Understanding the Biological Activities of Vitamin D in Type 1 Neurofibromatosis: New Insights into Disease Pathogenesis and Therapeutic Design

SIMPLE SUMMARY: We herein describe the relevance of Vitamin D for human health, with a special focus on its role in Neurofibromatosis type 1 (NF1) disease. Indeed, epidemiological studies revealed that low circulating vitamin D levels inversely correlate with cutaneous manifestations and bone abnormalities, clinical hallmarks of NF1. NF1 is an autosomal dominant syndrome with a severe predisposition in developing tumors and for which limited treatment options are thus far available. In this context, vitamin D or its analogues has been used to treat both skin and bone lesions in NF1 patients, alone or in association with other therapeutic agents. We provide an exhaustive and detailed analysis of the most relevant preclinical and clinical studies aimed at analyzing the correlation between vitamin D deficiency and NF1 lesion progression. This review can add a valuable contribution to the current knowledge of NF1 disease investigating possible therapeutic strategies to ameliorate NF1 conditions. ABSTRACT: Vitamin D is a fat-soluble steroid hormone playing a pivotal role in calcium and phosphate homeostasis as well as in bone health. Vitamin D levels are not exclusively dependent on food intake. Indeed, the endogenous production—occurring in the skin and dependent on sun exposure—contributes to the majority amount of vitamin D present in the body. Since vitamin D receptors (VDRs) are ubiquitous and drive the expression of hundreds of genes, the interest in vitamin D has tremendously grown and its role in different diseases has been extensively studied. Several investigations indicated that vitamin D action extends far beyond bone health and calcium metabolism, showing broad effects on a variety of critical illnesses, including cancer, infections, cardiovascular and autoimmune diseases. Epidemiological studies indicated that low circulating vitamin D levels inversely correlate with cutaneous manifestations and bone abnormalities, clinical hallmarks of neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant tumour predisposition syndrome causing significant pain and morbidity, for which limited treatment options are available. In this context, vitamin D or its analogues have been used to treat both skin and bone lesions in NF1 patients, alone or combined with other therapeutic agents. Here we provide an overview of vitamin D, its characteristic nutritional properties relevant for health benefits and its role in NF1 disorder. We focus on preclinical and clinical studies that demonstrated the clinical correlation between vitamin D status and NF1 disease, thus providing important insights into disease pathogenesis and new opportunities for targeted therapy.