An Egyptian case of congenital hyperinsulinism of infancy due to a novel mutation in KCNJ11 encoding Kir6.2 and response to octreotide
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- Sherif, E.M., Abdelmaksoud, A.A., Elbarbary, N.S. et al. Acta Diabetol (2013) 50: 801. doi:10.1007/s00592-010-0217-1
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Congenital hyperinsulinism of infancy (CHI) is a rare heterogeneous disease mostly attributable to mutations in the genes encoding the KATP channel subunits found in pancreatic β-cells. Here, we report a child presenting at day 1 with persistent hyperinsulinemic hypoglycemia and who underwent open laparotomy and subtotal pancreatectomy with resection of tail and body of pancreas at 30 days of age. Normoglycemia was restored by Octreotide that was discontinued when the child was 7-month old. However, 3 months later Octreotide was re-administered as hypoglycemic attacks recurred. On follow-up, the child has adequate glycemic control and is thriving well with no neurodevelopmental morbidity. Genetic analysis revealed the novel mutation c.407G > A [p.R136H] in KCNJ11 encoding Kir6.2, confirming the diffuse form of CHI. This is to our knowledge the first reported Egyptian case of CHI due to a mutation in KCNJ11.
KeywordsNeonatal hypoglycemiaHyperinsulinismKCNJ11 mutationOctreotide
Congenital hyperinsulinism of infancy
Hydroxyacyl coenzyme A dehydrogenase
- KATP channel
Adenosine triphosphate-sensitive potassium channel
Potassium inward rectifier
Persistent hyperinsulinemic hypoglycemia of infancy
Congenital hyperinsulinemia of infancy (CHI), or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a rare disease characterized by inappropriate insulin secretion in the presence of hypoglycemia. Severe neurodevelopmental morbidity among these patients is reportedly attributable to late diagnosis and/or inability to control the profound hypoglycemia.
CHI can be classified into two major subgroups: ‘channelopathies’ and ‘metabolopathies’ . Channelopathies refer to defects in the pancreatic β-cell ATP-sensitive potassium channels (KATP channels) that lead to unregulated insulin secretion. Metabolopathies cause CHI either by altering the concentration of intracellular signaling molecules (such as ATP/ADP) or by accumulating the intermediary metabolites . The commonest genetic causes of CHI are autosomal recessive mutations in the genes ABCC8 and KCNJ11 (encoding the two subunits sulfonylurea receptor (SUR1) and potassium inward rectifier (KIR6.2) of the pancreatic KATP channels [3–5]. Autosomal dominant mutations have also been described . Activating mutations in glutamate dehydrogenase (GDH) are the second commonest cause of CHI . Furthermore, activating mutations in the glucokinase (GCK) gene have now been reported as a cause of congenital hyperinsulinaemic hypoglycemia . SCHAD, encoded by the short-chain l-3 hydroxyacyl coenzyme A dehydrogenase (HADHSC) gene, is an intramitochondrial enzyme that have been reported causing CHI , and Foxa2 (HNF3β) has recently been shown to be involved in regulating the expression of the HADHSC gene . Moreover, two further genetic etiologies have been described causing transient neonatal hyperinsulinism: mutations in the hepatocyte nuclear factor 4A (HNF4A)  and mutations in the monocarboxylate transporter (SLC16A1) causes physical exercise–induced hyperinsulinism . The mode of inheritance depends on the genetic etiology; GCK, GLUD1, HNF4A, and SLC16A1 mutations are inherited in an autosomal dominant manner, while SCHAD mutations are autosomal recessive . Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin, and insulin-receptor stimulating antibodies, Beckwith–Wiedemann Syndrome, and congenital disorders of glycosylation . Treatment is directed toward normoglycemia including frequent carbohydrate-enriched feedings, medical compounds, and surgery.
Our patient is the second in order of birth, of 1st cousin parents. She was a full-term neonate born after an uneventful pregnancy and negative history of maternal diabetes, with a birth weight of 4,000 g (75th percentile). During the first day of life, she became irritable and subsequently lethargic with jitteriness and cyanosis, and a blood glucose level of 1.1 mmol/l was measured with absence of urinary ketones. Despite intravenous glucose administration, new episodes of hypoglycemia occurred, followed by generalized seizures. The finding of two sets of inappropriately high serum insulin levels at hypoglycemia (insulin 14.1 and 16.4 μIU/ml together with glucose of 1.5 mmol/l and 1.6 mmol/l) with insulin/glucose ratio of approximately 0.5 and C-peptide was 3.8 ng/ml in the presence of hypoglycemia established the diagnosis of CHI. Adequate carbohydrate was provided as intravenous glucose at high concentrations (16 mg kg−1 min−1), together with a nasogastric feeding tube 3 hourly bolus feeds failed to maintain normoglycemia. In addition, intensive medical treatment had been given. She was treated with oral diazoxide (10 mg kg−1 day−1) which did not result in good control of hypoglycemia within 5 days. With diazoxide appeared not to control hypoglycemia, nifedipine (1.5 mg kg−1 day−1) had been used which was also not effective in achieving good control of blood glucose. Somatostatin (Octreotide) was initiated with gradual increase in a dose up to 45 μg/6 h. However, fluctuating blood glucose levels persisted with values below 1.1 mmol/l, and the attacks did not get milder over time. Failure to show any response after receiving combination of frequent feeding and short courses of medical treatment made surgical intervention inevitable. While preparing for surgery, extensive investigations were done in the form of extended metabolic screening tests (serum ammonium levels, acylcarnitine analysis, urinary organic acids), hormonal profile (serum cortisol, TSH, IGF-1, growth hormone, FSH, and LH) all were within normal ranges. The pancreas was normal by ultrasonography, and MRI of the abdomen done at 2 weeks of age was unremarkable, apart from large size of pancreas for age. Unfortunately, the patient did not undergo either pancreatic venous sampling or 18FDOPA-PET before surgery because of unavailability of these procedures in Egypt.
Hence, at 1 month of age, laparotomy and subtotal pancreatectomy with resection of tail and body of pancreas (85% of pancreas) was done. Histopathology revealed pancreatic tissue with hyperplasia of the islets of Langerhans in relation to the acinar units with focal lymphocytic infiltrates, a picture consistent with islet cell hyperplasia. Post-operatively, transient hyperglycemia was followed by persistent hypoglycemia, so Octreotide was restarted at a dose of 10 μg/8 h that stabilized the blood glucose level. Octreotide was discontinued at an age of 7 months, but hypoglycemic attacks relapsed 3 months later, and re-administration of Octreotide at a dose of 10 μg/8 h was warranted again followed by gradual withdrawal until subsided completely at 12 months old with no side effects noticed.
The KCNJ11 gene was analyzed at the Department of Pediatrics and Centre for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway. The coding exon as well as the flanking intron sequences was amplified with PCR and both DNA strands were sequenced with standard methods. Genetic screening revealed the mutation c.407 G > A [p.R136H] in KCNJ11 in the homozygous state, thus the patient has the diffuse form of hyperinsulinism. The parents were found to harbor the mutation in the heterozygous state.
Our patient is now 14 months old (11 kg, 75th percentile) thriving well with normal mental and motor milestones with current fasting glucose tolerance off octreotide ranging from 5.5 to 7.5 mmol/l.
The syndrome of CHI was described more than 40 years ago by Mc Quarrie . This disorder affects about 1 in 50,000 live births and is characterized by continuous and unregulated insulin secretion in the face of very low blood glucose levels . Patients with this disorder usually present at birth or shortly afterward. In some cases, their blood glucose levels fall so low that they suffer brain damage as a consequence. Despite the inordinate amount of interest in this syndrome, the pathogenesis of the disease has not yet been completely elucidated. For decades, the disease has been ascribed to nesidioblastosis. This term, first coined by Laidlaw, describes the persistence of a diffuse and disseminated proliferation of islet cells budding off from ducts .
The concept of nesidioblastosis as the underlying condition of hyperinsulinism is still deeply rooted in the mind of many clinicians, although it has been questioned by several authors [17–19]. Indeed, observations based on quantitative immunohistochemical investigations have shown that nesidioblastosis is a common feature of the pancreas in normoglycaemic neonates and infants .
Progress in genetics and molecular biology has increased our understanding of the disease which has demonstrated mutations of the genes encoding both SUR1 [4, 20–22] and Kir6.2 . Insulin hypersecretion that characterizes CHI results from permanent depolarization of the β-cell membrane and thereby continuous Ca2+ influx and insulin secretion . The most common cause of CHI is mutations in ABCC8 (SUR1). Over 150 mutations have now been described contrasting only 24 mutations in KCNJ11 (Kir6.2) . This is perhaps not surprising given the fact that the KCNJ11 gene is much smaller than the ABCC8 gene . In our case, genetic screening revealed the mutation c.407 G > A [p.R136H] in KCNJ11 in the homozygous state. This mutation leads to a substitution of arginine for a histidine at codon 136 and has not been described previously although in the same codon it was recently reported that arginine has been replaced by leucine in patients with CHI , thus the outcome is unregulated insulin secretion. It was previously suggested that mutations in KCNJ11 cause HI by either reducing or by completely abolishing KATP channel activity in the surface membrane . In 2005, a novel mutation (H259R) was reported that affects both the trafficking and the function of the channel .
Two histopathologically and genetically distinct groups are recognized among patients with CHI due to ATP-sensitive potassium channel (KATP) defects: a diffuse type, which involves the whole pancreas, and a focal form, which shows adenomatous islet cell hyperplasia of a particular area within the normal pancreas . The characteristic differences between islets in both focal and diffuse forms of PHHI are analyzed by measuring the “β cell nuclear crowding” the nucleo–cytoplasmic ratio, the size of the β cell nuclei (mean nuclear radius) and morphometry. The diffuse form was associated with the presence of numerous abnormal large β cell nuclei and low nuclear crowding in the whole pancreas whereas, outside the lesion, no such nuclei were seen in the insular β cells of patients with a focal form of PHHI . Advances in genetic testing found that the typical diffuse form is most commonly due to recessive mutations in the genes encoding the two subunits of the KATP channel. Whereas the ‘focal’ form (focal adenomatous pancreatic hyperplasia) of CHI is found to be due to germline mutations in the paternal allele of ABCC8 and KCNJ11 genes, encoding SUR1 and KIR6.2, respectively, on chromosome 11p15 . In addition, the lesion exhibits a somatic loss of a part of the maternally inherited chromosome 11p which includes imprinted maternally expressed tumor suppressor genes (H19 and P57KIP2), paternally expressed insulin growth factor-2, as well as (non-imprinted) SUR1/Kir6. This results in a corresponding reduction to homozygosity of the paternal mutation, and the outcome is unregulated insulin secretion .
Advances in molecular genetics, radiological imaging techniques (such as Fluorine-18 l-3, 4-dihydroxyphenylalanine positron emission tomography (18FDOPA-PET) scanning) and laparoscopic surgery have completely changed the clinical approach to patients with the severe congenital forms of HH . 18FDOPA-PET scanning provide greater accuracy in pre-operative differentiation of focal and diffuse disease with 96% accuracy in diagnosing focal or diffuse disease and 100% accurate in localizing the focal lesion , earlier Otonkoski et al. presented preliminary data suggesting the usefulness of positron emission tomography with fluoro-l-dopa for localization of focal lesions . Moreover, the identification of abnormal β cell nuclei proved feasible, during surgery, on frozen sections of small pancreatic specimens taken from different parts of the gland. Thus, the morphological analysis of persurgical frozen sections might lead to the determination of the type of lesion (focal or diffuse), which would allow the surgeon to decide immediately during surgery on the most appropriate treatment localized or extensive resection .
Understanding the genetic basis of CHI has not only provided novel insights into beta-cell physiology but also aided in patient management and genetic counseling . Regarding medical treatment, diazoxide is the drug of first choice. Diazoxide increases the channel’s mean open probability, thus inhibiting insulin secretion, and is commonly used in states of unregulated insulin secretion, particularly insulinomas and some cases of CHI including those involving mutations in GCK, GLUD1, and SCHAD [32–35]. Mutations that decrease or destroy KATP channel activity will, however, result in continuous depolarization, and unregulated insulin secretion will not respond to diazoxide because a functional channel is required for these drugs to exert their effect . Thus, subjects with CHI due to homozygopus or compound heterozygous mutations in KCNJ11 or ABCC8 are usually diazoxide unresponsive. Nifedipine is a calcium channel antagonist and has been used in some patients with CHI, although the vast majority of patients fail to show any response. Despite this, there have been several reports of nifedipine-responsive CHI patients [37, 38].
In patients not responding to diazoxide, octreotide may prove effective. Al-Shanafey et al. studied 12 patients with CHI following laparoscopic pancreatectomy. Four (33%) were euglycemic with no medications. Three patients remained on octreotide post-operatively to be euglycemic, and three patients needed a combination of octreotide and diazoxide. One patient remained euglycemic for 10 months then started on octreotide because of recurrence of hypoglycemia . Semiz et al. reported a case of male neonate with diffuse form of CHI not responding to maximum doses of glucagon, prednisone, diazoxide, or octreotide and required maintenance on low-dose octreotide after subtotal pancreatectomy , while Mohnike et al. found that combination therapy of low-dose octreotide and subcutaneous glucagon infusion has been effective in preventing hypoglycemic episodes in severe CHI. Almost 80% of neonates with CHI fail to respond to medical treatment and require frequent oral feeding or near-total pancreatectomy . The role of surgery in focal CHI is relatively well defined because limited pancreatectomy is potentially curative for focal lesions. Monique et al. reported two patients with a focal form of the disease for whom diagnosis was made with laparoscopy. Laparoscopic enucleation of the lesion was curative. They concluded that laparoscopic investigation is worthwhile and feasible for any patient with CHI for whom medical treatment is insufficient to control insulin secretion . However, as the diffuse CHI is a heterogeneous disorder with respect to clinical presentation and response to medical therapy, the role of surgery is controversial. Two approaches of this condition are considered. One is surgical approach in performing near-total pancreatectomy which is a major operation. However; even after this procedure, normoglycemia is not always achieved and carries early mechanical, metabolic and infectious complications. Non-surgical therapy with frequent or continuous feeding, medication, and close monitoring is another alternative; this intervention can be complicated by unwarranted effects of medications and of invasive procedures. Diabetes occurs with both approaches but much less frequently and years later with non-surgical treatment . Definitely the rationale of therapy will depend on prevention of hypoglycemic episodes to avoid the high risk of permanent brain damage. In patients resistant to diazoxide, nifedipine, somatostatin analogues with frequent feeding regimens who failed to achieve stable euglycemia, the only remaining long-term option will be subtotal pancreatectomy. Early surgery (less than 100 days of age) is generally associated with improved neurodevelopmental outcomes and fewer endocrine and exocrine disturbances .
Diffuse congenital hyperinsulinism is predominantly an autosomal recessive disease, mostly arising from homozygous or compound heterozygous mutations in the genes encoding Kir6.2 or SUR1 and that often require a subtotal pancreatectomy. Still, it is not always possible to restore adequate glycemic control in patients with the diffuse form necessitating medical treatment to maintain normoglycemia. We here present the first Egyptian case of CHI due to a mutation in KCNJ11. In our subject with a homozygous and novel mutation (c.407G > A [p.R136H]) in KCNJ11, the patient failed to respond to medical treatment with the KATP agonist, diazoxide and Nifedipine. An 18FDOPA-PET scan was not available to confirm the nature of the disease, patient underwent 85% pancreatic resection and post-operatively, persistent hypoglycemia was manifested. We did, however, obtain good metabolic control with Octreotide with no signs of any side effects which was discontinued at 1 year of age. Thus, octreotide is a drug that may prove useful in diazoxide-unresponsive CHI due to mutations in KCNJ11.
We thank Janne Molnes for genetic analysis of the patient. Also, we would like to thank our patient and her family for consenting to present her case.