BSPED2008 Oral Communications Diabetes 2 (4 abstracts)
The genotype–phenotype relationship in congenital hyperinsulinism of infancy (CHI): the Northern Congenital Hyperinsulinism (NORCHI) Service 2 year experience
M Skae 1 , S Ellard 4 , O Blankenstein 3 , L Rigby 1 , L Patel 1 , R Amin 1 , M Didi 2 , I Banerjee 1 , P Clayton 1 & C Hall 1
1Royal Manchester Children’s Hospital, Manchester, UK; 2Royal Liverpool Children’s Hospital, Liverpool, UK; 3Charite University of Medicine, Berlin, Germany; 4Peninsula Molecular Genetics Laboratory, Exeter, UK.
CHI is a disorder of dysregulated insulin release characterised by severe recurrent hypoglycaemia. Mutations in genes encoding the beta-cell sulphonylurea receptor (ABCC8) and inward-rectifying potassium-channel (KCNJ11) are the commonest genetic cause of CHI, followed by that encoding glutamate dehydrogenase (GLUD-1). Histologically, disease pathology is subdivided into diffuse or focal disease; the latter associated with paternal mutations and somatic loss of maternal heterozygosity in potassium ATP sensitive (KATP) channels and reliably defined by 18Fluoro (F)-DOPA Positron Emission Tomography (PET)-CT imaging. Traditionally classification was based on therapeutic response, with pancreatic resection undertaken in cases unresponsive to first-line therapy (diazoxide).
Aims and methodology: A National Research Ethics Service (NRES) approved retrospective analysis of genotype–phenotype relationships in 49 CHI patients referred to the NORCHI service between April 2006 and 2008 was performed to establish associations between clinical characteristics, treatment and genotype.
Results: Twenty-six patients with persistent CHI were identified and genotyped with positive mutations in 18 (69%). ABCC8 mutations were most common (n=13; 4 novel, 1 mosaic, 1homozygous, 1 compound heterozygous), followed by KCNJ11 (n=4) and GLUD-1 (n=1). Screening of parental DNA was undertaken in 13 heterozygous cases, confirming 8 paternal, 3 maternal and 2 de novo mutations. No significant difference (χ2, P=0.355) was noted in the prevalence of mutations in diazoxide responsive (63%) and unresponsive (88%) patients. Ten patients with a genotype suggestive of possible focal disease (6 paternal, 3 no mutations, 1 de novo mosaic) underwent 18F-DOPA PET-CT scanning in Berlin, confirming focal lesions in 5 (50%; 2 diazoxide responsive).
Conclusion: We report that approximately 50% of referrals to NORCHI had persistent CHI with a high prevalence of KATP channel mutations. Approximately 40% of these had a genotype suggestive of possible focal disease and underwent 18F-DOPA PET-CT which confirmed focal disease in 50%. Rapid genetic analysis may not be predictive of severity of disease but can effectively guide decision making regarding PET-CT imaging and future surgery.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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