Novel features of PIK3CA-Related Overgrowth Spectrum: Lesson from an aborted fetus presenting a de novo constitutional PIK3CA mutation

PIK3CA-Related Overgrowth Spectrum (PROS) encompass a group of disorders which are mainly characterized by segmental overgrowth of several tissues as well as venous and lymphatic malformations. It is caused by heterozygous, usually somatic mosaic, pathogenic variants in the PIK3CA gene. However, some patients presenting mainly isolated megalencephaly or "Cowden-like" features have been described harboring constitutional mutations of PIK3CA. Here, we report the case of a woman whose pregnancy was interrupted at 34 weeks of gestation after the detection of the following ultrasound abnormalities: left diaphragmatic hernia with intrathoracic stomach, right deviation of heart, intrathoracic double bubble sign, macrocephaly and polyhydramnios. Fetal autopsy contributed to better characterize the phenotype, showing megalencephaly, left diaphragmatic eventration, facial dysmorphism (hypertelorism, abnormal hair line implantation) and duplication of distal portion of the small bowel. Clinical exome sequencing identified a de novo constitutional variant c.1030G> A p.(Val344Met) in PIK3CA. Although this mutation has been previously described (as constitutional variant) in pediatric patients, our case represents the first detailed description of the prenatal features found in association with a constitutional PIK3CA mutation. Moreover, this case contributes to delineate novel features (diaphragmatic eventration and duplication of the distal part of the small bowel) which could be identified in association with PROS.