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Presences of normal genes on the Y chromosome are essential for normal sex determination and sex differentiation of male genitalia. Several genes on the X chromosome and other autosomes have been shown to be anti-testes and have a detrimental effect on the development process of normal male genital system. The addition of X chromosomes to the 46, XY karyotype results in seminiferous tubules dysgenesis, hypogonadism, and malformed genitalia. We report an infant male with 49, XXXXY syndrome presenting with ambiguous genitalia and multiple extra-gonadal anomalies.

Sex is determined genetically in all birds, but the underlying mechanism remains unknown. All species have a ZZ/ZW sex chromosome system characterised by female (ZW) heterogamety, but the chromosomes themselves can be heteromorphic (in most birds) or homomorphic (in the flightless ratites). Sex in birds might be determined by the dosage of a Z-linked gene (two in males, one in females) or by a dominant ovary-determining gene carried on the W sex chromosome, or both. Sex chromosome aneuploidy has not been conclusively documented in birds to differentiate between these possibilities. By definition, the sex chromosomes of birds must carry one or more sex-determining genes. In this review of avian sex determination, we ask what, when and where? What is the nature of the avian sex determinant? When should it be expressed in the developing embryo, and where is it expressed? The last two questions arise due to evidence suggesting that sex-determining genes in birds might be operating prior to overt sexual differentiation of the gonads into testes or ovaries, and in tissues other than the urogenital system.

Objective To evaluate placental growth factor (P1GF) in abnormal early pregnancies. Methods Placental growth factor (P1GF) was retrospectively quantified (DELFIA DXpress; Perkin Elmer) in women with known pregnancy outcomes. Study group consisted of: (i) normal (n = 300); (ii) abnormal: trisomy 21 (n = 56), trisomy 18 (n = 23), trisomy 13 (n = 6), triploid (n = 15), monosomy X (n = 7). P1GF MoM values were calculated by LifeCycle v4 (Perkin Elmer), using lot specific derived polynomial regression curve. Results Median P1GF MoM values were depressed in pregnancies carrying a fetus affected with: trisomy 21 = 0.81 (95%CI 0.72-0.90), trisomy 13=0.87 (95%CI 0.79-0.95), trisomy 18 = 0.89 (95%CI 0.78-1.00) and triploidy = 0.68 (95%CI 0.59-0.77). However, in viable sex chromosome aneuploidy, such as monosomy X, P1GF proved less discriminatory with median MoM = 0.91 (95%CI 0.76-1.06). Conclusions The above findings support the inclusion of P1GF in the marker panel for first trimester screening for fetal aneuploidy. In addition to improving detection of fetal aneuploidy, P1GF has a role in first trimester detection of early onset pre-ecalmpsia1.

We report on a case of a female fetus found to be mosaic for Turner syndrome (45,X) and trisomy X (47,XXX). Chromosomal microarray analysis (CMA) failed to detect the aneuploidy because of a normal average dosage of the X chromosome. This case represents an unusual instance in which CMA may not detect chromosomal aberrations. Such a possibility should be taken into consideration in similar cases where CMA is used in a clinical setting.

In situ hybridisation technology provides a new tool for chromosome analysis of human spermatozoa. We have used dual-colour fluorescence in situ with probes specific for the X and Y chromosomes and chromosomes 1 and 12 to (a) identify the primary male gametic sex chromosome ratio; (b) assess the number of numerical sex chromosome abnormalities, and (c) quantify the incidence of diploid sperm. We have examined over 60,000 sperm from three normal males and found the primary sex ratio to be indistinguishable from unity. The frequency of hyperhaploid sperm was 0.8, 1.03 and 2.27 per thousand for XX, YY and XY respectively, whilst 1.67 per thousand sperm were diploid. A comparison of our results with estimates of sex chromosome aneuploidy in human populations suggests that sperm carrying two sex chromosomes may be at a selective disadvantage.

Pentasomy 49,XXXXY is a rare sex chromosome disorder usually presenting with ambigous genitalia, facial dysmorphism, mental retardation and a combination of cardiac, skeletal and other malformations. The incidence of the condition is estimated to be 1 in 85,000 male births. Previously, this condition was identified as a Klinefelter variant. The condition is suspected in a patient, by a combination of characteristic clinical findings, and the diagnosis is confirmed by chromosome culture and karyotyping. In the case we report here, the main presentation of ambiguous genitalia led to a suspicion of a sex chromosome aneuploidy which was subsequently confirmed by chromosomal analysis.

A girl with a 71,XXXXY karyotype is described. Internal and external genitalia were female despite the presence of a Y-chromosome.

Four specimens with an aberrant sex chromosome constitution were found in natural populations of the common vole (Microtus arvalis). Two females had an XO sex chromosome constitution and single males were 2n = 47, XXY and 2n = 47, XYY, respectively. No apparent phenotypical anomalies were recorded in the sex chromosome aneuploids, but their fertility may have been impaired. The incidence of sex chromosome aneuploidy seems to be unusually high in natural populations of the common vole (1.5 % of animals examined). Possible explanations for this are discussed.

Skeletal maturity, or "bone age," is one of the several criteria used to determine developmental or physiologic age as opposed to chronologic age. The purpose of this study of skeletal maturation of children with sex chromosome abnormalities (45,X, 47,XXX, 47,XXY, X-chromosomal mosaics) and controls is 2c-fold: (1) to investigate if children with sex chromosome aneuploidy ascertained in an unbiased fashion differ in skeletal maturation from their siblings and other normal healthy children born in Denver, Colorado, and (2) to assess if the skeletal age standards currently in use (Greulich-Pyle; Tanner- Whitehouse) are applicable to Denver children when evaluating radiographs for skeletal maturation. Mean chronologic and skeletal age were measured. Mean differences between skeletal and chronologic age for all groups across all measures were calculated. The 45,X females constitute the only group studied with bone ages lower than expected (0.05 greater than P greater than 0.01; two-tailed test). We found no other significant differences in skeletal maturation between Denver children with sex chromosome abnormalities and their siblings or the control sample of Denver children. Although we found the Tanner-Whitehouse standards to be more applicable for use with this population, all the Denver groups investigated yielded consistently lower bone ages than expected published norms. This is the first documentation in a group of children with sex chromosome abnormalities, ascertained in an unbiased fashion, that, with the exception of those with a 45,X karyotype, bone age is not significantly different from that of the normal population.

Not few reports of sex chromosome aneuploidy in association with the fragile site at Xq28 have appeared, suggesting other factors than pure coincidence. In the present report lymphocyte cultures from 23 obligate and 45 potential carriers have been examined cytogenetically. As expected, an increase in sex chromosome aneuploidy with increasing age was observed. However, it seemed that the increase of hyperdiploid cells was far in excess of the expected, and a difference between obligate and potential carriers was apparently also present. Hence, a disposition to non-disjunction of the fragile X chromosome is suggested.

Data are presented on four indicators of genetic effects from studies of children born to survivors of the atomic bombings of Hiroshima and Nagasaki. The indicators are frequency of untoward pregnancy outcomes (stillbirth, major congenital defect, death during the first postnatal weak); occurrence of death in live-born children, through an average of life expectancy of 17 years; frequency of children with sex chromosome aneuploidy; and frequency of children with mutation resulting in an eletrophoretic variant. In no instance is there a statistically significant effect of parental exposure; but for all indicators the observed effect is in the direction suggested by the hypothesis that genetic damage resulted from the exposure. On the basis of assumptions concerning the contribution that spontaneous mutation in the preceding generation makes to the indicators in question, it is possible to estimate the genetic doubling dose for radiation for the first three indicators (the data base is still too small for the fourth). The average of these estimates is 156 rems. This is some four times higher than the results from experimental studies on the mouse with comparable radiation sources, which have been the principal guide to the presumed human sensitivities. The relevance of these data in setting permissible limits for human exposures is discussed briefly.

A translocation line in Ceratitis capitata (2n = 12) linking the male-determining Y chromosome with the autosome carrying the alcohol dehydrogenase (Adh) locus was examined to assign the locus to its chromosome. Adh was assigned to chromosome 2, the largest autosome, representing the first correlation between genetic and cytological data in this species. During the study, male adults with 11 and 12 chromosomes were identified in the population and a model was proposed to account for the appearance of these individuals. Predictions made from the model were in general verified by the subsequent experiments. It was shown that 11-chromosome males were more fertile and produced more males than 12-chromosome males. Eleven-chromosome males produced 11- and 12-chromosome progeny, whereas 12-chromosome males produced only 12-chromosome male progeny. The results are discussed with relation to sex determination in this species and to the use of male-linked translocations for the development of genetic sexing techniques.Key words: Ceratitis, male determination, translocation, aneuploidy.

In the mid-1960.s, reports came from Scotland and England of a high frequency of gonosomal aberrations among male patients in maximum security hospitals (Jacobs et al., 1965; Casey et al., 1966). This led to a lively discussion. If these observations could be generalized so as to apply also to similar institutions in other countries, the question would be whether gonosomal aneuploidy had any bearing on the development of criminality and psychic diseases? In particular, the significance of a double Y condition as a predisposing factor was called in question. Unfortunately, from the outset the discussion became too categorical and oversimplified. When in subsequent studies socially well-adjusted individuals of normal intelligence were found, it was doubted whether aneuploidy had any importance at all. In a survey as recent as 1972, for example, Owen questions whether there is any connection at all between excess Y-chromosomes and behaviour disorders and mental diseases. Hook (1973), on the contrary, in a somewhat more detailed compilation, shows that there is a clear connection between the occurrence of double Y-chromosomes and individuals whom he defines as ‘mental-penal’. A common feature in all the literature, however, is that almost all writers insist on the importance of more research in this field.

A study of patients with sex chromosome aneuploidy supports the view that taurodontism, a rare anomaly of the pulp chamber, is related to the presence of additional X-chromosomes. However, taurodontism cannot be considered an obligatory part of the Klinefelter (XXY) syndrome.

SummaryThirty-seven cases of sex chromosome aneuploidy were detected on amniocentesis in our laboratory between 1980 and 1986. Genetic counselling was offered to the parents upon discovering these abnormalities. Information based on long term prospective studies of newborn was given and supplemented with information from our personal experience of similar patients. Twenty-three sets of parents decided to continue with their pregnancies and 14 elected abortion. The main reasons for abortion were because of physical congenital abnormalities (this applied principally to those fetuses with Turner's syndrome) and the risk of intellectual retardation in some XXX and XXY pregnancies although most of these continued to term. Two out of three XYY pregnancies and all those with a mosaic karyotype continued. The aborted fetuses were examined and the karyotype confirmed where possible. Support was offered to the parents during their decision making period and continued thereafter, whatever their decision.

This is a report of 327 phone calls to our center concerning the intrauterine diagnosis of sex chromosome abnormalities (SCA). The first author (A.R.) responded to each by counseling either the parents or the referring professional. Sixty-two percent continued the pregnancy. When the parents were counseled directly, the percentage continuing the pregnancy was significantly higher than when the information was transmitted through the professionals. Our results are different from most reports in these situations, and suggest that well-informed couples, counseled by geneticists, are more likely to continue these pregnancies. The possible occurrence of SCA should be considered in preamniocentesis counseling.

A study of 336 men attending a subfertility clinic but otherwise unselected, and a further 12 men studied as a part of the investigation of the female partner, revealed 10 with major chromosome anomaly and 3 with unambiguous chromosomal variants. In addition to those with sex chromosome aneuploidy, an extra, small marker chromosome and D/D Robertsonian translocations, anomalies which have been reported in other studies, there were 7 men with rearrangements, including a paracentric inversion of chromosome 7 and an X/21 reciprocal translocation. These would have been difficult or impossible to identify without good banded preparations, suggesting that such rearrangement may be more frequent in association with subfertility than was appreciated.

A case of 45,X karyotype in association with low maternal serum alpha-fetoprotein levels is reported. Previous cases of trisomy have been linked to low alpha-fetoprotein levels. Cases of sex chromosome aneuploidy may be included in the group of aneuploidies with low levels of maternal serum alpha-fetoprotein.

We report on cytogenetic analysis of 688 couples experiencing two or more first- and/or second-trimester abortions (less than 20 weeks). The overall abnormality rate was 6.83% (47 couples). However, exclusion of those anomalies not generally accepted as being causal in spontaneous abortion leaves an abnormality rate of only 2.33% (16 couples). We discuss the significance of balanced translocations, inversions, sex chromosome aneuploidies, and mosaicisms thereof in the causation of multiple abortions.

Reported anthropometric data on 121 subjects with 47,XYY,47XXY,47,XXX, and 45,X aneuploidies were compared to those from 578 male and female control subjects by use of a single, unisex reference person ("phantom"). Subjects and controls were geometrically scaled to a standard stature of 170.18 cm, thus eliminating variance due to height. Deviations of anthropometric variables from specified phantom values were expressed as standard z-scores. By comparing z-scores of individual aneuploidy classes with those of their controls, further differences in proportionality came to light. The stratagem disclosed a systematic proportionality pattern between subjects and controls which appeared to be related to each specific sex chromosome aneuploidy. The phantom stratagem for proportional growth assessment appears to merit further use in genetic investigations where individual differences in size and shape confound the analysis of anthropometric data.

The dermatoglyphic findings from 54 females with XXX sex chromosomes are reported. Sole prints were available for study in 33 cases. Compared with female controls, an excess of radial loops and arches and a reduced mean for total finger ridge-count were the main peculiarities on the fingers. On the palms, the absence of pattern in areas I and II, and wider ridges in the a-b interval were characteristics observed. Prevous findings by other authors with respect to: (1) zygodactylous tendency in the palms, (2) tendency for the ridge width to increase with the number of sex chromosomes, and (3) greater effect of an extra X chromosome in pattern size reduction but lesser influence on ridge width than an additional Y chromosome, were confirmed. On the soles, pattern intensity was above the control average. There was a significant deficit of proximal loops in area III but excess of proximal V together with triradius H. Triradius p" and zygodactylous z' were also significantly reduced in frequency. General findings with respect to the soles of patients with X,XXX,XXY, and XYY sex chromosomal abnormalities are also reviewed. Discrepancies are apparent and further studies are needed. Finally, a dictionary (Appendices 1 and 2) is provided which gives the frequencies of the complete pattern configurations on the palms and soles of XXX females.

In this paper we report on a third patient with Klinefelter syndrome and fragile X. In the Leuven experience the simultaneous occurrence of both conditions is 1:155 (3 fra(X) positive Klinefelter patients in a total number of 465 fra(X) positive males), a concurrence much higher than expected by chance considering the frequency of both conditions.

Down syndrome is unique because of its preeminent role in shedding light on the biology of mental retardation. Since this disorder was first described in 1866 by John Langdon Down, the study of Down syndrome has contributed important biological knowledge and insight into normal and abnormal human development. Furthermore, Down syndrome research has provided useful information to such disparate scientific fields as oncology, immunology, biochemistry, and the behavioral sciences. The discovery by Professor Lejeune, in 1959, of an extra number 21 chromosome in the cells of individuals with Down syndrome, along with the simultaneous discovery of sex chromosome aneuploidy, firmly established cytogenetics as a bona fide medical discipline.' Although much has been learned about Down syndrome in the past 120 years, many fundamental questions remain unanswered.2 These include, but are not limited to, questions regarding the basis for the relationship between maternal age and nondisjunction; the mechanisms resulting in predispositions toward leukemias; immunologic abnormalities inherent in Down syndrome; and the genes responsible for the clinical phenotype. With the advent of molecular biology, new research methods may now be applied to these previously elusive questions.

Summary Vectorcardiographic variables have beenstudied in patients with sex chromosome abnormalities and compared with normal controls. Several of these variables were found to be correlated with the number of sex chromosomes in the karyotype, some being related to the number of X chromosomes, some to the number of Y chromosomes, and others to both. The variables concerned included time intervals and vector magnitudes in both the QRS and ST-T wave complexes. The heart rate itself proved dependent on both the X and the Y chromosome complements. The correlations could not be explained by age, height, or weight differences between the seven different karyotype groups studied. The dependences of variables other than the heart rate remained after correction for between-group heart rate differences. The findings are discussed.

The doctrine of self-fulfilling prophecy has been invoked in studies of the effects of sex chromosome aneuploidy on human development as a reason for routine concealment of the diagnosis from affected children and their families. It has been assumed that knowledge of the existence of risk for deviance from normal development automatically creates a self-defeating emotional climate. This communication attempts to delineate both advantageous and deleterious aspects of self-fulfilling prophecy in the medical management of sex chromosome aneuploidy, presents an alternative approach, and reviews the experience in a prospective study of 52 families where a policy of disclosure was followed.