Neonatal ichthyosis-sclerosing cholangitis syndrome caused by a novel CLDN1 mutation: a case report and literature review

Neonatal ichthyosis-sclerosing cholangitis syndrome (NISCH) is an autosomal recessive disorder characterized by cholestasis, generalized ichthyosis, alopecia, and dental anomalies. As this is a rare syndrome, here we present a case caused by a novel mutation followed by a literature review of all published cases. This retrospective review includes all original articles on the clinical profiles of all 37 cases published through December 2024 using a PubMed search. The patient was a 2-month-old boy who presented with cholestasis, sparse hair, and generalized ichthyosis. Whole-exome sequencing revealed a novel pathogenic variation in exon 1 of the CLDN1 gene: (NM_021101.5) c.36dupT (p.Leu13SerfsTer56). The patient was symptomatically managed, and his condition improved. Among the 37 reported cases, the median age at diagnosis was 60 months (range, 1–636 months). Patients of Moroccan ethnicity were most commonly affected, and c.200_201delTT was the most common mutation. Among the clinical features, ichthyosis was universal (37 of 37 [100%]), followed by jaundice in 70.2% (26 of 37), pruritus in 38.2% (13 of 34), hepatomegaly in 43.3% (13 of 30), and splenomegaly in 23.8% (5 of 21) of patients. Portal hypertension (7 of 35 [20%]) and mental retardation (3 of 21 [14.2%]) were rare. The disease phenotype varied from no liver involvement or transient neonatal cholestasis to end-stage liver disease. Progressive liver disease was reported in 8 patients, five of whom underwent liver transplantation. NISCH is a rare syndrome with variable phenotypes ranging from no liver involvement and transient neonatal cholestasis to advanced liver disease requiring liver transplantation. Therefore, a multidisciplinary approach with close follow-up is required.