Diazoxide-unresponsive Congenital Hyperinsulinism Research Articles

Low-level mosaic GCK mutations in children with diazoxide-unresponsive congenital hyperinsulinism.

Some children with diazoxide-unresponsive congenital hyperinsulinism (HI) lack any detectable disease-causing mutation in peripheral blood DNA. To examine whether somatic post-zygotic mutations of known HI genes are responsible for disease in children with diazoxide-unresponsive HI requiring surgery with histology not classified as focal or Localized Islet Nuclear Enlargement (LINE), and without detectable mutations by standard genetic testing of peripheral blood DNA. Next-generation sequencing (NGS) was performed on specimens of pancreas from 10 children with diazoxide-unresponsive HI. Four unique GCK mutations were identified at low levels of mosaicism ranging from 4.4-10.1% in pancreatic DNA from five of these 10 children. The GCK mutations were not detectable in peripheral blood DNA by NGS in three cases from which peripheral blood DNA was available for testing. All four GCK mutations have been previously published as activating HI mutations. The histology was consistent with diffuse-HI in four of the five cases with mosaic GCK mutations. In one of these, hypomethylation of IC2 on chromosome 11p was identified in pancreatic and peripheral blood DNA. Histology of the fifth case revealed minor islet abnormalities suggestive of Beckwith Wiedemann Spectrum (BWSp) although molecular analysis for 11pUPD was negative in pancreas. These results indicate that post-zygotic somatic GCK mutations are responsible for some cases of non-focal diazoxide-unresponsive hyperinsulinism.

Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations. We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (KATP) channel variants were assessed using patch clamp recording and Western blot. Nine of 13 (69%) patients with ten different pathogenic variants (7 in ABCC8, 2 in KCNJ11 and 1 in GCK) were identified by the combined sequencing. The variant ABCC8 p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F KATP channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C KATP channels were defective in trafficking. One patient had a de novo dominant mutation in the GCK gene (p.I211F), and WES revealed mosaicism of this variant from another patient. Pathogenic variants in KATP channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the ABCC8 gene is highly suggestive of a founder effect. The I211F mutation in the GCK gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) KATP channels are also associated with the diazoxide-unresponsive phenotype.

Optimization of a glucagon-like peptide 1 receptor antagonist antibody for treatment of hyperinsulinism.

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic beta cell insulin secretion is excessive and results in hypoglycemia that can cause brain damage or death without treatment. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the beta cell ATP sensitive potassium channel (KATP), are unresponsive to diazoxide, the only FDA approved medical therapy, and require a pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent to inhibit insulin secretion in both congenital and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage-display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as Avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI as well as increased plasma glucose and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism.

Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in children. In addition to typical focal or diffuse HI, some cases with diazoxide-unresponsive congenital HI have atypical pancreatic histology termed Localized Islet Nuclear Enlargement (LINE) or mosaic HI, characterized by histologic features similar to diffuse HI, but confined to only a region of pancreas. Our objective was to characterize the phenotype and genotype of children with LINE-HI. The phenotype and genotype features of 12 children with pancreatic histology consistent with LINE-HI were examined. We compiled clinical features of 12 children with LINE-HI and performed next-generation sequencing on specimens of pancreas from eight of these children to look for mosaic mutations in genes known to be associated with diazoxide-unresponsive HI (ABCC8, KCNJ11, and GCK). Children with LINE-HI had lower birth weights and later ages of presentation compared to children with typical focal or diffuse HI. Partial pancreatectomy in LINE-HI cases resulted in euglycemia in 75% of cases; no cases have developed diabetes. Low-level mosaic mutations were identified in the pancreas of six cases with LINE-HI (three in ABCC8, three in GCK). Expression studies confirmed that all novel mutations were pathogenic. These results indicate that post-zygotic low-level mosaic mutations of known HI genes are responsible for some cases of LINE-HI that lack an identifiable germ-line mutation and that partial pancreatectomy may be curative for these cases.

Efficacy and safety of octreotide treatment for diazoxide-unresponsive congenital hyperinsulinism in China.

ABSTRACTImportanceOctreotide is an off‐label medicine for congenital hyperinsulinism (CHI), but is currently widely used for treatment of patients with CHI. Thus far, variable efficacy and adverse effects have been reported for octreotide.ObjectiveThe present study evaluated the efficacy and safety of a subcutaneous octreotide injection for treatment of diazoxide‐unresponsive CHI in China.MethodsThis study was a retrospective review of children with diazoxide‐unresponsive CHI who were treated with a subcutaneous octreotide injection. The efficacy and side effects of the treatment were assessed.ResultsTwenty‐five Chinese children (15 boys) were involved in the study. Their median age at diagnosis was 8 weeks (range, 1–24 weeks) and median age at the final follow‐up was 1.8 years (range, 0.3–3.3 years). Octreotide therapy effectively increased blood glucose levels in all patients. The intravenous glucose infusion rate was reduced in all patients. Twenty‐one patients gradually discontinued the intravenous glucose infusion while receiving octreotide combined with frequent carbohydrate/glucose‐rich feeding. Among patients with a monoallelic ATP‐sensitive potassium (KATP) channel mutation, 50.0% showed gradual remission during follow up, indicating that the octreotide treatment may be a feasible alternative to surgery, especially for patients with monoallelic KATP‐channel mutations. Transient elevation of liver enzymes occurred in 20.0% of patients, while asymptomatic gallbladder pathology occurred in one patient. The growth rates of these patients were normal (height standard deviation score was 0.3 ± 1.5 at the final follow‐up).InterpretationOctreotide was a well‐tolerated, effective therapy for most children with diazoxide‐unresponsive CHI.

SUN-270 Heterozygous Mutation in ABCC8 in a Pedigree with Congenital Hyperinsulinism, Multiple Macrosomic Stillbirths, and Adult-Onset Diabetes Mellitus

ABCC8 encodes the SUR-1 subunit of the ATP-sensitive potassium (K-ATP) channel on beta cells. Mutations in this gene are associated with K-ATP channel gain of function (diabetes mellitus) and loss of function (hyperinsulinism). We describe a family with a heterozygous variant of uncertain significance (VUS) in the ABCC8 gene that may be associated with both diabetes mellitus and congenital hyperinsulinism. A macrosomic boy (birth weight 3.86kg; >99th centile) was born to a mother with type 2 diabetes. On day 7 of life he was diagnosed with hyperinsulinism based on an insulin of 46.1mIU/L (2.6-24.9) and glucose of 2.2mmol/L. He responded to diazoxide and his hypoglycaemia appeared to resolve by 6 months old. The boy had an older half-sister who was also macrosomic at birth (>99th centile) and had diazoxide-responsive congenital hyperinsulinism which required treatment until two years of age. He also had an older brother who was stillborn with severe macrosomia at 36 weeks weighing 5.7kg (well above 99th centile). There was a family history of stillbirth of very macrosomic babies in five cases across two generations from three mothers. The boy’s mother was macrosomic and possibly hypoglycaemic as a neonate. She developed gestational diabetes in all of her pregnancies and diabetes at age 30 years. There is also adult-onset diabetes mellitus in the boy’s maternal grandmother, maternal great-aunt and maternal great-grandmother (diagnosed in the fourth or fifth decade). The cases of hyperinsulinism/foetal macrosomia and adult-onset diabetes follow an autosomal dominant pattern. Hyperinsulinism gene panel analysis revealed a heterozygous missense mutation in the ABCC8 gene (Ala1457Thr) in the boy, which was then found in his half-sister and mother. The VUS is in a highly conserved region of the SUR1 subunit and in-silico analysis tools suggest a deleterious effect. It has been reported in cases of hyperinsulinism (MacMullen 2011) and adult-onset diabetes mellitus (Ovsyannikova 2016), but never within the same pedigree. Genetic testing of other affected and unaffected family members is underway. This case suggests that a single heterozygous mutation (Ala1457Thr) in ABCC8, currently listed as VUS, may be responsible for both loss of function (hyperinsulinism) and gain of function (diabetes mellitus) of the K-ATP channel within a single pedigree. References MacMullen, C, Zhou, Q, Snider, E, Tewson, P, Becker, S, Aziz, A, Stanley, C. (2011). Diazoxide-Unresponsive Congenital Hyperinsulinism in Children With Dominant Mutations of the β-Cell Sulfonylurea Receptor SUR1. Diabetes, 60(6), 1797-1804. doi:10.2337/db10-1631 Ovsyannikova, A, Rymar, O, Shakhtshneider, E, Klimontov, V, Koroleva, E, Myakina, N, & Voevoda, M (2016). ABCC8 Related Maturity Onset Diabetes of the Young (MODY12) Clinical Features and Treatment Perspective. Diabetes Therapy, 7(3), 591-600. doi:10.1007/s13300-016-0192-9

Congenital Hyperinsulinism in China: A Review of Chinese Literature Over the Past 15 Years.

Objective:Congenital hyperinsulinism (CHI) is a rare but severe cause of hypoglycemia. The present study investigates the clinical presentation, therapeutic outcomes and genetic mutations of CHI in Chinese individuals over the past 15 years.Methods:The authors retrospectively reviewed one case in their department and 206 cases reported from January 2002 to October 2016 in China. PubMed, Ovid Medline, Springer and Wanfang Database, CBMD database, and CKNI database were the sources used to collect the data.Results:In total, 207 cases were recruited. Of these, the ages of 100 (48.3%) were within the 4th week after birth. Seventy-seven cases (37.2%) were born large for gestational age (LGA). Seizures occurred in 140 cases (67.6%). Among 140 cases (67.6%) who were administered diazoxide treatment, 90 (64.3%) were responsive. Seven cases (3.4%) received octreotide treatment and 19 cases (9.2%) underwent surgery. 63/129 cases (48.8%) were detected to have gene mutations, including ABCC8 (69.8%), KCNJ11 (12.7%), GLUD1, GCK, HADH, and HNF4A. Among the diazoxide-unresponsive cases, gene mutations were detected in 20/36 (55.6%) cases with ABCC8 and in 2 (5.6%) cases with KCNJ11. Among the diazoxide-responsive cases, gene mutations were detected in 8 patients with ABCC8, 4 with KCNJ11, 5 with GLUD1, and 1 with GCK.Conclusion:The present study indicates that most CHI cases occurred in neonates and that 1/3 of the cases were born LGA. ABCC8 and KCNJ11 are the most common gene mutations. More than half of the diazoxide-unresponsive CHI detected mutations are in ABCC8 and KCNJ11 genes. The GLUD1 gene mutations cause diazoxide-responsive CHI. Identifying the gene mutations can assist in the diagnosis and treatment of CHI.

A novel mutation ofABCC8gene in a patient with diazoxide-unresponsive congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is a rare condition that can cause irreversible brain damage during the neonatal period owing to the associated hypoglycemia. Hypoglycemia in CHI occurs secondary to the dysregulation of insulin secretion. CHI has been established as a genetic disorder of islet-cell hyperplasia, associated with a mutation of the ABCC8 or KCNJ11 genes, which encode the sulfonylurea receptor 1 and the inward rectifying potassium channel (Kir6.2) subunit of the ATP-sensitive potassium channel, respectively. We report the case of a female newborn infant who presented with repetitive seizures and episodes of apnea after birth, because of hypoglycemia. Investigations revealed hypoglycemia with hyperinsulinemia, but no ketone bodies, and a low level of free fatty acids. High dose glucose infusion, enteral feeding, and medications could not maintain the patient's serum glucose level. Genetic testing revealed a new variation of ABCC8 mutation. Therefore, we report this case of CHI caused by a novel mutation of ABCC8 in a half-Korean newborn infant with diazoxide-unresponsive hyperinsulinemic hypoglycemia.

A compound heterozygous mutation of ABCC8 gene causing a diazoxide-unresponsive congenital hyperinsulinism with an atypical form: Not a focal lesion in the pancreas reported by 18F-DOPA-PET/CT scan

Congenital hyperinsulinism (CHI) is a severe heterogeneous disorder due to dysregulation of insulin secretion from the pancreatic β-cells leading to severe hypoglycemia in infancy. 18-fluoro-l-3,4-dihydroxyphenylalanine positron emission tomography (18F‑DOPA‑PET)/CT is a useful tool in distinguishing between focal and diffuse disease preoperatively. But recent studies have suggested that the scanning may not be accurate as initially estimated. In this study we characterize a case of CHI with a compound heterozygous mutation of ABCC8 gene. The results of clinical investigation, gene mutation analysis, 18F‑DOPA‑PET/CT scan, and pathological examination showed some new characteristics that have never been reported. The patient was unresponsive to medical therapy with diazoxide and received pancreatectomy twice. Genetic analysis identified a compound heterozygous mutation in ABCC8 genes. Imaging with 18F‑DOPA‑PET/CT indicated a focal lesion in the head of the pancreas. The pathological diagnosis was an atypical form of CHI. The patient presented with a phenotype of atypical CHI unresponsive to diazoxide. It is considered that a relationship existed between the compound heterozygous mutation and the atypical form. 18F‑DOPA‑PET/CT is a useful tool in distinguishing between focal and diffuse forms preoperatively but the accuracy is not 100%. The scan result is best combined with genetic analysis and intra-operative biopsy to confirm the histological subtypes. The combination will provide the optimal strategy for the surgical treatment of patients with CHI.

Diazoxide-unresponsive congenital hyperinsulinism associated with ABCC8 nonsense mutation

Case presentation A baby boy with birth weight of 2.4kg at 35 weeks was born via Caesarian section. The boy was allowed feeding on demands, however he had the first onset of hypoglycemia at 2 hours of life. His blood sugar ranged from low reading to 2.5 mmol/L. The patient was treated with boluses of intravenous dextrose D10% followed by maintenance dextrose with its increasing strength in order to treat the refractory hypoglycemia. In addition to that intravenous hydrocortisone and glucagon infusion were started. The patient’s blood sugar could only be maintained > 3.0mmol/L after a glucose load of 30mg/kg/min and a glucagon infusion of 50mcg/kg/hour. During hypoglycemia, the insulin level was 19.6 pmol/L (17.8-173.0) and blood ketone was negative. Oral diazoxide was started at 5.0mg/kg/day in divided doses combined with chlorothiazide 7.0 mg/kg/day. Diazoxide was titrated up to 20.0mg/kg/day as he had a poor response even after 1 week of the treatment. Apart from that oral nifidipine 2.5 mg/kg/day in divided doses was also started after a few days with the combination therapy. Only after starting octreotide infusion a good rise of blood sugar was seen within 1 hour and the glucose load could be brought down and the other drugs were off. The boy was discharged with subcutaneous octreotide infusion at 2mcg/ hour via portable insulin pump. Results The boy is heterozygous for an ABCC8 nonsense mutation, p.R934*. A second ABCC8 mutation has not been found and sequencing of the KCNJ11 gene failed to detect a change from the normal sequence. He has inherited the mutation from his father; a focal lesion is therefore possible. 18F-DOPA PET-CT scanning is recommended and if a focal lesion is identified and surgically resected, microsatellite analysis of the DNA can be undertaken to confirm loss of heterozygosity.

Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: Few clinical features suggestive of Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome involving tumor predisposition. BWS is caused by various epigenetic or genetic alterations that disrupt the imprinted genes on chromosome 11p15.5 and the clinical findings of BWS are highly variable. Hyperinsulinemic hypoglycemia is reported in about half of all babies with BWS. We identified an infant with diazoxide-unresponsive congenital hyperinsulinism (HI) without any apparent clinical features suggestive of BWS, but diagnosed BWS by molecular testing. The patient developed severe hyperinsulinemic hypoglycemia within a few hours after birth, with macrosomia and mild hydronephrosis. We excluded mutations in the K(ATP) channel genes on chromosome 11p15.1, but found a rare homozygous single nucleotide polymorphism (SNP) of ABCC8. Parental SNP pattern suggested paternal uniparetal disomy in this region. By microsatellite marker analysis on chromosome 11p15, we could diagnose BWS due to the mosaic of paternal uniparental disomy. Our case suggests that some HI of unknown genetic etiology could involve undiagnosed BWS with no apparent clinical features, which might be diagnosed only by molecular testing.

A Dominantly Inherited KCNJ11 Q235E Mutation Leading to Diazoxide-Unresponsive Congenital Hyperinsulinism in a Chinese Child

A Dominantly Inherited KCNJ11 Q235E Mutation Leading to Diazoxide-Unresponsive Congenital Hyperinsulinism in a Chinese Child

ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism

BackgroundCongenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic β-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1...