Introduction Netherton syndrome is a primary immune disorder that presents with atopy, diffuse ichthyosis, growth retardation, variable immune defects, and elevated IgE levels. The disease is due to a mutation in the SPINK5 gene, which encodes a serine protease inhibitor, LEKTI, and is inherited in an autosome recessive pattern. We describe a case with features of Netherton syndrome found to have unique mutations in SPINK5 and the filaggrin gene (FLG). Case Description A 4-year-old male with a history of congenital hydrocephalus with meningocele, ADHD, seasonal rhinitis, reactive airway disease and severe eczema presented for eczema management. He has a limited family history of allergic disease. Physical exam documented his height as Discussion This patient presented with clinical features of Netherton syndrome, abnormal NK cells and a FLG mutation. We believe that this is reflective of a novel heterozygous mutation in the SPINK5 gene combined with the reduced expression of filaggrin.