How does 4p+ happen?

Rolling the Dice with 4p!

After receiving a diagnosis of a chromosomal rearrangement in either a child or yourself, one of the first questions that comes to mind is “how did this happen?” Actually, about 1 in 1000 people have been diagnosed with some kind of chromosomal disorder, like trisomy 4p. We think that there are about 100 children now diagnosed with trisomy 4p in the medical record, but there may be countless more who are/were undiagnosed.

There are several ways a rare chromosomal disorder like trisomy 4p can occur. This page focuses on de novo (“new” rearrangements) and inherited trisomies.

DE NOVO TRISOMY 4P

key term: de novo
 
De novo is Latin for “from the beginning”. When geneticists diagnose a case and write de novo, what they mean is it is a “new” case of Trisomy 4p and that the rearrangement is spontaneous in the individual and not inherited from a parent . There is no way for us to know what causes de novo trisomies; they are just random mutations. There is nothing parents could or couldn't have done to prevent it from happening. While one can never say it could never happen again to parents of children with de novo rearrangements, the chances of having another child with a chromosome rearrangement would be less than 1%.

INHERITED TRISOMY 4P
key terms: balanced translocation, unbalanced translocation, meiosis

About 75% of individuals who have a diagnosis of trisomy 4p have an inherited rearrangement of chromosomes. This means that one of their parents has a balanced translocation that involves the 4th chromosome. It is not linked to the sex chromosomes, so both men and women can have balanced translocations. It is thought that approximately 1 in 600 people in the general population have some kind of balanced translocation, which is usually a symptomless rearrangement. This can happen when there is a random combination of breakage and rejoining of two different chromosomes to each other. For some families, this first expresses itself through fertility issues. Another way some families learn about a balanced translocation is through the birth of a child with an unbalanced translocation. An unbalanced translocation can potentially involve a number of different chromosomes, but in trisomy 4p, the unbalanced translocation involves the short arm of the fourth chromosome (4p) and another chromosome.

In a balanced translocation, all the crucial chromosomal material is there, but some of it might be out of order. For example, in the case of a 4 and 22 balanced translocation, the two sets of 4p are there, but one is attached to 4 and the other is attached to 22. It’s rather like a book with two pages out of order but carefully swapped so no material is missing – half of page four is on page 22, and half of page 22 is on page 4! In a balanced translocation, we can imagine, using this book metaphor, that the rearrangement has made little book marks: The extra 4p on 22 sticks out a bit, and the shorter bit of 22p on 4 is like a bent down corner of the page. The body seems to be able to read these bookmarks, and to know where to find that half page of 4. People with balanced translocations are often unaware that they have any rearrangement in their chromosomes because this bookmarking system seems to work so well. Not all translocations involve 22; we’re only using 22 as an example, but balanced translocations with 4p commonly involve a particular set of chromosomes called the D and G groups (such as 13, 14, 15, 21, or 22). Balanced translocations occur in a de novo situation as well, when chromosomes break and divide unexpectedly. De novo balanced translocations are different than inherited ones, and sometimes affect the individual as an unbalanced one would.

In an unbalanced translocation, there is a bookmark, but the pages aren’t swapped evenly. In our hypothetical case of 4 and 22, an unbalanced translocation resulting in trisomy 4p would result in a book that had all of page 4 where it needed to be, but instead of the top part of page 22, the top half of page 4 would be repeated, and that part of page 22 altogether missing. The body gets to page 22 and sees the extra 4p, but says, ‘hey, where is the folded down page that shows me where to pick up on page 22?’ This extra material causes the differences in our trisomy 4p. It makes our children have trouble with feeding, respiratory illness, seizures, dental problems, scoliosis and/or other various health issues (but it also gives them awesome eyelashes, gorgeous shiny hair and belly laughs!). The extra material also causes developmental delay, or developmental disability (these terms are generally the same; some people use the latter to express the permanent nature of the developmental issues). It’s like a car with manual transmission: when you load up the trunk with a lot of luggage, it’s easy to stall the car even though you can drive it well without the extra weight. A car with extra weight doesn’t go as fast, and might not use gasoline as efficiently. Just like the heavy car that goes slower, our kids’ bodies work through the processes with extra chromosomes more slowly than those with ‘normal’ chromosomes or balanced chromosomes. How slowly do these cars run? Just the way intelligence and physical ability varies in the population with normal chromosomes, kids with trisomy 4p present a range of abilities, and each child is different. 

How do we get balanced or unbalanced translocations? The first person in a family with a balanced translocation is hard to pinpoint - it’s like asking ‘who was the first person in our family with blue eyes?’ 

When humans reproduce, each parent contributes half of their own genetic and chromosomal material to the embryo. All the cells in our body have two copies of each chromosome (see the first figure in “What is 4p+?” ). In the testes or the ovaries, however, cells split to create special cells: sperm and ova for reproduction. These special cells contain not all, but only half of the individual’s genetic and chromosomal material and are created through a process of cell division called meiosis. When an individual has a balanced translocation, the way the chromosome splits to form sperm or ova is the key factor for determining whether or not the couple will be able to carry a pregnancy to term, as well as what the child’s chromosomal arrangement will be.

Meiosis, which creates the reproductive cells, divide randomly (we think!). In the parent with a balanced translocation, they divide in different ways. Sometimes they are created from the building blocks of the “normal” versions of chromosome 4 and the other chromosome involved; in this case, the child will be born with “normal” chromosomes. Sometimes the creation of a reproductive cell involves the balanced versions of the two chromosomes. This means that even though the material isn’t in the place we expect it, it’s all there and the child will have all the material (and the bookmarks!) needed for his or her body to read the material and function as expected. In this situation, the child will have a symptomless balanced translocation like his or her parent.

In other cases, the reproductive cells split in ways that include the unbalanced half of 4p, but the normal part of the other (in our case, 22p). This means that half of 4p is missing from the parent’s contribution. This results in what we call a deletion of 4p arising from an unbalanced translocation. This is called Wolf-Hirschhorn Syndrome. There is a medical literature on this, and support groups such as this one (link).

In trisomy 4p, however, the uneven split has included the extra 4p, and when combined with the other parents’ cells, we get three copies of the 4p. This is why we say trisomy 4p (because there are three copies [=tri for trisomy]). Sometimes people say duplication or dup 4p because the duplication is smaller than the whole length of the short arm of 4. In general, these are overlapping terms with trisomy 4p suggesting a larger duplication and dup4p referring to any kind of duplication.

Here we’ve given four possible outcomes of reproduction involving a parent with a balanced translocation, but it’s not quite the whole picture. Given that meiosis happens for both the mother and the father, there are actually two sets of two chromosomes involved on each side – in our hypothetical case we’ve used 4 and 22 – two sets of 4 and 22 for the father and two sets of 4 and 22 for the mother. 2 x 2 x 2 x 2 = 16 possible chromosomal combinations!!! However, in the case we’ve used as an example, many of those combinations are likely to result in a combination that cannot survive the first trimester. This is why people with balanced translocations are more likely to experience miscarriage and infertility than those without. Many families in our group have had trouble conceiving. Some, however, have not, and we don’t know why some people find they hit certain combinations more often than others. The potential of these possibilities can be likened to rolling the dice. We know the potential, but we don’t know the real outcomes for each individual, because sometimes the dice are weighted towards particular combinations and we don’t know why (yet...).

But all the people involved with this website have hit on the combination of three copies (or partial copies) of 4p, usually with a deletion of another chromosome involved. Because 4p is usually the larger of the set (the chromosomes become smaller as the number grows larger), often the duplication of the large 4p takes precedence over the smaller deletion of another chromosome (like 21p or 22p) so trisomy 4p becomes the main diagnosis. Children with translocations on other, larger, chromosomes may experience further impact from their deletion.

Overall – what is the risk of having a child with a chromosomal disorder if you know you have a balanced translocation? Some people say about 10%. That’s true if you think about all the different possible combinations, including the combinations that do not result in viable pregnancies. If you have a viable pregnancy, your child will either have normal chromosomes, a balanced translocation, a deletion of 4p or a duplication of 4p. We don’t know why some combinations happen more often (or less often) but we do know that these four possibilities could happen. A consultation with a geneticist is important if you are thinking of having more children when you know you have a balanced translocation. Geneticists can give you the most detailed and up to date information on how you can make the best decision for you about family planning.

WHAT DOES THIS MEAN FOR FOR MY FAMILY?

A de novo or an inherited trisomy 4p via an unbalanced translocation: what does it mean? It means that your child is made differently than other children. It does not necessarily mean your child is sick. It definitely does not mean your child is unattractive (trisomy 4p kids have awesome eyelashes and gorgeous hair, did we mention that already? :) ).

If your child is diagnosed at birth, the medical and nursing staff around you may act strangely. Sometimes this because they have never encountered a baby with this kind of rare chromosomal arrangement before. They sometimes prepare themselves for the worst because of their lack of experience. If you feel everything is fine with your baby, don’t let this scare you. But if there is something to be concerned about, staff might act strangely because babies with trisomy 4p may need help and intervention right away, and they want to give it to your child as quickly as possible.

Like the heavy baggage making the car stall, the extra material in the trisomy can make it harder for your child to feed, sleep or grow like other children, but that is not an illness. It is part of their being. People with fair skin can suffer from very painful sunburns, but we don’t say that they are ‘sick’ because they get sunburned. Instead, we think that having fair skin means you have to be careful in the sun. Our kids are like that too. We have to be more careful with things like feeding and with common colds, because our children’s bodies are built differently than others. Their brains are wired differently, so sometimes they have seizures. As they grow, reading from the book of chromosomal material, their bodies and brains take extra time to learn why there is this extra part of page four on another page, and this extra part might be blocking out the information on another page. Their bodies take time to get used to reading all those pages, and bumping around looking for anything missing. Over time, some kids’ bodies get used to the pages being out of order, and they grow up strong, if a bit wobbly at times. It’s just their own personal storyline! Sometimes, though, the pages that are lost are too crucial to their story, and their bodies get lost looking for what they think might be the order in the mix. Everyone’s story is different, but we all are united in our search for making sense of our stories, learning from them as we read out the pages of our own stories from the short arm of the fourth chromosome.

* This information has been presented from a parents’ point of view, gathered from the medical experience we have had with doctors treating our children.  We are not doctors, but caregivers who have learned the basics along the way. If you have questions or suggestions for changes to this information, please contact friendsof4p+@gmail.com with your feedback. Always contact your doctor if you have specific or general concerns.