Structural chromosomal mosaicism and prenatal diagnosis

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Prenat Diagn 2004; 24: 101–103. Published online in Wiley InterScience ( DOI: 10.1002/pd.797


Structural chromosomal mosaicism and prenatal diagnosis E. Pipiras1 , C. Dupont1 , S. Chantot-Bastaraud,2 J. P. Siffroi2 , M. Bucourt3 , A. Batallan4 , C. Largilli`ere4 , M. Uzan4 , J. P. Wolf1 and B. Benzacken1* 1

Service d’Histologie Embryologie Cytog´en´etique BDR, Hˆopital Jean Verdier, Bondy, France Service d’Histologie, Biologie de la Reproduction et Cytog´en´etique, Hˆopital Tenon, Paris, France and Laboratoire de Cytologie Histologie, UFR Biom´edicale, Paris, France 3 Service de Foetopathologie, Hˆopital Jean Verdier, Bondy, France 4 Service de Gyn´ecologie-Obst´etrique, Hˆopital Jean Verdier, Bondy, France 2

True structural chromosomal mosaicism are rare events in prenatal cytogenetics practice and may lead to diagnostic and prognostic problems. Here is described the case of a fetus carrying an abnormal chromosome 15 made of a whole chromosome 2p translocated on its short arm in 10% of the cells, in association with a normal cell line. The fetal karyotype was 46,XX,add(15)(p10).ish t(2;15)(p10;q10)(WCP2+)[3]/46,XX[27]. Pregnancy was terminated and fetus examination revealed a growth retardation associated with a dysmorphism including dolichocephaly, hypertelorism, high forehead, low-set ears with prominent anthelix and a small nose, which were characteristic of partial trisomy 2p. Possible aetiologies for prenatal mosaicism involving a chromosomal structural abnormality are discussed. Copyright  2004 John Wiley & Sons, Ltd. KEY WORDS:

structural chromosomal mosaicism; trisomy 2p; prenatal diagnosis

INTRODUCTION Mosaicism for a structural chromosomal rearrangement is a common finding in prenatal diagnosis and is due most often to an abnormal chromosomal event, which occurs during amniocyte cell culture. However, in some cases, the existence of a balanced or unbalanced mosaic karyotype is related to a true foetal mosaicism and needs to be investigated properly for an accurate genetic counselling, especially when prenatal diagnosis is made for foetal ultrasound anomalies. Here, we describe a foetus carrying a mosaic unbalanced translocation involving the whole chromosome 2 short arm and we propose some guidelines for a correct evaluation of this type of chromosomal abnormality.


of the aggravation of the growth retardation (3rd percentile) and the occurrence of an oligohydramnios on ultrasound examination. Karyotype was performed on amniocytes using both conventional in situ and flask cell cultures and after R and G chromosome banding. It revealed a structural chromosome abnormality, made of a large amount of chromosomal material on the short arm of one chromosome 15, in 3 among 16 clones analysed from two different in situ culture slides. This abnormal chromosome 15 was then found in 10% of the cells collected from culture flasks. Therefore, foetal karyotype was 46,XX,add(15)(p10)[3]/46,XX[13]. After foetal blood sampling, chromosome analysis confirmed the presence of the derivative chromosome 15 in 3 of the 30 cells analysed (Figure 1a and b). An unbalanced translocation was ruled out by chromosome analysis in parents, which was normal. Whole chromosome analysis by fluorescence in situ hybridisation (FISH) using specific painting probes (Octochrome;

A 44-year-old Portuguese woman was referred to the hospital at 22 weeks of gestation for her second pregnancy. She had had a first child who died accidentally at the age of three. Her husband was a 35-year-old Asian man without any particular medical history. A second-trimester ultrasound examination showed a moderate intrauterine growth retardation (10th percentile). She first declined the amniocentesis but then accepted it for foetal chromosome analysis at 30 weeks because (a)

*Correspondence to: Dr B. Benzacken, Service d’Histologie Embryologie Cytog´en´etique BDR, Hˆopital Jean Verdier, Bondy, France. E-mail: [email protected]

Copyright  2004 John Wiley & Sons, Ltd.


Figure 1—Partial view of the abnormal chromosome 15 after (a) G banding and (b) R banding Received: 8 August 2003 Revised: 29 October 2003 Accepted: 4 November 2003



Cytocell) identified the additional segment on chromosome 15 as a fragment of chromosome 2 (Figure 2). Further chromosome analysis then characterised the material as an entire short arm of chromosome 2. Thus, the foetus presented a partial trisomy of chromosome 2 in mosaicism with a normal 46,XX cell line. The karyotype was 46,XX,add(15)(p10).ish t(2;15)(p10;q10)(WCP2+) [3]/46,XX[27]. After genetic counselling, parents chose to terminate the pregnancy at 37 weeks of gestation but declined any subsequent tissue and DNA sampling. External examination revealed a female foetus with a growth retardation associated with facial dysmorphism including dolichocephaly, hypertelorism, high forehead, low-set ears with prominent anthelix and a small nose (Figure 3a and b). Autopsy did not reveal any internal malformations, except a moderate renal hypoplasia. No abnormalities were visible on X-ray examination except for a bilateral brachymesophalangy.

Figure 2—Hybridisation with a specific chromosome 2 painting probe showing a fluorescent signal on the derivative chromosome 15



Figure 3—Aspect of the foetus showing dolichocephaly with (a) small nose and (b) hypertelorism Copyright  2004 John Wiley & Sons, Ltd.

DISCUSSION Whereas structurally aberrant mitoses are commonly found in the course of cytogenetic examinations, true mosaicisms involving a structural chromosomal abnormality, other than supernumerary marker chromosomes, are rare events. They include both balanced and unbalanced rearrangements. When diagnosed in blood cell cultures from newborns or children exhibiting various abnormal phenotypic features or a mental retardation, unbalanced structural chromosomal mosaicism do not present any particular diagnostic difficulties and may help to establish useful genotype–phenotype relationships (Pettenati et al., 1993; Gardner et al., 1994; Rudnik-Schoneborn et al., 1997; Stallings et al., 1997; Zaslav et al., 1999; Dufke et al., 2001; Reddy and Mak, 2001). However, when discovered in foetal cells, a mosaicism involving either a balanced or an unbalanced chromosomal rearrangement raises the question whether it may be due to a cell culture artefact, a confined placental mosaicism or a true foetal mosaicism. According to the usual guidelines for the diagnosis of chromosome mosaicism in amniocytes (Hsu et al., 1992), true foetal mosaicism has to be asserted by the observation of several abnormal cells from different culture flasks. In our case, both in situ and flask cultures containing abnormal cells allowed us to confirm the existence of a true mosaicism in amniocytes. However, this mosaicism could have been confined to the placenta with a foetus free of any chromosomal abnormality. Therefore, foetal blood sampling was proposed for evaluating the percentage of abnormal cells and revealed that the foetus actually carried a mosaicism and that it was not restricted to amniocytes. Moreover, the fact that it was a female foetus did not exclude the possibility that normal 46,XX amniocytes were of maternal origin and that the foetus was the carrier of a homogenous abnormal karyotype. Maternal cell contamination of amniotic fluid samples must be considered even when they do not appear bloody (McAdoo et al., 2002). It can be ruled out either by the existence of a chromosomal polymorphism between normal and abnormal cells or by performing a new foetal cell sampling. In our patient, polymorphic chromosomal regions allowed us to both eliminate a maternal cell contamination of cultures and to state that the abnormal chromosome 15 was of maternal origin (Figure 4a and b). Coexistence of an abnormal cell line, carrying an unbalanced translocation, with normal 46,XX cells could also be explained by the occurrence of a chimerism in the very early stages of pregnancy, as previously described (Nyberg et al., 1992, 1993; Cotter and Hirschhorn, 1998), although chimerism is an even rarer event than mosaicism. Comparing chromosomal polymorphisms can sometimes distinguish mosaicism from chimerism, but, in our case, they were not informative enough to settle the question. Only the analysis of parental and foetal DNA’s could have given this information, but parents declined it. Whatever mechanism leads to a double cell population in a foetus, it raises the question of the prognosis Prenat Diagn 2004; 24: 101–103.





in agreement with previous publications dealing with partial 2p trisomies, especially the prominent forehead and the hypertelorism (Lurie et al., 1995, Megarbane et al., 1997, Al-Saffar et al., 2000). In conclusion, true fetal mosaicism involving a structural chromosomal abnormality are rare events that need to be diagnosed precisely and correlated with ultrasound data for accurate genetic counselling.


Figure 4—Determination of the parental origin of the derivative chromosome 15 was possible by comparing chromosomal polymorphisms of the short arms. Both paternal chromosome 15 (a) exhibited large and strongly labelled short arms unlike maternal ones (b). Partial karyotype of both chromosomes 15 from the normal cell line of the foetus (c). In the translocated cell line, as shown in Figure 1b, the normal chromosome 15 always had the same aspect than paternal chromosomes, indicating that the translocated chromosome was of maternal origin

of such an observation in prenatal diagnosis. Among nearly 180 000 prenatal diagnosis cases collected from ten cytogenetic laboratories and two publications, Hsu et al. (1996) found 57 (0.03%) mosaics for an autosomal structural abnormality in 555 foetuses carrying a chromosome mosaicism. Karyotype–phenotype correlations were established in 95 cases from this study, from a previous survey and from published cases, and whose phenotypic outcome was known. These cases included both balanced and unbalanced karyotypes. Only one case carried a mosaicism for an unbalanced reciprocal translocation and resulted in a male newborn with multiple congenital abnormalities. In the same way, Wells et al. (1996) described a prenatally diagnosed double mosaicism for a dup(1q) and a del(Xq) in a child with multiple congenital malformations. Abnormal pregnancy outcome may also be encountered in foetuses carrying a mosaicism for a balanced chromosomal rearrangement like in the case published by Hastings et al. (1999), who had both a balanced t(3;10) translocation and a pericentric inversion of chromosome 6. In such a case, foetal malformations could be explained by the disruption of a particular gene in one or the other chromosomal breakpoint. On the other hand, mosaicism for an unbalanced reciprocal translocation may be compatible with the birth of an apparently normal child as in the case described by Cotter et al. (1998), who carried a de novo t(4;5) unbalanced translocation, although, in this case, the cytogenetic abnormality was found neither in foetal blood nor in the placenta after birth. From these very few prenatal cases, it appears that correlations between the type of cytogenetic abnormality and the foetal ultrasound survey then take on importance for the appropriate management of affected pregnancies. In our case, intrauterine growth retardation became more and more important as pregnancy progressed and parents decided to terminate it at 37 weeks of gestation, in accordance with French law. Foetal phenotype was Copyright  2004 John Wiley & Sons, Ltd.

Al-Saffar M, Lemyre E, Koenekoop R, Duncan AM, Der Kaloustian VM. 2000. Phenotype of a patient with pure partial trisomy 2p(p23→8pter). Am J Med Genet 94: 428–432. Cotter PD, Babu A, Willner JP, Desnick RJ. 1998. Prenatal diagnosis and outcome of mosaicism for a de novo unbalanced translocation identified in amniocytes. Prenat Diagn 18: 857–861. Cotter PD, Hirschhorn K. 1998. Chimerism detected by an unbalanced chromosome translocation: an alternative hypothesis. Clin Genet 53: 230. Dufke A, Mayrhofer H, Enders H, Kaiser P, Leipoldt M. 2001. Unusual chromosomal mosaicism as a cause of mental retardation and congenital malformations in a familial reciprocal translocation carrier, t(17;22)(q24.2;q11.23). Cytogenet Cell Genet 93: 168–170. Gardner RJ, Dockery HE, Fitzgerald PH, Parfitt RG, Romain DR, Scobie N. 1994. Mosaicism with a normal cell line and an autosomal structural rearrangement. J Med Genet 31: 108–114. Hastings RJ, Watson SG, Chitty LS. 1999. Prenatal finding of a fetus with mosaicism for two balanced de novo chromosome rearrangements. Prenat Diagn 19: 77–80. Hsu LY, Kaffe S, Jenkins EC, et al. 1992. Proposed guidelines for diagnosis of chromosome mosaicism in amniocytes based on data derived from chromosome mosaicism and pseudomosaicism studies. Prenat Diagn 12: 555–573. Hsu LY, Yu MT, Richkind KE, et al. 1996. Incidence and significance of chromosome mosaicism involving an autosomal structural abnormality diagnosed prenatally through amniocentesis: a collaborative study. Prenat Diagn 16: 1–28. Lurie IW, Ilyina HG, Gurevich DB, et al. 1995. Trisomy 2p: analysis of unusual phenotypic findings. Am J Med Genet 55: 229–236. McAdoo SL, Bleigh OC, Simmons GM Jr, Wenger SL. 2002. Maternal cell contamination in an amniotic fluid sample. Prenat Diagn 22: 737. Megarbane A, Souraty N, Prieur M, et al. 1997. Interstitial duplication of the short arm of chromosome 2: report of a new case and review. J Med Genet 34: 783–786. Nyberg RH, Haapala AK, Simola KO. 1992. A case of human chimerism detected by unbalanced chromosomal translocation. Clin Genet 42: 257–259. Nyberg RH, Haapala AK, Simola KO. 1993. Reply to the letter from Woods and Smith. Clin Genet 44: 224. Pettenati MJ, Teot LA, Smith C, et al. 1993. Unbalanced mosaic karyotype with different structural abnormalities involving a common chromosome region: report of two cases. Am J Med Genet 45: 365–369. Reddy KS, Mak L. 2001. Mosaic unbalanced structural abnormalities confirmed using FISH on buccal mucosal cells. Ann Genet 44: 37–40. Rudnik-Schoneborn S, Schubert R, Majewski F, Haverkamp F, Schwanitz G. 1997. Partial trisomy 6p from a de novo translocation (6;18) with variable mosaicism in different tissues. Clin Genet 52: 126–129. Stallings R, Vaughn D, Hall K, et al. 1997. Mosaicism for trisomy 3q arising from an unbalanced, de novo t(3;15). J Med Genet 34: 512–514. Wells SR, Kuller JA, Rao KW, Aylsworth AS. 1996. Multiple congenital malformations in an infant prenatally diagnosed with mosaicism for dup(1q) and del(Xq). Clin Genet 49: 216–219. Zaslav AL, Fallet S, Blumenthal D, Jacob J, Fox J. 1999. Mosaicism with a normal cell line and an unbalanced structural rearrangement. Am J Med Genet 82: 15–19. Prenat Diagn 2004; 24: 101–103.

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