1Department of Pediatrics, Division of 1Endocrinology and Division of 2Neonatology, Yuzuncu Yil University, School of Medicine, 65080 Van, Turkey 3Institute of Biomedical and Clinical Science, University of Exeter Medical School, UK
Received November 10th, 2016 - Accepted December 14th, 2016
Introduction Hyperinsulinism is the most common cause of both transient and persistent hypoglycemia in the neonatal period. Hyperinsulinism due to mutations in the ATP-sensitive potassium channel encoded by the KCNJ11 and ABCC8 genes cause the most common and severe form of hyperinsulinism. Herein, we present a case of congenital hyperinsulinism in which a novel KCNJ11 mutation was identified. Case Report An eight-day-old boy with a birth weight of 4,550 g born to a 32-year-old female with diabetes mellitus was transferred to our clinic with the diagnoses of respiratory distress syndrome, congenital heart disease and hypoglycemia. A diagnosis of congenital hyperinsulinism was made based on the presence of elevated serum insulin levels (109 μIU/mL [2.6-24]) during hypoglycemia. Levels of serum growth hormone, cortisol, ammonium, and lactate were normal. Metabolic screening tests for blood and urine ketones and fatty acid oxidation defects were found to be normal. Glucose infusion (14 mg/kg/min), glucagon infusion, and diazoxide were initiated based on the diagnosis of hyperinsulinemic hypoglycemia; however, glycemic control was only achieved after the addition of octreotide and nifedipine. There were no abnormal findings in sonography and abdominal magnetic resonance imaging (MRI). Molecular diagnosis ABCC8 and KCNJ11 mutation analyses was performed on the genomic DNA extracted from peripheral blood. A novel homozygous missense mutation (p.E126K) was detected in KCNJ11 confirming the diagnosis of congenital hyperinsulinism. Conclusion A novel homozygous missense mutation (p.E126K) was detected in our case, which resulted in hyperinsulinism.
Hyperinsulinemic hypoglycemia, KCNJ11 gene, homozygous (p.E126K) mutation
Hyperinsulinism is the most frequent cause of both transient and persistent hypoglycemia in the neonatal period . Biochemically, congenital hyperinsulinism is the inappropriate release of insulin from pancreatic β-cells despite hypoglycaemia. Its incidence is estimated to be 1: 40,000 to 50,000 in outbred populations . However, it has an incidence up to 1: 2,500 in some populations where consanguinity is widely practiced . Hyperinsulinism due to mutations in the KCNJ11 and ABCC8 genes which encode the pancreatic ATP-sensitive potassium [KATP] channel are the most common cause of hyperinsulinism. Histologically two different forms are recognised, diffuse and focal, with the diffuse form commonly inherited in an autosomal recessive manner. In contrast focal disease is usually sporadic. Patients with KATP channel mutations are often born macrosomic with severe hypoglycemia usually presenting immediately after birth [4, 5].
The diagnosis of congenital hyperinsulinism is made according to the following criteria: hyperinsulinemia (plasma insulin >2μU/mL), plasma free fatty acid level <1.5 mmol/L, hypoketonemia (plasma ß-hydroxi butirate level <2 mmol/L) in blood samples obtained during hypoglycemia (glucose <50 mg/dL), and excessive glycemic response to glucagon (delta glucose >30 mg/dL by 1 mg intravenous glucagon). A lack of ketosis during hypoglycemia can exclude many causes of hypoglycemia including insufficient calorie intake, hypopituitarism, adrenal insufficiency, congenital enzyme defects, galactosemia, and fructosemia .
An eight-day old boy with a birth weight of 4,550 g born to a 32-year old female with diabetes mellitus was admitted to our neonatal intensive care unit with respiratory distress syndrome, congenital heart disease and hypoglycemia (glucose 32 mg/dL). His parents were second-degree cousins and there was no known history of disease in the family. Physical examination revealed the following findings: weight: 4,550 g (>97 percentile); height: 50 cm (25 to 50 percentile); and head circumference: 35 cm (25 to 50 percentile). Systemic examination showed that the patient was tachypneic and dyspneic with a respiratory rate of 80/bpm, and heart rate of 160/ bpm. There was no abnormal finding other than systolic murmur. Patent ductus arteriosus, atrial septal defect, and focal septal hypertrophy (non-obstructive) were detected on an echocardiogram. Mechanical ventilation was then initiated. In the referral facility, glucose infusion (6 mg/kg/min) was initiated and was subsequently increased to 10 mg/kg/min due to the persistence of hypoglycemia . A diagnosis of congenital hyperinsulinism was made based on the presence of elevated serum insulin-c-peptide levels (109 μIU/ml [2.6-24] and 12 ng/ml [1-1.5], respectively) during hypoglycemia (Table 1). Levels of serum growth hormone, cortisol, ammonium, and lactate were normal. Metabolic screening tests for blood and urine ketones and fatty acid oxidation defects were also found to be normal. Glucose infusion (14 mg/kg/min), glucagon infusion, and diazoxide (initially 5 mg/kg which increased up to 20 mg/ kg) were initiated but glycemic control was only achieved when octreotide and nifedipine were intoduced to the treatment regimen (final doses were 30 μg/kg and 1.5 mg/ kg/day, respectively). An 18F-DOPA-PET CT scan was not performed as this is currently not available in our country.
Although nasogastric feeding was initiated, the patient was unable to tolerate total enteral nutrition. He was unable to be extubated and his neuorolgical status deteriorated. There was diffuse edematous cerebral hemispheres in cranial magnetic resonance imaging (MRI). Glycemic control was provided but he was died because of respiratory insufficiency.
ABCC8 and KCNJ11 mutation analyses were performed on genomic DNA extracted from the peripheral blood. A novel homozygous missense mutation (p.E126K) was detected in the KCNJ11 gene, confirming the diagnosis of congenital hyperinsulinism (genetic analysis was performed at the University of Exeter Medical School, Molecular Genetics, Exeter, UK). His unaffected parents were both heterozygous carriers of the same mutation.
Hyperinsulinism is the most common cause of persistent hypoglycemia in the neonatal period and early childhood. It is a heterogeneous disease in terms of the genetic, clinical and histological findings.
Genes in which mutations are known to cause congenital hyperinsulinism include ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1 and HNF4A . In one study ABCC8 gene mutations were reported in 45% of the affected individuals, whilst mutations in KCNJ11 were found in 5% of patients . These two genes encode the sulfonylurea receptor 1 (SUR-1) subunit and the inwardly rectifying potassium channel subunit (Kir6.2) of the pancreatic KATP channel respectively. Loss-of-function mutations in these genes result in hyperinsulinism where insulin is secreted regardless of the plasma glucose level.
In our case, a homozygous p.E126K mutation was detected in KCNJ11, confirming congenital hyperinsulinism. Although this mutation is present in the database of the center where the genetic studies were performed, having been identified in an unrelated patient with congenital hyperinsulinism, it has not reported in the literature to date.
Hyperinsulinism due to KCNJ11 and ABCC8 mutations are the most common cause of hyperinsulinism and result in the most clinically severe phenotype. Hyperinsulinism due to K-ATP channel mutations can result in either diffuse or focal histological disease. The identification of a homozygous KCNJ11 mutation is in keeping with diffuse disease in our patient. Patients with K-ATP channel mutations are often born macrosomic with severe hypoglycemia diagnosed immediately after birth [4, 5]. Our case with KATP channel hyperinsulinism was also a macrosomic infant with severe hyperglycemia presenting early.
Diazoxide treatment is ineffective in the majority of cases with K-ATP channel mutations as the drug exerts its effects by binding to and opening the KATP channel. However, of two cases reported by Shimomura et al. , no response was achieved with diazoxide treatment in one case who had a paternally inherited heterozygous T294M mutation in KCNJ11 whilst another case with the same heterozygous mutation inherited by their unaffected mother responded to treatment. Ilamaran et al.  also reported a good response to diazoxide treatment in a case with a KCNJ11 mutation suggesting that some cases with these mutations are amenable to treatment with diazoxide.
For some patients with K-ATP channel mutations who do not respond to diazoxide introduction of additional therapies such a Octreotide and Nifedipine can result in normoglycaemia . In keeping with this our case who was refractory to diazoxide treatment acheived good glycemic control when treated with a combination of octreotide and nifedipine.
In conclusion, hyperinsulinism is the most common cause of persistent hypoglycemia in the neonatal period. A novel homozygous KCNJ11 missense mutation (p.E126K) was detected in our case, which resulted in hyperinsulinism.
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This manuscript does not contain any studies with human or animal subjects performed by the any of the authors.
SEF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number:105636/Z/14/Z).
The authors declare that they have no conflict of interest.