Scratching and scratch-induced injuries including neuroanatomical alterations are key characteristics in chronic pruritus entities of different origin. The aim of this study was to link gene expression (array hybridization, qPCR) with DNA methylation (array hybridization) and neuroanatomy (PGP9.5 staining) in chronic nodular prurigo (CNPG), atopic dermatitis (AD), brachioradial pruritus (BRP) and matched healthy controls. Specific signatures of gene expression as well as DNA methylation clearly discriminated pruritic lesional from non-pruritic skin in CNPG and from healthy skin of volunteers, respectively. While intraepidermal nerve fiber density was indiscriminately reduced, the level of epidermal branching, assessed by a semi-quantitative pattern analysis, differentiated entities (CNPG>BRP>AD). Correspondingly, repellent SEMA3A showed highest expression in AD, while axonal growth promoting NGF was most prominent in CNPG and BRP. Overexpression of genes for nerve fiber regeneration (NELL2/NFKB/ARTN) was found in AD and CNPG, but not in BRP. Our findings suggest that differential branching patterns rather than mere innervation density separate chronic itch conditions and reflect disease-specific local expression profiles. In pruritic dermatoses (AD, CNPG), nerve injury and subsequent sprouting may primarily result from chronic scratching whereas genuine neuropathy is expected to underlie BRP.