clinical and molecular characterisation of hyperinsulinaemic hypoglicemia in infants born small for...

8/12/2019 Clinical and Molecular Characterisation of Hyperinsulinaemic Hypoglicemia in Infants Born Small for Gestation Ages

1/5

Clinical and molecular characterisation ofhyperinsulinaemic hypoglycaemia in infantsborn small-for-gestational age

Ved Bhushan Arya,1 Sarah E Flanagan,2 Anitha Kumaran,1 Julian P Shield,3

Sian Ellard,2 Khalid Hussain,1 Ritika R Kapoor1

1Developmental EndocrinologyResearch Group, MolecularGenetics Unit, London Centrefor Paediatric Endocrinologyand Metabolism, GreatOrmond Street Hospital forChildren NHS Trust, and TheInstitute of Child Health,University College London,London, UK2Institute of Biomedical andClinical Science, Universityof Exeter Medical School,

Exeter, UK3Department of Child Health,University of Bristol, and BristolRoyal Hospital for Children,Bristol, UK

Correspondence toDr Ritika R Kapoor,Developmental EndocrinologyResearch Group, MolecularGenetics Unit, Institute of ChildHealth, University CollegeLondon, 30 Guilford Street,London WC1N 1EH, UK;[email protected]

Received 23 August 2012Revised 3 January 2012Accepted 4 January 2013Published Online First29 January 2013

http://dx.doi.org/10.1136/fetalneonatal-2012-302546

To cite:Arya VB,Flanagan SE, Kumaran A,et al. Arch Dis Child Fetal

Neonatal Ed2013;98:F356F358.

ABSTRACTObjective To characterise the phenotype and genotypeof neonates born small-for-gestational age (SGA; birthweight 6 months. Normoglycaemia on diazoxide


2/5

Genetics

Genomic DNA was extracted from peripheral leukocytes usingstandard procedures and the coding regions and intron/exonboundaries of the ABCC8 and KCNJ11 genes were ampliedby PCR (primers available on request). Amplicons were subse-quently sequenced using the Big Dye Terminator CyclerSequencing Kit V.3.1 (Applied Biosystems, Warrington, UK)according to manufacturers instruction and reactions were ana-lysed on an ABI 3730 Capillary sequencer (Applied Biosystems,Warrington, UK). Sequences were compared with the referencesequences (NM_000525.3 and NM_000352.3) using MutationSurveyor v3.24 software (SoftGenetics, State College,Pennsylvania, USA).

RESULTSClinical characteristics and courseThe phenotypic details of 27 SGA infants with HH are sum-marised in table 1.

The plasma insulin levels were inappropriately elevated duringhypoglycaemia in 22 infants (81%). The remaining ve infants(19%) had inappropriately low -hydroxybutyrate and non-esteried fatty acids during hypoglycaemia as supportive biochem-ical evidence of HH. All infants required glucose infusion rate of8 mg/kg/min to maintain normoglycaemia (median 15.6 mg/kg/min). There was no correlation found between maximum glucoseinfusion rate to maintain normoglycaemia and plasma insulin levelduring hypoglycaemia (gure 1). Most (89%) responded to mild

moderate doses of diazoxide (5

10 mg/kg/day), with three infants(11%) needing high doses (1520 mg/kg/day).

Glucose prole and fasting responses at resolution ofhyperinsulinismIn all, 17 infants (63%) underwent a 24 h glucose prole and con-trolled fast after stopping diazoxide to demonstrate resolution ofhyperinsulinism. None of these infants recorded hypoglycaemiaduring a 24-h glucose prole. All infants maintained blood glucoseconcentrations above 3.0 mmol/l at the end of fast appropriate fortheir age, with 13 infants maintaining blood glucose concentra-

tions >3.5 mmol/l. All infants showed appropriate plasma insulinsuppression and elevation of plasma -hydroxybutyrate/non-esteried fatty acids as evidence of resolution of HH.

Genetic resultsSequencing did not reveal mutations in ABCC8/KCNJ11 genesin 25/27 DNA samples analysed.

DISCUSSIONThis is the largest case series of SGA neonates with HH thatreports the clinical characteristics and ABCC8/KCNJ11 sequen-cing results in a cohort of 27 subjects. Collins et al rstdescribed transient HH in three SGA infants and subsequently

reported HH in ve of 27 SGA neonates studied, suggesting it iscommon in SGA neonates.2 3 It is important to recognise this asneonates with HH are especially prone to the complications ofhypoglycaemia because of their inability to generate alternativefuels, such as ketone bodies.

In our study, despite other evidence of hyperinsulinism,plasma insulin levels were undetectable during hypoglycaemia in5/27 SGA neonates. We did not nd any correlation betweenthe maximum glucose infusion rate required to maintain normo-glycaemia and plasma insulin levels. This is explained by theshort half-life of insulin of 45 min and rapid clearance by theliver before it reaches peripheral circulation. In a study by Hoeet al,4 plasma insulin was inappropriately elevated in only 11 of

24 neonates who had transient prolonged neonatal hyperinsu-linism. Our results corroborate these ndings and highlight thevalue of other parameters (apart from plasma insulin) in thediagnosis of HH.

In this case study of SGA infants referred to two tertiary hos-pitals with HH, all infants responded to diazoxide, though thedose was variable ranging from 5 to 20 mg/kg/day. Diazoxidewas successfully stopped in 21 (78%) patients by 6 months ofage. In the remaining six infants, ve needed diazoxide until10 months of age and one infant needed prolonged treatmentuntil 22 months. In a study of 26 neonates with hyperinsulinismwhich included 7 SGA neonates, HH resolved by a median ageof 181 days (range, 18403 days).4 Fafoula et al5 also reportedprolonged transient HH up to 9 months in SGA infants.

In our cohort, no recurrence of HH was noticed after stop-ping diazoxide. This highlights that with the management proto-col whereby diazoxide was stopped when good glycaemiccontrol was maintained with diazoxide dose


3/5

treatment of this group of patients are important and may haveimportant implications for neurodevelopmental outcome ofthese patients. Plasma insulin levels during hypoglycaemia takenin isolation can miss the diagnosis of HH and hence other para-meters (such as glucose infusion rates and production of freefatty acids/ketone bodies during hypoglycaemia) must be consid-ered in the diagnosis. Withdrawal of diazoxide treatment whenglycaemic control is maintained at a dose of


4/5

doi: 10.1136/archdischild-2012-302880published online January 29, 2013

2013 98: F356-F358 originallyArch Dis Child Fetal Neonatal Ed

Ved Bhushan Arya, Sarah E Flanagan, Anitha Kumaran, et al.born small-for-gestational age

infantshyperinsulinaemic hypoglycaemia inClinical and molecular characterisation of

http://fn.bmj.com/content/98/4/F356.full.htmlUpdated information and services can be found at:

These include:

References

http://fn.bmj.com/content/98/4/F356.full.html#related-urlsArticle cited in:

http://fn.bmj.com/content/98/4/F356.full.html#ref-list-1This article cites 5 articles, 3 of which can be accessed free at:

Open Access

http://creativecommons.org/licenses/by-nc/3.0/legalcodehttp://creativecommons.org/licenses/by-nc/3.0/ andcompliance with the license. See:work is properly cited, the use is non commercial and is otherwise inuse, distribution, and reproduction in any medium, provided the originalCreative Commons Attribution Non-commercial License, which permitsThis is an open-access article distributed under the terms of the

service

Email alerting

the box at the top right corner of the online article.

Receive free email alerts when new articles cite this article. Sign up in

CollectionsTopic

(277 articles)Metabolic disorders(121 articles)Diabetes

(24 articles)Open access

Articles on similar topics can be found in the following collections

http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:

http://journals.bmj.com/cgi/reprintformTo order reprints go to:

http://group.bmj.com/subscribe/To subscribe to BMJ go to:

group.bmj.comon July 21, 2014 - Published byfn.bmj.comDownloaded from
http://fn.bmj.com/content/98/4/F356.full.htmlhttp://fn.bmj.com/content/98/4/F356.full.html#related-urlshttp://fn.bmj.com/content/98/4/F356.full.html#ref-list-1http://fn.bmj.com/cgi/collection/metabolic_disordershttp://fn.bmj.com/cgi/collection/metabolic_disordershttp://fn.bmj.com/cgi/collection/metabolic_disordershttp://fn.bmj.com/cgi/collection/metabolic_disordershttp://fn.bmj.com/cgi/collection/diabeteshttp://fn.bmj.com/cgi/collection/unlockedhttp://group.bmj.com/group/rights-licensing/permissionshttp://group.bmj.com/group/rights-licensing/permissionshttp://journals.bmj.com/cgi/reprintformhttp://journals.bmj.com/cgi/reprintformhttp://group.bmj.com/subscribe/http://group.bmj.com/http://group.bmj.com/http://fn.bmj.com/http://fn.bmj.com/http://group.bmj.com/http://fn.bmj.com/http://group.bmj.com/subscribe/http://journals.bmj.com/cgi/reprintformhttp://group.bmj.com/group/rights-licensing/permissionshttp://fn.bmj.com/cgi/collection/metabolic_disordershttp://fn.bmj.com/cgi/collection/diabeteshttp://fn.bmj.com/cgi/collection/unlockedhttp://fn.bmj.com/content/98/4/F356.full.html#related-urlshttp://fn.bmj.com/content/98/4/F356.full.html#ref-list-1http://fn.bmj.com/content/98/4/F356.full.html


5/5

Notes

http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:

http://journals.bmj.com/cgi/reprintformTo order reprints go to:

http://group.bmj.com/subscribe/To subscribe to BMJ go to:

group.bmj.comon July 21, 2014 - Published byfn.bmj.comDownloaded from
http://group.bmj.com/group/rights-licensing/permissionshttp://group.bmj.com/group/rights-licensing/permissionshttp://journals.bmj.com/cgi/reprintformhttp://journals.bmj.com/cgi/reprintformhttp://group.bmj.com/subscribe/http://group.bmj.com/http://group.bmj.com/http://fn.bmj.com/http://fn.bmj.com/http://group.bmj.com/http://fn.bmj.com/http://group.bmj.com/subscribe/http://journals.bmj.com/cgi/reprintformhttp://group.bmj.com/group/rights-licensing/permissions

clinical and molecular characterisation of hyperinsulinaemic hypoglicemia in infants born small for...

Documents