Successful treatment with dupilumab of an adult with Netherton syndrome
Thomas Holger Andreasen, Helena Gásdal Karstensen, Morten Dunø, Ulrikke Lei, Claus Zachariae, Jacob P. Thyssen
Abstract
Netherton syndrome (NS), also known as ichthyosis linearis circumflexa, is a rare autosomal recessive disorder. NS is caused by pathogenic loss‐of‐function variants in the serine protease inhibitor of the Kazal type 5 gene (SPINK5), which compromise the function of the lymphoepithelial Kazal inhibitor type 1 (LEKTI‐1) protein. The unopposed serine protease activity due to reduced LEKTI‐1 inhibition in NS, leads to premature degradation of corneodesmosomes, causing decreased stratum corneum cohesion and thinning. Reduced inhibition of kallikreins also leads to release of thymic stromal lymphopoietin and T helper (Th)2 cytokines as well as activation of Langerhans cells, which in turn further perpetuate the skin barrier dysfunction and cause inflammation. NS mimics atopic dermatitis (AD) or psoriasis in infancy and early childhood, potentially resulting in a wrong diagnosis. Children with NS may often develop allergic manifestations with high levels of IgE and presence of AD‐like inflammation. At present, there are no specific treatments available for patients with NS. Dupilumab is a fully human monoclonal antibody against the interleukin (IL)‐4α receptor subunit, and thereby limits signalling from IL‐4 and IL‐13. Both IL‐4 and IL‐13 are crucial cytokines in the Th2 pathways, and are key players in atopic diseases including asthma and AD.