Congenital Hyperinsulinism With Paternally Inherited ABCC8 Variants: A Single Center Experience Over a Decade in...

ABCC8 pathogenic variants have been found to cause neonatal diabetes mellitus (NDM), maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI), depending on the nature of the mutation. Few studies have reported on the carrier frequency of CHI-related ABCC8 variants. In Singapore, the carrier rate is 1 in 754. Paternally inherited ABCC8 recessive variants have been classically associated with focal lesions causing CHI. In our case series of five patients with paternally inherited ABCC8 variants, one patient had a second maternally inherited recessive variant, making him a compound heterozygous genotype presenting with severe, neonatal onset, diffuse disease that was not responsive to diazoxide. The remaining four patients had a single paternally inherited ABCC8 variant, of which three were previously reported to be recessive variants-only 1 had a focal lesion while the rest had diffuse disease. A comprehensive review of our cases suggests that patients with paternally inherited ABCC8 variants, whether autosomal recessive, heterozygous, or associated with genetic syndromes, were heterogeneous in their clinical manifestations and cannot be reliably distinguished based on their initial clinical presentation. A deeper understanding of the genotype-phenotype correlation of ABCC8-related CHI will require further research and functional analyses. Both a genetic diagnosis and imaging using ¹⁸F-DOPA-PET should be pursued in a timely manner once diazoxide unresponsiveness has been established. Single-stage near-total pancreatectomy may be considered for patients with diffuse disease.