ESPE2015 Poster Category 3 Hypo (26 abstracts)
Genotype–Phenotype Associations in 90 Children with Congenital Hyperinsulinism
Maria Melikyan a , Henrik Christesen b , Elena Petryakina c , Anatoly Tulpakov a , Julia Tihonovich a , Alexey Stepanov d , Maria Kareva a , Sarah Flanagan e , Sian Ellard e , Klaus Brusgaard b , Valentina Peterkova a & Khalid Hussain f
aEndocrine Research Center, Moscow, Russia; bH.C.Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark; cMorozovskaya Children City Clinical Hospital, Moscow, Russia; dRussian Children Clinical Hospital, Moscow, Russia; eUniversity of Exeter Medical School, Exeter, UK; fGreat Ormond Street Hospital for Children, London, UK
Background: Congenital hyperinsulinism (CHI) is a common cause of hypoglycaemia in neonates, infants and children. CHI is a heterogeneous disease in terms of clinical presentation, genetics and histology.
Objective and hypotheses: The aim of this study was to describe the clinical characteristics, genotype–phenotype correlations and treatment outcome of Russian patients with CHI.
Method: A total of 90 children with CHI were identified from 2009 till 2015 in Russia, of which 64 (71.1%) responded to the medical therapy (diazoxide and/or octreotide) and 26 (28.9%) were resistant and underwent subtotal or partial pancreatectomy.
Results: Mutations in ABCC8 and KCNJ11 genes were found in 28/86 patients (32.5%); 3/86 patients (3.4%) were found to carry heterozygous GCK mutations; 3/86 (3.4%) – GLUD1 mutations and one patient (1.1%) had HADH mutation. Among medically resistant cases, 17/26 patients (65.4%) had KATP genes mutations, of which nine were paternally inherited and represent focal HI, what was confirmed histologically and eight had diffuse disease (four heterozygous de-novo mutations and four homozygous and compound heterozygous mutations); one patient (3.8%) had severe GCK mutation; 8/26 patients had WT genes. Among medically responsive cases, 11/64 patients (17%) had mutations in KATP genes, interesting that two of them (both with heterozygous intronic mutations) spontaneously recovered during 6 months after diagnosis; 2/64 (3.1%) – in GCK, 3/64 (4.6%) – in GLUD1 and 1/64 (1.5%) – in HADH gene. Genotype–phenotype correlation revealed that mutations in KATP genes were associated with an increased birth weight and early age of presentation. Follow up studies showed high prevalence of severe developmental delay, cerebral palsy, and optic neuropathy (40, 26, and 7.5% respectively).
Conclusion: A genetic cause was detected in 26 and 69%, of children with mild, and severe CHI, respectively, in Russia. Mutations in ABCC8 and KCNJ11 were found to be the most common cause and associated with severe course of the disease and poor neurologic outcome.
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