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The great interest in identifying susceptibility genes in inflammatory bowel diseases (IBD) has recently triggered the aggregation of family trees throughout Europe and the United States. This has led to a better knowledge of empirical risk and clinical characteristics of familial IBD. One of the most consistent findings in families with Crohn’s disease was early onset in most affected children of an affected parent, with an average difference of 15 years. This may be a more general feature of familial IBD, as shown in this issue by Lee et al (see page 808) who observed a similar time span (16–18 years) between generations in 50 pure Crohn’s disease, 51 pure ulcerative colitis and 36 mixed disease families.
Genetic anticipation has been suggested as a possible explanation for this finding.1 This term denotes a decrease in the age of onset and an increase in severity as a disease is passed through generations.2 Genetic anticipation has been described in monogenic neurological illnesses such as Huntington’s disease, myotonic dystrophy and more recently Friedreich’s ataxia. In these diseases, there is firm evidence that anticipation reflects the effects of genetic factors and has a true molecular basis. Amplification of DNA triplet repeats within or adjacent to the disease gene occurs in successive generations and this DNA instability is associated with increasing disease severity and earlier age of onset.3 The list of conditions exhibiting anticipation has grown in the past few years, and recognition of anticipation would be very important for a proper understanding of inherited susceptibility in IBD.
There are difficulties in defining biological anticipation in polygenic disorders such as IBD as the epidemiological data supporting genetic anticipation may be subject to many biases, particularly in retrospective studies.4 ,5 Increased awareness and diagnostic acuity may influence age at diagnosis in the later generation. In Lee et al’s study and in a previous series6 there was a shorter time interval between symptom onset and age at diagnosis in children than in parents although the difference only accounted for two years. This ascertainment bias was controlled by Heresbach and colleagues,7 who compared the differences in age at diagnosis in second degree relatives and in parent and child. They found a similar inter-generation difference in the second degree relatives (16.5 years) and in first degree relatives (14.2 years) which was consistent with anticipation. Another complicating factor which is inherent in retrospective studies is the differential age at interview, which results in a greater chance of finding a later age at diagnosis in the older generation (recall bias).5 A third potential bias is the preferential ascertainment of parents with late age at diagnosis. The median age at IBD diagnosis in the affected parents was higher in all published familial series (41 years in Lee et al’s study) than that observed in sporadic cases. It might well reflect a selection bias (also called truncation bias) with less recruitment of parents with early onset and reduced fertility.4 This bias was displayed in two studies in which parent–child pairs were stratified according to age at diagnosis in the parents.6 ,7 No anticipation persisted in the “early diagnosed” parent–child pairs but did in a Jewish subsample. Finally, the main confounder in these familial studies, which was tackled properly by Lee et al, is the inadequate follow up of the younger generation. Using regression analysis Lee et al showed an inverse correlation between age at diagnosis and calendar year of birth both for patients with familial and non-familial IBD. They thus showed that IBD occurring later in life in the younger generation was not taken into account: the children have not yet lived through their years of susceptibility. This ascertainment bias artificially lowered the mean age of onset of the younger generation. Additional evidence against genetic anticipation was provided by the observation that there was no difference between disease extent (a marker of disease severity) in parent–child pairs. This is consistent with the similarity in clinical characteristics of familial and sporadic IBD. In a recent study no difference was observed between 152 patients with a positive familial history of Crohn’s disease and 1164 sporadic cases with regard to the importance of medical treatment and the incidence and extent of excisional surgery.8
In summary, assertion of genetic anticipation by mere observation of age at diagnosis and disease severity in complex disorders such as IBD is difficult.9 Lee et al’s study was itself not without methodological pitfalls such as the use of more than one child per parent. This does not mean that genetic anticipation is definitely excluded. As seen in Huntington’s disease, unstable DNA may be present even when the anticipation pattern is similar to regression to the mean, and cases of negative anticipation do occur.10 Expansion of the (CAG)n repeat has been reported in Crohn’s disease11 and in keeping with genetic heterogeneity, subsets of patients (e.g. Jewish) could yet exhibit genetic anticipation.7 In clinical practice, the only message available so far for affected parents is that the relative risk of IBD for their children is increased by a factor of 10 to 15 compared with the general population. Presently, we suggest genetic counselling should not be provided about age of onset and disease severity in IBD.
Supported by the Ministère de la Santé et de l’Action Humanitaire (Direction Générale de la Santé) and INSERM (Grant 92/R/2).