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Investigation of a Cluster of Children with Down's Syndrome Born To Occup Environ Med 2000;57:793–804 793 Occup Environ Med: first published as 10.1136/oem.57.12.793 on 1 December 2000. Downloaded from Investigation of a cluster of children with Down’s syndrome born to mothers who had attended a school in Dundalk, Ireland G Dean, N C Nevin, M Mikkelsen, G Karadima, M B Petersen, M Kelly, J O’Sullivan Abstract mothers of the aVected children attended Objectives—To investigate a reported the school concurrently and the origin of cluster of Down’s syndrome in oVspring of non-disjunction in one child was an error former pupils of a girls’ school in Ireland, occurring after conception. Some expo- to establish the prevalence of Down’s syn- sure essentially confined to girls attending drome among live births in the area the school at this time is a possible, around the school, and to review the although unlikely, explanation, but a re- literature on the possible causes of re- view of potential risk factors does not sug- ported clusters of Down’s syndrome. gest what this could be. Previous Methods—Questionnaire survey of obstet- suggestions that an influenza epidemic or ric and personal histories of women who contamination from the Windscale nu- had attended the girls’ school at Dundalk, clear reactor fire might be implicated, County Louth, Republic of Ireland, at both of which occurred in October 1957, some time during 1956–7, and also of can be eVectively dismissed because three women who had attended another, nearby, of the women with aVected oVspring had girls’ school during the same period. left the school by then and had moved Comparison of observed numbers of cases away from Dundalk, and Down’s syn- of Down’s syndrome identified by these drome in the child of another mother Medico-Social surveys with maternal age adjusted ex- originated in an error after fertilisation. Research Board (now Owing to the retrospective nature of the The Health Research pected numbers for the reported live Board), 73 Lower births. Laboratory tests were conducted to investigation and the characteristics of the Baggot Street, Dublin verify and characterise the cases of cases, chance is the most likely explana- 2, Ireland Down’s syndrome constituting the cluster. tion for the cluster. G Dean (emeritus) Retrospective collection and collation of (Occup Environ Med 2000;57:793–804) Department of data on Down’s syndrome occurring Keywords: Down’s syndrome; cluster; maternal expo- Medical Genetics, The among live births, and the compilation of sure Queen’s University of maternal age specific incidences, in Belfast, Belfast City County Louth and in Newry and Mourne Hospital, Lisburn District in neighbouring Northern Ire- In 1983, Sheehan and Hillary1 reported the Road, Belfast, BT9 7AB, Northern land, during 1961–80. These rates were preliminary findings of an investigation into an http://oem.bmj.com/ Ireland, UK compared with reference rates and rates unusual space-time cluster of six cases of N C Nevin for other areas of Ireland. Down’s syndrome associated with a small girls’ Results—Six children with Down’s syn- school in the town of Dundalk, County Louth, John F Kennedy drome were confirmed among 387 reported in the northeast of the Republic of Ireland. The Institute, Gl Landevej live births to women who had been pupils at cluster was characterised by births to young 7, DK-2600, Glostrup, Denmark the girls’ school in Dundalk during 1956–7, mothers who had attended the school during M Mikkelsen compared with 0.69 expected (nominal the 1950s and the authors proposed that some M B Petersen p<10-4). Five of the aVected births were to exposure of the mothers while pupils at the on October 2, 2021 by guest. Protected copyright. mothers under 30 years of age, against 0.15 school could be responsible for this unusual Department of expected (nominal p<10-6), although only aggregation of births with Down’s syndrome. Genetics, Institute of four of these mothers were attending the In subsequent correspondence, Sheehan and Child Health, Athens, 2 Greece school at any one time. The origin of the Hillary reported that they had learnt of a fur- G Karadima non-disjunction was found to be maternal ther two babies with Down’s syndrome born to M B Petersen first meiotic in four children, mitotic after these mothers, bringing the number of cases fertilisation in another (with the youngest constituting the cluster to eight, which com- Bawnmore, Limerick, mother), and in the remaining one could pares with an estimate of less than one Ireland, and St John of 3 God’s, Drumcar, not be determined. The marked excess of expected. 1 County Louth, Ireland Down’s syndrome in births to young moth- Sheehan and Hillary suggested that an out- M Kelly ers did not extend to oVspring of former break of illness similar to influenza that pupils of the other Dundalk girls’ school occurred at the school in October 1957 might Our Lady of Lourdes’ surveyed, or to live births in County Louth be relevant. However, the testing of serum Hospital, Drogheda, County Louth, Ireland generally or in adjacent Newry and Mourne samples from the mothers of the original six J O’Sullivan District. aVected children, from former pupils of this Conclusion—A striking, highly localised, and two other schools and from similarly aged Correspondence to: excess of Down’s syndrome in births to mothers of children with Down’s syndrome in Dr G Dean Ireland, for antibodies to several strains of [email protected] young mothers who had attended a girls’ school in Dundalk during 1956–57 has influenza and other infectious agents, showed Accepted 25 July 2000 been confirmed. However, not all of the nothing unusual.1 The authors further sug- www.occenvmed.com 794 Dean, Nevin, Mikkelsen, et al Occup Environ Med: first published as 10.1136/oem.57.12.793 on 1 December 2000. Downloaded from gested1 that radioactive contamination from School, checks were made on the identification the fire (the Windscale fire) in October 1957 at and diagnosis of these children, and on the Windscale No 1 Pile, a nuclear reactor at information about maternal attendance at the Sellafield in northwest England, could be a school during the 1950s. One of us (GD), with possible factor. In subsequent correspon- the cooperation of St Louis’ School, checked dence34it was pointed out that fallout from this the details of the mothers contained in fire did not make a significant contribution to Sheehan’s documents against school records. the radiation exposure of the population of Another of us (MM) had collaborated with either Dundalk in particular or Ireland in gen- Sheehan in a cytogenetic analysis of peripheral eral, and that evidence that exposure to blood lymphocytes sampled from the five ionising radiation increases the risk of Down’s aVected children who were alive in 1984 to syndrome in oVspring is weak. However, Sharp confirm Down’s syndrome. (One of these five and McConnell3 concluded that the cluster was died at the age of 19 years in 1985.) Blood had asuYciently unusual occurrence that alterna- also been sampled from the parents, so that tive explanations should be examined. The chromosomal fluorescence heteromorphisms existence of the cluster has been widely (method described by Mikkelsen et al5) could reported in the media. be used to find the origin of the supernumerary Sheehan continued her investigation of this chromosome 21 and the meiotic stage of cluster, but did not publish any further findings gametogenesis of the non-disjunction that led in the scientific literature before her death in to trisomy in the child. The results of this cyto- 1994. One of us (GD) has been given access to genetic analysis have not been previously Sheehan’s papers so that additional data from reported. More recently, the four surviving her study of the cluster could be collated and children and their parents have provided analysed. Also, data on the incidence of further biological samples, in all but one Down’s syndrome in Dundalk and its general instance blood, the exception being a buccal vicinity have been collected to assess whether smear from one of the fathers. Also, an infant the cluster is part of a broader phenomenon. In who was subsequently reported2 as aVected this paper we report the results of this work. We with Down’s syndrome and who died at the age also review the literature on what is known of of 8 weeks had had a necropsy, and blocks had the causes of Down’s syndrome. been kept; we were given access to this material, and the parents provided blood sam- Methods ples. Thus, biological material was available QUESTIONNAIRE SURVEY from five aVected people and their parents for A remark in 1974 by the mother of a child with analysis for DNA polymorphisms to find the Down’s syndrome about the number of her parental origin of the non-disjunction. Micros- schoolfriends with similarly aVected children atellite DNA polymorphisms spanning the led Sheehan to contact women whom she had entire 21q were detected after polymerase identified as attending St Louis’ Secondary chain reaction (PCR) amplification of genomic School for Girls in Dundalk at some time DNA.6 The 12 polymorphisms studied were between September 1951 and June 1961.12St the short sequence repeats at loci D21S369, Louis’ School was a small convent secondary D21S215, D21S258, D21S16, D21S11, school situated on the outskirts of Dundalk, D21S214, D21S210, D21S213, HMG14, http://oem.bmj.com/ attended by girls aged 11–18 years, which D21S212, D21S171, D21S1575. Amplifica- opened for day pupils in 1950 and for boarders tion of the PCR with end labelling of primers, in 1953.
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