Mosaicism for combined tetrasomy of chromosomes 8 and 18 in a dysmorphic child: A result of failed tetraploidy correction?
© Houge et al; licensee BioMed Central Ltd. 2009
Received: 03 October 2008
Accepted: 18 May 2009
Published: 18 May 2009
Mosaic whole-chromosome tetrasomy has not previously been described as a cause of fetal malformations.
In a markedly dysmorphic child with heart malformations and developmental delay, CGH analysis of newborn blood DNA suggested a 50% dose increase of chromosomes 8 and 18, despite a normal standard karyotype investigation. Subsequent FISH analysis revealed leukocytes with four chromosomes 8 and four chromosomes 18. The child's phenotype had resemblance to both mosaic trisomy 8 and mosaic trisomy 18. The double tetrasomy was caused by mitotic malsegregation of all four chromatids of both chromosome pairs. A possible origin of such an error is incomplete correction of a tetraploid state resulting from failed cytokinesis or mitotic slippage during early embryonic development.
This unique case suggests that embryonic cells may have a mechanism for tetraploidy correction that involves mitotic pairing of homologous chromosomes.
Unlike meiotic non-disjunctions, mitotic non-disjunctions are rarely observed in humans with the exception of mosaicism for trisomy 8, 9 or 20 [1, 2]. In some cases mosaic trisomy of more than one chromosome have been seen . Such mosaic variegated aneuploidy is due to mitotic errors, often associated with premature centromere division . In contrast to mosaic trisomies, the finding of mosaic whole-chromosome tetrasomy is without precedence. Here we present such a patient; a dysmorphic newborn child with mosaicism of leukocytes containing 50 chromosomes due to tetrasomy of chromosomes 8 and 18. This unique clinical case may have relevance concerning the origin of aneuploidy in cancer [5–8] because it indirectly suggests that there might be a mechanism for tetraploidy correction during fetal development that involves mitotic pairing of homologous chromosomes.
Results and Discussion
A re-examination of the original leukocyte cell culture suspension with FISH-probes for centromeres 8 and 18 explained the surprising CGH finding: In 2% of the metaphases (100 metaphases examined) and 15% of the interphases (200 nuclei examined) tetrasomy for both chromosomes were found (Figure 2, panels C and D). The discrepancy between the CGH-findings (50% dose increase for 8 and 18, suggesting that 50% of the cells had four chromosomes 8 and 18) and the cell culture findings (15% of the interphases had four chromosomes 8 and 18) were likely due to negative selection of double tetrasomic cells during PHA-stimulated culturing of blood leukocytes. This illustrates that conventional G-banded karyotyping may easily overlook such mosaicism. To investigate other tissues for similar mosaicism, a skin biopsy from the inside of the left thigh was collected for fibroblast culturing at age 4 months, and at age 14 months a buccal smear was collected. In none of these tissues double tetrasomic cells were found by interphase centromere 8+18 FISH with 200 nuclei examined in each case. At age 20 months, a new blood sample was taken, and the double tetrasomic cells could no longer be detected, neither by CGH nor by interphase FISH.
Allele sizes of polymorphic chromosome 8 and18 simple tandem repeats.
Position (Mb from pter)
Ratio m/p peak heights
The finding of tetrasomy for two autosomes in a newborn is without precedence. To the best of our knowledge, even single chromosome tetrasomy mosaicism has not previously been reported – except in cancer cells. The reason for the uniqueness of our finding is either that this indeed is a very rare chromosomal aberration, or that this type of malsegregation commonly occurs but is not detected due to negative selection against aneuploid cells during embryonic development and the culturing of blood cells for routine karyotyping. We were fortunate to observe this because we performed "unbiased" CGH analyses on leukocyte DNA from a newborn. Moreover, extra copies of both of the involved chromosomes are known to be compatible with sustained cell growth in the embryo, increasing the likelihood that a double tetrasomic cell line could survive to term. Notably, the initial cytogenetic investigation (G-banding) appeared normal – only a later reexamination by FISH revealed double tetrasomic cells and metaphases (Figure 2). Apparently, the short-term PHA-stimulated leukocyte culture decreased the number of aberrant cells from around 50% to 15%. Twenty months later the aberrant clone was undetectable in blood, probably because it was counter-selected in the bone marrow.
The patient's phenotypic features compared to cases with mosaic trisomy 8 or 18
Our patient: Double tetrasomy 8+18 mosaicism
High frontal hairline/prominent forehead
Low-set/posteriorly rotated ears
Crumpled ear helices
Narrow/atretic auditory canals
Middle ear abnormalities
Short palpebral fissures
Broad nasal bridge
Thin upper lip
Skin pigmentation anomalies
Ventricular septal defect (VSD)
Persistent ductus arteriosus (PDA)
Retinitis pigment.-like findings in retina
This case is of particular interest because it illuminates early events in embryogenesis that may have implications for tumor biology. Our data suggests that all four chromatids of the homologous pair were pulled to one daughter cell only by the mitotic spindle apparatus, analogous to the syntelic attachment of the mitotic spindle that may be seen in tetraploid yeast cells . Unlike other organisms, pairing of homologous chromosomes in somatic cells is commonly seen in Dipterians such as Drosophila and mosquitoes . Notably, homologous pairing in both meiosis and mitosis occurs independently of synapsis and recombination . Furthermore, the finding of (mosaic) segmental isodisomy as a disease mechanism in some cases of imprinting-related growth syndromes (e.g. Beckwith-Wiedemann syndrome and Russell-Silver syndrome, ) also indicates that mitotic homologous pairing takes place. That such pairing is not limited to imprinted chromosomes are illustrated by the reports of children with recessive diseases due to homozygocity for mutations carried by one of the parents only, the disease manifesting due to segmental isodisomy formation [16–19].
We believe that the most likely explanation for the double tetrasomy is that the starting point was a tetraploid state, which is the normal situation after S-phase, or a tetraploid cell line. If the origin was a tetraploid state, aborted S-phase (mitotic slippage) or interrupted M-phase (failed cytokinesis) are possible mechanisms. Chromatid non-disjunction is one suggested reason for failed cytokinesis [6, 8]. If the origin was a tetraploid cell line, there are scant indications that such cells may later become diploid. In Candida albicans tetraploid strains become diploid or near diploid through "concerted chromosome loss" . In hepatic cells being tetraploid after fusion to bone marrow stem cells, a "reduction mitosis" appears to be able to transform tetraploid hybrids into diploids . In both cases the mechanism is unknown. A variable number of tetraploid cells is commonly found in chorion villus or amniocyte cultures, but such cells are rarely found in liveborns . The origin can be meiotic or mitotic errors [23, 24].
This unique case indirectly suggests that a mechanism for tetraploidy correction involving pairing of homologues may be present in somatic cells, and that mosaicism originating in tetraploidization could be a cause of developmental abnormalities that usually remain undetected. When such a mechanism is dysfunctional, aneuploidy is a likely result – which is commonly found in many types of cancer.
The parents have given written consent to publication of the patient's pictures, and the parents have also seen and approved the publication of the disease history.
The scientific discussion and review of the manuscript by Helge Boman and Anders Molven was highly appreciated. Noralv Breivik has provided additional clinical information. Most of the laboratory work has been done in the diagnostic DNA and cytogenetic laboratories at Haukeland University Hospital, lead by Hanne M. Jacobsen and Kjetil Solland. This work could not have been done without the collaboration of the child's parents, to whom we are most grateful.
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