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 (NDM) 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 NDM 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 extrapancreatic features, including 8 (42%) with conditions affecting the duodenum and/or hepatobiliary 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 NDM, highlighting the need for clinical assessment of extrapancreatic features in individuals with NDM caused by PDX1 variants.