Expanding the spectrum of autosomal recessive congenital ichthyosis caused by variants in NIPAL4 and PNPLA1 and evaluation of biologics interventions

Autosomal recessive congenital ichthyosis is a heterogenous group of rare genetic disorders characterized by abnormal scaling and erythema. These disorders are caused by variants in 14 genes, including NIPAL4 and PNPLA1. In this study, we retrospectively analyzed the clinical characteristics and treatment response to biologics in Dutch patients with NIPAL4 and PNPLA1 variants. We performed deep-phenotyping and analyzed effect of off-label secukinumab (anti-IL17A) and dupilumab (anti-IL4/IL13) using patient and investigator reported outcome measures. We report 5 unrelated patients with 3 different NIPAL4 variants including 1 novel. Seven patients from 4 families displayed 3 different PNPLA1 variants, one with an additional variant in FLG. Both cohorts showed scaling (n=12), erythroderma (n=5), palmoplantar keratoderma (n=6) and collodion membrane at birth (n=4). We observed remarkable phenotypic variability between two brothers with identical homozygous PNPLA1 variants. Treatment with secukinumab (NIPAL4 n=3) showed initial improvement in IGA and IASI after 8 weeks in all patients, but in 2/3 patients relapse was seen and treatment was discontinued. Dupilumab (PNPLA1) showed improvement of NRS itch in 2/2 patients. This study demonstrates a heterogeneous clinical spectrum of NIPAL4 and PNPLA1 variants. There is no genotype/phenotype correlation. The varying effects of secukinumab in NIPAL4 variants support the hypothesis that IL-17 pathway is not the only factor involved in ichthyosis and that i.e. skin microbiome or (epi-)genetics and environment might be involved. Dupilumab is an option in case of a heavy itch.