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Running title:
CONGENITAL HYPERINSULINISM ASSOCIATED WITH ABCC8 NONSENSE
MUTATION: A CASE REPORT
Corresponding author:
SUHAIMI HUSSAIN
Email:
[email protected]
Full Address:
Universiti Sains Malaysia, Department of Paediatrics, School of
Medical Sciences, 16150 Kubang Kerian, Kelantan, Malaysia
Telephone:
09-767 6947
Fax:
09-7659057
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Title Page
Title:
Congenital Hyperinsulinism associated with ABCC8 Nonsense Mutation:
A Case report
Authors:
1. Suhaimi Hussain*
Affiliation:
Universiti Sains Malaysia, Department of Paediatrics, School of
Medical Scienes, 16150 Kubang Kerian, Kelantan, Malaysia
2. Sarah Flanagan
Affiliation:
Molecular Genetics Laboratory, Royal Devon and Exeter NHS Healthcare
Trust, Exeter, UK.
3. Sian Ellard
Affiliation:
Molecular Genetics Laboratory, Royal Devon and Exeter NHS Healthcare
Trust, Exeter, UK.
.
Manuscript Word Count:
1323
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Abstract
A baby boy with birth weight of 2.4kg at 35 weeks was born via Caesarian section. He had the
first onset of hypoglycemia at 2 hours of life. The infant required a glucose load of 30mg/kg/min.
Insulin level was 19.6 pmol/L (17.8-173.0) with negative ketone. He was resistant to oral
diazoxide but responded to octreotide infusion. The boy is heterozygous for an ABCC8 nonsense
mutation, p.R934*. Octreotide is proven to be safe and effective for treatment of diazoxide
resistance CHI.
Keywords: congenital hyperinsulinism, PHHI, ABCC8 mutation, diazoxide, octreotide, K ATP
channel
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Abbreviations
PHHI- persistent hyperinsulinaemic hypoglycemic of infancy
KATP channel – potassium ATP channel
CHI-Congenital Hyperinsulinism
SUF1-Sulfonyurea receptor 1
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Introduction
Congenital hyperinsulinism or Persistent Hyperinsulinaemic Hypoglycemic of Infancy (PHHI) is
a group of genetic diseases characterized by inappropriate insulin release during hypoglycemia
due to mutation in the β- cells of the pancreas.1 There are at least 8 genes with more than 100
mutations. It is clinically and genetically heterogenous condition. The most common mutation is
due to KATP channel mutation. The molecular diagnosis could only be found in about 45% of all
cases.2 There are many other genes that have yet to be discovered. Mutations of the β- cells of
the pancreas are basically divided into channelopathy (affecting KATP channel) or
metabolopathy (affecting other metabolites, transcription factors). 3
Case report
The proband is currently 1 year 9 months. He is the only child in the family with no history of
parental consanguinity. She was born at 35 weeks via emergency lower segment caesarian
section due to bleeding placenta praevia. His birth weight was 2.4 kg (<3rd percentile), length 44
cm (<3rd percentile) and head circumference 32 cm (< 3rd percentile). His Apgar score was good,
nine at 1 minute and ten at 5 minutes. He had the first onset of hypoglycemia at 2 hours of life
and despite on regular breastfeeding he continued to have multiple episodes of hypoglycemia
manifested as jitteriness. His capillary blood sugar ranged from low reading to 2.5 mmol/L. The
patient was then transferred to Neonatal Intensive Care Unit. He received boluses of intravenous
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dextrose D10% followed by maintenance dextrose solution of increasing strength in order to
treat the persistent hypoglycemia. In addition to that, intravenous glucagon and hydrocortisone
were started for persistent hypoglycemia. The patient’s blood sugar could only be maintained
more than 3.0 mmol/L after glucose load of 30mg/kg/min and a glucagon infusion of 50
mcg/kg/hour.
Oral diazoxide was started at 5.0mg/kg/day in divided doses combined with chlorothiazide
7.0mg/kg/day. As he had a poor response to oral diazoxide, it was titrated up to 20mg/kg/day.
Apart from that, oral nifidipine of 2.5mg/kg/day was also added with the combination therapy.
He only had a good rise of blood sugar within 1 hour after starting octreotide infusion.
Clinically, he had no phenotypic features to suggest Beckwidth Widemann syndrome. He had no
midline defects such as cleft lips and cleft palate. There were no neurocutaneous stigmata. He
had normal male external genitalia. There was no micropenis or undescended testes.
Other systemic examinations were unremarkable.
Discussion
There are many causes of recurrence, persistent hypoglycemia in the neonatal period.
Hyperinsulinism is the commonest cause for recurrence and persistent hypoglycemia. 4
Hyperinsulinism could be due to primary defect in the β-cells of the pancreas or secondary form
of hyperinsulinism .5 Mutation of the genes that regulate insulin secretion is a rare condition. It is
estimated to be 1 in 50000 live births worldwide. The prevalence is higher, about 1 in 2000 in
isolated population with high rate of consanguinity such as Saudi Arabia and Central Finland.6
The commonest gene mutation is due to mutation in the ABCC8 gene that encodes SUR1
subunit . Eighty percent of diazoxide resistance case of congenital hyperinsulinism is due to
KATP channel mutation. Other genes mutation that cause dysregulated insulin secretion by the βcells include KCNJ11, GLUD 1, GCK, HADH, HNF1A, HNF4A, SLC16A1 and UCP2 gene.7
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Secondary form of hyperinsulinism is a more common in conditions for example, large for
gestational age babies, perinatal asphyxia, macrosomic and syndromic babies but what triggers
excessive insulin release in those babies are unknown.8
Clues for hyperinsulinism in this patient include persistent hypoglycemia, a very high glucose
load more than 2-3 times the usual requirement, presence of insulin during hypoglycemia which
was 19.6 pmol/L (17.8-173.0) and absence of ketone during hypoglycemia. The fact that the boy
had a wonderful response to glucagon made metabolic causes for persistent hypoglycemia such
as glycogen storage and gluconeogenic enzymes deficiencies are not likely.9 Furthermore there
are not many causes of persistent hypoglycemia associated with negative ketone which are
congenital hyperinsulinism and defect in the β oxidation of the fatty acid. As ketone is present
during hypoglycemia, therefore congenital hyperinsulinism is more likely.
The choice of drugs to treat persistent hypoglycemia secondary to hyperinsulinism is limited.
The first line is oral diazoxide that acts by opening the KATP gate and thus turning off the insulin
production. The recommended dose is 5-20mg/kg/day in divided doses. It works synergistically
with chlorothiazide to reduce fluid retention. Nifidipine works by blocking the voltage gated
calcium channel as calcium is required for insulin exocytosis but the experience related to its
usage is limited. Octreotide is a somatostatin analog, suppressing insulin release by acting on
KATP channel and binding to somatostatin receptors. 10
The clinical parameters that may suggest the boy to have KATP channel mutation are the very
early onset of hypoglycemia at 2 hour of life, severe hypoglycemia and diazoxide resistance
.11Congenital hyperinsulinism is most often sporadic. 12 However it can also be familial.
Homozygous mutation is usually associated with severe disease, diazoxide resistance and KATP
channel mutation while those with autosomal dominant runs as a mild disease, diazoxideresponsive and non-KATP mutation .13 Genetic or molecular study can guide the treatment
options especially in a case of diazoxide resistance as it is highly suggestive of KATP channel
mutation. 14 Interestingly, CHI also has a unique genetic mechanism. Loss of heterozygosity is a
non -mendellian mechanism in which there is loss of normal maternal chromosome during fetal
life/embryonic development .The patient would only have a copy of mutant SUR1 genes from
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the unaffected father. Together with presence of growth stimulating gene and absence of growth
suppressing genes, the affected area would grow into a discrete focal lesion .15
Histologically, congenital hyperinsulinism is classified into focal or diffuse form. Focal form
contributes about 40% while diffuse form is 60 %.16 Eighty percent of diazoxide resistance case
is due to focal form of CHI. Surgical treatment of the focal form is curative and thus , the finding
of diazoxide resistance case should warrant further workup to look for the focal form of CHI as
the surgical treatment is curative.17
For the proband, analysis of coding and flanking intronic regions of the KCNJ11 gene ,all
coding regions and exon/intron boundaries of the ABCC8 gene (U63421 and L78208), P2
promoter, all coding regions and exon/intron boundaries of the HNF4A gene were performed by
Sanger sequencing. The boy had heterozygous nonsense mutation, p.Arg934Ter (p.R934*) and
involving the amino acids, c.2800C>T and this mutation resides in exon 23 of ABCC8 gene. He
inherited this from his unaffected father who had the same mutation. His mother was also
screened and no mutation was detected. As the boy had only inherit one copy from his father
and there is no other copy from the mother, it is highly likely that he had loss of heterozygosity
and his CHI is most probably focal in nature. The only way to confirm this is by extracting DNA
from the focal site during surgery. 18F-DOPA scan is required to localize the focal lesion before
surgery .18
The longest follow up on the use of octreotide was 5.9 years from the Japanese series. It has been
proven to be safe and effective for diazoxide resistance CHI. 19 The reported side effects include
drug induced hepatitis but this could be overcome by reducing the dose. 20 Serial liver enzymes
for this boy was fairly acceptable and the glycated hemoglobin A1c was between 4.8 – 5.9%
(Table 1).The boy has been on subcutaneous octreotide that was delivered via portable insulin
pump for almost 2 years. Even though his growth parameters are at the 3rd percentiles but he was
growing steadily following the curve towards his target height as both of his parents are also of
small built (Figure 1). Continuous glucose monitoring was done for 7 days and his blood sugar
pattern was 80 % within acceptable target of 4-8 mmol/L with the dose of octreotide at
10mcg/kg/day (Figure 2). This short review and follow up of a confirmed case of diazoxide
resistance congenital hyperinsulinism has proved that octreotide is effective to turning off the
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excessive insulin production and safe for a long term use while waiting for a more definitive
treatment.
Conclusion
KATP channel is the commonest cause for diazoxide resistant congenital hyperinsulinism and
octreotide is proven to be safe and effective for treatment of diazoxide resistance CHI.
References
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3. Meissner T, Mayatepek E. Clinical and genetic heterogeneity in congenital hyperinsulinism.
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Med Genet. 2009 May;46(5):289-99.
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of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor
mutations. Diabetes. 2001 Feb;50(2):322-8.
6. Bellanné-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, Arnoux JB,
Valayannopoulos V, Gobrecht S, Sempoux C, Rahier J, Fournet JC, Jaubert F, Aigrain Y,
Nihoul-Fékété C, de Lonlay P. ABCC8 and KCNJ11 molecular spectrum of 109 patients with
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Med Genet. 2009 May;46(5):289-99.
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8. Courtney B. Sweet, Stephanie Grayson, Mark Polak. Management strategies for neonatal
hypoglycemia.. J Pediatr Pharmacol Ther. 2013 Jul-Sep; 18(3): 199–208.
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26-Dec 9;18(21):1306-10.
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hypoglycemia due to congenital hyperinsulinism of infancy (HI). Pediatr Endocrinol Rev. 2004
Nov;2 Suppl 1:163-7.
11. Guerrero-Fernandez J, Gonzalez Casado I, Espinoza Colindres L, Gracia Bouthelier R.
[Congenital hyperinsulinism. Review of 22 cases]. An Pediatr (Barc). 2006 Jul;65(1):22-31.
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ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive
congenital hyperinsulinism. J Med Genet. Nov;47(11):752-9.
13. Sandal T, Laborie LB, Brusgaard K, Eide SA, Christesen HB, Sovik O, et al. The spectrum
of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy. Clin
Genet. 2009 May;75(5):440-8.
14. Hu S, Xu Z, Yan J, Liu M, Sun B, Li W, et al. The treatment effect of diazoxide on 44
patients with congenital hyperinsulinism. J Pediatr Endocrinol Metab.25(11-12):1119-22.
15. Fournet JC, Mayaud C, de Lonlay P, Verkarre V, Rahier J, Brunelle F, et al. Loss of
imprinted genes and paternal SUR1 mutations lead to focal form of congenital hyperinsulinism.
Horm Res. 2000;53 Suppl 1:2-6.
16. Sempoux C, Guiot Y, Jaubert F, Rahier J. Focal and diffuse forms of congenital
hyperinsulinism: the keys for differential diagnosis. Endocr Pathol. 2004 Fall;15(3):241-6.
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17. Hardy OT, Hernandez-Pampaloni M, Saffer JR, Suchi M, Ruchelli E, Zhuang H, et al.
Diagnosis and localization of focal congenital hyperinsulinism by 18F-fluorodopa PET scan. J
Pediatr. 2007 Feb;150(2):140-5.
18. Mohnike K, Blankenstein O, Minn H, Mohnike W, Fuchtner F, Otonkoski T. [18F]-DOPA
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octreotide in the treatment of congenital hyperinsulinism. J Pediatr. 1993 Oct;123(4):637-43.
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HbA1c (%)
AST (U/L)
ALP (U/L)
ALT (U/L)
22.03.14
35
320
45
14.04.14
48
422
38
13.07.14
43
339
20
14.07.14
4.8
10.03.15
5.9
56
394
26
15.09.15
5.3
45
345
15
29.12.15
47
342
14
10.4.16
5.2
51
317
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Table 1: Summary of main investigations during follow up to assess efficacy and safety of octreotide
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Figure 1: Growth chart for serial height and weight
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Figure 2: Seven days continuous glucose monitoring system
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