Chromosomal Mosaicism Detected at the Time of Chorionic Villus Sampling
Saturday, March 22, 2008
Kenneth F. Trofatter, Jr., MD, PhD
Thu Mar 20, 08:27:00 PM 2008, Anonymous has left a new comment on your post "Invasive Diagnostic Testing after Reassuring First...":
Dear Dr. Trofatter:
I am a 35 yr old who is 13 weeks pregnant. This is my first pregnancy and I am seeing a high risk specialist since I had bleeding from week 4-6. Two weeks ago, I had CVS and the preliminary results (I assume FISH) results showed a healthy baby girl without any chromosomal abnormalities. A week later the genetic specialist called me and told me the final results showed mosaic Turner's syndrome and that I need to have an early amniocentesis to determine if this finding is limited to the placenta only. Why did the preliminary results show a false negative? Should I rely on the FISH results from amniocentesis in order to make my decision regarding termination or wait for the final amniocentesis results? Thank you!
Sat Mar 22, 03:23:00 PM 2008, Kenneth F. Trofatter, Jr., MD, PhD said...
Chromosomal mosaicism is defined as the presence of two or more populations of cells having different chromosomal complements in the same individual. Usually, this involves one population of cells that is chromosomally “normal” and another that is not, often with either one extra (trisomy) or one too few (monosomy) chromosomes. Mosaicism can involve both the fetus (true fetal mosaicism) and the placental tissues or the placental tissues alone. The latter is termed “confined placental mosaicism” and was first described by Kalousek and Dill in 1983 (Science 1983;221:665-667).
Placental mosaicism has been found at the time (9-12 weeks’ gestation) of chorionic villus sampling (CVS) to occur in approximately 1-2% of all pregnancies (Hahnemann and Vejerslev, Prenat Diagn 1997;17:801-20; Grati, et al., Eur J Human Genetics 2006;14:282–288). Under most circumstances, mosaicism is though to result from either a chromosomal nondisjunction event in the early stages (zygote/blastocyst) after conception, generating a trisomic cell line (single extra chromosome) in an initially normal baby, or as the result of the loss of one chromosome in an initially trisomic baby (“trisomy rescue”). When the latter occurs, the resulting fetal and/or placental tissues can end up with two identical chromosomes from one parent (rather than two slightly different ones from each). This is termed “uniparental disomy (UPD)” and is a condition that itself has associated risks which will not be included in today’s discussion.
When placental mosaicism is found at the time of CVS, there is a 10-12% chance the baby (not just the placental tissues) will share the mosaicism. However, even if the baby is affected, it is highly variable as to what percentage of fetal cells and even which organs will be involved in the mosaicism. Generally, the earlier the nondisjunction event occurs, the greater the likelihood that a higher percentage of placental and fetal cells will be involved in the chromosomal abnormality.
In the case of confined placental mosaicism (CPM), when the baby is not affected directly by the aneuploid cell line, the outcome of the pregnancy is somewhat influenced by which (and how many) placental cells are affected by the mosaicism. Three types of CPM have been described and are based on which placental cells are affected (Kalousek, et al., Hum Genet 1992;88:642–646; Simoni and Sirchia, Prenat Diagn 1994;14:1185–1189). In type I, the abnormal cell line is confined to the cytotrophoblast; in type II, it affects only the mesenchymal cells of the stromal villous core; and in type III, it involves both tissues. Although the distribution of these types differs somewhat by the study reported, as an aexample of the same, Grati and colleagues (Eur J Human Genetics 2006;14:282–288) found mosaicism confined to the placenta in 177 cases (87.2%): 39.9% type I, 40.4% type II and 6.9% type III.
When CVS is done, usually samples of both cells lines (cytotrophoblasts and mesenchymal cells) are obtained. Chromosomal analysis of these cell lines can be performed by means of direct preparations (such as fluorescent in situ hybridization, or FISH), short-term cultures (cytotrophoblasts), or long-term cultures (mesenchymal cells) of the chorionic villi. With reference to the mechanisms of mosaicism we have discussed above, type I and II CPMs are usually the consequence of postconceptional nondisjunction events, and type III is the result of “trisomy rescue” (from a meiotic error of maternal or paternal gamete formation prior to conception). The latter is associated with an increased risk of pregnancy complications and of UPD in the 'rescued' diploid fetus (Robinson, et al., Am J Hum Genet 1997;60:917–927). In the case of type I and II CPM, the risk of UPD is very low (Kalousek, Am J Med Genet 2000;91:39–45).
For the purposes of counseling our reader, the type of CPM is very important and to some degree, the risk to the baby of sharing in the mosaicism, or of having UPD, is often reflected in the laboratory test results. Mosaicism not detected in the cultures, but only in the direct preparation is more likely to represent CPM. Furthermore, certain mosaicisms , such as those involving sex chromosomes (such as Turner syndrome, 45,XO) or trisomies 8, 9, 12, 13, 15, 18, 20, and 21 often involve the baby and are therefore considered high-risk for true fetal mosaicism and the consequences of the same (Association of Clinical Cytogeneticists Working Party on chorionic villi in prenatal diagnosis Prenat Diagn 1994;14:363-379; Hahneann and Verjeslev, Am J Med Genet 1997;70:79-187). Grati and colleagues (Eur J Human Genetics 2006;14:282–288) found that type I CPM was associated with a 2.4% risk of fetal mosaicism, type II with 12.8%, and type III with 46.1%.
As is in the case of our reader, when mosaicism is found after CVS, either in the direct preparation (cytotrophoblasts) and/or in the cultures (mesenchymal cells), amniocentesis is usually recommended to determine if the abnormal cell line is confined to the placenta. Ninety percent of the time, the amniotic fluid results are “normal” and truly reflect a chromosomally normal baby. However, even when the amniotic fluid chromosome results return normal, there is a small chance of pregnancy complications as the result of a low level of fetal mosaicism (cryptic fetal mosaicism), UPD, and placental dysfunction as a consequence of the aneuploid cell line.
Although most pregnancies with CPM continue to term with no complications and are accompanied by normal fetal development, if a significant percentage of placental cells are aneuploid, this could result in impaired growth or even the loss of a chromosomally normal baby, and is more likely to be seen with type III CPM. Furthermore, if the baby has UPD, and this results in metabolic dysfunction, even though the total number of chromosomes is normal, a poor outcome might also result.
Returning to our reader’s questions, I would offer the following responses: First, the fact that the direct preparation (FISH) demonstrated a normal fetal karyotype and the cultured preparation suggested a Turner’s mosaicism (45,XO) speaks to the inherent weakness of rapid preparations in accurately establishing a diagnosis. Their positive predictive values are good if an abnormality is found, but due to the small number of cells obtained, resulting in 'sampling error', their false negative rate is relatively high. For the same reason, I do not think you should necessarily rely on the FISH results alone from amniocentesis when you have that done, particularly, if your plans are to terminate the pregnancy if a Turner’s mosaicism is found. I would strongly suggest you get some good genetic counseling prior to making any final decision in that regard as well.
Thank you for reading, for sharing your story, for your excellent questions and for giving me the opportunity to expound on a very important subject that may affect many of our readers.
Dr T
Labels: aneuploidy, chorionic villus sampling, chromosomal mosaicism, first trimester screening
9 Comments:
At Thu Apr 03, 12:31:00 PM 2008,
Anonymous said…
Hello, I have severe acne for which I rely on some acne medications which are not safe to use during pregnancy or while trying to conceive. How long would you suggest that I stop taking these medications before I start to try to get pregnant. I just lost a pregnancy from Cystic Hydroma, so I am very fearful of everything that could be harmful during pregnancy as I don't want to lose another baby.
At Thu Apr 03, 04:25:00 PM 2008,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Apr 3: It depends on what medications you are using. If it is Accutane, you should be off that for AT LEAST 3 months before trying to get pregnant. That is a category X drug and puts you at high risk for major fetal malformations. Dr T
At Sun Nov 09, 12:06:00 AM 2008,
Anonymous said…
Hello, sadly I recently terminated a pregnancy at 19 weeks due to the baby having a major heart problem (only one valve) as well as other issues that were starting to present, bowel obstruction, increased fluid around the brain and heart, and slow growth (1.5-2 wks behind). The baby also had mosaicism, I had a CVS & it was confirmed with an amnio. The 'extra' DNA was so small the doc's couldn't say what chromosome it came from or even if it was related to the physical problems as it was in the 'non-active' part of the cells. Was in 70% of her cells. I am 32 & my husband 45. what I would like to know is could this happen again? We had our chromosomes checked and they were normal. Could my husband's age have any bearing? Is there anything else we should investigate before trying again?. Many thanks.
At Wed Oct 07, 02:16:00 PM 2009,
Anonymous said…
I know this was post a while back and I am not sure of the original posters outcome - but in case someone uses a search engine to look up a similar prenatal diagnoses, I thought I'd share.
My baby was diagnosed with a mosaic - 45X, 46XY at 20 weeks via amino, normal FISH - he was born at 40 weeks gestation with normal genitalia and a normal blood karotype. These tests can be wrong.
At Fri Oct 09, 09:54:00 AM 2009,
Kenneth F. Trofatter, Jr., MD, PhD said…
To anonymous Oct 7: Thank you for writing The test is not necessarily "wrong" but it may not accurately reflect the actual status of the baby and that can go both ways with mosaicism, good and bad!
Dr T
At Thu Jan 14, 02:57:00 PM 2010,
Wizzard said…
Thank you for all your posts. This week I got the FISH results for CVS and was told that they indicated TURNER syndrome in the fetus. I now got another call from the lab saying that so far the cultures are showing normal cells.... We will get the absolute final results tomorrow but I find the whole experience distressing.. Today I had an appt with a clinic today to discuss terminating the pregnancy and then now it sounds like we have a mixed result. Which is more reliable FISH or the cultures? It sounds like I am going to need to have an amnio, which means that being at 13 weeks now, I need to wait another two weeks for the test and then another week for results and by then I will be 16 weeks. By which point I might need to decide to have a termination.... In everything I have been able to decipher, I feel that the amnio is probably more reliable because it takes cells directly from the fetus. If I had known or understood this, I would not have chosen to have CVS done for the sake of getting a test earlier. This is way too distressing...
At Sat Jan 16, 06:01:00 PM 2010,
Kenneth F. Trofatter, Jr., MD, PhD said…
To wizzard Jan 14: I am going to make thing even more confusing to you. When there is a 'discrepancy' in the fetal chromosome results, it increases the chance that the baby has a chromosomal mosaicism - two separate chromosomal complements - in your case Turner's syndrome 45XO, combined with a normal population of cells (46XX or 46XY). Unfortunately that can be VERY difficult to sort out. Even if the amnio shows only normal cells, there is a small chance that the baby (and not just the placenta biopsied at the time of the CVS) still has some degree of mosaicism - the extent of which can be almost impossible to sort out prior to delivery. You need to talk with a very good genetic counselor once you get he final chromosome results from the cultures to decide where you go from here. Best wishes.
Dr T
At Sun Jan 17, 09:07:00 AM 2010,
Wizzard said…
Thanks for your response Dr. T. We got the final results from the CVS and it shows 100% normal cells so 46 XX. The FISH showed 92% abnormal cells so 46X and then they looked at the sample again and that subsequent analysis showed 84% abnormal cells. We still do not completely understand how the two tests can show 2 such different results since they come from the same sample. Can you explain?
We are now going to do the amnio and a level II ultrasound to look at the fetus anatomy. We were told that some places do the amnio at 16 weeks and in some cases we could do it earlier let's say 15 weeks. Obviously, we would rather do it sooner however not sure what would be most efficient.
Another question is : should we ask for the test to be conducted in a specific manner: you state that even if the amnio results show that cells are 100% , we still would not be 100% sure that the baby would not have chromosome mosaicism at birth. So how can we know from the results?
One last question is the placenta cells -- these cells and the fetus cells have the same make up or don't they? what's the difference?
One more question sorry!: any good genetic counsellor you can recommend in New York City: our CVS was done with Columbia however the Amnio may be done at the Petrie division/Family Planning unit of Beth Israel. We have seen genetic counselors from both units and we actually prefer the one we saw at Beth Israel because he seemed more knowledgeable but we're not experts....
Thanks so much for your responses.
At Wed Jan 20, 06:26:00 PM 2010,
Kenneth F. Trofatter, Jr., MD, PhD said…
To Wizzard: Even though the fetal and placental tissues started out the same (and in most pregnancies remain the same), occasionally, as the fetus or the placenta are differentiating (usually very early), an abnormal separation of the chromosomes occurs during mitosis that results in two populations of cells - the original normal 46XX cells and whatever abnormality occurs in a separate population of cells. As I said, this can involve the fetus, the placenta or BOTH depending on when in development the abnormal cell population arose. Hopefully, in your baby this is an isolated case of placental mosaicism, not involving the baby. The amnio can usually be done very safely by an experienced provider at 15-16 weeks. I do not have a specific recommendation for a genetic counselor, but at those institutions, they should be well-trained individuals so go with the person with whom you feel most comfortable. Still wishing you the best and am optimistic for a good outcome!
Dr T
Post a Comment
<< Home