The aim of this preliminary case study series was to investigate epidermal innervation in pediatric patients with significant neurological impairment and self-injurious behavior. We enrolled four pediatric patients with self-injury (two males, two females; mean age 12y, range 9-14y) and used archival specimens from healthy, age-matched children with typical development for comparison purposes. Epidermal nerve fiber density, peptide content, and mast cell degranulation patterns from non-damaged skin were tested between the patients and the comparison group. The male patients with self-injury had significantly increased epidermal nerve fiber densities, increased substance P positive fiber count and extensive mast cell degranulation compared with sex- and age-matched individuals with typical development. Our case series shows for the first time altered peripheral innervation from non-damaged tissue in children with significant self-injury and developmental disability compared with a healthy comparison group. Establishing the role of peripheral nociceptive and immune modulatory neural pathways may offer new treatment avenues for this devastating neurobehavioral disorder.