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Infantile exocrine pancreatic insufficiency due to a homozygous SPINK1 pathogenic variant in two siblings: A case
France Chalon1, Angélique Lhomme1, Marie Léonard1
1Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics University Hospital Liège and University of Liège Liège Belgium.
Insights
Two siblings with severe exocrine pancreatic insufficiency were diagnosed using rapid whole genome sequencing. A novel homozygous SPINK1 variant (c.27delC) was identified, offering new insights into pancreatic disease pathophysiology.
Area of Science:
- Genetics
- Gastroenterology
- Pediatrics
Background:
- Infantile exocrine pancreatic insufficiency (EPI) is rare, often linked to cystic fibrosis or Shwachman-Diamond syndrome.
- The SPINK1 gene encodes a trypsin inhibitor, crucial for preventing premature pancreatic enzyme activation.
- Pathogenic SPINK1 variants are associated with hereditary pancreatitis, but EPI without pancreatitis is less understood.
Purpose of the Study:
- To report two cases of severe EPI in siblings caused by a novel homozygous SPINK1 variant.
- To investigate the role of SPINK1 in EPI pathogenesis, particularly in the absence of pancreatitis.
- To highlight the diagnostic utility of rapid whole genome sequencing (WGS) in rare genetic disorders.
Main Methods:
- Case report of two siblings with severe EPI.
- Whole genome sequencing (WGS) was performed for diagnostic purposes.
- Genetic analysis focused on identifying pathogenic variants in the SPINK1 gene.
Main Results:
- A novel homozygous loss-of-function variant in SPINK1 (c.27delC) was identified in both siblings.
- Both patients presented with severe EPI but lacked clinical or biochemical signs of pancreatitis.
- Distinct initial clinical manifestations were observed, including hepatocellular dysfunction in one patient.
Conclusions:
- Homozygous loss-of-function variants in SPINK1 can cause severe EPI without pancreatitis.
- The SPINK1 c.27delC variant represents a newly identified cause of infantile EPI.
- Rapid WGS is a valuable tool for timely diagnosis and management of rare genetic gastrointestinal disorders.
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.
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