas and two immature, malignant teratomas were karyotyped and scored for centromeric heteromorphisms as part of an ongoing project to determine the chromosomal karyotype and the genetic origin of ovarian teratomas and to assess their utility for gene-centromere mapping. Karyotypic analysis of the benign cases revealed 95 46,XX teratomas and 7 chromosomally abnormal teratomas (47,XXX, 47,XX,+8 [two cases], 47,XX,+15, 48,XX,+7,+12 91,XXXX,-13 [mosaic], 47,XX,-15,+21,+mar). Our study reports on the first cases of tetraploidy and structural rearrangement in benign ovarian teratomas. The two immature cases had modal chromosome numbers of 78 and 49. Centromeric heteromorphisms that were heterozygous in the host were homozygous in 65.2% (n = 58) of the benign teratomas and heterozygous in the remaining 34.8% (n = 31). Chromosome 13 heteromorphisms were the most informative, with 72.7% heterozygosity in hosts. The cytogenetic data indicate that 65% of teratomas are derived from a single germ cell after meiosis I and failure of meiosis II (type II) or endoreduplication of a mature ovum (type III); 35% arise by failure of meiosis I (type I) or mitotic division of premeiotic germ cells (type IV).     

Molecular analysis of chromosome region 11p13 in patients with Drash syndrome

Summary The association of nephropathy, Wilms' tumour and genital abnormalities is known as Drash syndrome. Two of these features are also seen in the WAGR (Wilms' tumour, aniridia, genito-urinary abnormalities, mental retardation) complex, known to be associated with deletions of chromosome region 11p1S. We have carried out karyotypic and molecular studies in 10 Drash patients, 5 males and 5 females. All the males had a 46XY karyotype as did 3/5 of the phenotypic females, the other two having a 46XX karyotype. One of the 46XX females also had a deletion of region 11p13–p12, the only detectable autosomal chromosome abnormality in any of the patients studied. Lymphoblastoid cell lines were prepared from 6 of the Drash patients and were used in dosage studies using a variety of DNA probes from the 11p13 region. There was no evidence of microdeletions in any patient with a normal karyotype. Because of the 46XY karyotype in phenotypic females, selected X and Y chromosome loci were analysed and all found to be normal. Although Drash syndrome is likely to be of genetic origin, there are no readily detected deletions within the 11p13 region.     

EM studies of female meiosis in wood lemmings with different sex chromosome constitutions

The chromosomes were studied throughout meiotic prophase by electron microscopy of surface-spread oocytes from one XX, four X*X, and three X*Y female wood lemmings, Myopus schisticolor. The X* chromosome had originated from X by a deletion and an inversion in the short arm. The deletion was confirmed in pachytene cells from X*X females; a D-loop was present in the sex bivalent in 16.8% of the cells, and asynapsis of unequal ends was seen in 9.1% of other cells. At late pachytene the D-loop underwent synaptic adjustment. The breakpoints of the deletion are in G-light bands. No inversion loop was seen, which also is in agreement with Ashley's ('88) hypothesis; at least one of the presumed breakpoints of the inversion is in G-dark chromatin. Various types of synaptic abnormalities, such as nonhomologous pairing (triple pairing, interchange, self-synapsis), univalents, foldbacks, and broken lateral elements, were encountered in all types of female. X*Y females showed a high frequency of abnormal oocytes (70.7%), which significantly exceeded that of X*X (23.1%) and XX (8.1%). Univalents were particularly common in the X*Y females. J. Exp. Zool. 290:504-516, 2001.     

Inherited XX sex reversal in the cocker spaniel dog

Summary Nine XX true hermaphrodites and two XX males were discovered in a family of American cocker spaniels. The true hermaphrodites were partially-masculinized females with ovotestes; the XX males had malformed male external genitalia and cryptorchid aspermatogenic testes. Wolffian and Mullerian duct derivatives were present in both true hermaphrodites and XX males. All four sires of sex-reversed dogs were normal XY males; five of the dams were anatomically normal females and one was an XX true hermaphrodite. A second true hermaphrodite reproduced as a female, producing anatomically normal offspring.All matings that produced sex-reversed offspring were consanguineous. Matings of the parents of sex-reversed cocker spaniels to normal beagles with no family history of intersexuality produced only normal offspring. Examination of G-banded karyotypes of the affected animals, their parents, and siblings, revealed no structural anomalies of the chromosomes that were consistently associated with sex-reversal.In assays for serologically-detectable H-Y antigen, the group of XX true hermaphrodites and the group of XX males had mean levels of the antigen not significantly different from that in normal male controls. Female parents of sex-reversed dogs and some of their female siblings were typed H-Y antigen positive, but the mean level of the antigen in this group was less than that of normal male controls.It is proposed that XX sex reversal in cocker spaniels is due to a mutant gene which when homozygous in females, results in a level of H-Y antigen similar to that found in normal males and the gonads develop as ovotestes or testes. When the gene is heterozygous in females, the level of serologically-detectable H-Y antigen is lowr than that found in normal males and the gonads develop as normal ovaries. The persistence of Mullerian structures in the presence of testicular tissue suggests that Mullerian inhibiting substance is deficient or ineffective in its action in this condition.Supported by NIH Postdoctoral Fellowship IF32 HL05515, University of Pennsylvania Genetics Center Grant, No. GM 20138, and NIH grants AI-19456, HD 17049, and HD 14357; and a grant from the Mrs. Cheever Porter Foundation.     

黄颡鱼XX伪雄鱼诱导与全雌种群规模化繁育

研究利用3种雄性化因素, 包括17α-甲基睾丸酮(MT, 5 mg/kg)、来曲唑(LZ, 300 mg/kg)和高温(33.5℃) 联合处理12—65日龄黄颡鱼幼鱼, 并将性成熟的XX伪雄鱼与正常XX雌鱼进行人工繁殖, 开展了全雌黄颡鱼(Tachysurus fulvidraco)规模化繁殖与苗种培育工作。研究发现, MT、LZ和高温共同作用可诱导XX黄颡鱼逆转为生理型雄性, 完全性逆转个体运动型精子比例与XY雄鱼无显著性差异, 组织学切片也显示其精巢中存在大量精子细胞, 推测XX伪雄鱼具有正常的繁殖功能。随后, 以XX伪雄鱼为父本, 正常XX雌鱼为母本开展了规模化人工繁殖, 获得了57万尾基因型全部为XX的黄颡鱼苗种, 并将其成功培育成大规格鱼种。在幼鱼60日龄和120日龄时取样发现, 分别有2.8%和12.0%的个体发生了不同程度的雄性化, 推测其可能受到池塘自然高温的影响而发生了性逆转。其余XX雌鱼卵巢发育良好, 来年繁殖季节可作为规模化人工繁殖的雌性亲本。研究成功开展了全雌黄颡鱼规模化繁育工作, 为全雌黄颡鱼规模化繁育体系的建立提供了基础, 也为黄颡鱼新品种选育中雌性选育提供了保障。     

Fast-developing preimplantation embryo progeny from heterogametic females in mammals.

Karyotyping and cell number estimates in preimplantation embryos from heterogametic (XY*) and homogametic (XX) females of the field mouse Akodon azarae were studied to determine whether XX-XY-XY* differences exist in the rate of preimplantation development. At the morula stage, XY embryos from heterogametic mothers had twice the mean number of cells compared with XX embryos. However, this difference in cell numbers was not seen between XX and XY embryos from homogametic mothers. In this case, mean cell numbers were similar despite embryos being XX or XY. Furthermore, the mean cell number for XX and XY morulae from homogametic females was comparable to that for XX embryos from heterogametic females. It is concluded that XY* embryos (which will develop into heterogametic females) show an accelerated rate of preimplantation development.     

A thoracal spinal cord teratoma associated with Taussig-Bing anomaly in a newborn

BACKGROUND: Teratomas are the most common type of childhood germ cell tumor, arising in both ovary and extragonadal locations. From 40% to 50% of the extragonadal teratomas occur in the sacrococcygeal region. Teratomas in the head, neck, brain, mediastinum, abdominal, and spinal cord locations are seen less frequently. Congenital anomalies are observed up to 26% of the cases with teratoma. METHODS: A 2-day-old newborn was admitted to the hospital because of a mass in the interscapular region. She was evaluated for this and other anomalies. The mass was excised totally, and histopathologic evaluation was done. RESULTS: Histopathologic examination of the mass revealed a mature teratoma. In addition, the child had a Taussig-Bing anomaly of the heart. CONCLUSIONS: This appears to be the first report of the association between congenital thoracic spinal cord teratoma and Taussig-Bing anomaly, a specific type of transposition of the great arteries.     

Accidental X-Y recombination and the aetiology of XX males and true hermaphrodites

Accidental recombination between the differential segments of the X and Y chromosomes in man occasionally allows transfer of Y-linked sequences to the X chromosome leading to testis differentiation in so-called XX males. Loss of the same sequences by X-Y interchange allows female differentiation in a small proportion of individuals with XY gonadal dysgenesis. A candidate gene responsible for primary sex determination has recently been cloned from within this part of the Y chromosome by Page and his colleagues. The observation that a homologue of this gene is present on the short arm of the X chromosome and is subject to X-inactivation, raises the intriguing possibility that sex determination in man is a quantitative trait. Males have two active doses of the gonad determining gene, and females have one dose. This hypothesis has been tested in a series of XX males, XY females and XX true hermaphrodites by using a genomic probe, CMPXY1, obtained by probing a Y-specific DNA library with synthetic oligonucleotides based on the predicted amino-acid sequence of the sex-determining protein. The findings in most cases are consistent with the hypothesis of homologous gonad-determining genes, GDX and GDY, carried by the X and Y chromosomes respectively. It is postulated that in sporadic or familial XX true hermaphrodites one of the GDX loci escapes X-inactivation because of mutation or chromosomal rearrangement, resulting in mosaicism for testis and ovary-determining cell lines in somatic cells. Y-negative XX males belong to the same clinical spectrum as XX true hermaphrodites, and gonadal dysgenesis in some XY females may be due to sporadic or familial mutations of GDX.     

Sex differences in diurnal rhythms of food intake in mice caused by gonadal hormones and complement of sex chromosomes

We measured diurnal rhythms of food intake, as well as body weight and composition, while varying three major classes of sex-biasing factors: activational and organizational effects of gonadal hormones, and sex chromosome complement (SCC). Four Core Genotypes (FCG) mice, comprising XX and XY gonadal males and XX and XY gonadal females, were either gonad-intact or gonadectomized (GDX) as adults (2.5 months); food intake was measured second-by-second for 7 days starting 5 weeks later, and body weight and composition were measured for 22 weeks thereafter. Gonadal males weighed more than females. GDX increased body weight/fat of gonadal females, but increased body fat and reduced body weight of males. After GDX, XX mice had greater body weight and more fat than XY mice. In gonad-intact mice, males had greater total food intake and more meals than females during the dark phase, but females had more food intake and meals and larger meals than males during the light phase. GDX reduced overall food intake irrespective of gonad type or SCC, and eliminated differences in feeding between groups with different gonads. Diurnal phase of feeding was influenced by all three sex-biasing variables. Gonad-intact females had earlier onset and acrophase (peak) of feeding relative to males. GDX caused a phase-advance of feeding, especially in XX mice, leading to an earlier onset of feeding in GDX XX vs. XY mice, but earlier acrophase in GDX males relative to females. Gonadal hormones and SCC interact in the control of diurnal rhythms of food intake.     

Three cases of ring chromosome 2, one derived from a paternal 2/6 translocation

Summary This paper reports an attempt to determine whether the short arm of one of the X chromosomes in XX males is longer than normal. In a blind study comparing coded photomicrographs of 15 G-banded mitoses from each of five XX males and five control females, the results were ambiguous and somewhat contradictory, but gave the impression of, or were compatible with, an XXp+ phenomenon in at least two of the five XX males. Measurements of the X chromosomes from the above cells and, in addition, from 15 mitoses from each of six XXY males, failed to disclose any XXp+ phenomenon. Statistical analysis indicated that in the five XX males there was no difference in the lengths of the two Xp arms. The reasons for the apparent discrepancy between the results of ocular inspection and measurement are discussed. The putative heteromorphism might be an alteration in shape, staining intensity, or position of bands, neither of which necessarily leads to an increase in length. We conclude that our results do not indicate any XXp+ phenomenon in the five XX males tested. However, the presence or absence of XXp+ is not in itself evidence for or against interchange between the X and Y in the paternal meiosis. Our results emphasize that the etiology of XX males is likely to be heterogeneous.     

Mapping the testis determinants by an analysis of Y-specific sequences in males with apparent XX and XO karyotypes and females with XY karyotypes.

A number of patients with paradoxical sex chromosome complements (so-called XY females, XX and XO males) have been investigated with a series of 19 Yp and 4 Yq DNA probes to establish which region of the Y is essential for male sexual differentiation. Of the 23 XX males, 18 possessed one or more Yp probe sequences with only 5 lacking such sequences. Of 9 XY females examined, only one showed evidence of a deletion in Yp occurring either as a result of X-Y interchange or interstitial deletion. This suggests that the majority of XY females are not commonly deleted for those Y sequences which are found to be transferred to the X in XX males. The DNA of two XO males both contained different portions of the Y. From a comparison of the patterns of Yp sequences in these patients, it has been possible to elaborate a model of Yp in terms of the order of probe sequences and to suggest a location for the testis determining region in distal Yp.     

Novel karyotypic changes detected by comparative genomic hybridization in a case of congenital cervical immature teratoma

BACKGROUND: Cervical immature teratoma is a rare congenital tumor, and very few cases have been studied cytogenetically. CASE: In this article, we describe a case of this tumor type and present the findings of the karyotype of the lesion, which was performed with the bacterial artificial chromosome arrays using the comparative genomic hybridization method. The chromosomal abnormalities that we found included an amplification on 1p21.1, a 9p22 deletion, and a 1-copy gain of 17q21.33. CONCLUSIONS: None of the identified chromosomal aberrations have been previously associated with congenital extragonadal teratomas. Important genes that lie in these DNA regions may be implicated in the pathogenesis of congenital teratomas.     

六例性反转综合征患者的分子遗传学分析

对六例性反转综合征患者(3例XX男性)(3例XY女性)用Y-特异性DNA探针进行了Southern印迹杂交分析,并用PCR技术扩增了SRY基因部分序列。结果表明,1例XX男性缺乏源于Y染色体的杂交信号,也无SRY基因;其余2例XX男性和3例XY女性都检测到Yp-DNA序列和SRY基因。这对进一步阐明性反转综合征的病因和SRY基因的作用机制具有重要意义。     

Aberrant chromosomal sex-determining mechanisms in mammals, with special reference to species with XY females

Both mouse and man have the common XX/XY sex chromosome mechanism. The X chromosome is of original size (5-6% of female haploid set) and the Y is one of the smallest chromosomes of the complement. But there are species, belonging to a variety of orders, with composite sex chromosomes and multiple sex chromosome systems: XX/XY1Y2 and X1X1X2X2/X1X2Y. The original X or the Y, respectively, have been translocated on to an autosome. The sex chromosomes of these species segregate regularly at meiosis; two kinds of sperm and one kind of egg are produced and the sex ratio is the normal 1:1. Individuals with deviating sex chromosome constitutions (XXY, XYY, XO or XXX) have been found in at least 16 mammalian species other than man. The phenotypic manifestations of these deviating constitutions are briefly discussed. In the dog, pig, goat and mouse exceptional XX males and in the horse XY females attract attention. Certain rodents have complicated mechanisms for sex determination: Ellobius lutescens and Tokudaia osimensis have XO males and females. Both sexes of Microtus oregoni are gonosomic mosaics (male OY/XY, female XX/XO). The wood lemming, Myopus schisticolor, the collared lemming, Dirostonyx torquatus, and perhaps also one or two species of the genus Akodon have XX and XY females and XY males. The XX, X*X and X*Y females of Myopus and Dicrostonyx are discussed in some detail. The wood lemming has proved to be a favourable natural model for studies in sex determination, because a large variety of sex chromosome aneuploids are born relatively frequently. The dosage model for sex determination is not supported by the wood lemming data. For male development, genes on both the X and the Y chromosomes are necessary.     

Karyological characteristics of Down's syndrome: clinical and theoretical aspects

These data have been collected from St. Petersburg Down Syndrome Register that comprises information on 1778 liveborn children with the Down syndrome, including three twin sets, ascertained within 1970-1996. Karyotypes were obtained in 1223 cases, of which 1119 (90.7%) displayed regular trisomy. Mosaicism was found in 44 cases (3.6%), including 21 males and 24 females, and among these one familial case of mosaicism in a daughter and in a healthy mother. Of 70 cases of translocations, 41(5.7%) were Robertsonian D ones. 21 (17 inherited, 16 de novo and 8 of unknown origin), 28 translocations of isochromosomes 21q; 21q (1 inherited translocation 21; 22, 22 de novo and 5 of unknown origin). One child received the anomaly from his 46XX/45XX, t(D;G) mother-carrier. In 6 cases, free trisomy 21 was associated with structural or numerical anomalies: 46XY,t(13;14)mat + 21 in twins, 47XY,t(C;C) + 21, 47XY,t(10;15)pat + 21, 47XY,inv(19)mat + 21, 47XX + 21/48XX + 21 + ring, 48XXX + 21. In 12 families parental mosaicism was shown or suspected. In 6 families one parent had chromosome anomaly, in three cases it was not inherited: t(15;22) and t(6;21) in mothers and an additional small marker in a father. In cases confirmed cytogenetically an increased sex ratio was shown (679 males and 551 females, SR = 1.23), but it was not shown in patients not tested cytogenetically (264 males and 275 females, SR = 0.96, different from the expected 297 males and 242 females, P < 0.01).