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Objectives: Pregnancies affected by Down syndrome (DS) have a greater risk of spontaneous fetal loss than those that are unaffected. In this article, we investigate the relationship between maternal age and the risk of spontaneous fetal loss in DS pregnancies., Methods: Fetal loss at different maternal ages were estimated by survival analysis using follow-up of 5177 prenatally diagnosed cases. The maternal age effect on loss rate was subsequently confirmed by a re-analysis of published comparisons of the maternal age-specific prevalence of DS at different gestational ages., Results: The average fetal loss rate between the time of chorionic villus sampling (CVS) and term was 32% (95% CI: 26-38), increasing from 23% (95% CI: 16-31) for women aged 25 to 44% (33-56) for women aged 45. The average fetal loss rate between the time of amniocentesis and term was 25% (21-31), increasing from 19% (14-27) to 33% (26-45) across the same age range., Conclusion: The fetal loss rate in DS pregnancies increases with maternal age, and this has consequences when estimating the live birth prevalence of DS in the presence of prenatal diagnosis and termination, and when assessing the performance of prenatal screening techniques., (Copyright 2006 John Wiley & Sons, Ltd.)

Objectives: To determine the recurrence risk of a free trisomy 21 pregnancy., Methods: Data from the National Down Syndrome Cytogenetic Register (NDSCR), which contains information on nearly all cases of Down syndrome between 1989 and 2001 in England and Wales were used. Among 11 281 women with a Down syndrome pregnancy who had had at least one previous pregnancy there were 95 women who had had a previous Down syndrome pregnancy., Results: Women who have had a previous Down syndrome pregnancy have a constant absolute excess risk above their maternal age-related risk of having a subsequent affected pregnancy. This absolute excess risk is determined by the age at which the affected pregnancy occurred and is higher for younger than for older women. For example, after a Down syndrome pregnancy at age 20, this excess is 0.62% (95% CI: 0.24 to 1.15%) at early second trimester, and, after one at age 40, it is 0.04% (95% CI: 0.01 to 0.07%)., Conclusion: More precise risk estimates by single year of maternal age for use in genetic counselling are provided, but they need validation from other studies before they are incorporated in the risk estimation routines used in Down syndrome screening programmes., (Copyright 2005 John Wiley & Sons, Ltd)

Objectives: To determine the risk of a Down syndrome (DS) live birth for women 45 years of age and over., Methods: A meta-analysis of data from five published articles, 13 EUROCAT congenital anomaly population registers and two unpublished sources., Results: Information was available on the number of DS live births occurring amongst 13,745 live births to women 45 years of age and over. Information was also available on DS pregnancies diagnosed prenatally that were subsequently terminated. These pregnancies were adjusted for expected fetal loss to estimate the number of live births that would have occurred in the absence of prenatal diagnoses, when a total of 471 DS live births were estimated to have occurred. The risk of a DS birth did not increase for women 45 years of age and over. The average risk was 34 per 1000 births (95% CI: 31-37)., Conclusion: The risk of a DS live birth for women 45 years of age and over is considerably lower than has often been previously assumed. The most likely explanation is that women of this age are more likely to miscarry DS pregnancies than younger mothers.

The chance of two chromosome abnormalities occurring in one conceptus is very small. However, some authors have suggested that double aneuplodies (DAs) might be more common than the product of their individual frequencies. The nonrandomness of such DA events was considered to be evidence that nondisjunction (NDJ) may be genetically determined. Data collected from the National Down syndrome Cytogenetic Register (NDSCR) in England and Wales and from the literature indicate that the frequencies of all nonmosaic DAs, except for 48,XXY,+21, are lower than expected, probably because of strong intrauterine selection against such pregnancies. Collectively, we identified 52 cases of nonmosaic 48,XXY,+21; 28 cases of 48,XYY,+21; and 14 cases of 48,XXX,+21 in liveborns and 13 cases of 48,XXY,+21; four cases of 48,XYY,+21; and two cases of 48,XXX,+21 after prenatal diagnoses. Among these cases, analysis of the published unbiased cytogenetic surveys of liveborn DS revealed 24 cases of 48,XXY,+21; nine cases of 48,XYY,+21; and seven cases of 48,XXX,+21. These figures are different from the expected proportion of 1:1:1 (P < 0.001), with carriers of XXY overrepresented in the group of carriers of DA. Mechanisms put forth to account for the higher occurrence of 48,XXY,+21 may include greater accessibility of disomic ovum to Y-carrying sperm, and promotion of NDJ in ovum by Y-bearing sperm. 48,XXY,+21 DA was found to be age-dependent, as the proportion of mothers over age 35 (x = 33.0) was increased over the general population. This is in contrast to the apparently age-independent 48,XYY,+21 DA, with a mean maternal age of 24.7 (P < 0.001). Paternal ages were also remarkably different between the groups, with a mean age of 37.9 in 48,XXY,+21 cases and a mean age of 27.9 in 48,XYY,+21 cases (P < 0.01). Maternal age-related factors, rather than genetic predisposition, may play a more important role in the etiology of the most common DA, 48,XXY,+21.

Objectives: To display and compare the different published formulae that specify the association between maternal age and the risk of a Down syndrome live birth., Methods: Papers published since 1987 on the prevalence of Down syndrome live births in relation to maternal age were located using MEDLINE and the references given in other papers. The data series and the models fitted to them were plotted to obtain a visual idea of their similarities and differences., Results: The observed and modelled age-specific rates for Down syndrome births were remarkably similar in all published series of data for women up to the age of 35, were reasonably similar for women aged 35 to 45, but differed for women older than 45., Conclusion: In practice, the overall small differences in age-related risk between the different studies did not materially affect the performance of antenatal screening for Down syndrome. If a choice is to be made, the analysis based on the National Down Syndrome Cytogenetic Register (NDSCR) has marginal advantages since it is based on the largest data set and the corresponding model fits the data well. More data is needed to clarify the pattern of risk with maternal age among women over 45 years of age., (Copyright 2003 John Wiley & Sons, Ltd.)

Data from the New York State Chromosome Registry on over 10,000 cases of Down syndrome reported from 1977 to 1996 confirm findings in the England and Wales Cytogenetic Register that in mosaic 46/47,+21 cases of Down syndrome the male/female ratio (as inferred from XY and XY karyotypes respectively) is less than 1.0 as opposed to the ratio in nonmosaic 47,+21 cases in which the ratio is close to 1.2, or in the general background population with ratio of about 1.05. These results may reflect in part differential pairing in 47,+21 somatic cells of X and Y chromosomes with a 21 chromosome and/or in in-utero selection.

The pregnancy outcomes on cases of Down syndrome diagnosed prenatally in which the mother did not elect termination were evaluated in data reported to a comprehensive Register of Down syndrome for England and Wales for 1989-94. In the 168 cases in which placental biopsy was not used, the overall rate of spontaneous loss was 35%, but this figure masks considerable heterogeneity by gestational stage at ascertainment. Data on ages at diagnostic procedure and on pregnancy termination enabled a more precise survival analysis. The loss rates were approximately 50% for those fetuses ascertained at 15-17 completed wk, 43% at 18 wk, 31% at 19 wk, 25% at 20 wk, and then a leveling off at approximately 20%-25% for fetuses ascertained at 21-28 completed wk. For fetuses ascertained prior to 18 wk, there was no evidence that maternal age was associated with fetal loss, consistent with earlier reports. At 18 wk and after, however, maternal age was on the average approximately 3 years greater in fetuses that were lost. Comparison of successive gestational birth cohorts provided no evidence in these 168 cases that the diagnostic procedure itself had any effect on loss or that selective ascertainment of mothers in risk of loss had any effect on the results. In contrast, in the 21 cases in which placental biopsy had been undertaken, the overall loss rates were not only higher when appropriate comparisons could be made, but there was some evidence for selective ascertainment and/or procedure-associated losses.(ABSTRACT TRUNCATED AT 250 WORDS)

The national register of chromosomal anomalies that lead to Down's syndrome has enabled the monitoring of change in prenatal diagnosis for this condition, and the factors which affect the change. The proportion of cases of cytogenetically diagnosed Down's syndrome in England and Wales detected prenatally rose to 46% in 1991-2 from 31% in 1988-9, a 1.5-fold increase (95% confidence interval 1.3 to 1.7). The increase was confined to mothers under 40 years and was due to the introduction of screening by maternal serum analysis and ultrasound. Over a quarter of affected pregnancies in women aged 25-29 were detected prenatally in 1991-2 compared with less than 10% in 1988-9. Analysis of the data showed regional differences in prenatal diagnosis rates, and in the length of time elapsing between the diagnostic test and termination of an affected pregnancy. An inexplicable finding was that this period varied with the sex of the fetus, being on average a day longer for females than for males.

Objective: To examine the feasibility of a national register of Down's syndrome and its effectiveness in evaluating prenatal screening for the syndrome., Design: Information for the register was obtained from all eligible cytogenetic laboratories on relevant cytogenetic diagnoses, including date and place of birth or termination, maternal age, indication for karyotyping, and type of diagnostic test used., Setting: Cytogenetic laboratories in England and Wales., Subjects: All fetuses with trisomy 21 diagnosed prenatally and live births with Down's syndrome diagnosed at birth., Main Outcome Measures: Number of prenatal and postnatal diagnoses of Down's syndrome. National and maternal age specific prevalence of Down's syndrome., Results: For 1989 there were 1060 registrations--323 prenatal diagnoses and 737 postnatal diagnoses--after exclusion of postnatally diagnosed miscarriages and stillbirths. The estimated national rate of affected births for mothers resident in England and Wales was 1.4/1000 live births, assuming no terminations of affected pregnancies and after correction for natural losses which would have occurred in the absence of termination. The corrected maternal age specific rates were close to those found in previous population based studies. The proportion of affected pregnancies diagnosed prenatally in mothers aged 35 to 39 was 44%, and for those aged 40 or more it was 71%. Abnormal findings on ultrasonography played an unexpectedly important part in initiating cytogenetic investigation (13% of the prenatal diagnoses)., Conclusions: The findings establish the feasibility of a national Down's syndrome register and its use in evaluating prenatal screening services. Together with information held by the Office of Population Censuses and Surveys on congenital malformations, data from the register will permit studies of environmental variables affecting the prevalence of the syndrome.

Nineteen children with the clinical features of Prader-Willi syndrome were karyotyped, using both routine Giemsa banding and high-resolution techniques. Chromosome abnormalities involving chromosome 15 were found in 10, entirely normal chromosomes in five and for the remaining four the findings were either equivocal or difficult to interpret. There was no clinical distinction between cases with and without the chromosome anomaly. Examination of three parents and a group of controls showed that the proximal end of the long arm of chromosome 15 may have a considerable degree of normal variation, which can make interpretation difficult.

Among 88 children with speech and language problems from whom chromosome results were obtained, four were identified with a chromosome anomaly. Three had sex chromosome aneuploidy and had developmental problems, particularly with articulation. The fourth child had low-grade trisomy 21 in blood, with minimal signs of Down's syndrome but with bilateral conductive hearing loss. It is suggested that delay in speech development is one facet of the developmental problems that may be significant in later behavioural problems in adolescent and adult males with X and Y aneuploidy.

Three new cases of trisomy 8 mosaicism are presented; two have features corresponding with those usually found in this syndrome, whereas one is highly atypical. In view of the almost universal mosaicism of these patients, the literature is reviewed with an emphasis on the patterns of mosaicism found. There is little correlation between degree of mosaicism and extent of clinical abnormality. The degree of mosaicism differs in different tissues, fibroblasts being more informative of aneuploidy than lymphocytes, and there is some evidence that the degree of mosaicism varies with time. The reasons for these findings are discussed, with particular reference to the raised paternal age found in a proportion of the reported cases.

The growing complexity and volume of workload in a Clinical Genetics Centre can rapidly swamp the available clerical facilities. The multiuser database described gives facilities not only for administrative control and documentation but also for the production of data for clinical and scientific analysis. The close link between clinical and laboratory databases gives great versatility and easy expansion as new tests and disciplines are applied to clinical genetic problems.

Application of a fluorescence technique for the detection of the human Y chromosome in interphase nuclei indicates that the best results may be obtained from the study of lymphocytes in blood smears. The most satisfactory Y-fluorescence is obtained with the use of buffered quinacrine mustard dihydrochloride. The method can be complemented by other standard techniques to obtain a clear idea of the sex-chromosome complement of the individual. The application of this technique to clinical and chromosomal diagnosis and to the prenatal detection of the Y chromosome in amniotic cells seems at least as promising as has proved the earlier identification of the Barr body.