Risk and Recurrence Risk of Down Syndrome

Children with Down Syndrome (DS) account for one of every 800 births. The risk of chromosome disorders like DS, trisomy 13 and trisomy 18 increases with maternal age. The incidence of DS at birth is lower at age 20 (1/1600) than at age 35 ( 1/370), but many more younger women have children than older women. So most (75-80%) DS children are born to younger women. If a couple has a child with DS, there is usually an increased risk for a second affected child.

Genetic Forms of DS

All individuals with DS have extra chromosome 21 material. There are 3 genetic mechanisms for trisomy 21. The first and most common, is called non-disjunction, where there is an entire extra chromosome 21 in all cells. A chromosome study (karyotype) of trisomy 21 is shown in Fig. 1.
	Figure 1

The second is mosaic DS, where trisomy 21 cells are mixed with a second cell line, usually "normal" (46,XX or 46,XY). Individuals with this form of DS are frequently a bit milder in their presentation, depending on the proportion of normal cells.

The third is a translocation DS, about 3-5% of the total, where part or all of chromosome 21 is translocated to another chromosome, usually 14. Translocation DS does not vary with age. Children with translocation DS are indistinguishable from individuals with the usual form of DS.

Trisomy 21

An extra whole chromosome 21 in all cells examined is found in about 92 per cent of all DS individuals. This is shown in Figure 1. DS is common enough that it may appear that there is an excess cluster or hot spot when several DS children are born in the same area, but this is just chance and statistical variation.

As far as we know, there is no relationship between DS and diet, drugs, economic status, or life style. Some evidence suggests that it is a little more common in families with Alzheimer's disease in one or more older family members.

Non-disjunction results from unequal chromosome division, usually in the mother's egg production. This is the form of DS that increases in incidence with increased maternal age. But DS is so common, it is not rare in young parents.

If a couple has a child with DS, the risk is higher for the next pregnancy (1/100). Obviously, this means that the risk is 99% that the next child will NOT have DS. If the risk is already 1/220 at birth, the risk at age 37, the risk is usually estimated as twice the risk for age. Risks for amniocentesis results are higher because half to three-quarters of DS fetuses die before birth of natural causes.

The risk of DS does not appear increased in siblings of trisomy 21 individuals.

Prenatal testing is always recommended for couples who are worried about a second affected child. But prenatal testing procedures may not be for everyone, since they are expensive and many parents may not want to know or act on the information.

The testing is more than 99 per cent reliable in most genetic centers, only rarely is there a sampling of maternal cells, failure of cells to grow or bacterial or yeast contamination.

Mosaic Trisomy 21

A mosaic DS child has two populations of cells, the trisomy 21 cells, and a second cell line, usually normal. This form is 2-4 % of the DS population. The physical features may be milder in these individuals, particularly if there is a large proportion of normal cells.

It was once thought that the unequal chromosome division of mosaic DS takes place early after fertilization, and is a defect in mitotic cell division. However, CVS studies have shown that a fetus with 47 (XX or XY) + 21 chromosomes can lose an extra 21 chromosome in some cells, providing an alternate mechanism for the mosaic result. Thus, Mosaic DS may also be related to maternal age. This also means that an increased recurrence risk is theoretically possible, and prenatal studies for subsequent pregnancies would be recommended.

Translocation Trisomy 21

In 3 - 4% of DS the extra chromosome 21 is permanently attached to another chromosome causing a translocation. "Translocation" refers to one type of rearrangement of chromosomal material; in DS almost all translocations are Robertsonian translocations, named for Dr. Roberts, an Australian chromosome expert who originally described this type of translocation.

A Robertsonian translocation is formed when one chromosome 21 attaches to another chromosome, forming a single new, chromosome. The recipient chromosome is usually chromosome 14 and the combination of 2 chromosomes is called a fourteen, twenty one translocation, written t(14;21) or t(14q21q). The q refers to the long arm of a chromosome. Here, the long arm of 21 is attached to the long arm of 14.

Karyotypes with a Robertsonian translocation can be balanced or unbalanced. Individuals who have one 21, one 14, and a t(14;21) are balanced: there is no extra or missing chromosomal material. Here there are 45 instead of the usual 46 chromosomes. The one translocation chromosome now carries the original 2 chromosomes. A translocation DS karyotype is shown in Figure 2.
		Figure 2

Down syndrome results when there are two chromosomes 21, one 14, and one t(14q21q) because this combination has 3 chromosomes 21, a trisomy 21 by a different genetic mechanism. Sometimes, a Robertsonian translocation is formed between a 21 and a chromosome other than a 14. There are Robertsonian translocations between 13 and 21; 15 and 21; and 21 and 22. The recurrence risks for DS for balanced carriers with these other translocations is taken to be the same as that for the t(14;21).

In about one-fourth of translocation DS individuals, the translocation is inherited. When it runs in families, the carriers are usually unaware they have a translocation because there are no problems for the balanced translocation carrier. Only with the birth of a DS child or DS fetus by miscarriage, does the couple find out one parent is a translocation carrier.

A carrier parent can have a chromosomally normal child, or a child who is a balanced carrier like the parent, or a DS child. Curiously, the chance that such a couple will have another DS child depends on which parent is the carrier. When the mother is a balanced carrier of a t(14;21), there is about a 12% risk for another DS child to be born in each subsequent pregnancy. When the father is the carrier, the observed risk drops to about 3% for DS. The reason for this difference in risks is not at all clear. A balanced translocation karyotype is shown in Figure 3.

Figure 3

In about three-fourths of translocation DS neither parent is a carrier, and a mutation in the germ cells of one parent has caused the translocation. No one knows what causes these mutations. In cases of a new, or de novo, Robertsonian translocation, the risk of a couple producing a second DS is low, estimated to 2-3 %. There are rare instances of recurrence on record, and prenatal testing in subsequent pregnancies should be considered.

One might think that translocation DS accounts for most of the cases occurring in younger ("age-independent") mothers but the evidence shows this is not true. Translocation DS occurs with about equal frequency in younger and older women.

There are other rare translocations leading to DS. One is a Robertsonian translocation between two chromosomes 21, t(21;21); this has a 100% risk for DS when transmitted by a carrier parent. Also rare is a non-Robertsonian translocation formed by the union of two 21's such that the translocation forms a mirror image of the normal 21.

Finding professionals with a positive outlook and who have personal knowledge of the potential and the accomplishments of individuals with DS will be a big help in dealing with the DS child. No matter what the genetic mechanism, some DS children do better than others.