Microphthalmia with linear skin defects syndrome (MLS): a male with a mosaic paracentric inversion of Xp

Abstract

The microphthalmia with linear skin defects syndrome (MLS) is an X-linked dominant disorder with male lethality. In the majority of the patients reported, the MLS syndrome is caused by segmental monosomy of the Xp22.3 region. To date, five male patients with MLS and 46,XX karyotype (“XX males”) have been described. Here we report on the first male case with MLS and an XY complement. The patient showed agenesis of the corpus callosum, histiocytoid cardiomyopathy, and lactic acidosis but no microphthalmia, and carried a mosaic subtle inversion of the short arm of the X chromosome in 15% of his peripheral blood lymphocytes, 46,Y,inv(X)(p22.13∼22.2p22.32∼22.33)[49]/46,XY[271]. By fluorescence in situ hybridization (FISH), we showed that YAC 225H10 spans the breakpoint in Xp22.3. End-sequencing and database analysis revealed a YAC insert of at least 416 kb containing the genes HCCS and AMELX, and exons 2–16 of ARHGAP6. Molecular cytogenetic data suggest that the Xp22.3 inversion breakpoint is located in intron 1 of ARHGAP6, the gene encoding the Rho GTPase activating protein 6. Future molecular studies in karyotypically normal female MLS patients to detect submicroscopic rearrangements including the ARHGAP6 gene as well as mutation screening of ARHGAP6 in patients with no obvious chromosomal rearrangements will clarify the role of this gene in MLS syndrome.

Congenital Linear Streaks on the Face and Neck and Microphthalmia in an Infant Girl

“…Both HCCS and COX7B are involved in mitochondrial respiration and apoptosis (7)(8)(9). Exceptional cases of male infants with MLS phenotype have been reported (10,11). A high degree of intrafamilial phenotypic variability has already been emphasized in this syndrome, even between identical twins (2,4,10) and this tendency is very strikingly illustrated by our observation with complete absence of clinical features in the mother, carrying the same genetic abnormality as her affected daughter.…”

Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome

“…The majority of patients had a chromosomal abnormality resulting in monosomy for the Xp22.2 region. MLS syndrome mainly affects females, however, ten males with an XX karyotype and Y-chromosomal material or 46,XY and a mosaic inversion involving the band Xp22.2 are known [11,15,29,32-36]. Finally, HCCS turned out to be the culprit gene in Xp22.2 [4] and is implicated in all chromosomal rearrangements reported in MLS syndrome-affected individuals to date.…”

“…Patients with an intragenic mutation or a (submicroscopic) deletion covering HCCS can show the full-blown MLS phenotype associated with other anomalies, the classical combination of microphthalmia/anophthalmia and linear skin defects, isolated ocular manifestations, aplastic skin areas restricted to face and neck with no additional abnormalities or no symptoms at all [4,5,10,11,13-15]. As possible explanations for this great clinical variability somatic mosaicism for the mutation and the degree of skewed X chromosome inactivation (XCI) in different tissues have been discussed [4,14,16,17].…”

Microphthalmia with Linear Skin Defects: A Case Report and Review

“…Microphthalmia with linear skin defects syndrome has also been known in the past as MIDAS syndrome, Xp deletion syndrome, Gazali–Temple syndrome, and Xp22.3 microdeletion syndrome (4,5). To date, there have been 41 well‐described cases of MLS syndrome reported in the English literature (1–25). Table 1 summarizes the reported cases.…”

“…In addition, many of the published cases of MLS syndrome describe genitourinary malformations including ambiguous genitalia, penile hypospadias, and bicornuate uterus (2,12,15,17,19,23). The described congenital heart defects include hypertrophic cardiomyopathy, atrial and ventricular septal defects, supraventricular tachycardia, ventricular fibrillation, and other arrythymias (2,10,11,14,16,17,19,(21)(22)(23)(24)(25).…”