biostudies-literatureMasson EThe Institut National de la Santé et de la Recherche Médicale (INSERM), the Association des Pancré-atites Chroniques Héréditaires, and the Association Gaétan Saleün, France.998https://www.ebi.ac.uk/biostudies/studies/S-EPMC12469571biostudies-literatureUnknown16(9)<h4>Background/objectives</h4>While complete loss-of-function (LoF) <i>SPINK1</i> variants in the simple heterozygous state cause chronic pancreatitis, biallelic complete LoF variants result in a rare pediatric disorder termed severe infantile isolated exocrine pancreatic insufficiency (SIIEPI). To date, only two individuals with a null <i>SPINK1</i> genotype have been reported-one homozygous for a whole-gene deletion and the other for an <i>Alu</i> insertion in the 3' untranslated region. Here, we report the genetic basis of a third SIIEPI case, presenting in early infancy with severe exocrine pancreatic insufficiency and diffuse pancreatic lipomatosis.<h4>Methods</h4>Targeted next-generation sequencing (NGS) was used to analyze the entire coding region and exon-intron boundaries of the <GenesCompound Heterozygous Complete Loss-of-Function &lt;i&gt;SPINK1&lt;/i&gt; Variants as a Novel Cause of Severe Infantile Isolated Exocrine Pancreatic Insufficiency.PMC12469571Not applicableMasson EWangermez MFerec CTougeron DRebours VChen JMfalseCompound Heterozygous Complete Loss-of-Function &lt;i&gt;SPINK1&lt;/i&gt; Variants as a Novel Cause of Severe Infantile Isolated Exocrine Pancreatic Insufficiency.<h4>Background/objectives</h4>While complete loss-of-function (LoF) <i>SPINK1</i> variants in the simple heterozygous state cause chronic pancreatitis, biallelic complete LoF variants result in a rare pediatric disorder termed severe infantile isolated exocrine pancreatic insufficiency (SIIEPI). To date, only two individuals with a null <i>SPINK1</i> genotype have been reported-one homozygous for a whole-gene deletion and the other for an <i>Alu</i> insertion in the 3' untranslated region. Here, we report the genetic basis of a third SIIEPI case, presenting in early infancy with severe exocrine pancreatic insufficiency and diffuse pancreatic lipomatosis.<h4>Methods</h4>Targeted next-generation sequencing (NGS) was used to analyze the entire coding region and exon-intron boundaries of the <2025-01-01T00:00:00Z2025 Aug2026-05-03T03:14:43.644Z2026-05-03T03:11:00.297ZS-EPMC124695714100994610.3390/genes16090998