Heterozygous pathogenic variants in SERPINB7 potentially associated with Nagashima-type palmoplantar keratoderma and...

Nagashima-type palmoplantar keratoderma (NPPK) is an autosomal recessive disorder caused by biallelic loss-of-function variants in the SERPINB7 gene, whereas Hashimoto's thyroiditis (HT) is a common autoimmune endocrine disease. The co-occurrence of NPPK and HT has not been previously reported. This study aims to present this novel association and investigate a potential underlying immunogenetic mechanism. We describe a 10-year-old boy presenting with fever, seizures and a long-standing history of palmoplantar erythema and hyperkeratosis. Diagnostic work-up included neurological evaluation, thyroid function tests, cytokine profiling and whole exome sequencing (WES). Laboratory findings during the acute phase revealed elevated anti-thyroid antibodies (anti-thyroid peroxidase antibodies, anti-thyroglobulin antibodies) and pro-inflammatory cytokines (interleukin [IL]-6, IL-10, interferon-γ). Skin examination confirmed NPPK, and WES identified compound heterozygous pathogenic SERPINB7 mutations (c.522dupT; p.V175Cfs*46). The patient was diagnosed with NPPK, HT and Hashimoto's encephalopathy. Treatment with levothyroxine and levetiracetam led to the resolution of neurological symptoms and normalisation of thyroid function. This first report of coexisting NPPK and HT suggests a potential novel role for SERPINB7 in immune dysregulation beyond its known cutaneous functions. The findings advocate considering thyroid screening in patients with NPPK and expand the phenotypic spectrum of SERPINB7-related disorders, warranting further research into its extracutaneous immunological roles.