Plasma VEGF - a candidate biomarker for response to treatment with bevacizumab in HHT patients.

BACKGROUND: Recurrent epistaxis is the principal symptom of hereditary hemorrhagic telangiectasia (HHT). Currently, there is no standard therapy for this condition. Bevacizumab (anti-VEGF) treatment has been under intense investigation but treatment effects vary greatly between individuals. There are currently no markers to predict anti-VEGF therapeutic response in HHT patients. METHODS: We evaluated plasma VEGF levels in 13 HHT patients and correlated values with i) degree of epistaxis, measured by visual analog scale (VAS), epistaxis severity score (ESS), and patient bleeding diaries ii) the prevalence of extranasal manifestations, iii) the HHT subtype and iv) the treatment response to intranasal submucosal bevacizumab. RESULTS: Plasma VEGF was elevated in all 13 HHT patients compared to reference levels and showed a moderate correlation with VAS and duration of moderate bleeding events. In patients treated with intranasal submucosal bevacizumab plasma VEGF levels showed a strong correlation with the degree of reduction of mild bleeding events and VAS. CONCLUSIONS: The role of plasma VEGF as a potential predictive biomarker for therapeutic response to bevacizumab treatment warrants further investigation in larger prospective studies.

Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype.

RASopathies are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS-mitogen activated protein kinase (RAS-MAPK) pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins; however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma.