Compound Heterozygous Complete Loss-of-Function <em>SPINK1</em> Variants as a Novel Cause of Severe Infantile Isolated Exocrine Pancreatic Insufficiency

While complete loss-of-function (LoF) SPINK1 variants in the simple heterozygous state predispose to or cause chronic pancreatitis, biallelic complete LoF variants result in severe infantile isolated exocrine pancreatic insufficiency (SIIEPI). To date, only two individuals with a null SPINK1 genotype have been reported—one homozygous for a full-gene deletion and the other for an Alu insertion in the 3′ untranslated region. Here, we report a third case of SIIEPI, presenting in early infancy with severe exocrine pancreatic insufficiency and diffuse pancreatic lipomatosis, without extra-pancreatic involvement. Targeted next-generation sequencing (NGS) identified compound heterozygous complete LoF SPINK1 variants. One was the known c.180_181delAT variant, inherited from the father. The second, initially detected as an exon 2 deletion and confirmed by quantitative fluorescent multiplex PCR (QFM-PCR), was further characterized by long-range PCR as a complex rearrangement. This variant includes a 1,185 bp deletion removing exon 2, a 118 bp templated insertion followed by a non-templated nucleotide, and an 8 bp deletion—consistent with serial replication slippage or template switching involving translesion synthesis. This maternally inherited variant has not been previously reported. Our findings expand the mutational spectrum of SPINK1-related SIIEPI and suggest that this distinct pediatric disorder may be underrecognized in clinical practice.