Widening the phenotypic spectrum caused by pathogenic PDX1 variants in individuals with neonatal diabetes

Abstract

Introduction: Biallelic PDX1 variants are a rare cause of isolated pancreatic agenesis and neonatal diabetes without exocrine pancreatic insufficiency, with 17 cases reported in the literature. Research Design and Methods: To determine the phenotypic variability caused by this rare genetic aetiology, we investigated 19 individuals with neonatal diabetes resulting from biallelic disease-causing PDX1 variants. Results: Of the 19 individuals, 8 (42%) were confirmed to have exocrine insufficiency requiring replacement therapy. Twelve individuals (63.2%) had extra-pancreatic features, including 8 (42%) with conditions affecting the duodenum and/or hepato-biliary tract. Defects in duodenum development are consistent with previous Pdx1 ablation studies in mice which showed abnormal rostral duodenum development. Conclusions: Our findings show that recessive PDX1 variants can cause a syndromic form of neonatal diabetes, highlighting the need for clinical assessment of extra 36 pancreatic features in individuals with neonatal diabetes caused by PDX1 variants.