Clinical and Molecular Spectrum of Sporadic Vascular Malformations: A Single-Center Study

Abstract

Sporadic vascular malformations (VMs) are a large group of disorders of the blood and lymphatic vessels caused by somatic mutations in several genes—mainly regulating the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. We performed a cross-sectional study of 43 patients affected with sporadic VMs, who had received molecular diagnosis by high-depth targeted next-generation sequencing in our center. Clinical and imaging features were correlated with the sequence variants identified in lesional tissues. Six of nine patients with capillary malformation and overgrowth (CMO) carried the recurrent GNAQ somatic mutation p.Arg183Gln, while two had PIK3CA mutations. Unexpectedly, 8 of 11 cases of diffuse CM with overgrowth (DCMO) carried known PIK3CA mutations, and the remaining 3 had pathogenic GNA11 variants. Recurrent PIK3CA mutations were identified in the patients with megalencephaly–CM–polymicrogyria (MCAP), CLOVES, and Klippel–Trenaunay syndrome. Interestingly, PIK3CA somatic mutations were associated with hand/foot anomalies not only in MCAP and CLOVES, but also in CMO and DCMO. Two patients with blue rubber bleb nevus syndrome carried double somatic TEK mutations, two of which were previously undescribed. In addition, a novel sporadic case of Parkes Weber syndrome (PWS) due to an RASA1 mosaic pathogenic variant was described. Finally, a girl with a mild PWS and another diagnosed with CMO carried pathogenic KRAS somatic variants, showing the variability of phenotypic features associated with KRAS mutations. Overall, our findings expand the clinical and molecular spectrum of sporadic VMs, and show the relevance of genetic testing for accurate diagnosis and emerging targeted therapies.

The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms

“…In most VAs that occur sporadically, postzygotic somatic mutations are detected. In their case, a somatic mosaicism is present, and the genetic testing is usually performed from the affected tissue obtained by surgical or skin biopsy [ 76 , 96 ]. In the case of germline mutations (present in all body cells in affected individuals), testing can be done from any type of tissue (e.g., skin, blood, hair, or saliva) [ 76 ].…”

Mosaic RASopathies: A review of disorders caused by somatic pathogenic variants in the genes of the RAS/MAPK pathway

“…The differential diagnosis of mosaic RASopathies mostly relies on other congenital/early onset segmental overgrowth syndromes associated with somatic mosaic pathogenic variants in the PI3K/AKT/ mTOR or the vascular proliferation pathways, like PIK3CA-related overgrowth spectrum (PROS) (Canaud, Hammill, Adams, Vikkula, & Keppler-Noreuil, 2021;Chang et al, 2021;Diociaiuti et al, 2022;Keppler-Noreuil et al, 2015;Lalonde et al, 2019;Mussa, Carli, Cardaropoli, Ferrero, & Resta, 2021) Cancer risk in germline and mosaic RASopathies is debated (Kontaridis et al, 2022). It is likely increased in individuals harboring pathogenic mosaic somatic variants in HRAS and KRAS, as it has been largely demonstrated in individuals with germline Costello syndrome (Davies et al, 2022) but not yet defined for those with mosaic RASopathies caused by pathogenic variants in other genes.…”

“…The differential diagnosis of mosaic RASopathies mostly relies on other congenital/early onset segmental overgrowth syndromes associated with somatic mosaic pathogenic variants in the PI3K/AKT/mTOR or the vascular proliferation pathways, like PIK3CA ‐related overgrowth spectrum (PROS) (Canaud, Hammill, Adams, Vikkula, & Keppler‐Noreuil, 2021; Chang et al, 2021; Diociaiuti et al, 2022; Keppler‐Noreuil et al, 2015; Lalonde et al, 2019; Mussa et al, 2022; Mussa, Carli, Cardaropoli, Ferrero, & Resta, 2021). Similarly to PROS, mosaic RASopathies have highly variable phenotypes depending on the involved tissues and the level of hyperactivation of the RAS/MAPK pathway.…”

“…Isolated mosaic RASopathies involving the vascular system include low‐flow and arteriovenous vascular malformations with pathogenic variants in the KRAS , NRAS , BRAF , MAP2K1 , and RASA1 genes (Al‐Olabi et al, 2018; Diociaiuti et al, 2022) and lymphatic anomalies with pathogenic variants in SOS1 , KRAS , ARAF , BRAF , NRAS , and CBL (Foster et al, 2020; Li et al, 2019; Liu et al, 2022; Mäkinen et al, 2021; Manevitz‐Mendelson et al, 2018; Zenner et al, 2022).…”

“…These phenotypes largely overlap with the PROS spectrum and with that of somatic variants in the vascular proliferation pathway genes (Chang et al, 2021; Diociaiuti et al, 2022). Differently from many PROS, in these forms of LO, the degree of progression of tissue growth is likely less severe and slowly progressing over time.…”