MICROPHTHALMIA WITH LINEAR SKIN DEFECTS SYNDROME IN A MOSAIC FEMALE INFANT WITH MONOSOMY FOR THE XP22 REGION - MOLECULAR ANALYSIS OF THE XP22 BREAKPOINT AND THE X-INACTIVATION PATTERN

This paper describes a female infant with microphthalmia with linear s kin defects syndrome (MLS) and monosomy for the Xp22 region. Her clini cal features included right microphthalmia and sclerocornea, left corn eal opacity, linear red rash and scar-like skin lesion on the nose and cheeks, and absence of the corpus callosum. Cytogenetic studies revea led a 45,X[18]/46,X,r(X)(p22q21) [24]/46,X,del(X)(p22)[58] karyotype. Fluorescence in situ hybridization analysis showed that the ring X chr omosome was positive for DXZ1 and XIST and negative for the Xp and Xq telomeric regions, whereas the deleted X chromosome was positive for D XZ1, XIST, and the Xq telomeric region and negative for the Xp telomer ic region. Microsatellite analysis for 19 loci at the X-differential r egion of Xp22 disclosed monosomy for Xp22 involving the critical regio n for the MLS gene, with the breakpoint between DXS1053 and DXS418. X- inactivation analysis for the methylation status of the PGK gene indic ated the presence of inactive normal X chromosomes. The Xp22 deletion of our patient is the largest in MLS patients with molecularly defined Xp22 monosomy. Nevertheless, the result of X-inactivation analysis im plies that the normal X chromosomes in the 46,X,del(X)(p22) cell linea ge were more or less subject to X-inactivation, because normal X chrom osomes in the 45,X and 46,X,r(X)(p22q21) cell lineages are unlikely to undergo X-inactivation. This supports the notion that functional abse nce of the MLS gene caused by inactivation of the normal X chromosome plays a pivotal role in the development of MLS in patients with Xp22 m onosomy.