MPO-0287R Med Pediatr Oncol 2002;00:1–2
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Letter to the Editor: ‘‘Two Hits’’ in utero?
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To the Editor: In the genetic counseling process of the family of the 14-year-old boy with the Williams syndrome (WS) we reported recently, we concluded the parents have normal karyotypes as follows: 46,XX (mother) and 46,XY (father) [1]. The karyotype of the proband was as follows: 46, XY. ish del (7)(q11.23q 11.23) in the peripheral blood. The hyperploid bone marrow during acute lymphoblastic leukemia (ALL): 57,XY þ 1B þ 4C þ 2D þ 1E þ 1F þ 2G (80%) indicates he, in fact, has a de novo mutation. WS is a relatively rare (1:20,000) autosomal dominant multisystem developmental disease attributed to a microdeletion involving the elastin gene locus on chromosome 7 [2]. Dutly and Schinzel carried out molecular genetic studies in 15 families with WS [3]. They demonstrated deletion of elastin in all of the probands. The 15 families consisting of patients, parents, and paternal or maternal grandparents were genotyped using microsatellites adjacent to the centromeric or telomeric end of ELNQ1. They demonstrated that in 10 out of 15 WS families (67%) with a de novo deletion within 7q11.23, the segment flanking the deleted region contained recombined haplotypes. These recombination events indicated that deletion was the result of an unequal crossing over event between the chromosome 7 homologs during gametogenesis. In 5 of the 15 families, there was no recombination on either side of the deletion. Dutly and Schinzel postulated that in these families there might be intrachromosomal recombination. They noted that unequal recombination events are mediated by related gene sequences or repetitive elements and that the elastin gene has relatively large introns characterized by repetitive elements [3]. Frangiskakis et al. reported that breakpoints in the LIM kinase-1 gene (LIMK1; 601329), which is adjacent to ELN, occur within Alu repeats [4]. Dutly and Schinzel concluded that a practical consequence of their findings is improved prediction of risks for sibs of a WS-affected proband, since a recombination event around the deleted segment indicates meiotic recombination, which is unlikely to recur [3]. Although the cause of most acute leukemias is not known, certain major factors have been implicated in some cases. Ionizing radiation, certain types of chemicals, especially organic solvents (benzene), and at least one virus (HTLV-I) can contribute to leukemogenesis as agents or major risk factors [5]. ß 2002 Wiley-Liss, Inc. DOI 10.1002/mpo.10155
Clinically evident symptoms of childhood ALL are generally present only for a few weeks before diagnosis, and rarely for several months. The development of acute lymphoblastic leukemia probably, therefore, involves a covert or clinically silent phase between initiation and the onset of symptoms. Given the young age of most children who have acute lymphoblastic leukemia and the latency expected for clonal evolution of cancer, it is possible that the disease originates before birth in utero. The only evidence to support this hypothesis has, however, been weak and indirect, since it was derived from epidemiologic associations with radiation or viral exposures during pregnancy [6]. Concordant leukemia has been reported in monochorionic and dichorionic infant twins, each pair with a clonal, nonconstitutional rearrangement of MLL gene. In addition, a pair of identical twins, aged 9 and 11 years at diagnosis, showed the same clonal T cell malignancy. The prenatal origin of leukemia has been directly demonstrated in three patients with 4;11. Moreover, two twins with ALL and t(12;21), aged 3, 5, and 5 years at diagnosis, showed the same sequence of the ETV6-AML1 fusion could be originated in utero, from data presented by Cazzaniga and Biondi at the 10th Annual Meeting of the International BFM Study Group in 1999. Genetic mapping studies have led to the identification of the first molecular correlate of human non-disjunction; i.e., altered levels and positioning of meiotic recombination events have been observed in all human trisomic conditions yet studied. These observations have led to the idea that human meiotic non-disjunction requires ‘‘two hits’’: first, the establishment in prophase I of a ‘‘vulnerable’’ bivalent and second, abnormal processing of the bivalent at metaphase I or II [7]. Recent research on the mechanism of action of the cellular components that segregate chromosomes accurately during mitosis or meiosis has served to highlight the number of potential targets for disruption. The process of chromosome segregation represents an orchestrated chain of events centred on the activities of cellular
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*Correspondence to: Vida Culic, MD, MA, Pediatrician, Pediatrics Clinic, Medical School, Clinical Hospital Split, Split, Croatia. E-mail:
[email protected] Received 20 March 2002; Accepted 24 April 2002
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Culic et al.
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kinesins and dyneins. These ‘‘motors’’ are involved in arranging chromosomes at the metaphase plate, providing the spindle tension necessary for progression, and the actual segregation of the chromosomes to the poles [8–18]. In this case, there were two changes or two ‘‘hits,’’ one that led to mutation in WSCR1 and the other that led to made ALL with hyperploidy. Both ‘‘hits’’ could have happened in utero.
9. McKim KS, Hawley RS. Chromosomal control of meiotic cell division. Science 1995;270:1595–1601. 10. Kaufman MH. New insights into triploidy and tetraploidy, from an analysis of model systems for these conditions. Hum Reprod 1991;6:8–16. 11. Haaf T, Mayer WG, Smith A, et al. Behaviour of parental chromosomes after fertilization. Cytogenet Cell Genet 1999;85 (Suppl)5:7. 12. Ferguson LR, Allen JW, Mason JM. Meiotic recombination and germ cell aneuploidy. Environ Mol Mutagen 1996;28:192–210. 13. Preston RJ. Aneuploidy in germ cells: Disruption of chromosome mover components. Environ Mol Mutagen 1996;28:176–181. 14. Eichenlaub-Ritter U. Parental age-related aneuploidy in human germ cells and offspring: A story of past and present. Environ Mol Mutagen 1996;28:211–236. 15. Bishop JB, Dellarco VL, Hassold T, et al. Aneuploidy in germ cells: Etiologies and risk factors. Environ Mol Mutagen 1996; 28:159–166. 16. Hulten MA. The origin of aneuploidy: Bivalent instability and the maternal age effect in trisomy 21 Down syndrome. Am J Med Genet 1990;7 (Suppl):160–161. 17. Abruzzo MA, Hassold TJ. Etiology of nondisjunction in humans. Environ Mol Mutagen 1995;25 (Suppl)26:38–47. 18. Day T, Taylor PD. Chromosomal drive and the evolution of meiotic nondisjunction and trisomy in humans. Proc Natl Acad Sci USA 1998;95:2361–2365.
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REFERENCES
1. Culic V, Culic S, Armanda V, et al. Single signal of the William’s syndrome chromosome region 1 gene in hyperploidic bone marrow cells of acute lymphoblastic leukemia William’s syndrome patient. Med Pediatr Oncol 2002;38:205–207. 2. Mc Kusick V. Mendelian inheritance in man: Catalogues of autosomal dominant, autosomal recessive, and X-linked phenotypes. OMIM database 3. Dutly F, Schinzel A. Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams–Beuren syndrome. Hum Mol Genet 1996;5:1893–1898. 4. Frangiskakis JM, Ewart AK, Morris CA, et al. LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 1996;86:59–69. 5. Greaves MF. Aetiology of acute leukaemia. The Lancet 1997; 349(9048):344–349. 6. Wiemels JL, Cazzaniga G, Daniotti M, et al. Prenatal origin of acute lymphoblastic leukemia in children. Lancet 1999;354 (9189):1499–1503. 7. Hassold T. The origin of human nondisjunction: Two hits to trisomy. Cytogenet Cell Genet 1999;85 (Suppl)5:9. 8. Mailhes JB. Important biological variables that can influence the degree of chemical-induced aneuploidy in mammalian oocyte and zygotes. Mutat Res 1995;339:155–176.
Vida Culic, MD, MA, Pediatrician* Srdjana Culic, MD, MA, Pediatrician Biserka Reisic, MD, PhD, Pediatrician Clinical Hospital Split Medical School, Pediatrics Clinic Split, Croatia
Q1: Please clarify.
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