A practical approach to the examination of the malformed fetal brain: impact on genetic counselling

Abstract

Birth defects of the brain result from malformation and disruptions. They remain an important cause of childhood morbidity and mortality. Effective treatments are scarce and prevention strategies limited. As aetiological screening is costly and uncertain, genetic counselling remains empirical in most cases. A pathological study of the malformed brain is the best approach to establish the diagnosis of a brain malformation. It relies on a thorough description of the brain, including its size, external pattern and/or internal configuration. When evaluating a malformed brain two major factors should be considered: (1) malformations result from an arrest of the development at a given time, interfering with subsequent stages of development, leading to a sequence of malformations where the 'primary event' should be distinguished from 'secondary changes'; (2) there is no obvious causal relationship when the final morphology of the central nervous system is considered. For example, mutations in different genes involved in a signalling pathway may result in a similar pattern of malformations. In addition, signalling pathways may be a possible target of toxic agents, mimicking malformations caused by genetic factors. A precise diagnosis will allow rational aetiological screening, with direct benefit for the family, which may serve other families. In addition, it helps to establish a quality assurance process for medical practice, collect solid epidemiological data and conduct research studies. Because of discrepancies observed between human diseases and animal models, research on human material is mandatory. This requires collection of organs, tissues and cells within a legal and ethical framework.