PA09 Clinical characterization of a cohort of KRAS-associated low-flow vascular anomalies

Abstract Low-flow vascular malformations with associated overgrowth are most often caused by somatic activating variants in the gene PIK3CA. Discovering the genetic basis in this cohort has transformed treatment prospects and enabled targeted medical therapy with inhibitors of the phosphoinositide 3-kinase–AKT–mammalian target of rapamycin pathway. However, a small number of patients are negative for PIK3CA mutations, and identification of such individuals is important to enable stratification for appropriate targeted medical therapies. We report here three patients with low-flow vascular anomalies secondary to somatic activating KRAS variants, highlighting key clinical features and the clinical course in this cohort. Case 1 is an 18-year-old man with a left-leg low-flow vascular malformation associated with overgrowth and notably prominent distended tortuous superficial veins and hyperpigmentation. He previously underwent epiphysiodesis and is currently being treated conservatively with a shoe raise and compression garments. Next-generation sequencing of DNA extracted directly from affected skin demonstrated a mosaic KRAS c.35GA, p.Gly12Asp variant in 6% of reads. Case 2 is a 13-year-old girl with a capillary malformation of the left leg with overlying hyperpigmentation, and prominent distended veins associated with prominent leg length discrepancy (left longer than right). She is currently pending epiphysiodesis and reports frequent left-knee pain. Next-generation sequencing of DNA extracted directly from affected skin demonstrated a KRAS c.64CA, p.Gln22Lys variant in 3% of reads. Case 3 is a 17-year-old girl with a capillary malformation of the left leg with associated with overgrowth, hyperpigmentation and distended superficial veins. She required epiphysiodesis to correct leg length discrepancy and reports significant pain in her left knee. She also has left-sided visual impairment and previous focal seizures. Next-generation sequencing of DNA extracted directly from affected skin demonstrated a mosaic KRAS c.35GT, p.Gly12Val variant in 2% of reads. We describe a cohort of three patients with low-flow vascular malformations secondary to somatic variants in KRAS. Clinical features common to our three patients and potential clues to the underlying genetic diagnosis were associated hyperpigmentation, the progressive development of superficial dilated veins, and progressive overgrowth of the affected limb requiring surgical intervention. Targeted therapy in this cohort could potentially be achieved with the use of mitogen-activated protein kinase kinase inhibitors, which have been shown to be effective in the treatment of KRAS-driven arteriovenous and lymphatic malformations. This series highlights the importance of early genotyping in patients with segmental overgrowth syndromes and vascular anomalies to inform prognosis and to stratify patients for targeted medical therapies.