Abstract
Background: Loss of function mutations in the genes encoding the pancreatic β-cell ATP-sensitive potassium (KATP) channel are identified in approximately 80% of patients with diazoxide unresponsive hyperinsulinemic hypoglycemia (HH). For a small number of patients HH can occur as part of a multisystem disease such as Beckwith–Wiedemann syndrome (BWS). In approximately 20% of patients, BWS results from chromosome 11 paternal uniparental disomy (UPD), which causes dysregulation of imprinted growth regulation genes at 11p15.5. There is a considerable range in the clinical features and phenotypic severity associated with BWS which is likely to be due to somatic mosaicism. The cause of HH in these patients is not known. Research Design and Methods: We undertook microsatellite analysis of 12 markers spanning chromosome 11p in two patients with severe HH and diffuse disease requiring a pancreatectomy. In both patients mutations in the KATP channel genes had not been identified. Results: We identified segmental paternal UPD in DNA extracted from pancreatic tissue in both patients. UPD was not observed in DNA extracted from the patient’s leukocytes or buccal samples. In both cases the UPD encompassed the differentially methylated region at chromosome 11p15.5. Despite this neither patient had any further features of BWS. Conclusion: Paternal UPD of the chromosome 11p15.5 differentially methylated region limited to the pancreatic tissue may represent a novel cause of isolated diazoxide unresponsive HH. Loss of heterozygosity studies should therefore be considered in all patients with severe HH who have undergone pancreatic surgery when KATP channel mutation(s) have not been identified.
Highlights
Hyperinsulinemic hypoglycemia (HH) is a heterogeneous disorder characterized by dysregulated insulin secretion
We report two cases with severe, medically unresponsive hyperinsulinemic hypoglycemia (HH) and diffuse histological disease in whom paternal uniparental disomy (UPD) of the chromosome 11p15.5 imprinted region was found within pancreatic tissue
Microsatellite analysis revealed a loss of the maternal chromosome 11p15.5 allele in DNA extracted from pancreatic tissue in two patients with diazoxide unresponsive HH and diffuse pancreatic disease
Summary
Hyperinsulinemic hypoglycemia (HH) is a heterogeneous disorder characterized by dysregulated insulin secretion. Loss of function mutations in the genes encoding the pancreatic β-cell ATP-sensitive potassium (KATP) channel are identified in approximately 80% of patients with diazoxide unresponsive hyperinsulinemic hypoglycemia (HH). Research Design and Methods: We undertook microsatellite analysis of 12 markers spanning chromosome 11p in two patients with severe HH and diffuse disease requiring a pancreatectomy. In both patients mutations in the KATP channel genes had not been identified. UPD was not observed in DNA extracted from the patient’s leukocytes or buccal samples In both cases the UPD encompassed the differentially methylated region at chromosome 11p15.5. Despite this neither patient had any further features of BWS. Loss of heterozygosity studies should be considered in all patients with severe HH who have undergone pancreatic surgery when KATP channel mutation(s) have not been identified
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