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TRISOMY 2 MOSAICISM
Complete trisomy 2 contributes significantly to first trimester pregnancy losses, occurring in 0.16% of clinically recognized pregnancies. Trisomy 2 seems to only be compatible with life in a mosaic state and if the trisomy is confined predominantly to placental tissues.
Mosaic trisomy 2 presents one of the more difficult counselling situations despite that a number of cases of prenatally detected trisomy 2 mosaicism have been identified. Outcome ranges from normal to neonatal death. Oligohydramnios (low amniotic fluid) and poor intrauterine growth were the most common features. Abnormal outcome is probably predominantly a consequence of high levels of trisomy in the placenta as well as possible presence of low level trisomy in the baby itself.
An imprinting effect of maternal uniparental disomy (UPD) for chromosome 2 is unlikely. Five cases of maternal UPD2 diagnosed in association with trisomy mosaicism showed IUGR, oligohydramnios, and pulmonary and genital hypoplasia. However, as two cases of full maternal UPD2 diagnosed in a children and an adult had normal phenotypes, it is unlikely that maternal UPD2 has any significant effects postnatally.
Trisomy 2 detected on CVS
Diagnosis of trisomy 2 on CVS should be followed up with amniocentesis and serial ultrasound. UPD2 testing is not normally preformed as it currently has no clear predictive value (see below). In most cases where trisomy is found on CVS but not on amniocentesis, the outcome is normal. However, an abnormal outcome can also occur. Shaffer et al (1996) reported on nine cases of confined placental mosaicism for trisomy 2. All nine cases demonstrated biparental inheritance of chromosome 2. Outcome was normal in 6 cases, intrauterine growth retardation (IUGR) was found in two while in the last case, the pregnancy was terminated and no outcome data was available. In two cases the CVS samples showed 100% trisomic cells, despite a normal outcome and low levels of trisomy in the term placenta. Thus levels of trisomy detected on CVS should not be used to predict outcome. As both cases with IUGR were ascertained because of IUGR detected on ultrasound, the true incidence of poor outcome may be less than the 2/8 indicates.
Trisomy 2 which is confined to the placenta (CPM) appears to be primarily of mitotic origin, thus explaining the generally good outcome. Those cases associated with a poor outcome showed a maternal meiotic origin of the trisomy. However, Roberts et al. (2003) reported a case of trisomy 2, most likely confined to the placenta, of maternal meiotic origin with a normal phenotype at birth. On CVS, all of the cells karyotyped were 47,XY +2. At 17 weeks, the pregnancy was complicated by numerous factors, including IUGR. An amniocentesis was performed at 20 weeks, and the cell population was found to be mosaic, with 8 out of 89 trisomic for chromosome 2. UPD testing was performed; all informative markers showed biparental inheritance. Serial ultrasounds were performed, and at 24 weeks gestation oligohydramnios and absent end diastolic flow was noted. These complications were still present at 26 weeks and the family elected to have a Caesarian section. A phenotypically normal baby boy was born weighing in the 0.4th centile, but died 3 days later because of complications of severe prematurity. All peripheral blood cells karyotyped were 46,XY, but some of the placental and cords cells were trisomic. Given the normal phenotype and karyotype of the baby at birth, genuine fetal mosaicism is unlikley but cannot be ruled out.
Several additional cases have been reported with 100% trisomy 2 on CVS with normal fetal chromosome studies. e.g. Fryburg et al (1992) reported an infant who was born at 37 weeks gestation and experience normal growth and development. De Andreis et al (1992) described one case which resulted in intrauterine death of the fetus and another case which was terminated at 20 weeks. The baby that was terminated appeared to have normal development. Sago et al (1997) reported on a liveborn infant with intrauterine growth retardation (IUGR), hydronephrosis, and cardiac abnormalities detected on ultrasound. The child experienced significant growth failure and developmental delay. Chromosomes were normal in blood and skin, but there were trisomy 2 cells found on liver biopsy.
Trisomy 2 detected on amniocentesis.
The risk of poor outcome is significant when trisomy 2 is detected in amniotic fluid. Hsu et al (1997) summarized the outcome of 11 cases of trisomy 2 mosaicism detected in amniotic fluid. Of these, 1 resulted in an apparently normal live birth; 1 in a livebirth with IUGR, 1 in a livebirth with IUGR plus multiple anomalies, 3 in stillbirths or intrauterine deaths, and 4 in elective terminations (all with abnormal findings).
Uniparental Disomy (UPD 2)
Based on the information reported to date on 6 cases of maternal UPD2 it appears that maternal UPD2 is unlikely to be associated with imprinting effects. No cases of paternal UPD2 have been reported as yet.
Four cases of maternal UPD2 have been reported in association with intrauterine growth restriction and varying abnormalities associated with oligohydramnios (low amniotic fluid). However, three of these four cases were identified through diagnosis of trisomy 2 mosaicism in the placenta. Although not confirmed to be present in fetal tissues tested in any of these cases, trisomy was found in amniotic fluid (which should reflect fetal tissues) in both cases where this was adequately evaluated. A ‘cryptic’ trisomic lineage seems likely to explain the abnormal outcomes in these cases, since similar phenotypes can result from low-level trisomy 2 mosaicism even when UPD is not found in the diploid cell line.
Two cases of UPD2 have been ascertained in healthy females. One case of maternal UPD2 was found in a phenotypically normal adult female ascertained through the cytogenetic finding of a double isochromosome for 2p and 2q (Bernasconi et al, 1996 ). Based on this case alone, an imprinting effect forUPD2 could not be fully excluded as it is possible that mosaicism with a completely normal (non-UPD) cell line could conceivably occur in some cases with an isochromosome and result in a milder phenotype. However another case of maternal UPD2 heterodisomy was inadvertently identified through paternity exclusion testing in a healthy 3 year old girl (Heide et al, 2000). The two cases together make it unlikely that there are any major clinical consequences due to maternal UPD2.
One case of segmental UPD2 has been reported in a normal 22 year old female (Stratakis et al, 2001). In this case maternal UPD was observed only for markers in 2p16 and thus was likely the consequence of a somatic recombination event in early development.
Link to What is UPD?
Link to Maternal UPD 2 page
Link to Paternal UPD 2 page
Internet Links
- HUGO Chromosome 2 - Chromosome 2 specific sites
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Human Chromosome 2 - Provides links to gene maps, sequences, associated genetic disorders, nonhuman genetic models, identified genes, research efforts and laboratories, and other information as available. Links are very scientific.
References
Bernard LE, Kalousek DK, Langlois D, Barrett IJ, Hansen WF, Aylsworth AS, Smith DI, Rao KW. (1995) Confined placental mosaicism for trisomy 2 with fetal maternal uniparental disomy of chromosome 2. American Journal of Human Genetics, 57: A51
Bernasconi F, Karaguzel A, Celep F, Keser I, Luleci G, Dutly F, Schinzel AA. (1996) Normal phenotype with maternal isodisomy in a female with two isochromosomes: i(2p) and i(2q). American Journal of Human Genetics59(5):1114-1118 PubMed
De Andreis D, Pariani S, Maggi F, Lingeri R, Grimoldi MG, Bellotti M, Simoni G. (1992). Trisomy 2 confined to the placenta in 2 cases with intrauterine growth delay. Acta Med Auxol., 24:21-24
Fryburg JS, Dimaio MS, Mahoney MJ. (1992). Postnatal placental confirmation of trisomy 2 and trisomy 16 detected at chorionic villus sampling: a possible association with intrauterine growth retardation and elevated maternal serum alpha-fetoprotein. Prenatal diagnosis, 12:157-162 PubMed
Gibbons B, Cheng HH, Yoong AK, Brown S. (1997) Confined placental mosaicism for trisomy 2 with intrauterine growth retardation and severe oligohydramnios in the absence of uniparental disomy in the fetus. Prenatal Diagnosis 17:689-690. PubMed
Hansen WF, Bernard LE, Langlois S, Rao KW, Chescheir NC, Aylsworth AS, Smith DI, Robinson WP, Barrett IJ, Kalousek DK. (1997) Maternal uniparental disomy of chromosome 2 and confined placental mosaicism for trisomy 2 in a fetus with intrauterine growth restriction, hypospadias, and oligohydramnios. Prenatal Diagnosis 17(5):443-50. PubMed
Harrison K, Eisenger K, Anyane-Yeboa K, Brown S. (1995) Maternal uniparental disomy of chromosome 2 in a baby with trisomy 2 mosaicism in amniotic fluid culture. American Journal of Medical Genetics, 58(2):147-151. PubMed
Heide E, Heide K-G, Rodewald A. (2000) Maternal uniparental disomy (UPD) for chromosome 2 discovered by exclusion of paternity. Am J Med Genet 92:260-263 PubMed
Hsu LY, Yu MT, Neu RL, Van Dyke DL, Benn PA, Bradshaw CL, Shaffer LG, Higgins RR, Khodr GS, Morton CC, Wang H, Brothman AR, Chadwick D, Disteche CM, Jenkins LS, Kalousek DK, Pantzar TJ, Wyatt P. (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):201-242. PubMed
Ledbetter DH, Engel E. (1995) Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis. Human Molecular Genetics 4:1757-1764 PubMed
Robinson WP, Barrett IJ, Bernard L, Telenius A, Bernasconi F, Wilson RD, Best RG, Howard-Peebles PN, Langlois S, Kalousek DK. (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):917-927. PubMed
Roberts E, Dunlop J, Davis GS, Churchill D, Davidson EV. (2003) A further case of confined placental mosaicism for trisomy 2 associated with adverse pregnancy outcome. Prenatal Diagnosis 23: 564-565. PubMed
Sago H, Chen E, Conte WJ, Cox VA, Goldberg JD, Lebo RV, Golabi M. (1997) True trisomy 2 mosaicism in amniocytes and newborn liver associated with multiple system abnormalities. American Journal of Medical Genetics, 72:343-346. PubMed
Shaffer LG, Langlois S, McCaskill C, Main DM, Robinson WP, Barrett IJ, Kalousek DK. (1996) Analysis of nine pregnancies with confined placental mosaicism for trisomy 2. Prenatal Diagnosis. 16(10):899-905. PubMed
Stratakis CA, Taymans SE, Schteingart D, Haddad BR (2001) Segmental uniparental isodisomy (UPD) for 2p16 without clinical symptoms: implications for UPD and other genetic studies of chromosome 2. J Med Genet 38:106-109 PubMed
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. PubMed |