Mosaicism in women with focal dermal hypoplasia

Summary This report from Germany and France describes four women with focal dermal hypoplasia (FDH), a genetic condition affecting the skin, skeleton, teeth and eyes. FDH is caused by a mutant (abnormal) gene called PORCN, found on the X chromosome. Male embryos with the mutant gene do not usually survive. Females are more complicated. Firstly, they have two X chromosomes, but for FDH to show up it only needs the mutant gene to be present on one of them. Secondly, soon after conception one of the two X chromosomes in each cell of the embryo is randomly deactivated. Cell lines (daughter cells) from cells where the normal X chromosome remains active develop normally ; cell lines where the abnormal X chromosome remains active develop abnormally owing to the mutant gene. This phenomenon, where cell lines in an individual represent different genetic populations, is called mosaicism (and, incidentally, explains why tortoiseshell cats are always female). The FDH mutation also frequently happens spontaneously after fertilisation, in the earliest stages of development, but before X chromosome deactivation. The main message from this report is that one cannot exclude FDH simply by using standard genetic tests on blood alone. In affected women, in whom the clinical signs may be subtle and a blood test negative, because of mosaicism the abnormal gene may still be found in those skin cells where the X chromosome carrying it remains active. Importantly, the ovaries may also contain such cells, in which case the condition could be passed on to children.