Netherton syndrome (NS) is a rare autosomal recessive disorder caused bySPINK5mutations, resulting in a deficiency in its processed protein LEKTI. It is clinically characterized by the triad of congenital ichthyosis, atopic diathesis, and hair shaft abnormalities. TheSPINK5(NM_006846.4): c.1258A>G polymorphism (rs2303067) shows a significant association with atopy and atopic dermatitis (AD), which share several clinical features with NS. We describe an NS patient, initially misdiagnosed with severe AD, who carried the heterozygous frameshift (null) mutation (NM_006846.4): c.957_960dup combined with homozygous rs2303067 in theSPINK5gene. Histopathological examination confirmed the diagnosis, whereas an immunohistochemical study showed normal epidermal expression of LEKTI, despite the genetic findings. Our results corroborate the hypothesis that haploinsufficiency ofSPINK5, in the presence of aSPINK5null heterozygous mutation in combination with homozygousSPINK5rs2303067 polymorphism, can be causative of an NS phenotype, impairing the function of LEKTI despite its normal expression. Due to the clinical overlap between NS and AD, we suggest performingSPINK5genetic testing to search for theSPINK5(NM_006846.4): c.1258A>G polymorphism (rs2303067) and ensure a correct diagnosis, mainly in doubtful cases.