Confined placental mosaicism (CPM) represents a discrepancy between the chromosomal makeup of the cells in the placenta and the cells in the baby. CPM was first described by Kalousek and Dill in 1983. CPM is diagnosed when some trisomic cells are detected on chorionic villus sampling and only normal cells are found on a subsequent prenatal test, such as amniocentesis or fetal blood sampling. In theory, CPM is when the trisomic cells are found only in the placenta. CPM is detected in approximately 1-2% of ongoing pregnancies that are studied by chorionic villus sampling (CVS) at 10 to 12 weeks of pregnancy. Chorionic villus sampling is a prenatal procedure which involves a placental biopsy. Most commonly when CPM is found it represents a trisomic cell line in the placenta and a normal diploid chromosome complement in the baby. However, the fetus is involved in about 10% of cases.
CPM occurs in one of two ways:
- Mitotic CPM - Mitotic non-disjunction can occur in a trophoblast cell or a non-fetal cell from the inner cell mass creating a trisomic cell line in the tissue which is destined to become the placental mesoderm.
- Meiotic CPM - Alternatively, CPM can occur through the mechanism of trisomic rescue. If a trisomic conception undergoes trisomic rescue in certain cells, including those that are destined to become the baby, then the remaining trisomy cells may be confined to the placenta.
Several factors influence the pattern of normal and abnormal cells in the developing embryo. Reduced or improved replication rates of the trisomic cells could affect the number of abnormal cells compared to the number of normal cells. The abnormal cells may fail to differentiate or function properly and could be lost. It is also possible that there is no selection against the abnormal cells, but their presence could compromise the pregnancy on a whole.
Types of CPM
There are three types of confined placental mosaicism depending on the cells involved at the time of the error:
- Type 1 CPM– The error occurs in a trophoblast cell, and thus only trophoblast cells are affected. This type of mosaicism is most often associated with normal pregnancy outcome.
- Type 2 CPM– The error occurs in a non-fetal cell of the inner cell mass. This trisomy is confined to the chorionic villus stroma. This type of mosaicism is described in normal pregnancies and is sometimes associated with delayed growth of the fetus.
- Type 3 CPM– Trisomic cells are seen in trophoblast cells and the villus stroma, but are absent in the embryo. This type of mosaicism is more commonly associated with delayed growth in the fetus.
What does CPM mean for a pregnancy?
Most pregnancies that are diagnosed with confined placental mosaicism continue to term with no complications and the children develop normally.
However, some pregnancies with CPM experience prenatal or perinatal complications. The pregnancy loss rate in pregnancies with confined placental mosaicism, diagnosed by chorionic villus sampling, is higher than among pregnancies without placental mosaicism. It may be that sometimes the presence of significant numbers of abnormal cells in the placenta interferes with proper placental function. An impaired placenta cannot support the pregnancy and this may lead to the loss of a chromosomally normal baby. On the other hand, an apparently normal diploid fetus may experience problems with growth or development due to the effects of uniparental disomy. Intrauterine growth retardation (IUGR) has been reported in a number of CPM cases. In follow-up studies adequate postnatal catch-up growth has been demonstrated, which may suggest a placental cause of the IUGR.
When predicting the likely effects (if any) of CPM detected in the first trimester, several potentially interactive factors may be playing a role, including:
- Origin of error: Somatic errors are associated with lower levels of trisomy in the placenta and are expected usually to involve only one cell line (i.e.: the trophoblast cells or the villus stroma cells). Somatic errors are thus less likely than meiotic errors to be associated with either ultrasound abnormalities, growth problems or detectable levels of trisomy in small samples of prenatal CVS. Currently, there is no evidence that somatic errors, which lead to confined placental trisomy, are of any clinical consequence. Errors of meiotic origin are correlated with higher levels of trisomy in placental tissues and may be associated with adverse pregnancy outcome. The cell type in which the abnormality is seen is also an important factor in determining the risk of fetal involvement. The villus stroma or mesenchymal core is more likely than the cytotrophoblast to be reflective of the fetal genotype.
- Level of mosaicism: There is a correlation between a high number of aneuploid cells detected at CVS with poor pregnancy progress. This includes an association between high levels of abnormal cells in placental tissue and concerns with the growth of the baby. However, it is not accurate to use these associations to try to predict pregnancy outcome based on the percent of trisomic cells in a first trimester CVS result.
- Specific chromosomes: The influence of CPM on fetal growth is chromosome specific. Certain chromosomes carry imprinted genes involved in growth or placental function, which may contribute to impaired pregnancy progress when CPM is detected. Different chromosomes are observed at different frequencies depending on the type of CPM observed. The pregnancy outcome is strongly chromosome specific. The most frequently seen trisomic cells in confined placental mosaicism involve chromosomes 2, 3, 7, 8 and 16. The next frequently involved are 9, 13, 15, 18, 20 and 22. It has been observed that CPM involving the sex chromosomes usually has no adverse effects on fetal development. The common autosomal trisomies (21, 18, 13) made up a smaller number of cases of mosaicism detected on CVS, but were more often confirmed in fetal tissue (19%). On the other hand, the uncommon autosomal trisomies accounted for a greater number of placental mosaicism cases, but were less often confirmed in fetal tissue (3.2%). When CPM is detected on CVS involving certain chromosomes which are known or suspected to carry imprinted genes, molecular investigations should be performed to exclude fetal UPD. We will explore chromosome specific cases in the chromosome specific section.
- Type of chromosome abnormality: The factor that had the highest predictive value as to whether the fetus was affected or not was the type of chromosome abnormality. Marker chromosomes were more often confirmed in the fetus than trisomies. For example, of 28 cases of mosaic polyploidy detected on CVS, fetal mosaicism was confirmed in only one case. This is compared to marker chromosomes detected on CVS, in which mosaicism was confirmed in 1/4 of the fetuses.
- ^ Kalousek DK, Dill FJ (August 1983). "Chromosomal mosaicism confined to the placenta in human conceptions". Science 221 (4611): 665–7. doi:10.1126/science.6867735. PMID 6867735.
- ^ a b c Robinson WP, Barrett IJ, Bernard L, et al. (April 1997). "Meiotic origin of trisomy in confined placental mosaicism is correlated with presence of fetal uniparental disomy, high levels of trisomy in trophoblast, and increased risk of fetal intrauterine growth restriction". American Journal of Human Genetics 60 (4): 917–27. PMC 1712477. PMID 9106539. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1712477/.
- ^ a b c d e Phillips OP, Tharapel AT, Lerner JL, Park VM, Wachtel SS, Shulman LP (March 1996). "Risk of fetal mosaicism when placental mosaicism is diagnosed by chorionic villus sampling". American Journal of Obstetrics and Gynecology 174 (3): 850–5. doi:10.1016/S0002-9378(96)70312-5. PMID 8633655.
- ^ Wolstenholme, J. (1996). "Confined placental mosaicism for trisomies 2, 3, 7, 8, 9, 16, and 22: Their incidence, likely origins, and mechanisms for cell lineage compartmentalization". Prenatal Diagnosis 16 (6): 511–524. doi:10.1002/(SICI)1097-0223(199606)16:6<511::AID-PD904>3.0.CO;2-8. PMID 8809892.
- ^ Tyson RW, Kalousek DK (1992). "Chromosomal abnormalities in stillbirth and neonatal death". In Dimmick JE and Kalousek DK. Developmental pathology of the embryo and fetus. Philadelphia: Lippincott. pp. 103–109. ISBN 978-0-397-51040-5. OCLC 23868557.
- ^ Fryburg JS, Dimaio MS, Yang-Feng TL, Mahoney MJ (June 1993). "Follow-up of pregnancies complicated by placental mosaicism diagnosed by chorionic villus sampling". Prenatal Diagnosis 13 (6): 481–94. doi:10.1002/pd.1970130610. PMID 8372074.
- ^ a b Wolstenholme J, Rooney DE, Davison EV (May 1994). "Confined placental mosaicism, IUGR, and adverse pregnancy outcome: a controlled retrospective U.K. collaborative survey". Prenatal Diagnosis 14 (5): 345–61. doi:10.1002/pd.1970140505. PMID 8084856.
- ^ Benn, Peter A.; Lillian Y. F. Hsu. "Prenatal Diagnosis of Chromosomal Abnormalities through Amniocentesis". In Aubrey Milunsky. Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment. Baltimore: Johns Hopkins University Press. pp. 214–296. ISBN 978-0-8018-7928-9. OCLC 52887000. http://books.google.com/books?id=_is2Nk8E3TcC&pg=PA214.
- ^ Farra C, Giudicelli B, Pellissier MC, Philip N, Piquet C (March 2000). "Fetoplacental chromosomal discrepancy". Prenatal Diagnosis 20 (3): 190–3. doi:10.1002/(SICI)1097-0223(200003)20:3<190::AID-PD777>3.0.CO;2-A. PMID 10719319.
- ^ Goldberg JD, Wohlferd MM (June 1997). "Incidence and outcome of chromosomal mosaicism found at the time of chorionic villus sampling". American Journal of Obstetrics and Gynecology 176 (6): 1349–52; discussion 1352–3. doi:10.1016/S0002-9378(97)70356-9. PMID 9215195.
- Almeida PA, Bolton VN (1996). "The relationship between chromosomal abnormality in the human preimplantation embryo and development in vitro". Reproduction, Fertility, and Development 8 (2): 235–41. doi:10.1071/RD9960235. PMID 8726861.
- Bianchi DW, Wilkins-Haug LE, Enders AC, Hay ED (June 1993). "Origin of extraembryonic mesoderm in experimental animals: relevance to chorionic mosaicism in humans". American Journal of Medical Genetics 46 (5): 542–50. doi:10.1002/ajmg.1320460517. PMID 8322818.
- Bui TH, Iselius L, Lindsten J (1984). "European collaborative study on prenatal diagnosis: mosaicism, pseudomosaicism and single abnormal cells in amniotic fluid cell cultures". Prenatal Diagnosis 4 (7): 145–62. doi:10.1002/pd.1970040710. PMID 6463032.
- Chernos JE (1994). "Prenatal genetic counselling corner, unexpected chromosome results detected at prenatal diagnosis: II. Mosaicism". Bulletin of the hereditary diseases program of Alberta 12 (2). ISSN 0844-1316.
- Gardner, R. J. M.; Grant R. Sutherland (1996). Chromosome abnormalities and genetic counseling. Oxford: Oxford University Press. ISBN 978-0-19-510615-2. OCLC 33949819.
- Hahnemann JM, Vejerslev LO (September 1997). "Accuracy of cytogenetic findings on chorionic villus sampling (CVS)--diagnostic consequences of CVS mosaicism and non-mosaic discrepancy in centres contributing to EUCROMIC 1986-1992". Prenatal Diagnosis 17 (9): 801–20. doi:10.1002/(SICI)1097-0223(199709)17:9<801::AID-PD153>3.0.CO;2-E. PMID 9316125.
- Hahnemann JM, Vejerslev LO (May 1997). "European collaborative research on mosaicism in CVS (EUCROMIC)--fetal and extrafetal cell lineages in 192 gestations with CVS mosaicism involving single autosomal trisomy". American Journal of Medical Genetics 70 (2): 179–87. doi:10.1002/(SICI)1096-8628(19970516)70:2<179::AID-AJMG15>3.0.CO;2-G. PMID 9128940.
- Harper JC, Delhanty JD (2000). "Preimplantation genetic diagnosis". Curr Opin Obstet Gynecol 12 (2): 67–72. doi:10.1097/00001703-200004000-00002. PMID 10813565.
- Hassold TJ, Jacobs PA (1984). "Trisomy in man". Annual Review of Genetics 18: 69–97. doi:10.1146/annurev.ge.18.120184.000441. PMID 6241455.
- Hsu LY, Benn PA (November 1999). "Revised guidelines for the diagnosis of mosaicism in amniocytes". Prenatal Diagnosis 19 (11): 1081–82. doi:10.1002/(SICI)1097-0223(199911)19:11<1081::AID-PD682>3.0.CO;2-Z. PMID 10589067.
- Hsu LY, Yu MT, Neu RL, et al. (March 1997). "Rare trisomy mosaicism diagnosed in amniocytes, involving an autosome other than chromosomes 13, 18, 20, and 21: karyotype/phenotype correlations". Prenatal Diagnosis 17 (3): 201–42. doi:10.1002/(SICI)1097-0223(199703)17:3<201::AID-PD56>3.0.CO;2-H. PMID 9110367.
- Kalousek DK (March 2000). "Pathogenesis of chromosomal mosaicism and its effect on early human development". American Journal of Medical Genetics 91 (1): 39–45. doi:10.1002/(SICI)1096-8628(20000306)91:1<39::AID-AJMG7>3.0.CO;2-L. PMID 10751087.
- Kalousek DK, Barrett IJ (1994). "Genomic imprinting related to prenatal diagnosis". Prenatal Diagnosis 14 (13): 1191–1201. doi:10.1002/pd.1970141305. PMID 7617566.
- Kalousek DK, Vekemans M (1996). "Confined placental mosaicism". Journal of Medical Genetics 33 (7): 529–33. doi:10.1136/jmg.33.7.529. PMC 1050657. PMID 8818935. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1050657/.
- Ledbetter DH, Engel E (1 September 1995). "Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis". Human Molecular Genetics 4 (Review Issue 1): 1757–64. PMID 8541876. http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=8541876.
- Los FJ, van Opstal D, van den Berg C, et al. (July 1998). "Uniparental disomy with and without confined placental mosaicism: a model for trisomic zygote rescue". Prenatal Diagnosis 18 (7): 659–68. doi:10.1002/(SICI)1097-0223(199807)18:7<659::AID-PD317>3.0.CO;2-K. PMID 9706646.
- Robinson WP (May 2000). "Mechanisms leading to uniparental disomy and their clinical consequences". BioEssays 22 (5): 452–9. doi:10.1002/(SICI)1521-1878(200005)22:5<452::AID-BIES7>3.0.CO;2-K. PMID 10797485.
- Robinson WP, Bernasconi F, Lau A, McFadden DE (1999). "Frequency of meiotic trisomy depends on involved chromosome and mode of ascertainment". American Journal of Medical Genetics 84 (1): 34–42. doi:10.1002/(SICI)1096-8628(19990507)84:1<34::AID-AJMG8>3.0.CO;2-7. PMID 10213044.
- Sachs ES, Jahoda MG, Los FJ, Pijpers L, Reuss A, Wladimiroff JW (October 1990). "Interpretation of chromosome mosaicism and discrepancies in chorionic villi studies". American Journal of Medical Genetics 37 (2): 268–71. doi:10.1002/ajmg.1320370222. PMID 2248296.
- Shaffer LG, McCaskill C, Adkins K, Hassold TJ (October 1998). "Systematic search for uniparental disomy in early fetal losses: the results and a review of the literature". American Journal of Medical Genetics 79 (5): 366–72. doi:10.1002/(SICI)1096-8628(19981012)79:5<366::AID-AJMG7>3.0.CO;2-H. PMID 9779803.
- Simoni G, Sirchia SM (December 1994). "Confined placental mosaicism". Prenatal Diagnosis 14 (13): 1185–9. doi:10.1002/pd.1970141304. PMID 7617565.
- Smith K, Lowther G, Maher E, Hourihan T, Wilkinson T, Wolstenholme J (September 1999). "The predictive value of findings of the common aneuploidies, trisomies 13, 18 and 21, and numerical sex chromosome abnormalities at CVS: experience from the ACC U.K. Collaborative Study". Prenatal Diagnosis 19 (9): 817–26. doi:10.1002/(SICI)1097-0223(199909)19:9<817::AID-PD647>3.0.CO;2-8. PMID 10521838.
- Stavropoulos DJ, Bick D, Kalousek DK (December 1998). "Molecular cytogenetic detection of confined gonadal mosaicism in a conceptus with trisomy 16 placental mosaicism". American Journal of Human Genetics 63 (6): 1912–4. doi:10.1086/302149. PMC 1377663. PMID 9837845. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1377663/.
- Van Opstal D, Van den Berg C, Deelen WH, et al. (January 1998). "Prospective prenatal investigations on potential uniparental disomy in cases of confined placental trisomy". Prenatal Diagnosis 18 (1): 35–44. doi:10.1002/(SICI)1097-0223(199801)18:1<35::AID-PD214>3.0.CO;2-L. PMID 9483638.
- Wallerstein R, Yu MT, Neu RL, et al. (February 2000). "Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: karyotype-phenotype correlations". Prenatal Diagnosis 20 (2): 103–22. doi:10.1002/(SICI)1097-0223(200002)20:2<103::AID-PD761>3.0.CO;2-K. PMID 10694683.
- Winsor EJ, Tomkins DJ, Kalousek D, et al. (July 1999). "Cytogenetic aspects of the Canadian early and mid-trimester amniotic fluid trial (CEMAT)". Prenatal Diagnosis 19 (7): 620–7. doi:10.1002/(SICI)1097-0223(199907)19:7<620::AID-PD599>3.0.CO;2-E. PMID 10419609.