HAND2 and neuroblastoma: Neuroblastoma predisposition may be caused by a deleterious gain-of-function which results in increased proliferation of sympathetic neurons, since sympathetic neural proliferation is controlled by the interaction of HAND2 and PHOX2B. The differential effects of PHOX2B mutations in the sympathetic and parasympathetic ganglia may, in part, be explained by different regulatory mechanisms and, specifically the role of HAND2. PHOX2B mutation variants have different functional consequences depending interaction with other mediators, expression levels or post-inscriptional modifications.