Chromosomal Mosaicism Detected at the Time of Chorionic Villus Sampling

Since the widespread acceptance of first trimester screening for fetal chromosomal abnormalities (aneuploidy), and following the recommendations that this should be offered to all pregnant women, not just those considered to be ‘at risk’ for indications such as ‘advanced maternal age’, early invasive testing by chorionic villus sampling (CVS) has become more widely employed as a means of diagnosing aneuploidy. Any diagnostic procedure has its risk and limitations. The comment from the reader below is related to one of the major ‘risks’ of CVS, that is the risk associated with the interpretation of the significance of the test results themselves when the diagnosis of ‘mosaicism’ returns from the laboratory…

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

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Abnormal Sperm Morphology and Recurrent Pregnancy Loss?

The following comment was recently received with the request to comment upon the possible association of "poor sperm quality" and recurrent pregnancy loss...

Posted by Concerned_in_Canada to Fruit of the Womb at Thu Jan 31, 11:59:00 AM 2008 "Early Pregnancy Loss - 2":

This is a great thread! Anyway, I have a question regarding recurrent miscarriage and sperm quality. I'm currently facing my third miscarriage in 8 months.(I'm having an ultrasound tomorrow to confirm things...HCG wasn't doubling, now it is but still not looking too good) Anyway, I'm 33 and had my first loss in June 2007 at 6 1/2 weeks, the cause unknown as they don't test first pregnancies. The second was in September at 7 weeks and turned up as a trisomy. Now I'm pregnant again, the levels have been rising but slowly, they've picked up the last few days to double correctly but considering my history I'm not holding my breath for a good result. So, considering we keep getting told by doctors that they are 'sporadic' and 'bad luck' I'm concerned there is more to these chromosomal problems than just chance. We have both had the karyotype testing and all is fine, however my husband has terrible quality sperm with extremely low morphology. His DNA fragmentation is fair. Why with such deformed sperm are our doctors not taking the chromosomal abnormalities more seriously? Can poor morphology increase the risk of miscarriage?
Sorry for the long post...but it’s been a frustrating few months and I'm really starting to lose hope for a healthy pregnancy.

To Concerned in Canada: I thought this was an excellent question and quite frankly I did not have a ready answer. I am not a specialist in Reproductive Endocrinology and even less of one in evaluation of infertility from the male factor (andrology) side of things. The obvious situation in which the male can contribute to recurrent early pregnancy loss is when he is the carrier of a balanced chromosomal rearrangement, such as a Robertsonian translocation, in which he has the correct total amount of genetic material but has a high risk of making sperm that have an incorrect amount and we have discussed this situation in previous posts. Too much or too little genetic material usually results in early miscarriage. We also know that males, who have low sperm counts or very high percentages of abnormal-appearing sperm, have lower chances for achieving conception with their partners. However, our reader asks the question, does the male who is chromosomally normal, but has a high percentage of abnormal-appearing sperm, also contribute to a higher rate of miscarriage in his partner once conception has occurred?

Although the medical literature has supported mixed opinions on this subject over the years, a recent review by Puscheck and Jeyendran (Curr Opin Obstet Gynecol 2007;19:222-28) suggests that “the male contributes to recurrent pregnancy loss due to genetic factors, semen factors, or due to other factors such as age” and sperm morphology may reflect these underlying deleterious conditions. In 1991, Kobayashi and colleagues (Hum Reprod 1991;6:983-6) demonstrated in in vitro fertilization cycles that low percentages of normal sperm morphology were associated not only with lower successful fertilization rates and pregnancy rates per cycle, but also with a greater risk for miscarriages even if embryo transfer was successful.

Egozcue and colleagues (Hum Reprod Update 2000;6:93-105) reported that among infertile couples in which the males were chromosomally normal and there was no identifiable source of infertility in the females, there were greater frequencies of chromosomally abnormal sperm produced by the males as the result of ‘meiotic disorders’ – meiosis being the final stage of sperm production in which the normal chromosomal complement of 46 (23 pairs) is supposed to be halved to just 23 different chromosomes. Among these males they found a greater percentage of sperm with two copies (or none) of single chromosomes, such as chromosome 21 or other autosomes (non-sex chromosomes), two copies (or none) of sex chromosomes (rather than just one X or Y), and sperm that were still diploid, containing 46 chromosomes rather than 23. Obviously, under any of these circumstances, if these abnormal sperm got together with an egg that had a normal number of 23 chromosomes, the resulting baby would end up with too many or too few and the likelihood of miscarriage in early pregnancy would be high.

The results and conclusions of this study were supported by Carrell and colleagues (Obstet Gynecol 2003;101:1229-35) who found the sperm aneuploidy (chromosomal abnormalities) rate in couples with recurrent pregnancy loss to be about twice that of the general population and this was accompanied by diminished percentages of sperm with normal morphology. Similarly, Bernadini and colleagues (Reprod Biomed Online 2004;9:312-20) reported that among men with recurrent pregnancy loss and poor semen quality, elevated frequencies of sperm aneuploidy were found in about 10% of these men who had, individually, sperm aneuploidy rates between 30-34%. In some instances, the high aneuploidy rate may be related to mosaicism (separate populations of cells, one chromosomally normal and the other chromosomally abnormal) that is confined to the germ lines (sperm-producing cells) in the testes (Somprasit, et al., Reprod Biomed Online 2004;9:225-30). Such individuals would appear to be ‘chromosomally normal’ except where it counts!

In addition to sperm aneuploidy, other parameters of sperm evaluation, DNA fragmentation and high DNA stainability, have also been correlated with both abnormal sperm morphology and recurrent pregnancy loss. Carrell and colleagues (Arch Androl 2003;49:49-55) found higher rates of sperm DNA fragmentation in couples with recurrent early pregnancy loss following spontaneous conception. Similarly, Borini and colleagues (Hum Reprod 2006;21:2876-81) found higher early pregnancy loss rates in couples undergoing assisted reproductive technologies, both by in vitro fertilization (IVF) and by conception with intracytoplasmic sperm injection (ICSI) when high sperm DNA fragmentation and abnormal morphology were present. In a very recent (as yet unpublished) study by Lin and colleagues (Fertil Steril abstract online September 2007), abnormalities of sperm DNA structure, high DNA fragmentation and high DNA stainability (HDS), were not correlated with IVF or ICSI fertilization rates, ‘good embryo’ rates or pregnancy rates, but did appear to be correlated higher postimplantation spontaneous abortion rates.

So, in conclusion and in response to our reader’s question, there is evidence to support the premise that in couples with recurrent early pregnancy loss, abnormalities of sperm morphology can reflect underlying abnormalities of chromosome number and DNA structure that may subsequently increase the risk of early miscarriage even after successful conception, spontaneous and assisted. What to do about that is truly outside my realm of expertise, but can probably be addressed by an REI or Andrology specialist! Thanks again for a great question and best of luck to you…
Dr T

Labels: aneuploidy, recurrent pregnancy loss, sperm morphology

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Chromosomal Abnormalities and Multiple Gestations - 2

…After talking with one of our genetic counselors, I went back into the room (see previous post). By this time, they had both used some tissues and were ready to talk more. They agreed to see the counselor and we walked across the hall to her office. (We are blessed with great genetic counselors). Over the course of 30-40 minutes, she explained ‘nondisjunction’ as the cause of increased risk for chromosomal abnormalities with advancing age, the actual risk for aneuploidy in midtrimester at age 40 in singleton (1/75 for Down syndrome; 1/44 for all aneuploidy) and twin pregnancies (about twice these risks that one of the babies will be abnormal in twins from different eggs), the diagnostic procedures that could be done to confirm the diagnosis, the benefits of knowing if the baby has a chromosomal abnormality with regard to decision-making during and after the pregnancy, and specific information with regard to the presumptive diagnosis of trisomy 18.

The patient was then asked if she wanted an amniocentesis and both she and her husband agreed that, based on what we had told them, they needed to know if the baby had a chromosomal problem, even though “we only want the procedure done on the baby that appeared abnormal.” (I wish I could accurately portray here the skepticism that was conveyed in the way the word “appeared” was inflected, but never being one to take away all hope, I just let it slide). I told them that under the circumstances, that was a very reasonable request. The normal ‘growth and appearance’ of the other baby probably reduced her risk for a chromosomal abnormality by as much as 90%. The procedure was then explained to them, including the small risks, and a consent was signed. As I always do under these circumstances, I made it quite clear that if the baby was lost following the amniocentesis, it would be much more likely due to the condition of the baby rather than to the procedure itself. She nodded that she understood. When asked if they had any questions, the only query was the inevitable, “I heard these things are awful…does it really hurt.” Welcoming the query, I gave her my patented reply that “it is going to be the most painful thing you have ever been through in your entire life and the large nurses in the room are here to hold you on the table.” She smiled and we did the procedure without any complications.

The amniotic fluid was sent for fetal karyotype studies by both fluorescent in situ hybridization (FISH) and routine culturing techniques. She was offered the FISH and told that a ‘presumptive diagnosis’ could be back within 48-72 hours and the routine culturing studies (results available in 10-14 days) could be used to confirm the FISH results and/or identify other chromosomal abnormalities not detected by the FISH assays; and, she readily accepted this approach. We would notify her directly as soon as any results were back and arrange for her to return to discuss the findings and options for follow-up depending on the diagnosis and her own needs.

A few days later, unfortunately, but as expected, the baby’s karyotype by FISH came back as 47XY,+18 (trisomy 18). When she was called, her immediate response was, “Some friends told me the FISH has lots of false-positives, so the baby could still be all right, right? Don’t we have to wait for the final results of the cultures?” Again, not to mince words, I told her that it was very unlikely the cultures would change the FISH results. In fact in 20 years, I have not seen a single FISH diagnosis of aneuploidy be overturned by the culture technique (although I have seen ‘negative’ FISH studies in circumstances where the final results demonstrated a chromosomal abnormality not included in the FISH profile). The silence that followed was deafening, and the crying that followed that was heartbreaking, but when she finally asked between tears, “Where do we go from here?,” I knew we were going to be alright. “Why don’t you come back to talk with us when you are ready; we’ll work you in on a moment’s notice if necessary…”

Labels: amniocentesis, aneuploidy, chromosomal abnormalities, FISH, trisomy 18, twins

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Chromosomal Abnormalities and Multiple Gestations - 1

In our practice, we see many cases of multiple gestations (mostly twins and not more, thank goodness) that come about as the result of the success of our colleagues in Reproductive Endocrinology and Infertility (REI). In general, these patients tend to be older, have underlying medical problems, and are at greater risk for a wide range of complications during pregnancy including diabetes, pregnancy-induced hypertension, cervical incompetence, and premature labor and delivery. Their pregnancies are also at greater risk for babies with congenital birth defects and chromosomal abnormalities beyond the typical risks associated with “advanced maternal age.”

Recently, we were asked to perform a “targeted ultrasound” to assess fetal growth and anatomy on a set of IVF twins in a 40 year old woman (who had had many years of primary infertility) at about 20 weeks gestation. After conception, and documentation of fetal viability by our REI group, she reestablished care in the office of her usual OB/GYN providers. Because of her age, the option for aneuploidy screening was discussed with her by our REI docs even before she left their care and apparently again once she crossed the threshold of her private doctors’ office. Her response of “What would I do about it anyway?” is one that I have heard too many times before to mention, but it usually leads to an immediate cessation of information exchange between patient and busy provider. I am sorry to say, I have come to realize that this is more related to denial mechanisms on the part of both patient and provider rather than a true lack of desire for information. Regardless, as part of her scheduled visit with us, a pre-ultrasound genetic counseling session was offered and also declined.

During the course of her ultrasound, it became readily apparent we had problems that required discussion. The baby girl was perfectly normal in size for her well-documented gestational age and had absolutely no visible gross abnormalities or soft markers for a chromosomal abnormality. The little boy, on the other hand, was two weeks behind in size, symmetrically ‘growth-restricted’, had intracranial abnormalities, micrognathia (small and recessed chin), and a complex congenital heart defect. The babies’ abdomens, side-by-side, were so strikingly different in size that the patient herself immediately recognized the difference and sat bolt upright in the bed the minute the image was displayed on the overhead monitor. “What’s wrong with my babies,” she asked? “Is this the twin-to-twin transfusion syndrome I have been reading about on the internet?”

In my position, the ‘buck stops here’, so I am not much for mincing words. I explained to her that her baby girl was normally grown and appeared to have no visible abnormalities. There was no evidence of a twin-to-twin transfusion sequence and that would be extraordinarily uncommon in babies from separate eggs, different genders, and completely separate placentas. Then I detailed the findings of her little boy. Before I could tell her why I thought the baby had these abnormalities, she interrupted and asked, “Can they be fixed inside or do we have to wait until after delivery?” It was at this point that I told her that it was very unlikely they could be fixed because the baby probably had a severe chromosomal abnormality – trisomy 18 – and was at high risk of either not surviving the pregnancy or dying shortly after birth. “How can that be?” she asked, “No one in my family has that or has ever had a baby with that kind of problem?”

“I’m sorry,” I said, “But this is something that you had no control over. The same conditions that increase your risk with age for having a baby with Down syndrome (trisomy 21), a process called nondisjunction, also can result in babies with other chromosomal abnormalities.” It was at this point that I saw in the dimly lit room, her husband, who had been completely silent to that point, gently sobbing in his chair. I picked up the ever-present box of tissues, walked around the examination table to him, held his shoulder, and told both of them that “I have just given you an awful lot of information. I am going to leave you alone for a few minutes and then we can talk some more. I would like to see if our Genetic counselor can spend a few minutes with you too….”

Labels: aneuploidy, Multiple gestations, trisomy 18

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Robertsonian Translocations

One of our readers left the comments/questions below that were worthy of a post for general consumption by interested readers...

Anonymous has left a new comment on your post "Recurrent Early Pregnancy Loss - 3 - Chromosomal C...": Hi-I am 30 years old and have suffered 3 miscarriages. After my third, my Dr. did a karotype and found that I have a Robertsonian translocation between 13 & 14. From what I've learned researching this topic, is that I have a 50-50 shot of producing an egg with the correct number of chromosomes or with the same translocation as I have. Is that assumption correct?Also, is IVF w/PGD our best bet in having a healthy baby? Is it also true that if I have this translocation that chances are one of my parent's have it and/or my sibling's?Thanks so much!! My anxiety has been sky-high ever since I found this out and I can't see a genetic counselor until November 1st. Gina

Gina, all of these are great questions, and as so much in this world of medicine, not as easily answered as you might like…

Under normal (euploid) circumstances, humans have 46 chromosomes in each of the cells that make up their bodies. The complement of 46 chromosomes is composed of 22 pairs of ‘autosomes’ and 1 pair of sex (either XX = female, or XY = male) chromosomes – half of the total complement being inherited from each parent. Individual chromosomes are quite distinct in their appearance and most have long (= p) and short (= q) ‘arms’ that are connected by a structure called the centromere. When cells replicate to make another cell, they first duplicate their chromosomes and centromeres. The centromeres then connect to the structures in the cell that help separate these duplicated chromosomes from each other so that each new cell which results gets exactly the same chromosomal complement that was present in the ‘mother’ cell. This event is called mitosis.

To produce gametes (ova and sperm), a slightly different process is involved. Following duplication of the chromosomes, the overall complement of chromosomes delivered to each gamete must be reduced to half (23) that found in other cells in the body. This is two-step process called meiosis in which the centromeres also play a key role. During meiosis, the individual chromosomes (that were inherited from each of your parents) segregate more or less randomly into the resulting gametes, providing the great variability seen in our offspring.

Five of our chromosomes (13, 14, 15, 21 and 22) have ‘short arms’ that are very small and which contain no essential genetic material. These 5 chromosomes are called acrocentric chromosomes, or ‘acrosomes.’ Acrosomes have a tendency to fuse at the centromeres with other acrosomes, thus producing a ‘single’ larger chromosome made up of the ‘long arms’ of the chromosomes of origin, connected by a single centromere. When this occurs it is known as a ‘Robertsonian translocation.’ If no essential genetic material is lost (or gained) in the process, the individual with such a chromosome is said to have a ‘balanced’ translocation and appears ‘normal’ although they now have only 45, rather than 46, chromosomes in each cell.

Robertsonian translocations can occur between any of the acrosomes although this is not entirely random and the most common forms of these occur between chromosomes 13 and 14 (75%), 14 and 21 (10%), and 21 and 22. Individuals with Robertsonian translocations can have these as the result of a spontaneous event occurring during the meiosis (in either parent) that produced the egg or sperm from which they were made, shortly after conception, or from the inheritance of the same from one of their parents.

Robertsonian translocations are present in approximately 1/1,000 newborns. Individuals with balanced translocations are usually healthy and often unaware of their condition, especially if there is no prior family history that has led to the diagnosis, and often their chromosomal ‘abnormality’ will not be discovered until they have difficulty having children. The problem arises when individuals with Robertsonian translocations try to make gametes. In the case of our reader, who apparently has a balanced 13;14 translocation, the possible gametes she will produce (don’t ask me to explain why at this point) during meiosis may contain:

• 1) One free copy of chromosome (chr) 13 and one free copy of chr 14.
• 2) The translocation (chr 13;14) chromosome alone (which contains one copy of chr 13 fused with one copy of chr 14).
• 3) Chr 13;14 + one free copy of chr 13 (essentially, a gamete with TWO copies of chr 13 rather than just one).
• 4) One free copy of chr 13 (and NO copy of chr 14).
• 5) Chr 13;14 + one free copy of chr 14 (TWO copies of chr 14 rather than just one).
• 6) One free copy of chr 14 (and NO copy of chr 13).

Obviously, 3 through 6 are gametes that have the incorrect number of chromosomes (either too little or too much genetic material). When these gametes get together with the, presumably, ‘normal’ gametes from her partner (which contain one free copy of chromosome 13 and 14), the following possibilities result (in the same order as above):

• 1) Two free copies of chr 13 + two free copies of chr 14 = NORMAL
• 2) Chr 13;14 + one free copy of chr 13 + one free copy of chr 14 = translocation ‘carrier’ (just like Mom) with NORMAL TOTAL amount of genetic material
• 3) Chr 13:14 + TWO free copies (one EXTRA from Mom and one from Dad) of chr 13 + one free copy (from Dad) chr 14 = TRISOMY 13
• 4) Two free copies chr 13 (one from Mom and one from Dad) + ONE free copy of chr 14 (NONE from Mom and one from Dad) = MONOSOMY 14
• 5) Chr 13:14 + one free copy of chr 13 (from Dad) + TWO free copies (one EXTRA from Mom and one from Dad) chr 14 = TRISOMY 14
• 6) ONE free copy chr 13 (NONE from Mom and one from Dad) + two free copies of chr 14 (one from Mom and one from Dad) = MONOSOMY 13.

Therefore, to answer one of our reader’s questions, mathematically, she has only a 2 in 6 (33.3%) chance of having a baby that has the right TOTAL amount of genetic material; one of these will be entirely chromosomally normal and the other will be a translocation ‘carrier’ just like herself. Two-thirds of her babies are at risk for being chromosomally ABNORMAL.

But, as I mentioned at the outset, things are not quite that simple. Indeed, her actual risk for having a baby with a chromosomal abnormality is much lower than this. The monosomy 13 and 14 embryos will not be successful at all and the trisomy 14 embryos also have very little chance of surviving much of the first trimester. Most trisomy 13 embryos will also be lost early in first trimester and the few that survive will have only a small chance of surviving the pregnancy and even a smaller chance of living more than a few hours or days after birth. These babies all have severe congenital malformations and if they manage to survive birth and the neonatal period, profound metabolic disturbances, and mental retardation. Indeed, the ‘selective forces’ are so strong against these chromosomally abnormal conceptuses that at least two-thirds of her pregnancies in which a pregnancy is actually confirmed will be chromosomally normal and the chances of actually DELIVERING a chromosomally abnormal baby are probably only about 1%! The overall risk of miscarriage is about 25%.

With regard to the question of IVF (in vitro fertilization) and PGD (prenatal genetic diagnosis), I have a significant amount of ambivalence. If you have the money to burn, these are certainly options, but they are very expensive procedures. And, if you have no difficulty conceiving and are willing to trust nature to do the right thing, as pointed out above, the risk for actually having a baby with an unbalanced karyotype is so small, that it is often simply waiting until the dice roll correctly to have a normal baby. I know that can be difficult psychologically and at times physically. However, because there is nothing that can be done to correct a translocation, if one can accept the fact there is an increased risk for miscarriages, and that when these occur, it is probably the result of an aneuploid fetus, dealing with the pain of pregnancy loss may be a little bit easier.

There is a lot we have not discussed about Robertsonian translocations in this post, but I would like to make a few recommendations in closing (and we can always use these other issues as an excuse to write another post). First, I would suggest that any couple with a known Robertsonian translocation, consider having combined first trimester screening for aneuploidy performed and seriously consider a chorionic villus sampling if this is 'abnormal'. Secondly, even if this is reassuring, consider having a fetal karyotype done by amniocentesis. Thirdly, once an individual with a Roberstonian translocation has been identified, I think it is important to let other family members (male or female) of reproductive age know so that they can be screened as well. It may save a lot of anguish down the line.

Anyway, Gina, thanks again for your questions. I am wagering right now that your pregnancy quest will be rewarded in the end. Best of luck to you and your husband and thanks for reading!
Dr T

Labels: aneuploidy, Robertsonian translocation

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Fetal Cystic Hygromas in First Trimester

Today I received another comment to a post I wrote awhile back on aneuploidy (chromosomal abnormality) from a reader who has a first trimester baby that was found to have a cystic hygroma. With the growing acceptance of first trimester screening for aneuploidy as a 'standard of care' in the U.S. (the rest of the world discovered this several years back!), we are identifying more and more fetal abnormalities early in pregnancy. Since this too is becoming a topic of widespread general interest, I thought it would be worthwhile to highlight three of the comments/questions that were addressed to me so that other readers can hear about real situations and have a point of reference to current thought on this important issue. With apologies to the readers who left the original comments, I have modified the comments as necessary to the best of my understanding so that other readers will more easily understand their concerns...


Sat Jun 09, 09:10:00 AM 2007, Laura said:
My name is Laura and I am 24 years old. Me and my husband went for our first 12 week ultrasound scan a couple of days ago and to our shock we were told that our unborn child has a cystic hygroma, which we are told is fluid underneath the skin at the back of the babies neck (the nuchal translucency) measuring 6 mm. We are devasted at this news because we are told the outlook is not good. It is our first pregnancy and it has taken us so long to get pregnant due to my polycystic ovaries, it just makes it so much harder to deal with. We decided to have a CVS (chorionic villus sampling). They took a biopsy from the placenta which they are now going to test. We should have the rapid test results for Down syndrome, Turner syndrome, and Edwards syndrome by 13th June. We are praying that they will come back clear. They are also going to do routine chromosomal studies to look for other chromosomal abnormalities that are not detected by the rapid test. They said if all the tests are normal, and if the fluid drains away by 18-20 weeks we may have a chance. Its just so hard to understand how some fluid behind the neck could indicate these sort of problems. I am only 24 years old, and so is my husband. We are young, fit and eat a very healthy diet, it just seems so unfair. Do you have any idea of our odds. What is the percentage of babies that do get over this? Have you had any success stories that could give us some hope? Thank you for your time and we hope to hear back soon. Laura

Tues Jun 12, 09:10:00 AM 2007, Kenneth F. Trofatter, Jr., MD, PhD responded:
I know this is hard, especially in a first pregnancy you have had so much trouble getting to because of your polycystic ovary syndrome. Unfortunately, finding the cystic hygroma in first trimester is associated with a very high risk for a baby that has a chromosomal abnormality, most often Down syndrome (trisomy 21 = 47,+21)), Turner syndrome (45XO,missing one sex chromosome), or Edwards syndrome (trisomy 18 = 47,+18). Sometimes cystic hygromas are associated with gene defects and not chromosomal abnormalities per se. Examples of the latter include Noonan syndrome, Roberts syndrome, polysplenia syndrome, multiple pterygium syndrome, and others. At times the baby has no chromosomal abnormality or obvious genetic condition. Under these circumstances, there is an increased risk for a major heart abnormality as an underlying cause, although we do not entirely understand why babies develop cystic hygromas under these circumstances. The prognosis for the baby depends on what problems the baby has, chromosomal, genetic, and/or associated structural. If the baby has no chromosomal abnormality and does not go into heart failure (develop hydrops fetalis), it may well survive the pregnancy. If no syndromic problems, chromosomal mosaicism, or gene defects are discovered after delivery, the baby may have a reasonable chance at doing well. Your doctors will discuss this more with you after they get your test results back. At that point (if they haven't already), they will probably refer you to a genetic counselor to get more information. Good luck to both of you and thank you for reading. By the way, it is highly unlikely that anything you have any control over caused this to happen. If you will, let me know what the tests show and how the pregnancy turns out...


Sun June 24 11:50 AM 2007, Anonymous said:
Dr. Trofatter, I am 41 year old with a 14 week pregnancy. Due to AMA (advanced maternal age) I elected to have a nuchal translucency (NT) scan done and the perinatologist found a large cystic hygroma; I was told extremely large 180mm3 and the doc was not optimistic. He performed CVS that day and we just recieved news that the FISH results were normal. Because there are no genetic defects, I was told we are looking at heart abnormalities, probably severe. My husband and I are deciding whether to terminate but the normal chromosome results makes this decision difficult. I have been doing research on the web for days now and I find myself unable to take care of myself and my family. I am reading the prognosis is poor and if I wait beyond 18 weeks I cannot terminate the pregnancy in my state. My question is can or should I get repeated ultrasound hoping the hygroma goes down and how often is an ultrasound indicated for this? Will the hygroma go down all at once or little by little or how much at a time? Please help me. Thank you

Tues June 26 02:47 PM 2007, Kenneth F. Trofatter, Jr., MD, PhD responded:
Large cystic hygromas have a very poor prognosis, even if the baby is chromosomally normal. Even if the FISH results are reassuring at this point, your baby could have a chromosomal abnormality that was not detected by FISH. Your doctors have counseled you that this baby could also have a major cardiac malformation or other major abnormality that impedes return of fluid and lymph to the heart, even in the absence of a chromosomal abnormality. If the baby develops a condition called hydrops fetalis, this would indicate heart failure for any reason and the prognosis is usually fatal at that point. If the baby is chromsomally normal, has no other genetic or syndromic problem, has no major heart abnormality, and resolves the cystic hygroma, it may well survive and do quite well in the long term. I would recommend another ultrasound before 18 weeks. In many cases, major heart and other abnormalities can be identified by that time and you will have the final results of the fetal chromosome studies back to guide your decision. I am so sorry. It is difficult to be in your situation. If you have not seen a specialist in Maternal-Fetal medicine, I suggest you consider that. Thank you for reading and best wishes to you and your family.


Tues Aug 21 01:55 PM 2007, Ed said:
Doctor, on our 1st trimester baby scan we were told that baby had a 5mm NT (nuchal translucency). We hoped that the consultant could give us some better news on a scan a few days later, but we have the terrible news that it was not simply a wide NT, but a large cystic hygroma of 7mm, extend down the back to the lumbar region. She gave us an 85% chance of choromsome problem and cardiac anomalies even if normal. Also of possible intrauterine death. We are choosing to terminate, we can't wait in hope for a CVS or amniocentesis that MAY indicate the baby is chromosomally normal because it is more likely abnormal. But we have terrible guilt in termination too, as the baby seems ok at the moment. From what I read on the internet, there is a glimmer of hope that the babies do turn out normal. Is this just crazy hope or not?Ed


Wed Aug 22, 04:55:00 PM 2007 Kenneth F. Trofatter, Jr., MD, PhD said...
Although the prognosis is poor, there is always a "glimmer of hope." With your ambivalence and guilt related to pregnancy termination, why don't you have the CVS done and wait just a couple of days. Most labs can give you an answer in as little as 72 hours if they do a "direct prep" for the more common chromosomal abnormalities found with cystic hygromas. If the baby ends up being chromosomally normal, or has a potentially viable condition such as Turner's syndrome, the "glimmer" may improve if the baby survives the first part of the pregnancy....and even if it is chromosomally normal and succumbs, you can walk away having given it the "best shot" and it sounds like that is important for you. Just a thought. Good luck to both of you.


Dr T

Labels: amniocentesis, aneuploidy, CVS, cystic hygroma, first trimester screening

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How to Interpret a "Positive" First Trimester Screen

A reader left the following comment on a post I wrote regarding "Abnormal First Trimester Screening Results." I have gotten this question repeatedly since we have begun offering this procedure for early aneuploidy (chromosomal abnormalities) screening, so I thought both the question and the response might be of general interest to our readers...

"We learned yesterday from first-trimester screening results that we have a 1 in 110 risk of having a baby with Down Syndrome (decreased from my age-related risk at age 41 of 1 in 34). I was told this is still considered a "positive" result, because the standard is 1 in 240. Hearing the counselor call our results "positive" for Down Syndrome was frightening. I appreciate your description of what these results mean. This has helped me to put it in perspective and understand what the risks really are. I'm not sure that labels such as "positive" or "negative" are very helpful in these cases." Anonymous, July 17, 2007

To Anonymous July 17: The results are what they are. You have a 1 in 110 chance of having a baby with Down syndrome. That means you have a 109 out of 110 chance of having a baby that does NOT have Down syndrome. In other words, of 110 women with any combination of the variables (age, blood test results, nuchal translucency measurement, etc.) that produced your 'results' from the database, only 1 of those would be expected to have a baby with Down syndrome (trisomy 21).

Personally, I do not like the "screen positive and negative" way of presenting things to patients. That may suffuce for research purposes but it makes us sound like we're talking out of both sides of our mouths! This is not a black or white test result and it's not fair to present the information to patients in that way! Could you have a baby with Down syndrome? Sure, someone has to be the one; that's true even if you have a 1 in 10,000 result. There are shades of gray that contribute to the interpretation of the test result, and those are the factors you bring to the table. How you use the number to make further decisions regarding additional screening and/or diagnostic testing depends on your personal level of risk tolerance. Do you view the cup as half empty, or half full? Do you bet nickels in Vegas, or $100 dollar bills? How comfortable does the test result make you feel?...and, many other factors that make you who you are.

In the end, if you opt for a diagnostic test, I would suggest an amniocentesis at 16 weeks. The risk of that procedure in experienced hands is generally less than 1 in 1000. The other alternative is to simply consider having a "genetic sonogram" at 18-20 weeks. If the baby is growing well and there are no fetal abnormalities or significant "markers" for aneuploidy (e.g., thickened nuchal skin fold, hypoplastic nasal bone or middle phalanx of the fifth digit, etc.) at that point (again, by an experienced examiner), your a priori risk based on the first trimester screen result (not your age alone) is reduced by at least 60-80% (I usually quote people 90%). Do what is MOST COMFORTABLE for you. Thanks for reading and for your good question.

Labels: aneuploidy, first trimester screening

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