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Indian Pediatr 2020;57:
474-475 |
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Spontaneous Resolution of Congenital Hyperinsulinism With
Octreotide Therapy
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Suresh Chandran1*, Wai Lin Tun2, Phyo Thandar Htay2 and
Khalid Hussain3
1Departments of
Neonatology, KK Womens and Childrens Hospital, Singapore; 2Children’s
Hospital, Mandalay, Myanmar and 3Pediatric
Endocrinology, Sidra Medicine, Doha, Qatar.
Email:
[email protected]
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Hyperinsulinemic hypoglycemia is caused by dysregulated
insulin secretion from the pancreatic b-cells. Congenital
hyperinsulinism (CHI) is caused by genetic mutations in twelve
known genes. Histologically, lesions can be focal or diffuse.
Focal forms are often associated with paternal heterozygosity in
KCNJ11/ABCC8 genes, whereas diffuse forms are seen in patients
with maternal heterozygous, homozygous or compound heterozygous
mutations. 18F-DOPA PET/CT imaging can precisely localize the
lesion in focal forms, thereby facilitating cure by focal
lesionectomy unlike diffuse form is mostly resistant to medical
treatment and needs subtotal pancreatectomy [1].
We
report the case of a term non-dysmorphic male baby (weight 2400
g) born to a non-consanguineous couple in Myanmar. He was born
through meconium stained liquor with low Apgar scores, required
resuscitation and was ventilated for ten days. Hypoglycemia (1.6
mmol/L) was noted at six hours of age, which required mini bolus
followed by glucose infusion rate of 5.6 mg/kg/min. On day six,
he developed seizures with hypoglycemia and GIR was gradually
escalated to 19.5 mg/kg/min. Diagnosis of hyperinsulinemic
hypoglycemia was made in the presence of detectable insulin
(10.7 mU/L) with hypoglycemia (0.3 mmol/L) and hypoketonemia
(0.3 mmol/L). Medical treatment was initiated with nifedipine
while awaiting supply of diazoxide. Diazoxide was initiated at a
dose of 5 mg/kg/day and was gradually increased to 15 mg/kg/day
over a week with discontinuation of nifedipine. Subcutaneous
octreotide (dose of 7.5 mcg/kg/day) was added as GIR continued
to rise on diazoxide. With adequate response to octreotide,
diazoxide was later discontinued.
DNA samples of the
proband and parents were sent to UK for genetic study. A novel
heterozygous KCNJ11 missense variant, c.866G>C p. (Gly289Ala)
was identified in the proband. Sequencing of the ABCC8 gene was
normal. Sanger sequencing of KCNJ11 gene for the familial
variant indicated heterozygous mutation in father whereas the
mother was negative. The clinical significance of the P.
(Gly289Ala) variant is uncertain. A focal lesion was suspected
with the paternal mutation and 18F-DOPA PET/CT scan was
recommended.
DOPA PET/CT scan was unavailable in Myanmar
and there was no funding source for overseas transfer. Treatment
with octreotide was continued and GIR was successfully weaned
off with feeding increments to achieve full feeds by six months
of age. At nine months of age, octreotide dose was auto-tapered
to 3 mcg/kg/day while maintaining normoglycemia and discontinued
at 9.5 months of age. His glucose profile remained stable on
follow-up but neurodevelopmental assessment at 22 months of age
showed moderate mental and motor retardation. Vision and hearing
tested normal. He is currently enrolled in an early intervention
programme.
CHI is a heterogeneous disease caused by
mutations in at least twelve known genes [1]. Loss-of-function
mutations in KATP channel regulating genes constitute nearly 90%
of cases of diazoxide-unresponsive CHI, of which KCNJ11 is
associated in 10% [2].
The index case had
diazoxide-unresponsive CHI that detected a novel paternally
inherited KCNJ11 missense variant of uncertain significance at
p. (Gly289Ala). A different missense variant at the same residue
was previously reported by Mohnike, et al. [2] in a patient with
diazoxide-responsive CHI, which was shown to have arisen de novo
in the proband.
Similar spontaneous resolution has been
reported at 1.6 and 1.9 year in patients with CHI [3,4]. DOPA
tracer uptake may not correlate with the capacity of the
pancreatic lesion to secrete insulin and the clinical remission
of CHI could be a functional process without apoptosis of
mutated b-cells [5]. This finding prompts long-term follow-up of
our case to ensure optimal glucose regulation.
Most
patients with KATP channel gene mutations do not respond to
diazoxide treatment as it exerts its effects by keeping the
channel open, preventing b-cell membrane depolarization and
release of insulin. Octreotide reduces insulin secretion by
inhibiting intracellular entry of calcium and by decreasing the
insulin gene promoter activity [6]. These differences in the
site action possibly explain the treatment response in the index
case.
In summary, normoglycemia should be maintained to
prevent brain injury with high GIR and/or high caloric enteral
feeds in infants with CHI. Octreotide can be tried in diazoxide
unresponsive patients and spontaneous resolution can be seen in
CHI. Genetic studies help indicate the type of mutation.
DOPA-PET scan confirms nature of lesion prior to surgery, which
however remain poorly accessible in resource-limited settings.
Acknowledgements: Dr Sara E Flanagan PhD, Sir Henry Dale
Fellow, Genetic laboratory services, University of Exeter
Medical School, United Kingdom for the genetic study and
assistance with the preparation of the manuscript. Dr Eddy
Saputra Leman, PhD, Sr Scientific Editor, Duke-NUS Medical
School, Singapore and Prof Divakaran Liginlal (Carnegie Mellon
University, Pittsburgh, Pennsylvania) for editing the
manuscript.
Contributors: SC: clinical management,
reviewed and edited the manuscript; WLT and PTH: patient
management, outline of the case report and discussion; KH:
contributed to the genetic section of the case report and
reviewed and finalized the manuscript.
Funding: None;
Competing interest: None stated.
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