Clustering of anophthalmia and microphthalmia

A few years ago public concern was raised in England by the appearance of apparent clusters of cases of anophthalmia and microphthalmia.¹ The pesticide benomyl, and later on its derivative carbendazim, was suspected to be the cause of the alleged clustering. In response to a press campaign the government in 1993 commissioned further research, although without clearly indicating the direction for the investigations. In this week’s issue Dolk et al publish the results of that research (p 905).² Although they did not confirm clustering, their results raise further, interesting, questions.

Microphthalmia is a general term used to describe a broad range of improperly developed, small eyes in newborn children. One end of the range is marked by babies with complete absence of eyes—that is, anophthalmia—whereas at the other end are cases that are rather arbitrarily diagnosed because no clear cut border exists between mild microphthalmia and small normal eyes. Often the eye abnormality is part of a syndrome and is accompanied by other clinical features. Individual cases may differ widely in their cause. Specific genetic factors, such as chromosomal abnormalities and inherited mutations in developmental genes,³ may form the underlying cause. Or the disorder may result from environmental influences on fetal development, such as exposure to certain infectious agents or teratogenic chemicals.^4–6 Cases without any obvious cause are generally ascribed to a combination of environmental factors and genetic susceptibility.

Three fundamental questions can be asked about the cases that occurred in England. Firstly, could benomyl cause the disorder? Secondly, is there convincing evidence for a clustered prevalence of anophthalmia and microphthalmia? Thirdly, is there any obvious link between benomyl and the regions of increased prevalence? Animal studies have already shown that benomyl can induce anophthalmia and microphthalmia.⁷ The doses used, however, were about 1000 times higher than the expected dose received by farm workers handling the pesticide. Taking this into account, the alleged clustering could simply be explained by assuming that people in the areas of clustering had been exposed to higher concentrations of benomyl than those in the surrounding regions. Alternatively, the areas of clustering might harbour subpopulations with a higher genetic susceptibility to the compound. In principle, these potential explanations could be investigated, but before embarking on such research one would like to answer the second question.

In this respect the results of Dolk et al are of fundamental importance. In fact, Dolk et al were not able to show statistically significant regional variation in the presence of anophthalmia and microphthalmia in England between 1988 and 1994. Moreover, no convincing evidence of localised clusters was obtained when mild cases and cases with a known cause were omitted. Although the results depend on the intrinsic limitations of epidemiological approaches to the concept of clustering, as outlined in the commentary (p 910), they indicate that further research based on the alleged clustering is probably bound to fail and will not provide useful data. In this respect the government’s earlier dilemma of whether to pursue the relation between pesticides and clustering or to investigate the major causes of anophthalmia and the possibilities for prevention seems to have been resolved.

The results of Dolk et al suggest that there no longer seems to be a serious reason for public concern. Indeed, some may wonder whether all the commotion has been for nothing. This is certainly not so. Any suspected increase in prevalence of disorders such as anophthalmia, which interfere with life expectancy or quality of life, demands proper attention. This is especially so where clustering of cases is suspected, since this might serve as an efficient tool to unravel the causes of the disorder. Few will doubt that the observation of an increased incidence of cancer in the Chernobyl region would eventually have led to the detection of its cause. Furthermore, epidemiological studies often unearth unexpected findings or new insights—as with the association between socioeconomic status and the prevalence of neural tube defects and the subsequent links to diet and folic acid.⁸,⁹ For this reason Dolk et al’s finding of an inverse relation between the prevalence of anophthalmia and population density merits further investigation.

Papers p 905