Mother and daughter with a terminal Xp deletion: implication of chromosomal mosaicism and X-inactivation in the high clinical variability of the microphthalmia with linear skin defects (MLS) syndrome.

The microphthalmia with linear skin defects (MLS or MIDAS) syndrome is a rare X-linked dominant inherited disorder with male lethality, associated with segmental aneuploidy of the Xp22.2 region in most of the cases. However, we recently described heterozygous sequence alterations in a single gene, HCCS, in females with MLS. Beside the classical MLS phenotype, occasional features such as sclerocornea, agenesis of the corpus callosum, and congenital heart defects can occur. Although the majority of cases are sporadic, mother-to-daughter transmission has been observed and a high intra- and interfamilial phenotypic variability exists. We describe an asymptomatic mother and her daughter presenting with the typical features of MLS syndrome. By cytogenetic analysis both females were found to have a terminal Xp deletion with the breakpoint in Xp22.2, mapping near to or within the MSL3L1 gene which is located centromeric to HCCS. FISH analysis revealed that the mother is a mosaic with 45,X(11)/46,X,del(X)(p22.2)(89), while in all cells of the MLS-affected daughter a hybridization pattern consistent with a 46,X,del(X)(p22.2) karyotype was detected. By haplotype analysis we identified the paternal X chromosome of the mother to carry the terminal Xp deletion. X-inactivation studies showed a completely skewed pattern in mother and daughter with the deleted X chromosome to be preferentially inactivated in their peripheral blood cells. We suggest that both chromosomal mosaicism as well as functional X chromosome mosaicism could contribute to the lack of any typical MLS feature in individuals with a heterozygous MLS-associated mutation. The 45,X cell population, that most likely is also present in other tissues of the mother, might have protected her from developing MLS. Nonetheless, a non-random X-inactivation pattern in favor of activity of the wild-type X chromosome in the early blastocyte could also account for the apparent lack of any disease sign in this female.