Focal congenital hyperinsulinism resulting from biallelic loss of function of KCNJ11 gene

Abstract

Congenital hyperinsulinism (CHI) characterised by inappropriate secretion of insulin despite low blood glucose can result in irreversible brain damage if not promptly treated. The most common genetic cause of hyperinsulinism is the pathogenic variants in ABCC8 and KCNJ11, causing dysregulated insulin secretion. Rapid testing is crucial for all patients because finding a mutation significantly impacts this condition’s clinical management. We report a rare case of focal CHI after a homozygous KCNJ11 mutation who underwent a selective lesionectomy and required octreotide for euglycaemia.

Background

Congenital hyperinsulinism (CHI) is a rare and heterogeneous genetic disorder that affects pancreatic β-cell functions to cause refractory hypoglycaemia due to an uncontrolled insulin release. About one-third to two-third of CHI patients have mutations in KCNJ11 or ABCC8 genes, which, respectively, encode pore-forming and regulatory subunits of ATP-sensitive potassium channels in β-cells.^{1 2} While KCNJ11 is mutated less commonly than ABCC8,³ at least 205 pathogenic variants of KCNJ11 have been described in CHI patients with refractory hypoglycaemia that requires multidisciplinary management.^{3 4} Most of the homozygous KCNJ11 mutations have been reported to cause diffuse CHI affecting almost all β-cells of the pancreas.³ We report an infant with focal CHI secondary to a homozygous KCNJ11 mutation.

Case presentation

The male baby, firstborn of second-degree consanguineous marriage, was delivered vaginally at term, with a weight of 3.5 kg and Apgar scores of 8 and 9 at 1 min and 5 min, respectively. His 22-year-old mother had been diagnosed with gestational diabetes mellitus (DM) in the third trimester and was treated with insulin and oral hypoglycaemic agents. Both father and paternal grandmother of the baby had type 2 DM, managed with oral hypoglycaemic agents.

Investigations

From day 2 of life, the baby had hypoglycaemic seizures. These were initially managed with intravenous glucose infusions and increasing glucose infusion rate. A critical sample obtained at the time of hypoglycaemia (blood glucose=18 mg/dL) revealed elevated levels of insulin (36 mU/L), high C peptide (9.56 ng/mL) and normal levels of cortisol. Given hyperinsulinaemia, octreotide and hydrocortisone were administered, in addition to glucose infusion and antiseizure drugs. In this case, the glucose infusion rate was 14.5 mg/kg/min with a minimal blood glucose of 0.75 mmol/L. Serum insulin and C peptide levels were 36 mU/L and 9.56 ng/mL, with branched-chain amino acids being 62.566 μM for valine and 105.6 μM for leucine-isoleucine, and fatty acids of C8 being 0.014 μM.⁶⁸Ga-labelled (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-1-NaI3-octreotide (⁶⁸Ga-DOTANOC) positron emission tomography (PET) scan, performed on day 43 of life, revealed selectively increased octreotide receptor expression in the distal body of pancreas. A distal pancreatectomy was performed 5 days later to control the hypoglycaemia unresponsive to pharmacotherapy. Histopathological examination of the resected tissue and immunohistochemistry for the general endocrine marker synaptophysin revealed a restricted pancreatic area with adenomatous β-cell hyperplasia lesion comprising of confluent islets of Langerhans (figure 1).

Figure 1.

Distal pancreatectomy performed revealing on histopathology (A, B). (A) Immunohistochemistry showing positivity for synaptophysin in islets of Langerhans. (B) H&E high power showing an increase in the number of islets of Langerhans in intimate association with ducts and ductules together forming ductoinsular complexes suggestive of nesidioblastosis. (C) Gallium positron emission tomography scan demonstrated increased uptake of ⁶⁸Ga-labelled (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-1-NaI3-octreotide in the distal body of the pancreas.

Molecular gene-targeted testing for KCNJ11 and ABCC8 genes using Sanger sequencing showed the boy to be homozygous for pathogenic KCNJ11 missense variant mutation, confirming autosomal recessive CHI. The missense mutation identified KCNJ11 gene located on chromosome 11 in this patient was c.844G>A (g.17408795, NM_000525.3.), leading to p.(Glu282Lys). Both parents were heterozygous for the same mutation.

Differential diagnosis

Hyperinsulinism can be transient, resulting from perinatal stress in neonates with fetal distress, birth asphyxia, small for gestational age and infants born to diabetic mothers. Hence a birth history helps look for these factors before testing for genetic mutations leading to CHI. Insulinomas, proinsulinaemic hypoglycaemia and hyperinsulin-like hypoglycaemia, are rare, but plausible causes to be looked for.⁵

Outcome and follow-up

Blood sugar level stabilised after the surgery, and oral feeding was gradually established. At age 64 days, the baby was discharged on breastfeeding with supplemental formula feeds, octreotide and phenobarbitone. At the last follow-up, at age 10 months, the boy had no visual impairment, could stand with support, cruise around furniture and speak monosyllables.

Discussion

Though rare, with an estimated incidence of sporadic CHI varying from 1 in 27 000 to 1 in 50 000 live births, CHI is a complicated and challenging paediatric endocrine disorder.^{6 7} The recurrent hypoglycaemic episodes in this disorder have neurodevelopmental sequelae, and hence early identification and treatment are the cornerstones for the optimal outcome. Disease onset with hypoglycaemic seizures has been reported from day 2, as in our case, till few months of age. The the most common presentation of CHI is refractory hypoglycaemia requiring high glucose infusion rates with detectable insulin in blood during hypoglycaemic episodes. Diagnostic biochemical criteria for hyperinsulinaemic hypoglycaemia include a glucose infusion rate >8 mg/kg/min with blood glucose <3 mmol/L and serum with detectable insulin and low ketones, fatty acids and branched-chain amino acids, which was evident in this case.

Besides octreotide and glucagon, diazoxide helps control hypoglycaemia in cases where the potassium channel is present on the β-cell surface. Due to unavailability, we could not assess the diazoxide response and hence continued on octreotide. PET with ¹⁸F-dihydroxyphenylalanine (18F-DOPA) as the tracer is considered the first-line imaging method in diagnosing and localising focal CHI,⁸ but 18F-DOPA is not readily available because of difficulty in manufacturing the radiopharmaceutical agent. The ⁶⁸Ga-DOTANOC that we used has suboptimal sensitivity (78%) and negative predictive value (67%) in detecting focal CHI.⁸ The scan revealed selective increased octreotide receptor expression in the distal body of the pancreas (figure 1). Differentiation of CHI into diffuse or focal type helps in formulating management strategies. In focal CHI, selective lesionectomy/partial pancreatectomy can resolve hypoglycaemic episodes, as was seen in our case.

Genetic mutations lead to CHI in 40% of children. Most of these genetic mutations occur in KCNJ11/ABCC8 that form ATP-sensitive potassium channels in pancreatic β-cells. The effect of the mutation on the expression and function of the channel determines the clinical phenotype. Our patient had pathogenic missense mutations in KCNJ11 as determined by targeted Sanger sequencing for genes KCNJ11 and ABCC8. Homozygous KCNJ11 mutation was identified in the baby. The c.844G>A missense mutation leading to p.Glu282Lys amino acid change, inherited from both parents.

There have been case reports of CHI in Indian babies with most mutations in ABCC8, but few in KCNJ11, as seen in our case.⁹ Although the biallelic loss of function of KCNJ11 leads to diffuse CHI, in our case, the homozygous KCNJ11 mutation caused focal CHI. Imaging and genetic studies are essential for diagnosing CHI and planning its management. The recurrence risk for de novo mutations is none, while it is almost negligible in the focal form.¹⁰ For consanguineous parents, the paternal mutation responsible for a focal state in a family should be screened in the mother for the next pregnancy to look for a homozygous mutation carried by each parent, leading to diffuse hyperinsulinism.^{9 11} As hypoglycaemia has long-term sequelae like visual disturbances, motor dysfunction, intellectual disabilities, somatic and attention-related issues, it needs to be identified and corrected at the earliest.^{12 13} There is an urgent need for novel therapies that do not necessitate pancreatectomy and its long-term complications.

Learning points.

• Congenital hyperinsulinism involving KCNJ11 gene mutations mostly results in diffuse cases, rarely being focal.

• The timely diagnosis of the underlying cause for resistant hypoglycaemia is not only life-saving in neonates, but also crucial for predicting outcomes.

• There is a need for research for novel therapies to avoid surgery in such scenarios.