Melanocyte development is orchestrated by a complex interconnecting regulatory network of genes and synergistic interactions. Piebaldism and Waardenburg syndrome are neurocristopathies that arise from mutations in genes involved in this complex network. Our understanding of melanocyte development, Piebaldism, and Waardenburg syndrome has improved dramatically over the past decade. The diagnosis and classification of Waardenburg syndrome, first proposed in 1992 and based on phenotype, have expanded over the past three decades to include genotype. This review focuses on the current understanding of human melanocyte development and the evaluation and management of Piebaldism and Waardenburg syndrome. Management is often challenging and requires a multidisciplinary approach.

The neural crest (NC) is a transient dynamic structure of ectodermal origin, found in early vertebrate embryos. The multipotential NC cells migrate along well defined routes, differentiate to various cell types including melanocytes and participate in the formation of various permanent tissues. As there is only limited information about the molecular mechanisms controlling early events in melanocyte specification and development, we exploited the AMV v-Myb transcriptional regulator, which directs differentiation of in vitro chicken NC cells to the melanocyte lineage. This activity is strictly dependent on v-Myb specifically binding to the Myb recognition DNA element (MRE). The two tamoxifen-inducible v-Myb alleles were constructed one which recognizes the MRE and one which does not. These were activated in ex ovo NC cells, and the expression profiles of resulting cells were analyzed using Affymetrix microarrays and RT-PCR. These approaches revealed up-regulation of the BMP antagonist Gremlin 2 mRNA, and down-regulation of mRNAs encoding several epithelial genes including KRT19 as very early events following the activation of melanocyte differentiation by v-Myb. The enforced v-Myb expression in neural tubes of chicken embryos resulted in detectable presence of Gremlin 2 mRNA. However, expression of Gremlin 2 in NC cells did not promote formation of melanocytes suggesting that Gremlin 2 is not the master regulator of melanocytic differentiation.