Epilepsy with faint capillary malformation or reticulated telangiectasia associated with mosaic AKT3 pathogenic variants

De Bortoli, Martina [UCL] Ivars, Marta [ospital Sant Joan de Deu] Revencu, Nicole [UCL] Nassogne, Marie-Cécile [UCL] Lavarino, Cinzia [Hospital Sant Joan de Déu] Paco, Sonia [Hospital Sant Joan de Déu] Lammens, Martin [University of Antwerp] Renders, Anne [UCL] Dumitriu, Dana Ioana [UCL] Helaers, Raphaël [UCL] Boon, Laurence M. [UCL] Baselga, Eulalia [Hospital Sant Joan de Déu] Vikkula, Miikka [UCL] et al.[show all]

Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.3% of newborns. They are usually caused by somatic pathogenic variants in GNAQ or GNA11. PIK3CA and PIK3R1, part of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin pathway, are mutated in fainter CMs such as diffuse CM with overgrowth and megalencephaly CM. In this study, we present two young patients with a CM-like phenotype associated with cerebral anomalies and severe epilepsy. Pathogenic variants in PIK3CA and PIK3R1, as well as GNAQ and GNA11, were absent in affected cutaneous tissue biopsies. Instead, we identified two somatic pathogenic variants in the AKT3 gene. Subsequent analysis of the DNA obtained from surgically resected brain tissue of one of the two patients confirmed the presence of the AKT3 variant. Focal cortical dysplasia was also detected in this patient. Genetic analysis thus facilitated workup to reach a precise diagnosis for these patients, associating the vascular anomaly with the neurological symptoms. This study underscores the importance of searching for additional signs and symptoms to guide the diagnostic workup, especially in cases with atypical vascular malformations. In addition, it strongly emphasizes the significance of genotype-phenotype correlation studies in guiding clinicians' informed decision-making regarding patient care.