Infantile exocrine pancreatic insufficiency due to a homozygous SPINK1 pathogenic variant in two siblings: A case report

Abstract Infantile exocrine pancreatic insufficiency is a rare condition, most often encountered in the context of cystic fibrosis or Shwachman–Diamond syndrome. The SPINK1 gene encodes a trypsin inhibitor protein that prevents the premature activation of digestive enzymes in pancreatic tissue. Heterozygous pathogenic SPINK1 variants are known to predispose individuals to hereditary pancreatitis. We report two cases of severe exocrine pancreatic insufficiency without signs of pancreatitis, caused by the same SPINK1 pathogenic variant in siblings, each presenting with distinct initial clinical manifestations, including one patient with biochemical signs of hepatocellular dysfunction. Patient 1 was enrolled in a rapid whole genome sequencing study, which promptly identified a homozygous loss‐of‐function variant in SPINK1 (c.27delC). To our knowledge, this specific variant has not been previously reported in association with exocrine pancreatic insufficiency, providing new insights into the disease's pathophysiology. This case also underscores the utility of rapid whole genome sequencing in facilitating timely diagnosis and management.