Indian Pediatr 2011;48: 733-734
Congenital Hyperinsulinism Caused by Mutations
in ABCC8 (SUR1) Gene
Seema Thakur, *Sarah E Flanagan, *Sian Ellard and IC Verma
From the Department of Genetic Medicine, Sir Ganga Ram
Hospital, New Delhi, India; and *Institute of Biomedical and Clinical
Science, Peninsula Medical School, University of Exeter, UK.
Correspondence to: Dr Seema Thakur, Consultant,
Department of Genetic Medicine,
Fortis Hospital, New Delhi, India. Email:
Received: January 11, 2010;
Initial review: May 7, 2010;
Accepted: June 28, 2010.
Congenital hyperinsulinism is the most frequent cause of severe,
persistent hypoglycemia in infancy and childhood. We report a 2.5 year
old girl with severe congenital hyperinsulinism. Mutation analysis
showed that the child is a compound heterozygote for two missense
mutations in the ABCC8 gene.
Key words: Congenital hyperinsulinism, Hypoglycemia,
Octreotide, ABCC8 gene.
It is a major cause of hypoglycemia in newborns and infants . The
incidence of CHI is estimated to be 1 in 40,000-50,000 in the
general population, while it is 1 in 2500 in some isolated
communities with high rates of consanguinity . There is a marked
heterogeneity in the clinical presentation, molecular mechanisms and
histological basis of the disease .
Congenital hyperinsulinism (CHI) is biochemically characterized by
the deregulated secretion of insulin from pancreatic
This girl presented to us at 2.5 years of age.
Her mother was pregnant (gestation of 6 weeks), and wanted prenatal
diagnosis. The couple did not want recurrence of problem that
occurred in the first child (brain damage due to hypoglycemia). She
was born at term by spontaneous vaginal delivery; her birthweight
was 3.2 kg and there was no history of birth asphyxia. Antenatally
there was no history of diabetes mellitus in the mother. The patient
became lethargic within hours after birth. Blood glucose was (27 mg/dL)
and there was no acidosis, and urinary ketones were normal. She was
able to maintain normal blood glucose only with IV glucose solutions
and milk fortified with sugar. On day 3 of life, she was transferred
to a tertiary care centre for management. In view of the high serum
insulin level (13.4 µIU/mL) at the time of hypoglycemia, she was
diagnosed with congenital hyperinsulinism. Serum growth hormone,
cortisol, ammonia and lactate were normal. She was discharged after
one week on hydrocortisone, octreotide and diazoxide. At 3 months of
age her parents discontinued the treatment, as there was no
response. The parents were given the option of pancreatectomy but
they did not agree. Since then she is on antiepileptic drugs for
seizures and is not receiving any treatment for hyperinsulinism. She
developed meningitis at around 8 months of age and a VP- shunt was
done following the identification of hydrocephalus on a CT scan. At
presentation, she had global developmental delay and was completely
bed-ridden with high seizure frequency.
Molecular diagnosis: Genomic DNA was
extracted from peripheral blood from the affected child and both
parents. Mutation analysis of ABCC8 (encoding SUR1) and
KCNJ11 (encoding Kir6.2) genes was undertaken according to the
protocol described previously(7). The child was found to be a
compound heterozygote for the missense mutations R74Q and G111R in
exons 2 and 3 of the ABCC8 gene. This result confirmed a
diagnosis of autosomal recessive congenital hyperinsulinism.
Sequencing analysis of ABCC8 gene showed that her father was
heterozygous for the G111R mutation, while mother was heterozygous
for the R74Q mutation. The risk that their next child will be
affected by congenital hyperinsulinism was 25%. As the lady was
pregnant, prenatal testing was done. This showed the fetus to be
affected and parents chose to abort the pregnancy.
Congenital hyperinsulinism is the most common
cause of persistent neonatal hypoglycemia and should be considered
in every infant presenting with unexplained hypoglycemia. High
birthweight for gestational age and elevated glucose requirement to
prevent hypoglycemia strongly suggest the diagnosis of
hyperinsulinism. Diagnostic biochemical features for congenital
hyperinsulinism include glucose infusion rate > 8 mg/kg/minute; and
laboratory values - blood glucose <3 mmol/l with detectable serum
insulin/ C-peptide, low serum ketone bodies, low serum fatty acids
and low branch chain amino acids [2,5]. Our patient had high serum
insulin at the time of hypoglycemia. This strongly suggested the
Infants with Beckwith-Wiedemann syndrome may have
hyperinsulinemic hypoglycemia. Congenital deficiency of cortisol or
growth hormone may first present with hypoglycemia. Growth hormone
and cortisol levels were normal in our case. Defects in fatty acid,
glucose, and aminoacid metabolism are rare, but they frequently
present with hypoglycemia. To exclude other potential causes of
hypoglycemia, plasma samples for C-peptide, free fatty acids, beta-hydroxybutyrate,
acetoacetate, lactic acid, carnitine, growth hormone, cortisol, and
thyroid hormones should be done. Hypoglycemia has been reported in
cases of congenital disorders of glycosylation - CDG Ia, CDG-Ib
and in a case of CDG-Id, and hence testing is required to
Mutations in seven different genes have been
described that lead to dysregulated insulin secretion .
Mutations in these genes account for about 50%
of the known causes of CHI .
Congenital hyperinsulinism, caused by
mutations in either ABCC8 or KCNJ11, is the most
common form. These genes regulate the ATP sensitive potassium
channel (KATP), which is
involved in insulin secretion in relation to meals. CHI can be
inherited as autosomal recessive or dominant. Our patient had
missense mutations in exons 2 and 3 of the ABCC8 gene.
The G>A mutation at nucleotide 221 (c.221G>A) results in the
substitution of glutamine for arginine at codon 74 (p.Arg74Gln) and
has been reported previously . The G>A mutation at nucleotide 331
(c.331G>A) results in the substitution of arginine for glycine at
codon 111 (p.Gly111Arg) and has also been reported previously .
Mutation in ABCC8 and KCNJ11 gene also cause diabetes mellitus and
there has been reports of the mutations in these genes in diabetes
from India .
Contributors: ST: clinical diagnosis,
collecting data and preparing manuscript; ICV: clinical diagnosis
and revising manuscript; SEF: molecular diagnosis of hyperinsulinism;
and SE: molecular diagnosis of hyperinsulinism, drafted the paper.
Competing interests: None stated.
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