Pediatric reference values of VEGF-D derived from a German population-based cohort of healthy children.

Background: Vascular endothelial growth factor D (VEGF-D) is a growth-factor involved in the development of blood vessels and lymphatics in tissues all over the human body. Interestingly, VEGF-D serum levels are increased in certain tumor entities. For tuberous sclerosis complex (TSC), a rare genetic disease associated with (benign) tumor growth, VEGF-D is already implemented as a diagnostic and therapeutic biomarker to monitor onset and progress of lymphangioleiomyomatosis (LAM), one of the noncancerous tumor manifestations in mainly female adult TSC patients. To date only adult VEGF-D serum cut off values are established and used as a diagnostic tool in LAM. Neither cut off nor pediatric reference values for VEGF-D serum levels are known, our study aims to provide reliable pediatric VEGF-D results in samples from healthy children and adolescents.

Methods: We analyzed 2003 samples provided by healthy children aged 0.25-18 years participating in the prospective longitudinal population-based cohort study "LIFE Child" in Leipzig, Germany. Serum VEGF-D levels were measured by enzyme-linked immunoassay.

Results: VEGF-D levels in healthy children and adolescents show age-and gender specific variations. We showed a significant difference between girls and boys in post pubertal VEGF-D levels. Especially the fact, that girls showed higher VEGF-D levels with advancing stages of puberty is underlining the importance of estrogen metabolism in context of VEGF-D mediated cell proliferation, angiogenesis and associated disease mechanisms.

Conclusion: Knowing VEGF-D levels in growing healthy young children and adolescents could help to recognize early disease progression of LAM in individuals at risk especially young women suffering from TSC. Further studies are needed on VEGF-D serum levels in children, especially the impact of estrogen metabolism on VEGF-D should be investigated further.