Background <p>Neonatal ichthyosis sclerosing cholangitis (NISCH) syndrome is a rare autosomal recessive syndrome due to mutations in the claudin-1 gene (CLDN1). Defective expression of claudin-1 protein manifests with involvement of the liver and skin. Phenotypic expression of the disease varies from cholangitis resolving on supportive management to severe liver damage requiring liver transplantation.</p> Case presentation <p>We hereby discuss an Indian infant presenting with neonatal cholestasis and ichthyosis, carrying a novel nonsense mutation in exon 3 of the CLDN1 gene (p.Pro154LeufsTer2). We also report a striking association between NISCH syndrome and hyperferritinemia; the pathophysiology for the same is yet to be elucidated. The patient’s clinical condition improved after supportive management, including vitamin supplementation, ursodeoxycholic acid, and emollients.</p> Conclusion <p>Awareness, early diagnosis, genotype-phenotype correlation, and timely and appropriate management are key to the prognostication of the patient.</p>