title: Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time.
abstract: Patients with Congenital Hyperinsulinism (CHI) due to mutations in K-ATP channel genes (K-ATP CHI) are increasingly treated by conservative medical therapy without pancreatic surgery. However, the natural history of medically treated K-ATP CHI has not been described; it is unclear if the severity of recessively and dominantly inherited K-ATP CHI reduces over time. We aimed to review variation in severity and outcomes in patients with K-ATP CHI treated by medical therapy.
  
  
  
  Twenty-one consecutively presenting patients with K-ATP CHI with dominantly and recessively inherited mutations in ABCC8/KCNJ11 were selected in a specialised CHI treatment centre to review treatment outcomes. Medical treatment included diazoxide and somatostatin receptor agonists (SSRA), octreotide and somatuline autogel. CHI severity was assessed by glucose infusion rate (GIR), medication dosage and tendency to resolution. CHI outcome was assessed by glycaemic profile, fasting tolerance and neurodevelopment.
  
  
  
  CHI presenting at median (range) age 1 (1, 240) days resolved in 15 (71%) patients at age 3.1(0.2, 13.0) years. Resolution was achieved both in patients responsive to diazoxide (n = 8, 57%) and patients responsive to SSRA (n = 7, 100%) with earlier resolution in the former [1.6 (0.2, 13.0) v 5.9 (1.6, 9.0) years, p = 0.08]. In 6 patients remaining on treatment, diazoxide dose was reduced in follow up [10.0 (8.5, 15.0) to 5.4 (0.5, 10.8) mg/kg/day, p = 0.003]. GIR at presentation did not correlate with resolved or persistent CHI [14.9 (10.0, 18.5) v 16.5 (13.0, 20.0) mg/kg/min, p = 0.6]. The type of gene mutation did not predict persistence; resolution could be achieved in recessively-inherited CHI with homozygous (n = 3), compound heterozygous (n = 2) and paternal mutations causing focal CHI (n = 2). Mild developmental delay was present in 8 (38%) patients; adaptive functioning assessed by Vineland Adaptive Behavior Scales questionnaire showed a trend towards higher standard deviation scores (SDS) in resolved than persistent CHI [-0.1 (-1.2, 1.6) v -1.2 (-1.7, 0.03), p = 0.1].
  
  
  
  In K-ATP CHI patients managed by medical treatment only, severity is reduced over time in the majority, including those with compound heterozygous and homozygous mutations in ABCC8/KCNJ11. Severity and treatment requirement should be assessed periodically in all children with K-ATP CHI on medical therapy.
authors.affiliation: Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals, Oxford Road, Manchester, M13 9WL, UK. maria.salomonestebanez@postgrad.manchester.ac.uk.|Faculty of Biology, Medicine and Health, University of Manchester, Oxford Rd, Manchester, M13 9PL, UK. maria.salomonestebanez@postgrad.manchester.ac.uk.
authors.forename: Maria
authors.initials: M
authors.lastname: Salomon-Estebanez
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, Barrack Road, Exeter, EX2 5DW, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, Barrack Road, Exeter, EX2 5DW, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals, Oxford Road, Manchester, M13 9WL, UK.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Rigby
authors.affiliation: Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals, Oxford Road, Manchester, M13 9WL, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Bowden
authors.affiliation: Department of Paediatric Endocrinology and Diabetes, Nottingham Children's Hospital, Nottingham University Hospitals, Derby Road, Nottingham, NG7 2UH, UK.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Mohamed
authors.affiliation: Paediatric Psychosocial Department, Royal Manchester Children's Hospital, Central Manchester University Hospitals, Oxford Road, Manchester, M13 9WL, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Nicholson
authors.affiliation: Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals, Oxford Road, Manchester, M13 9WL, UK.
authors.forename: Mars
authors.initials: M
authors.lastname: Skae
authors.affiliation: Therapy and Dietetic Department, Royal Manchester Children's Hospital, Central Manchester University Hospitals, Oxford Road, Manchester, M13 9WL, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hall
authors.affiliation: Department of Paediatric Surgery, Royal Manchester Children's Hospital, Central Manchester University Hospitals, Oxford Road, Manchester, M13 9WL, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Craigie
authors.affiliation: Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals, Oxford Road, Manchester, M13 9WL, UK.
authors.forename: Raja
authors.initials: R
authors.lastname: Padidela
authors.affiliation: Department of Diabetes and Endocrinology, Children's University Hospital, Temple Street, Dublin, Ireland.
authors.forename: Nuala
authors.initials: N
authors.lastname: Murphy
authors.affiliation: Department of Paediatric Endocrinology and Diabetes, Nottingham Children's Hospital, Nottingham University Hospitals, Derby Road, Nottingham, NG7 2UH, UK.
authors.forename: Tabitha
authors.initials: T
authors.lastname: Randell
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Rd, Manchester, M13 9PL, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Cosgrove
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Rd, Manchester, M13 9PL, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dunne
authors.affiliation: Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals, Oxford Road, Manchester, M13 9WL, UK.|Faculty of Biology, Medicine and Health, University of Manchester, Oxford Rd, Manchester, M13 9PL, UK.
authors.forename: Indraneel
authors.initials: I
authors.lastname: Banerjee
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D003981:Diazoxide / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics; D015282:Octreotide / Q000627:therapeutic use
chemical_list: D018528:ATP-Binding Cassette Transporters; D003981:Diazoxide; D015282:Octreotide
keywords: Congenital hyperinsulinism; Diazoxide; Genetics; Hypoglycaemia; Insulin; Mutations; Neurodevelopment; Octreotide