PS has been hypothesized to have a genetic origin. Here we describe a couple of MZ twin girls both presenting with PS. Phenotype concordance in monozygotic twins affected by a disease is generally accepted as evidence supporting the hypothesis that this disease is under genetic control. In this view, the fact that both our twin girls exhibited pectoral muscle hypoplasia might contribute to support the hypothesis of a genetic control of PS.
Both twins exhibited skeletal anomalies, one of the two showing a more severe phenotype. Discordance in disease manifestation between affected monozygotic twins has already been reported and attributed to different patterns of X chromosome inactivation, epigenetic mechanisms involving differences in methylation patterns, somatic mutations casually occurring during development, or environmental factors [22–24]. The differences in the phenotype of our twin girls could otherwise be related to the effects of vascular interruptions during their embryonic life due to thrombosed microvasculature caused by predisposing genetic factors, as also recently proposed to explain the origin of PS in a sporadic case .
Notably, PS was previously reported in only one of two identical twin girls , indicating the complexity of genetic mechanisms underlying PS. Our twin girls share a heterozygous 126 Kbp interstitial deletion at chromosome 11q12.3 spanning 5 genes. This specific deletion, not known to be associated with any specific genetic disorders, could be considered as a candidate region having a role in PS development. We investigated the function and expression of the 5 genes with the aim to explore their involvement in patients’ clinical manifestations.
All forelimb elements, including skeletal structures, proximal and distal muscles, and sternum, seem to develop according to a unique program . Thus, all tissues involved in PS could develop under the control of the same group of genes whose mutations may account for the various features characterizing the PS phenotype. According to this hypothesis, we considered as less likely candidate genes those lacking a clear role in the development of tissues involved in PS, as LGALS12, which encodes a member of the beta-galactoside-binding lectin family expressed by adipocytes.
The remaining four genes, namely HRASLS5, RARRES3, HRASLS2, and PLA2G16, are members of the HREV107 type II tumor suppressor gene family known to regulate cellular growth, differentiation, and apoptosis, mainly through the Ras-mediated signaling pathways . In particular, RARRES3, a retinoid-inducible growth regulator, was shown to reduce the level of activated Ras . HRAS activation was reported to inhibit skeletal myogenesis by favoring proliferation of myoblasts and by blocking their differentiation into muscle cells [29–32]. For these reasons, one may speculate that, in our patients, the heterozygous deletion of RARRES3 suppressor gene could have induced an enhancement of HRAS expression and activity interfering with correct skeletal muscle differentiation.
We searched for mutations in all genes involved in the deletion in a panel of 30 PS patients. Rare variants with no clear direct causative effects were found. Only one unreported variant was found in one patient, a missense variant in the HRASLS5 gene (Arg28Gln) transmitted to the PS patient by his healthy father. Thus, it is reasonable to exclude a direct causative role in PS of this variant, that could rather act as a predisposing factor. On the one hand, absence of mutations in a relatively small cohort of patients suggests that the analyzed genes are not frequently involved in PS, on the other hand, the question whether the detected rare variants could exert a modifying effect on the PS phenotype is still controversial.