Neonatal Diabetes: A Case Series - Indian Pediatrics · indian pediatrics 33 volume 54__january 15,...

INDIAN PEDIATRICS 33 VOLUME 54__JANUARY 15, 2017

Neonatal Diabetes: A Case SeriesRAMASWAMY GANESH, NATARAJAN SURESH, THIRUVENGADAM VASANTHI AND *KG RAVIKUMARFrom Departments of Pediatrics and *Endocrinology, Kanchi Kamakoti CHILDS Trust Hospital and The CHILDS Trust MedicalResearch Foundation, Chennai, Tamil Nadu, India.

Monogenic diabetes results from theinheritance of a mutation or mutations in asingle gene [1], and accounts for 1-5% ofall childhood diabetes [2]. Neonatal

diabetes mellitus (NDM) and maturity-onset diabetes ofthe young (MODY) are the two main forms of monogenicdiabetes. NDM first occurs in newborns and younginfants; MODY usually first occurs in children oradolescents but may be mild and not detected untiladulthood. Most patients with monogenic diabetes areincorrectly diagnosed as either type 1 or type 2 diabetes.Identifying this entity correctly not only helps to initiateappropriate treatment but also helps us to explain theother associated clinical features and offer geneticcounseling to the family for subsequent pregnancies [3].An earlier study from Chennai [4] had reported 28children with neonatal diabetes (0.05%) and 12 childrenwith diabetes onset between 6 months to 1 year of age outof 506 diabetic children registered in their institute. Thecommon gene mutations reported in their series wereABCC8 followed with EIF2AK3 and KCNJ11. Wedescribe the clinical features and follow-up of childrenwith neonatal diabetes from an urban children’s hospitalin Chennai, India.

METHODS

A retrospective analysis of case records of childrenadmitted with neonatal diabetes mellitus in theDepartment of Pediatrics and Endocrinology of KanchiKamakoti CHILDS Trust hospital, Chennai from January

2004 to December 2014 were analyzed. The study wasapproved by the institutional review board. A diagnosis ofneonatal diabetes mellitus was established in infants whohad their onset of diabetes within the first 6 months of lifeand presented with features of polyuria, polydipsia,weight loss, DKA and had their fasting blood sugar >126mg/dL with HbA1C >6.5%. The case records of infantswith neonatal diabetes mellitus were analyzed for birthweight, the age at onset of symptoms, the clinicalfeatures, laboratory investigations (FBS, HbA1C values),Genetic mutation testing results, treatment and follow-updetails. We collected 3 mL of whole blood in EDTA tubefrom the proband and their parents, and sent it to RoyalDevon and Exeter NHS Foundation Trust laboratory,Exeter, UK for genetic analysis. Molecular genetictesting included gene sequencing by PCR technique. Allinfants were treated with subcutaneous insulin at 05 -0.8U/kg/day and were followed up.

RESULTS

During the study period, a total of 137 children werediagnosed as Type 1 diabetes mellitus as per WHOdiagnostic criteria and 10 (5 boys) were diagnosed asneonatal diabetes mellitus. The age range at onset wasfrom 3 days to 160 days. Six children were born to parentswith consanguineous marriage and none had history ofdiabetes in their first degree relatives. All were born at termand six were born with a birth weight <2.5 kg. Diabeticketoacidosis was the mode of presentation in 3 (30%)children (INS,EIF2AK3 and NEUROD1 gene). Glutamic

Correspondence to:Dr Ramaswamy Ganesh,Consultant Pediatrician,Kanchi Kamakoti CHILDS TrustHospital, Chennai 600 034, [email protected]: October 26, 2015;Initial review: January 11, 2016;Accepted: September 02, 2016.

Background: Neonatal diabetes mellitusis a rare disorder with an incidence of 1 in 2,60,000live births. Methods: Retrospective analysis of clinical and genetic profile of childrenadmitted with neonatal diabetes mellitus in a tertiary-care hospital in Chennai, India over 11years. Results: Ten children were diagnosed with neonatal diabetes of whom 9 hadpermanent neonatal diabetes mellitus. The age range at onset was from 3 days- 5 months.Of the 9 children, KCNJ11 gene mutation was positive in one, and ABCC 8 and INS genemutation in two children each. Children with KCNJ11 and ABCC 8 gene mutations wereswitched over to oral sulfonyl urea therapy. Conclusion: Few genotypes causing NDM canbe managed effectively with oral sulfonyl ureas.

Keywords: Diabetes mellitus, Genetics, Permanent, Transient.

Published online: November 05, 2016. PII:S097475591600020

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Copyright of Indian Pediatrics 2017 For personal use only. Not for bulk copying or unauthorized posting to listserv/websites




GANESH, et al. NEONATAL DIABETES

TABL

E 1

CLIN

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plet

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5 m

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D d

iffer

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gree

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eter

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utat

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acid decarboxylase and islet cell autoantibodies werenegative in all children. The mean blood sugar was 499mg/dL. Of the 10 children, one child had transient neonataldiabetes mellitus and nine had permanent neonataldiabetes mellitus. The child with transient neonataldiabetes presented with hyperglycemia on D3 of life,required insulin for 5 months, and mutation analysisrevealed complete loss of methylation on chromosome 6q24. She is off insulin and at her 16 month follow-up, she isgrowing well. Of the nine children with permanentneonatal diabetes mellitus, KCNJ11 gene mutation waspositive in 1, ABCC 8 gene and INS gene mutation in 2each, PDX1 gene mutation in 1, NEURO D1 mutation in 1,EIF2AK3 mutation in 1 and SLC19A2 gene mutation in 1child. Children with KCNJ11 gene mutation and ABCC 8gene mutation were treated with oral sulfonyl urea andothers were treated with Insulin. On follow up, the childwith Wolcott Rallison Syndrome died and other patientsare growing well without problems. The details are shownin Table I.

DISCUSSION

Nine children were diagnosed with permanent NDM inthe present series. Heterozygous activating mutations inthe KCNJ11 gene, that encodes the KATP channel subunitKir6.2, accounts for 47% of permanent NDM [5,6] and afew cases of treatment NDM [7,8]. Similarly mutations inABCC8 gene which encodes the SUR1 regulatory subunit

of the ATP-sensitive potassium channels in beta cells cancause both permanent and transient neonatal diabetes. Inclinical practice it is difficult to differentiate betweenpatients with KCN J11or ABCC8 mutations and oralsulfonyl urea becomes the treatment of choice fordiabetes resulting from both these mutations [9,10]. Ourpatients were switched on treatment from insulin to oralglibenclamide (0.5 mg/kg/day) once the geneticdiagnosis was established, and on follow up theirglycemic control was good.

The present study describes the clinical and geneticprofile of children with neonatal diabetes mellitus. As themolecular genetic testing is expensive, we suggest analgorithm to approach a child with neonatal diabetes forordering genetic testing in resource limited setting likeours (Fig. 1). Molecular genetic testing has a big impacton management of NDM as switching over to oralsulfonyl urea is required in children with KCNJ11/ABCC8 gene mutation. Complete history, thorough clinicalexamination with a high suspicion and correlation withphysical findings may help us to guide further thegenotype work up of neonatal diabetes mellitus.Acknowledgements: Prof Sian Ellard, Consultant MolecularGeneticist, Peninsula Medical School (Royal Devon and ExeterNHS Foundation Trust, Exeter) and Professor Karen Temple,Wessex Regional Genetics laboratory, University ofSouthampton School of Medicine for carrying out the moleculargenetic work-up.

Neonatal diabetes mellitus

Associated clinical featuresNo associated clinical features

↓↓ ↓

Do KCNJ11 /ABCC 8 mutation

Negative- but Transient NDM

↓

↓

↓ZAC/HYMA1 gene mutation

Positive

Spontaneous resolutionby 12 weeks; close follow

up of these patients

↓

↓

Relapse; Treat accordingly↓

Negative but Permanent NDM↓

Positive; treat with sulfonylurea ↓

USG abdomen to look at pancreas

Normal Abnormal

INS gene mutation PDX/IPF, PTF1A,GATA6 mutations

Wolcott Rallison syndrome (EIF2AK3 gene)Thiamine responsive megaloblastic anemia (SLC19A2 gene)

Wolfram syndrome (WFS1 gene)

↓

↓↓ ↓

↓ ↓

FIG. 1 Proposed algorithm for ordering genetic mutation testing in patients with neonatal diabetes (NDM).

↓






Contributors: RG, NS, TV: reviewed literature, draftedmanuscript and were involved in patient management; KGR:reviewed manuscript for intellectual content and will act as theguarantor.Funding: None; Competing interests: None stated.

REFERENCES

1. Hattersley A, Bruining J, Shield J, Njolstad P, DonaghueKC. The diagnosis and management of monogenic diabetesin children and adolescents. Pediatric Diabetes.2009;10:33-42.

2. National diabetes information clearing house. MonogenicForms of Diabetes: Neonatal Diabetes Mellitus andMaturity-onset Diabetes of the Young. Available from:www.diabetes.niddk.nih.gov. Accessed February 24, 2012.

3. Slingerland AS. Monogenic diabetes in children and youngadults: Challenges for researcher, clinician and patient. RevEndocr Metab Disord. 2006;7:171-85.

4. Varadarajan P, Sangaralingam T, Senniappan S, Jahnavi S,Radha V, Mohan V. Clinical profile and outcome ofinfantile onset diabetes mellitus in southern India. IndianPediatr. 2013;50:759-63.

5. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ,

WHAT THIS STUDY ADDS?

• The present study reports the molecular genetics of nine children with permanent neonatal diabetes mellitus.

Slingerland AS, et al. Activating mutations in the geneencoding the ATP-sensitive potassium channel subunitKir6.2 and permanent neonatal diabetes. N Engl J Med.2004;350:1838-49.

6. Hattersley AT, Ashcroft FM. Activating mutations inKir6.2 and neonatal diabetes: new clinical syndromes, newscientific insights, and new therapy. Diabetes. 2005;54:2503-13.

7. Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P,Pearson ER, et al. Relapsing diabetes can result frommoderately activating mutations in KCNJ11. Hum MolGenet. 2005;14:925-34.

8. Colombo C, Delvecchio M, Zecchino C, Faienza MF,Cavallo L, Barbetti F. Transient neonatal diabetes mellitusis associated with a recurrent (R201H) KCNJ11 (KIR6.2)mutation. Diabetologia. 2005;48:2439-41.

9. Pearson ER, Flechtner I, Njolstad PR, Malecki MT,Flanagan SE, Larkin B, et al. Switching from insulin to oralsulfonylureas in patients with diabetes due to Kir6.2mutations. N Engl J Med. 2006;355:467-77.

10. Babenko AP, Polak M, Cave H, Busiah K, Czernichow P,Scharfmann R, et al. Activating mutations in the ABCC8gene in neonatal diabetes mellitus. N Engl J Med.2006;355:456-66.




Neonatal Diabetes: A Case Series - Indian Pediatrics · indian pediatrics 33 volume 54__january 15,...

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