Confined Placental Mosaicism
Germinal mosaicism, in contrast, includes two or more genetically distinct cell lineages including in the germ cells. This means that this kind of mosaicism can result in abnormal offspring of the affected individual.
Both somatic and germinal mosaicism can be of single genes or of whole chromosomes.
Confined Placental Mosaicism
This phenomenon was identified as a critical determinant of survival in some aneuploid babies. It was discovered that in all liveborn babies with trisomy 13 or trisomy 18, there was, in the placenta, a normal cell line. That is, survival beyond the fetal period and resultant live birth only arises in these conditions when a spontaneous reversion to a normal chromosome makeup occurs by chance in the cell lineages that give rise to the placenta (rescue in an otherwise uniformly lethal condition). This observation helped to explain why many babies with these trisomies are miscarried or are stillborn while others are born alive. Presumably trisomy 13 or trisomy 18 results in serious abnormalities of placental function and these placental functional abnormalities are what result in intrauterine death.
Confined Placental Mosaicism and Prenatal
In fact, chorionic villus biopsy allows sampling of two different tissue types. Direct chromosomal studies are of cytotrophoblast cells. Cultured cells for chromosomal investigation are of the mesenchymal cells of the placental stroma. So, confined placental mosaicism can be of different types.
Types of confined placental mosaicism
Type I almost never includes chromosomal abnormality in the fetus and almost always implies a good outcome of pregnancy. It is, then, mostly a troubling prenatal finding that creates anxiety until the cultured chromosome results are available.
Types II and III are more worrisome in terms of fetal outcome. In part, predictions appear to depend on which chromosome pairs are involved. If chromosome 13, 18, 21 or a sex chromosome is found in abnormal number, almost always this means that the fetus is also cytogenetically abnormal. In contrast, if chromosomes 2, 3, 7 or 8 are found in CVS mesenchyme they seem to have no effect. And finally, trisomy 16 when present only in the placenta seems to have a clear correlation with an increased risk of intrauterine growth retardation.
In fact, understanding the effects of confined placental mosaicism is an extraordinarily complicated topic. Effects may vary by timing of the chromosomal accident, by the type of confined placental mosaicism that results, by the proportion of normal and abnormal cells present, by which chromosome is involved, and so forth.
How bad effects might arise.
Secondly, we have to consider how confined placental mosaicism could arise and how that might affect the genetic makeup of the fetus. First, a zygote might be chromosomally normal and then an accident of mitosis could result in a cell line with a chromosomal abnormality confined to the placenta. That mechanism will probably usually give rise to normal babies, unless the dysfunction of the placenta itself is so severe as to cause problems with survival or growth. Secondly, and more interesting, the zygote might be chromosomally abnormal but then a spontaneous correction or rescue results in a chromosomally normal cell line. Lets suppose that this rescue-derived line then gives rise to all fetal tissues. Why should we expect the fetus to be anything but perfectly normal?
An example might best explain this. Lets suppose that nondisjunction in an egg or sperm results in a newly fertilized zygote with three copies of chromosome 7 instead of the usual two. Two of these would come from one parent (lets say for this example from the mother) and one from the other parent. Now lets correct this trisomy through a second chance event loss of one of the three chromosome 7s. Two-thirds of the time one of the maternal 7s will be lost and everything will, presumably, be ok. However, one-third of the time the paternal 7 will be lost and what will remain are two maternal 7s. So, the developing embryo will have the right number of chromosome 7s, but both will be derived from one parent. This is termed uniparental disomy.
Uniparental disomy can have bad effects in two ways. First it makes more likely homozygosity (a double dose) of harmful recessive genes, since only one parent need be a carrier of a particular harmful gene. If this is a lethal recessive, then this might result in intrauterine death. Secondly, we now know that copies of genes from our mother and father function differently - a phenomenon call imprinting. This means that it does matter where the two chromosome copies come from. Imprinting problems secondary to uniparental disomy also could cause bad outcomes, including intrauterine death.
Confined placental mosaicism and intrauterine
Rather than searching for bad outcomes among those with identified confined placental mosaicism, one could, of course, look for confined placental mosaicism in spontaneous abortions or stillbirths. But here, too, the data are very uncertain. Griffin et al. found discrepant placental karyotypes in 4 of 65 informative spontaneous abortions a bit higher than would be expected, while Kalousek identified confined placental mosaicism in 11 of 54 spontaneous abortions much greater than population expectations. It isnt at all clear what accounts for this difference.
Nor have any good studies been done on stillborn infants. I have reviewed WiSSP data and have found two, and possibly three, instances of apparent confined placental mosaicism one of chromosome 2, one of chromosome 6 and possibly one of chromosome 12. That is only 3 out of 1206 stillborns and only 3 out of 494 (0.6%) in whom successful cytogenetics was obtained. Even this latter proportion is no greater than that to be expected by chance. Thus, while a well designed and well controlled study of confined placental mosaicism in stillborns is clearly needed, data do not support incorporation of such studies into routine protocols, at least not yet.
Artan S, Basaran N, Hassa H, Ozalp S, Sener T, Sayli BS, Cengiz C, Ozdemir M, Durak T, Dölen I, Ozgünen T, Tuna M: Confined placental mosaicism in term placentae: Analysis of 125 cases. Prenat diag 15:1135-1142, 1995.
Griffin DK, Millie EA, Redline RW, Hassold TJ, Zaragoza MV: Cytogenetic analysis of spontaneous abortions: Comparison of techniques and assessment of the incidence of confined placental mosaicism. Am j med genet 72:297-301, 1997.
Hahnemann JM, Vejerslev LO: European collaborative research on mosaicism in CVS (EUCROMIC) - Fetal and extrafetal cell lineages in 192 gestation with CVS mosaicism involving single autosomal trisomy. Am j med genet 70:179-187, 1997.
Kalousek DK: Confined placental mosaicism and intrauterine fetal development. Placenta 15:219-230, 1994.
Kalousek DK, Barrett I: Confined placental mosaicism and stillbirth. Pediat pathol 14:151-159, 1994.
Kalousek DK, Vekemans M: Confined placental mosaicism. J med genet 33:529-533, 1996.
Leschot NJ, Schuring-Blom GH, Van Prooijen-Knegt AC, Verjaal M, Hansson K, Wolf H, Kanhai HHH, Van Vugt JMG, Christiaens GCML: The outcome of pregnancies with confined placental chromosome mosaicism in cytotrophoblast cells. Prenat diag 16:705-712, 1996.
Robinson WP, Barrett IJ, Bernard L, Telenius A, Bernasconi F, Wilson RD, Best RG, Howard-Peebles PN, Langlois S, Kalousek DK: Meiotic origin of trisomy in confined placental mosaicism is correlated with presence of fetal uniparental disomy, high levels of trisomy in trophoblasts, and increased risk of fetal intrauterine growth restriction. Am j hum genet 60:917-927, 1997.
Wolstenholme J: Confined placental mosaicism for trisomies 2,3,7,8,9,16 and 22: Their incidence, likely origins, and mechanisms for cell lineage compartmentalization. Prenat diag 16:511-524, 1996.
Wolstenholme J, Rooney DE, Davison EV: Confined placental mosaicism, IUGR, and adverse pregnancy outcome: A controlled retrospective U.K collaborative survey. Prenat diag 14:345-361, 1994.
*Copies of these and other relevant articles are available for personal use by request from WiSSP.