Expansion of the Phenotype of Lymphatic Anomalies Caused by Somatic Activating BRAF Variant

Abstract

Background

The somatic activating variant in BRAF (p.V600E) was recently described as a novel cause of macrocystic head and neck lymphatic malformations in three individuals. Other recent studies profiling the genetic causes of more complex lymphatic anomalies identified this same pathogenic BRAF variant. Our aim was to expand the phenotypic description of the somatic BRAF p.V600E variant in individuals with vascular anomalies.

Procedure

We searched the database of individuals with vascular anomalies at our institution for those identified as having complex lymphatic anomalies and somatic BRAF p.V600E variants. A comprehensive retrospective review of identified individuals’ electronic health records was conducted.

Results

Six individuals with complex lymphatic anomalies had the BRAF p.V600E variant. All individuals had diffuse lymphatic malformations and abnormal lymphatic conduction. The conduction abnormalities were observed only after surgical interventions in five of the patients, in some cases, manifesting years later. There was immense phenotypic heterogeneity within the cohort.

Conclusions

Complex lymphatic anomalies are an important new phenotype associated with the pathogenic BRAF p.V600E variant. Even in initially asymptomatic individuals within this patient population, longitudinal follow-up is necessary, and surgical intervention should be pursued with caution. Further investigation is needed to better understand the etiology of the conduction problems associated with this pathogenic variant to inform the multidisciplinary approach to treatment.