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Year : 2021  |  Volume : 1  |  Issue : 2  |  Page : 124-126

Congenital hyperinsulinism: A case report and challenges in management

1 Department of Pediatrics, V.M.M.C. and Safdarjung Hospital, New Delhi, India
2 Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India

Date of Submission04-Mar-2021
Date of Decision03-May-2021
Date of Acceptance05-May-2021
Date of Web Publication31-May-2021

Correspondence Address:
Dr. Shobhna Gupta
Department of Pediatrics, V.M.M.C. and Safdarjung Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_76_21

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Background: Congenital hyperinsulinism (CHI) is a rare condition that usually presents in the newborn period. It is characterized by hypoketotic hypoglycemia due to excessive insulin secretion. We describe below a case of CHI due to a paternally inherited mutation of the ABCC8 gene and the challenges in its management. Clinical Description: A term female appropriate for gestational age baby with an uneventful antenatal period and delivery presented at 46 h of life with fever, decreased oral acceptance, lethargy, and hypoglycemic seizures. On examination, the baby was febrile but hemodynamically stable with no other clinical evidence of sepsis. Management: Child had recurrent episodes of hypoglycemia and required a glucose infusion rate of 12 mg/kg/min for maintaining euglycemia. The baby required diazoxide and octreotide for maintaining euglycemia. The hypoglycemia was nonketotic and associated with hyperinsulinism. 18-fluoro-dihydroxyphenylalanine positron emission tomography-computerized tomography scan showed diffuse uptake in the pancreas suggestive of diffuse hyperinsulinism. However, genetic testing showed heterozygous mutation for paternally transmitted pathogenic ABCC8 splicing variant. The child was stabilized and discharged on oral diazoxide and long-acting octreotide. Conclusion: CHI is an important cause of persistent hypoglycemia in neonates. Early diagnosis and management are important to prevent long-term sequalae. Establishing a correct molecular diagnosis is essential to decide about appropriate line of management (surgical/conservative) and provide genetic counseling to the family.

Keywords: Hyperinsulinism, neonate, octreotide, refractory hypoglycemia

How to cite this article:
Goel N, Gupta S, Sharma R, Arya S. Congenital hyperinsulinism: A case report and challenges in management. Indian Pediatr Case Rep 2021;1:124-6

How to cite this URL:
Goel N, Gupta S, Sharma R, Arya S. Congenital hyperinsulinism: A case report and challenges in management. Indian Pediatr Case Rep [serial online] 2021 [cited 2021 Sep 21];1:124-6. Available from: http://www.ipcares.org/text.asp?2021/1/2/124/317367

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoketotic hypoglycemia in neonates and infants.[1] The clinical manifestations of hyperinsulinism are due to hypoglycemia and include features such as floppiness, jitteriness, poor feeding, lethargy, irritability, and later as seizures, coma, and even neonatal death. Timely identification of hypoglycemia and its cause and initiation of treatment are essential to prevent neurological complications and long-term neurodevelopmental deficits.[2]

This case report describes the challenges faced in the diagnosis and management of CHI such as need for nuclear radio imaging such as18-fluoro-dihydroxy phenylalanine (18F-DOPA) positron emission tomography-computerized tomography (PET-CT) scan and genetic tests to determine etiology. Along with intensive clinical monitoring, transfer of care to parents before discharge is an important part of management. CHI due to monoallelic paternally transmitted recessive KATP pathogenic variant (ABCC8 splicing) predicts focal hyperinsulinism with 97% sensitivity and 90% specificity.[3] This case was unique as baby had a diffuse insulinoma on PET scan which changed the line of management from surgical to medical conservative therapy.

  Clinical Description Top

A female baby was born out of nonconsanguineous marriage to 26-year-old primigravida at 38 weeks of gestation. The antenatal period was uneventful with no history of drug intake during pregnancy. The child was delivered vaginally with APGAR score of 8, 9. Baby was appropriate for gestational age with birth weight of 3000 g and age-appropriate length and head circumference. She had normal systemic examination with no apparent congenital abnormalities at birth. Baby started taking breast feeds soon after birth. Baby was well till 46 h of life when she presented with complaints of fever (38.5°C), decreased oral acceptance, lethargy, and one episode of seizure in the form of uprolling of eyeballs and tonic–clonic movements. On examination, the baby was hemodynamically stable, febrile (38.5°C), and hypoglycemic (37 mg/dL). Keeping a provisional diagnosis of early onset sepsis, sepsis screen, and lumbar puncture were done which showed no evidence of sepsis or meningitis. Ultrasound cranium was normal.

Management and outcome

The baby was given a bolus of 10% intravenous dextrose and started on glucose infusion rate (GIR) @6 mg/kg/min which had to be gradually increased to a GIR of 12 mg/kg/min in view of recurrent episodes of hypoglycemia on lower GIRs. Whenever GIR was stepped down and oral feeds were started, baby had episodes of hypoglycemia. In view of persistent hypoglycemia, differential diagnosis of inborn errors of metabolism such as galactosemia, causes of hyperinsulinism, endocrine disorders such as hypopituitarism and adrenal insufficiency were kept, and further workup was done.

Critical samples at the time of hypoglycemia were negative for plasma ketones and showed hyperinsulinism (insulin = 3.2 uIU/mL). Metabolic workup including lactate, ammonia, urine for reducing substances, tandem mass spectroscopy, gas chromatography–mass spectrometry, and Galactose-1-Phosphate Uridyltransferase (GALT) assay were within normal limits. Cortisol, thyroid profile, and growth hormone levels were normal. Glucagon challenge test showed a glycemic response of >30 mg/dL on administration of 0.03 mg/kg of glucagon injection intravenously which supported the diagnosis of hyperinsulinism. The baby was given oral diazoxide at 5 mg/kg/day in three divided doses which was gradually increased to 15 mg/kg/day to maintain blood sugars. As sugars could not be controlled on the same, injection octreotide was introduced at 10 mcg/kg/day and increased to 20 mcg/kg/day every 6 hourly. Once blood sugar levels were stabilized on injection octreotide, diazoxide was stopped. In view of labile blood sugar levels even on diazoxide, nuclear imaging and genetic studies were planned.

18F-DOPA PET-CT scan showed diffuse uptake in the pancreas suggestive of diffuse hyperinsulinemia. Genetic studies done on child and parents using next-generation sequencing – targeted (tNGS) gene panels showed a heterozygous pathogenic mutation for a paternally inherited pathogenic ABCC8 splicing variant [Figure 1]. Sequence analysis includes the coding exons and flanking intronic regions (50 bp upstream–10 bp downstream of each exon). Confirmation of mutations identified by tNGS is undertaken by Sanger sequencing. Both the parents were fine and did not have any significant history of similar illness.
Figure 1: Details of genetic mutation

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Magnetic resonance imaging Brain done at 1 month of age showed cystic encephalomalacia with surrounding gliosis in bilateral parieto-occipital lobes and frontal lobes suggestive of brain injury due to hypoglycemia.

Final diagnosis was made as congenital diffuse hyperinsulinism with paternally inherited pathogenic heterozygous ABCC8 splicing variant mutation with neonatal hypoglycemic brain injury.

Once the baby was able to maintain blood sugar levels (till 4–5 h postinjection) on subcutaneous injections of octreotide, the mother was taught to monitor blood glucose by glucometer and technique of giving octreotide injection subcutaneously. Baby was discharged on monthly intramuscular injection of 2 mg Octreotide long-acting Release (LAR). Parents were counseled regarding frequency of feeding, daily home blood glucose monitoring, medicine delivery, and possible side effects of hypoglycemia or infection at home. Baby was followed up till 9 months of age when she was maintaining euglycemia on the same. She had started sitting without support, developed stranger anxiety, and able to speak bisyllables with palmar grasp present. Hearing and vision were normal. Baby's weight and length were 7.5 kg, 67 cm, respectively (appropriate as per the WHO growth charts) at 9 months of age.

  Discussion Top

CHI in young infant usually results from inappropriate, excessive secretion of insulinor deficiency of one of the hepatic glucoregulatory enzymes. CHI may have devastating consequences in this age group and demands early recognition and effective treatment. Signs and symptoms are mostly nonspecific such as lethargy, poor feeding, jitteriness, apnea, and seizures, but the associated hypoglycemia can be easily diagnosed with a glucometer. The challenge lies in maintaining euglycemia, which requires very high GIR. The diagnosis of CHI is suspected if there is the presence of persistent/recurrent hypoglycemia on a GIR >8 mg/kg/min. Increased levels of serum insulin and/or serum c-peptide levels at the time of hypoglycemia are diagnostic of CHI. Glucagon challenge test supports the diagnosis. The goal of management is to maintain euglycemia to prevent brain damage and sudden deaths due to hypoglycemia. The recommended levels of blood glucose level for babies with suspected CHI is >3.9 mmol/L (70 mg/dL).[4] Medical management consists primarily of frequent feeding, nasogastric feeding may be required to be given by infusion and highintravenous GIR to maintain blood sugar levels.[5] The main drugs for treatment are diazoxide (a potassium ATP channel agonist), octreotide (somatostatin analog), glucagon, glucocorticoids. Diazoxide keeps KATP channel found across cell membranes in the beta cells of the pancreas open, thereby inhibiting insulin secretion. The dose of diazoxide used is 5–20 mg/kg/day 8 hourly. Octreotide causes activation of somatostatin receptors 5, stabilizes KATP channel, and inhibits calcium channels, thereby inhibiting insulin release. Dose used is 5–25 mcg/kg/day subcutaneous injections three or four times a day. Glucagon injections (0.5–1 mg, subcutaneous) in episodes of acute symptomatic hypoglycemia or as a continuous intravenous infusion @ 1–20 mcg/kg/h for short-term maintenance of glucose levels along with octreotideare also used.

CHI has a strong genetic basis and mutations in the key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A, and UCP2) regulating insulin secretion have been identified.[6] The ABCC8 gene provides instructions for making the sulfonylurea receptor 1 protein, subunit of the KATP channels found across cell membranes in the beta cells of the pancreas. The KATP channel controls the secretion of insulin from beta cells into the bloodstream. Recessive inactivating mutations in ABCC8 and KCNJ11 genes, which alter the function of KATP channels causing unregulated insulin secretion unresponsive to diazoxide, are the most common causes of severe CHI found in 50% of the patients.[5] CHI can be focal, diffuse, or atypical but clinically indistinguishable.[7] Confirmed cases of CHI can be differentiated into focal and diffuse forms using 18F-DOPA-PET scan.

CHI with a paternally inherited heterozygous mutation mostly suggests focal hypersecretion of insulin.[3] On review of literature, very few case reports with similar associations were found; however, none of them was reported from India.[8],[9],[10]

Follow-up of all cases should be done to look for any neurodevelopment delay, cerebral palsy, epilepsy, vision issues, and to initiate early intervention. Genetic counseling is an important part of management. It includes genetic testing of both the parents and discussion about the risk of recurrence and need for prenatal testing in future pregnancies.

Early and prompt diagnosis of CHI with aggressive management to maintain euglycemia is crucial for an intact survival of baby. Genetic studies especially in babies unresponsive to diazoxide therapy are important in finding out the mutations and genetic defects. These help in decision of definitive management and counseling of the parents for prognosis of this baby as well as for future pregnancies.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Demirbilek H, Hussain K. Congenital hyperinsulinism: Diagnosis and treatment update. J Clin Res Pediatr Endocrinol 2017;9:69-87.  Back to cited text no. 1
Aynsley-Green A, Hussain K, Hall J, et al. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000;82:F98-107.  Back to cited text no. 2
Snider KE, Becker S, Boyajian L, et al. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab 2013;98:E355-63.  Back to cited text no. 3
Thornton PS, Stanley CA, De Leon DD, et al. Recommendations from the pediatric endocrine society for evaluation and management of persistent hypoglycemia in neonates, infants, and children. J Pediatr 2015;167:238-45.  Back to cited text no. 4
Vora S, Chandran S, Rajadurai VS, et al. Hyperinsulinemic hypoglycemia in infancy: Current concepts in diagnosis and management. Indian Pediatr 2015;52:1051-9.  Back to cited text no. 5
Mohammed Z, Hussain K. The genetics of hyperinsulinemic hypoglycemia. Neo Rev 2013;14:179-88.  Back to cited text no. 6
Yorifuji T, Kawakita R, Nagai S, et al. Molecular and clinical analysis of Japanese patients with persistent congenital hyperinsulinism: predominance of paternally inherited monoallelic mutations in the KATP channel genes. J Clin Endocrinol Metab 2011;96:E141-5.  Back to cited text no. 7
Ros-Pérez P, Golmayo L, Cilleruelo ML, et al. Octreotide-related exocrine pancreatic insufficiency (EPI) in congenital hyperinsulinism. J Pediatr Endocrinol Metab 2020;33:947-50.  Back to cited text no. 8
Tung JY, Lai SH, Au SL, et al. Coexistence of paternally-inherited ABCC8 mutation and mosaic paternal uniparental disomy 11p hyperinsulinism. Int J Pediatr Endocrinol 2020;2020:13.  Back to cited text no. 9
Chandran S, Peng FY, Rajadurai VS, et al. Paternally inherited ABCC8 mutation causing diffuse congenital hyperinsulinism. Endocrinol Diabetes Metab Case Rep 2013;2013:130041.  Back to cited text no. 10


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