Multiple Genomic Technologies Validate Rare Novel Variant and Direct Medical Care in Vascular Anomalies

Some vascular anomalies, such as hamartomas associated with PTEN hamartoma tumor syndrome (PHTS) and fibroadipose vascular anomaly (FAVA, often due to PI3KCA variants), share similar clinical, radiological, and histopathological presentations that challenge clinicians to provide an accurate diagnosis. Genetic testing can help clinicians differentiate these two vascular anomalies to provide proper treatment for patients. An 11-year-old female with macrocephaly presented with a painful lesion in her right ankle and was initially diagnosed with FAVA and treated with sirolimus. Initial genetic testing from a biopsy sample was negative. Subsequently, however, repeat clinical genetic testing and research deep exome sequencing from a second tissue biopsy sample identified a mosaic variant in PTEN (NM_00314.7) c.683delA p.Asn228Ilefs*28 with a variant allele fraction (VAF) of 2.0%-2.1%, ultimately changing the diagnosis from FAVA to a PTEN hamartoma. To evaluate the germline status of this patient, PTEN sequencing and deletion duplication testing was sent from saliva and identified a different variant in PTEN (NM_000314.4) c.202_209+18delins27, estimated to be 20%-30% VAF. Sanger sequencing validated this novel variant as germline, leading to cancer screening in the patient. This case exemplifies the need for genetic reevaluation as sequencing technology continues to update rapidly, repeat sampling in cases of suspected mosaicism, the two-hit hypothesis in the development of vascular malformations, and emphasizes the importance of genetic diagnosis in vascular malformations, especially in this case which led to the identification of a cancer predisposition syndrome.