Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI. NS patients present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). Here the inventors employed a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells and allergic phenotypes of NS-ILC and NS-SE patients. In particular, they studied a cohort of 13 NS patients comprising 9 NS-ILC and 4 NS-SE. Integrated multi-omics revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesion skin and in blood in both NS endotypes. This study thus identifies IL-17/IL-36 as predominant signaling axes in both NS endotypes and unveils molecular features distinguishing NS-ILC and NS-SE. In particular, blocking of IL36 signaling would therefore represent a novel therapeutic strategy for NS, in particular in NS-SE patients.