Down syndrome is caused by the presence of three chromosomes 21 in the cells of a child or fetus (Photographs). In 95% it will affect every cell of the body and in each cell each chromosome will express its genes producing a surplus of the gene products of chromosome 21 perhaps causing unbalanced development. In 95% of cases the error occurs during meiosis, the process leading to formation of the gametes, the egg and sperm. In about 90% of these the error occurs in the mother during her development as a foetus. The 8% of paternal errors occur during spermatogenesis. In a few cases the error will occur after conception of the child as a mitotic non-disjunction and some of these will be mosaic for normal and abnormal cells.
Reasons for referral for cytogenetic diagnosis
Reasons for postnatal referral of babies or children with Down syndrome are nearly always the clinical signs of the syndrome. These commonly include slanting eyelids, a fold of skin at the inner end of the eyelid, crowded facial features, low-set ears and a single palmar crease. None of these are in themselves diagnostic and only cases where a chromosome study has been successfully completed are included in the Register. A small number of infants are not diagnosed in the neonatal period but present in infancy with diagnoses such as 'failure to thrive'. These may include an excess of cases with a mosaic karyotype where the clinical signs may be minimal.
A positive result from a prenatal screening test for Down syndrome is now the most common reason for a prenatal referral. This is in contrast to when the register started in 1989, when advanced maternal age was the most common reason. Please see the Annual Reports for details about the types of screening tests that are currently identifying women with affected pregnancies and the changes that have occurred in the frequency of their use since 1989.
A number of cases are referred because of a previous affected child or a history of DS in the family (see Recurrence). A few cases are also diagnosed after extreme maternal anxiety, or where there was another indication for fetal cell examination.
The numbers of diagnoses we have enables an accurate assessment of the single year maternal age risk for DS. Two papers have been published comparing the age related risk with previously published data.
The summary findings are that mothers below 25 have an average risk of a DS pregnancy of about 1:1400 rising to about 1:350 at 35 and 1:40 at age 43.
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A woman who has had a Down Syndrome pregnancy is at an increased risk of a subsequent affected pregnancy. At present, the risk is assumed to be about 0.4% higher than their age-related risk. (See Maternal age related risk). We are currently using the data in the register to derive more accurate estimates. Recurrence can occur for a number of recognised reasons.
- A familial translocation carried by one parent. Such an anomaly may be between two acrocentric chromosomes (chromosomes with very short short arms; referred to as a Robertsonian translocation) or between a 21 chromosome and some other chromosome, a reciprocal translocation. Where mother is the carrier of a Robertsonian translocation the increased risk is said to be about 15%. Paternal carriers are less likely to produce trisomic conceptions (refer back to earlier section).
- One parent may be mosaic for a mixture of normal and trisomic cells. If the gonads are affected, ova or sperm cells may be disomic for chromosome 21 (two copies instead of the normal one copy) leading to trisomic conceptions. While this is rare it is a known cause for recurrence particularly in younger parents.
- There may be some other ' non-contributive' (i.e. not involving chromosome 21) translocation present which leads to imbalance during gametogenesis that may result in trisomic conceptions. This is unproven as yet, but we have families that may be cases of this sort.
- There may be other genetic conditions leading to non-disjunction (the process by which chromosomes separate normally). This might be in the germ cells or in body cells. The occurrence of regular trisomy in a wider pedigree could support this theory. Several cases with regular trisomy are registered with us where cousins, aunts or uncles are affected.
Twins or higher order births occur at a rate of about 2% in the NDSCR, a total of 244 twin pairs (some prenatally diagnosed), including 29 pairs where each had trisomy 21. Nine sets of triplets are represented on the NDSCR, each with one affected child. Monozygosity (identical twins) cannot be presumed in twin pairs where both have the syndrome, one registered DS pair are of unlike sex. In a small number of cases we were informed that the affected pregnancy was assisted using hormones or donor gametes. 69% of affected twins are live born, 5% are stillborn or die in the neonatal period. In 26% the diagnosis was made prenatally and either the pregnancy was terminated, or selective feticide was carried out in early pregnancy.
As in all published data, in trisomy 21 about 54% are male fetuses or babies, against the normal birth sex ratio of 51% male. In the discordant twin pairs the sex ratio of the affected child is 49% male . For the twins where both are affected the sex ratio is 57% male. An original finding from the NDSCR was that in mosaic trisomy 21 the sex ratio is only 39% male (Mutton et al 1996). This finding has subsequently been confirmed elsewhere (Hook et al 1999), but remains unexplained.
A study using the Register data has not identified any evidence of variation in season, by year or by Health Authority area in the rate of DS diagnoses (Morris et al 1998). Further studies are in hand working with smaller populations and also looking at `deprivation' on the incidence of DS (David Neasham). Studies on the frequency of Down syndrome in relation to proximity to potentially toxic landfill sites have also been carried out (M Vrieheid et al 2002).
