Endocrine Abstracts

JOINT809

Background: Hyperinsulinaemic hypoglycaemia (HH) is a heterogeneous disease entity characterized by failure to suppress insulin secretion from the pancreatic beta cells during hypoglycaemia. Persistent non-syndromal CHI can be caused due to inherited mutations in a number of known genes. But in 40 – 50% of affected patients the genetic basis is unexplained. The two main histologically forms are diffuse and focal CHI. The diffuse form is an apparently normally structured islet. The focal form is characterized by the presence of a small endocrine lesion in the pancreas. The histology in some patients differ from these main forms. This form is referred to as CHI with atypical histology. We present molecular characterization of variants in this latter group. Atypical congenital hyperinsulinism (CHI) is characterized by distinct pancreatic histology that differs from classical KATP-channel diffuse or focal CHI and Beckwith-Wiedemann Syndrome (BWS). Its genetic basis remains largely unclear.

Aim: To explore genotype-histotype-phenotype correlations in atypical CHI within a single-center cohort.

Methods: Genetic analysis involved sequencing CHI-related genes in blood and pancreatic tissue, with BWS testing when appropriate. For negative cases, a targeted 140-gene panel, including the non-coding HK1 region, was performed on blood, pancreatic tissue, and laser-microdissected (LCM) islets. Pancreatic tissue was evaluated through histological, immunohistochemical, and morphometric studies.

Results: Atypical CHI was observed in 5/70 (7.1%) surgically treated patients. Median birth weight was 2965 g (range: 2650–3385 g), with disease onset at a median of 93 days (range: 1–259 days). 18F-DOPA PET/CT showed diffuse labeling in all cases. Genetic findings revealed low-grade mosaic HK1 intron 2 mutations in three patients: de novo germline, somatic mosaic in the whole pancreas, or isolated islets. One patient had a CACNA1D frameshift mutation of uncertain significance, while no abnormalities were identified in another. Histological analysis revealed lobule-specific enlarged islets with increased insulin-producing cell volume, interspersed with diffusely distributed shrunken islets. Nuclear enlargement was observed in isolated islets from one patient.

Conclusion: This is the first study to describe how low grade de novo variants in the beta-cell of the pancreatic islet can explain the atypical form of Hyperinsulinaemic hypoglycaemia. Rare atypical CHI cases display unique histological patterns restricted to specific lobules and are frequently associated with HK1 intron 2 mosaic variants. Detection of low-grade mosaicism may necessitate laser-microdissected islet analysis.