Insurance ovulation, embryo mortality and twinning.

The 'insurance ova' hypothesis (Anderson, 1990) views dizygotic twinning as a by-product of selection for multiple ovulation which sometimes--in error--results in the birth of twins. From this viewpoint, polyovulation is a mechanism which reduces the risks of fertilization failure or embryo defect/mortality. If DZ twin births are a 'side-effect' of a mechanism which compensates for defective embryos one might predict that embryo defect rates and twinning rates will covary. This prediction is tested using national-level data on twinning rates and rates of trisomy-21 (Down's syndrome), and a strong positive correlation is found, even when controlling for maternal age. One suggestion that follows from this finding is that intra- and interpopulation variation in both twinning rates and Down's syndrome rates may result, in part, from individual variation in pre-implantation rejection of embryos in the very early stages of pregnancy. In this paper it is proposed that the 'insurance ova' explanation for twinning in humans could be expanded to incorporate a model of rejection of anomalous embryos, be they anomalies of number or type. Variation in the efficiency of an embryo rejection mechanism, combined with variation in frequency of polyovulation, would have consequences for individual reproductive success.     

Non-random centromere division: a mechanism of non-disjunction causing aneuploidy?

Early centromere separation was investigated in 12 normal children, 14 patients with Down's syndrome and in 12 patients of children with autosomal trisomies. A significantly non-random centromere division of chromosomes was found in each of the cases. A higher frequency of early separated G chromosomes was observed in Down's syndrome. In 2 mothers of trisomy-18 patients, the early division of chromosomes 18, generally seen in normal individuals, could not be demonstrated. The possible assoication between altered sequence of centromere disision and non-disjunction needs further confirmation.     

Changes in the mole fraction ratio of lactate dehydrogenase subunits in the lymphocytes of Down's syndrome patients]

A comparative study of the total activity and mole quota ratio of lactate dehydrogenase subunits in lymphocytes of 14 patients with Down's syndrome (trisomy-21) and in 10 healthy persons is carried out. Differences in the total activity in both groups were insignificant. In patients with Down's syndrome the mole quota ratio of H and M subunits of LDH was found to be significantly altered (p greater than 0.999): H = 33.2%, M - 66,8%, as compared to 51.5% and 48.4% in the control (healthy) group respectively. These differences are evaluated as a result of changed gene expression of both loci controlling H and M polypeptide chains of heteromeric enzyme molecule.     

Cytogenetic studies of a family with trisomy 21 mosaicism in two successive generations as the cause of Down's syndrome

Summary A family with trisomy-21 mosaicism in two successive generations and a Down's syndrome child in the third generation is presented. Cytogenetic studies of eight individuals of this family showed a marker chromosome 15ph+ and a heteromorphic chromosome 18 in some members. The standard trisomy 21 in the proband was derived from a trisomy-21 oogonium by secondary nondisjunction in his mother.     

Distribution of extracellular matrix components in nuchal skin from fetuses carrying trisomy 18 and trisomy 21

We have investigated histologically the elevations of the skin in dorsal and lateral neck (nuchal) regions of human fetuses carrying karyotypes of trisomy 18 (Edwards' syndrome) and trisomy 21 (Down's syndrome). Cavities filled with interstitial fluid were found in the dermis, epidermal basement membrane and occasionally in the epidermis of trisomy-18 fetuses, but were not delineated by an epithelium or basement membrane as judged by the absence of immunostaining for laminin, collagen IV and collagen VII. Dilated vessels were also found at the interface between dermis and subcutis. Neither normal fetal skin nor that of trisomy-21 fetuses contained cavities or dilated vessels. In order to detect possible alterations of the extracellular matrix in trisomy-18 and trisomy-21 skin, the distribution of glycoproteins, glycosaminoglycans and proteoglycans was studied immunohistochemically. In trisomy-21 and control skin, the dermis stained intensely for fibronectin, whereas the subcutis reacted only weakly. In trisomy-18 skin, the stronger staining for fibronectin appeared in the subcutis, and the prevailing collagen type was collagen III, collagen type I being absent. In the skin of trisomy-21 fetuses, collagen VI was more irregularly arranged and densely packed, whereas collagen I was more widely spaced than in normal fetuses. More hyaluronan was present in the dermis and subcutis of trisomy-21 fetuses than in that of trisomy-18 and control fetuses. A correlation seems to exist between undelimited cavities and collagen III in trisomy-18 skin, and between hyaluronan and the specific arrangement of collagen in trisomy-21 skin.Abbreviations bm Basement membrane - ep epidermis - d dermis - sc subcutis - hf hair follicle - c capillary This article is dedicated to Professor Dr. Konrad Märkel on the occasion of his 70^th birthday     

A family with three sibs carrying trisomy 21.

A family with three sibs, including a pair of dizygotic twins, all affected by Down's syndrome with regular trisomy 21, is described. The chromosome counts carried out on prolonged fibroblasts cultures of the mother, revealed the presence of the trisomy 21 in 6 out of 688 scored mitoses. The cytological findings give support to the hypothesis of a chromosome mosaicism in one of the normal parents, as a cause of the recurrence of the trisomy 21.     

Protease inhibitor (Pi) locus,fertility and twinning

Summary In a sample of 160 Dutch twin pairs and their parents, we found that mothers of dizygotic twins had frequencies of the S and Z alleles at the protease inhibitor (Pi) locus that were 3 times higher than a control sample. Mothers of identical twins also had a higher frequency of S than controls. The S allele may thus both increase ovulation rate and enhance the success of multiple pregnancies. There was also an increased frequency of the S allele in fathers of dizygotic twins; however, this may be a secondary effect of assortative mating for family size (indicating by the number of siblings of the parents), for which a correlation of 0.2 was observed. Parents of dizygotic twins came from larger families than parents of monozygotic twins, but no effect of Pi type on family size was seen.     

Satellite association in Down's syndrome

Summary The frequency of association of acrocentric chromosomes is examined in 20 Down's syndrome children, their parents, and 60 controls. Chromosome 21 enters into satellite associations most frequently, and chromosome 15 least. The parents of Down's syndrome children do not show any increased tendency for satellite association of chromosome 21 or indeed any other acrocentric.     

Sensori-neural deafness and hypothyroidism: autoimmunity causing 'pseudo-Pendred syndrome'

Male, dizygotic twins were diagnosed with sensori-neural deafness at ages 5 and 21 months and later developed hypothyroidism at ages 24 and 28 months, respectively. Analysis for anti-DEP-1/CD148 autoantibodies described in Cogan syndrome proved positive. As these antibodies are directed against endothelial cells as well as sensory epithelial cells the children need long-term monitoring for associated complications.     

Unusual genotypes in the COL6A1 gene in parents of children with trisomy 21 and major congenital heart defects

Collagen type VI is a candidate for a role in the pathogenesis of congenital heart defects (CHD) in Down's syndrome. Three restriction fragment length polymorphisms of the COL6A1 gene were used to determine COL6A1 genotypes in 50 families of affected children with trisomy 21 (29 with congenital heart defects and 21 without) and 37 unrelated volunteers. We found seven unusual genotypes in the parents of affected children with Down's syndrome, five being unique to the parents of children with trisomy 21 and CHD. There were no unusual genotypes associated with other chromosome 21 loci. No single COL6A1 genotype was associated with CHD. Thus, the unusual genotypes unique to parents of affected children suggest that genetic variation in the COL6A1 gene region contributes to the pathogenesis of CHD in Down's syndrome.     

Down's syndrome: chromosome analysis of 362 cases in Hungary.

A survey is given of the karyotypes observed in 362 children clinically diagnosed as cases of Down's syndrome from whom material was sent to 8 collaborating cytogenic laboratories in Hungary during the period 1965-1974. The sample studied cytogenetically constitutes about 20% of all children born in Hungary in this decade with Down's syndrome. The ways in which patients were selected for cytogenetic examinations could not be specified. In the sample, standard trisomy 21 was found in 91.7%, translocations in 3.9% and mosaicism in 4.4%. The mean age of the mothers of the children investigated was 29.05 years, a relatively low figure which may be explained by the decrease of the mean maternal age over the last decades.     

Inherited pericentric inversion of Y-chromosome with trisomy 21. A case report

A 13-year-old boy with clinical features of Down syndrome was investigated. His karyotype was 47,X,inv(Y),+21. The proband's father and two elder brothers were also found to have the inv(Y). A spontaneous chromatid break was observed in the long arm of the X chromosome[? fra (X)] in 2% of the cells. The mother had two spontaneous abortions. This is the first case of trisomy-21 with inv(Y) in our population. This finding might be fortuitous. The frequency of inv(Y) in Down syndrome is not known.     

Monthly trend and seasonal variation in twinning rate in Japan, 1975–1994

We examined birth records from Japanese statistics, 1975–1994, to investigate the seasonality of twin births. We could identify 198 924 pairs of twins (97.9% of all the registered twin records) and estimated the numbers of mono- and dizygotic twin pairs. The seasonal index of the twinning rate for each month was calculated by dividing the crude rate by the estimated trend value for the month. There were significant variations in the seasonal index for overall, dizygotic and monozygotic twinning rates. Peak months with values more than 3% higher than expected were July and October–December for dizygotic twins, and April and June for monozygotic twins; these seasonalities were statistically significant by analysis of variance and the patterns were similar in recent years, with a sharp increase in the total twinning rate. When observed year-by-year, however, there were years that did not show these typical seasonalities. It is suggested that the mechanisms for probable seasonal variations in twinning rates are different for dizygotic and monozygotic twin pregnancies, and that factors involved in these variations are not effective every year. Received: 2 September 1998 / Revised: 6 May 1999 / Accepted: 26 May 1999     

Fathering of Dizygotic Twins and Risk of Prostate Cancer: Nationwide,Population-Based Case-Control Study

Background

An association between male fertility and risk of prostate cancer has been suggested, possibly through lower androgen levels in subfertile men. We evaluated male fertility in relation to risk of prostate cancer by assessing the frequency of fathering of dizygotic twins, a marker of high fertility, among cases of prostate cancer and controls.

Methods

We performed a case-control study in Prostate Cancer data Base Sweden (PCBaSe), a nationwide, population-based cohort. PCBaSe was linked to the Swedish twin register for information on zygosity for same-sex twins and to other nationwide health care registers and demographic databases for information on socioeconomic factors, comorbidity, and tumor characteristics for 96 301 prostate cancer cases and 378 583 matched controls. To account for the influence of in vitro fertilization on dizygotic twinning, analyses were restricted to men who had fathered children before 1991, when in vitro fertilization was still uncommon in Sweden.

Results

1 112 cases and 4 538 controls had fathered dizygotic twins. Men with dizygotic twins had no increased risk of prostate cancer compared to fathers of singletons; neither for total prostate cancer odds ratio (OR) 0.95(95% CI 0.89–1.02), nor for any risk category, OR 0.97 (95% CI 0.84–1.12) for low-risk disease, and OR 1.04 (95% CI 0.90–1.22) for metastatic disease.

Conclusion

The lack of association between fathering of dizygotic twins and prostate cancer risk give no support for an association between male fertility and prostate cancer risk.     

The effects of assisted reproduction on the trends and zygosity of multiple births in England and Wales 1974-99.

Assisted reproductive techniques have led to an increase in the proportion of maternities that are multiple. Though predominantly dizygotic, they are at greater risk of monozygotic division than those spontaneously conceived. England and Wales data 1974-99 on stillbirths and livebirths were analysed for 4 periods: 1974-80 (pre-assisted reproduction; 1982-8; 1989-91 (pre-redefinition of stillbirth); 1993-9 (post-redefinition of stillbirth). For twin data, Weinberg's rule was applied to estimate the proportions that were mono- (MZ) and dizygotic (DZ). Compared with the period before assisted reproduction, the most recent period shows an increase in twin maternities of 3.81 per 1,000 comprised of 3.22 (95% CI 3.10 to 3.33; p < 0.0001) DZ and 0.60 (95% CI 0.51 to 0.68; p < 0.0001) MZ twins. It is estimated that 15.7% of assisted reproduction twins are MZ. Higher order multiple births showed an increase of 3.06 (95% CI 2.85 to 3.29; p < 0.0001) per 10,000 maternities. Stillbirth rates in MZ twins are of the same order of magnitude as those in higher order multiple births but higher than those in DZ twins. The improvement in stillbirth rates over the 26 year study period is of the same order magnitude in singletons, DZ and MZ twins and higher order multiples. Assisted reproduction has led to a significant increase in the proportion of MZ twins. These are at high risk of fetal death and this needs to be considered when local stillbirth and perinatal mortality rates are used in auditing obstetric services.     

Genetic risk factors in tumours of the testis: lessons from twin studies.

A threefold increase for testicular carcinoma has been reported in male dizygotic twins. In this comment we suggest the hypothesis that over-exposure to endogenously hypersecreted Follicle Stimulating Hormone (FSH) may underlie the pathogenesis. This is supported by several findings. 1) FSH hypersecretion in mothers of dizygotic twins is most likely an autosomal trait implicating the possibility of male offspring with the same hormone characteristic. 2) In testicular carcinoma higher levels of cyclin D2 are found. This is an FSH dependent stimulatory regulator of mitosis. 3) There is a marked similarity between geographical distribution in occurence of dizygotic twinning and testicular carcinoma. 4) Men undergoing surgery for testicular carcinoma have higher FSH concentrations and males with Down syndrome have higher FSH levels and are more at risk to develop testicular carcinoma. We suggest to study FSH secretion in males of familial dizygotic twins and furthermore the risk of developing testicular carcinoma in males with elevated FSH. These men with one testicle and/or with dysfunctioning Sertoli/Leydig cells.     

A Service for Human Chromosome Studies in Saskatchewan

A service has been developed in Saskatchewan to make available the results of studies of human chromosomes, the material being forwarded to the laboratory by local transport facilities. During the first year of this project chromosome studies were requested for five doubtful cases of trisomy-21 (two were found to be normal) and for 20 definite cases of trisomy-21 in young patients (two had translocations but the parents of both these children had normal karyotypes). Eleven confirmed cases of Turner''s syndrome, two of Klinefelter''s syndrome, and one each of the D and E syndromes were also studied. The largest group for which studies were requested comprised 36 patients with mental retardation; only two abnormal karyotypes were encountered in this group.     

Twin concordance for a binary trait. II. Nested analysis of ever-smoking and ex-smoking traits and unnested analysis of a "committed-smoking" trait

Twin concordance rates for a binary trait can provide information about causes of trait variation. However, if trait prevalence varies with age (or birth cohort) or between the sexes, trait concordance rates will be artificially inflated because of the matching within pairs of twins. Our previous paper showed how to minimize the effects of such confounding by using logistic regression to model trait prevalence as a function of age and sex and that the binary correlation coefficient was useful as a measure of concordance that can be adjusted for trait prevalence. This method is extended here to allow for nested analyses and is applied to the smoking habits of a sample of 3,807 pairs of adult twins. For monozygotic (MZ) twins, the correlation coefficients for the binary trait of "ever-smoking" (males: .50 +/- .04; females: .60 +/- .02) were significantly greater than for dizygotic (DZ) twins (males: .37 +/- .05; females: .31 +/- .04; unlike-sex pairs: .21 +/- .03). For "giving-up smoking," given that both twins were previously smokers, the correlations for MZ twins (males: .37 +/- .07; females: .29 +/- .05) were also greater than for DZ twins (males: .11 +/- .09; females: .26 +/- .08; unlike-sex pairs: .13 +/- .06), although the difference was not statistically significant for females. Current smokers who had been smoking for at least 10 years were arbitrarily defined as "committed-smokers." The binary trait of "committed-smoking" was more strongly correlated in MZ twins (males: .41 +/- .06; females: .41 +/- .04) than in DZ twins (males: .22 +/- .08; females: .18 +/- .05; unlike-sex pairs: .16 +/- .05). These observations suggest that as well as depending on socially determined environmental factors, smoking behavior is influenced by genetic factors and/or by environmental factors unique to the MZ twin environment, which are of particular importance as determinants of "committed-smoking." There is a need for further research to investigate the personal characteristics of "committed-smokers" and to seek intervention strategies that are more suited to the needs of individual smokers.     

Double trisomy (48,XXY,+21) in monozygotic twins: case report and review of the literature

The occurrence of double aneuploidy in the same individual is a relatively rare phenomenon. We describe twin newborns with typical clinical features of Down's syndrome, of which one revealed 48,XXY,+21 GTG-band karyotype. The second newborn died 2 days after its birth, and was clinically diagnosed having Down syndrome. Due to the same clinical features of the twins, the common placenta and amniotic sac, we speculate that they were monozygotics and as a result the second newborn should also be a Klinefelter. The purpose of this report is to present a rare case of possible coincidence of double aneuploidy in newborn twins. A review of the literature showed that double trisomy (48,XXY,+21) in a twin newborn infant has never occurred.