A Reliable Automated Synthesis of 6-[18F]Fluoro-L-DOPA and the Clinical Application on the Imaging of Congenital Hyperinsulinism of Infants

6-[18F]fluoro-L-DOPA is a radiotracer widely used in the diagnosis of a range of diseases, including neuro-oncology, endocrinology, and Parkinson’s disease. To meet the fast growing clinical need for this radioactive compound, this study reports an optimized radiosynthsis of this molecule, which proved to be highly reliable and compatible with different types of automated radiosynthesizers. Moreover, with 6-[18F]fluoro-L-DOPA, the PET/CT imaging of a total of 23 patients has been conducted, further demonstrating this radiotracer as a clinically valuable reagent to diagnose congenital hyperinsulinism (CHI) of infancy and, more importantly, localize the exact lesion on pancreas.

PNC2 (SLC25A36) deficiency associated with the hyperinsulinism/hyperammonemia syndrome

Context The hyperinsulinism/hyperammonemia (HI/HA) syndrome, the second most common form of congenital hyperinsulinism, has been associated to dominant mutations in GLUD1, coding for the mitochondrial enzyme glutamate dehydrogenase, that increase enzyme activity by reducing its sensitivity to allosteric inhibition by GTP. Objective To identify the underlying genetic aetiology in two siblings who presented with the biochemical features of HI/HA syndrome but did not carry pathogenic variants in GLUD1, and to determine the functional impact of the newly identified mutation. Main Outcome Measures The patients were investigated by whole exome sequencing. Yeast complementation studies and biochemical assays on the recombinant mutated protein were performed. The consequences of stable slc25a36 silencing in HeLa cells were also investigated. Results A homozygous splice site variant was identified in solute carrier family 25, member 36 (SLC25A36), encoding the pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine as well as guanine nucleotides across the inner mitochondrial membrane. The mutation leads to a 26 aa in-frame deletion in the first repeat domain of the protein which abolished transport activity. Furthermore, knockdown of slc25a36 expression in HeLa cells caused a marked reduction in the mitochondrial GTP content which likely leads to an hyperactivation of glutamate dehydrogenase in our patients. Conclusions We report for the first time a mutation in PNC2/SLC25A36 leading to HI/HA and provide functional evidence of the molecular mechanism responsible for this phenotype. Our findings underscore the importance of mitochondrial nucleotide metabolism and expand the role of mitochondrial transporters in insulin secretion.

A novel disease mechanism leading to the expression of a disallowed gene in the pancreatic beta-cell identified by non-coding, regulatory mutations controlling HK1

Gene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function. This silencing is largely controlled by non-coding elements and their disruption might cause human disease. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo mutations affecting a 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 (HK1), a pancreatic beta-cell disallowed gene. We demonstrated that these mutations resulted in expression of HK1 in the pancreatic beta-cells causing inappropriate insulin secretion and congenital hyperinsulinism. These mutations identify a regulatory region critical for cell-specific silencing. Importantly, this has revealed a new disease mechanism for non-coding mutations that cause inappropriate expression of a disallowed gene.

Health-Related Quality of Life of Children and Adolescents With Congenital Hyperinsulinism – A Scoping Review

IntroductionDespite improvements in diagnosis and therapeutic advances in treatment, congenital hyperinsulinism (CHI) remains a severe disease with high patient impairment. We aimed to review the literature on Health-related Quality of Life in children and adolescents with congenital hyperinsulinism and summarize the findings.Materials and MethodsFor this scoping review, a literature search was conducted in PubMed and Web of Science in May 2021. Inclusion and exclusion criteria for the selection of articles were defined a priori.ResultsTwo hundred and forty-five (245) articles were identified through the search and screened on the basis of title and abstract. The full texts of forty articles were then assessed. Finally, four articles (published 2012-2020) describing Health-related Quality of Life in children and adolescents with congenital hyperinsulinism were included. The study designs were heterogeneous and included cross-sectional observational studies (n=2), clinical trials (n =1), and case reports (n=1) with different sample sizes. Three studies were conducted in European countries and one in Japan. The results for Health-related Quality of Life revealed inconsistencies.ConclusionThere are only a few studies looking at Health-related Quality of Life in children and adolescents with congenital hyperinsulinism. To gain a comprehensive understanding of the impact of congenital hyperinsulinism on Health-related Quality of Life in children and adolescents, it is necessary to use both generic and condition-specific instruments to measure Health-related Quality of Life of young patients in larger samples, to collect longitudinal data, and to consider qualitative research approaches.

The invaluable role of consanguinity in providing insight into paediatric endocrine conditions: Lessons learned from congenital hyperinsulinism, monogenic diabetes, and short stature

Consanguineous families have often played a role in the discovery of novel genes, especially in paediatric endocrinology. At this time, it has been estimated that over 8.5% of all children worldwide have consanguineous parents. Consanguinity is linked to demographic, cultural and religious practises and is more common in some areas around the world than others. In children with endocrine conditions from consanguineous families, there is a greater probability that a single gene condition with autosomal recessive inheritance is causative. From 1966 and the first description of Laron syndrome, through the discovery of the first KATP channel genes ABCC8 and KCNJ11 causing congenital hyperinsulinism in the 1990s, to recent discoveries of mutations in YIPF5 as the first cause of monogenic diabetes due to the disruption of the endoplasmic reticulum (ER)-to-Golgi trafficking in the β-cell and increased ER stress; positive genetic findings in children from consanguinity have been important in elucidating novel genes and mechanisms of disease, thereby expanding knowledge into disease pathophysiology. The aim of this narrative review is to shed light on the lessons learned from consanguineous pedigrees with the help of three fundamental endocrine conditions that represent an evolving spectrum of pathophysiological complexity – from congenital hyperinsulinism, a typically single cell condition, to monogenic diabetes which presents with uniform biochemical parameters (hyperglycaemia and glycosuria), despite varying aetiologies, up to the genetic regulation of human growth – the most complex developmental phenomenon.

Transient congenital hyperinsulinism and hemolytic disease of a newborn despite rhesus D prophylaxis: a case report

Background In neonates, rhesus D alloimmunization despite anti-D immunoglobulin prophylaxis is rare and often unexplained. Rhesus D alloimmunization can lead to hemolytic disease of the newborn with anemia and unconjugated hyperbilirubinemia. In past reports, transient congenital hyperinsulinism has been described as a rare complication of rhesus D alloimmunization. Our case report illustrates that rhesus D alloimmunization can result in a pseudosyndrome with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia, despite correctly administered anti-D immunoglobulin prophylaxis. Case presentation We report of a 36-year-old, Caucasian gravida 1, para 1 mother with A RhD negative blood type who received routine antenatal anti-D immunoglobulin prophylaxis. Her full term newborn boy presented with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia up to 295 µmol/L (ref. < 9), accounting for 64% of the total bilirubin. Syndromic congenital hyperinsulinism was suspected. Examinations showed a positive direct antiglobulin test, initially interpreted as caused by irregular antibodies; diffuse congenital hyperinsulinism by 18F-DOPA positron emission tomography/computed tomography scan; normal genetic analyses for congenital hyperinsulinism; mildly elevated liver enzymes; delayed, but present bile excretion by Tc99m-hepatobiliary iminodiacetic acid scintigraphy; and cholestasis and mild fibrosis by liver biopsy. The maternal anti-D titer was 1:16,000 day 20 postpartum. Y-chromosome material in the mother’s blood could not be identified. This could, however, not exclude late intrapartum fetomaternal hemorrhage as the cause of immunization. No causative genetic findings were deetrmined by trio whole exome sequencing. The child went into clinical remission after 5.5 months. Conclusion Our case demonstrates that rhesus D alloimmunization may present as a pseudosyndrome with transient congenital hyperinsulinism, anemia, and inspissated bile syndrome with conjugated hyperbilirubinaemia, despite anti-D immunoglobulin prophylaxis, possibly due to late fetomaternal hemorrhage.

Diazoxide for the Treatment of Transitional Neonatal Hypoglycemia: A Systematic Review

Background: Neonatal hypoglycemia is widely recognized as a common, preventable cause of brain injury in infants. Early use of diazoxide, which attenuates insulin secretion, is a possible treatment strategy for neonates that fail first-line management of hypoglycemia. Objective: To systematically evaluate the effectiveness and safety of diazoxide compared to placebo or no diazoxide treatment for improving short- and long-term outcomes in neonates born at ≥35 weeks’ gestation who require treatment for transitional hypoglycemia. Methods: MEDLINE, SCOPUS, EMBASE, and Cochrane databases were searched from inception until November 2020. We included all published randomized and nonrandomized controlled studies of diazoxide therapy in neonates that reported 1 or more prespecified outcomes. We excluded studies that primarily reported on neonates born at <35 weeks, with congenital hyperinsulinism or inborn errors of metabolism, or who started treatment after 1 month of age. Two authors independently performed screening, risk of bias assessment, data extraction, and rating of evidence certainty (GRADE). Meta-analysis was performed in RevMan (inverse variance, fixed effects). Results: A total of 161 studies were screened, 7 reviewed in full, and 1 included (N = 30). Low-certainty evidence suggested that diazoxide, compared with placebo, is associated with a shorter duration of intravenous fluids (mean difference [MD] –50 h, 95% confidence interval [CI] −94, −6), decreased time to achieve full enteral feeding (MD –49 h, 95% CI −91, −7), and euglycemia (MD –33 h, 95% CI −66, −0). Conclusions: Diazoxide may promote metabolic transition in late preterm and term neonates with transitional hypoglycemia. Further high-quality randomized trials are needed to assess short- and long-term effects of diazoxide therapy.

Genetic pathogenesis, diagnosis, and treatment of short-chain 3-hydroxyacyl-coenzyme A dehydrogenase hyperinsulinism

Congenital hyperinsulinism (CHI), a major cause of persistent and recurrent hypoglycemia in infancy and childhood. Numerous pathogenic genes have been associated with 14 known genetic subtypes of CHI. Adenosine triphosphate-sensitive potassium channel hyperinsulinism (KATP-HI) is the most common and most severe subtype, accounting for 40–50% of CHI cases. Short-chain 3-hydroxyacyl-coenzyme A dehydrogenase hyperinsulinism (SCHAD-HI) is a rare subtype that accounts for less than 1% of all CHI cases that are caused by homozygous mutations in the hydroxyacyl-coenzyme A dehydrogenase (HADH) gene. This review provided a systematic description of the genetic pathogenesis and current progress in the diagnosis and treatment of SCHAD-HI to improve our understanding of this disease.

Congenital insulin resistance in the practice of the pediatrician and pediatric endocrinologist -path to diagnosis

Introduction. Hyperinsulinemic hypoglycemia in children is most commonly due to congenital hyperinsulinism. When hyperinsu-linemia is accompanied by fasting hypoglycemia and postprandial hyperglycemia, rare syndromes of severe insulin resistance, which include Rabson - Mendenhall syndrome, should be suspected. This article provides an analytical review of current data on this rare genetic pathology and presents a clinical case of a previously undescribed combination of Rabson-Mendenhall syndrome with mutations in the insulin receptor gene INSR in the compound heterozygous state with multiple congenital anomalies of other organs.Clinical case. Patient N, 5.5 months old boy, with suspected congenital hyperinsulinism due to episodes of frequent severe hypoglycemia from the first day of life. At the age of 5 months, an episode of hypoglycemia up to 2.2 mmol/L was registered at an appointment with a pediatric endocrinologist. An examination was ordered, which found that against a background decrease in blood glucose to 1.9 mmol/L, C-Peptide level >5000 ng/mL, insulin level >300 lU/mL, cortisol - 971 nmol/L, TSH -3.88 mlU/L, free T4 - 10.53 pmol/L (10-23.2).The importance of early diagnosis of severe insulin resistance to prevent developmental disorders in children is emphasized. The issue of organizing multiple effective monitoring of a patient’s glycemia required special attention in this clinical case. Due to the features of metabolism in young children, we abandoned flash glucose monitoring systems and used a modern glucose meter with an integration program with a mobile application and the ability to generate reports for subsequent analysis as a reliable means of glycemic control.Summary. Based on the results of the genetic study in association with the clinical phenotype, age of debut, the patient was clinically diagnosed with Rabson-Mendenhall syndrome.Discussion. The paradoxical nature of glycemic fluctuations (severe fasting hypoglycemia and postprandial diabetic hyperglycemia) is quite typical for syndromes of severe insulin resistance and should draw the attention of an informed primary care physician.Conclusion. Careful attention to the symptoms of hypoglycemia, especially with a debut in the neonatal period, recurrent episodes, and the severity of the decrease in blood glycemia. If normal or elevated levels of insulin and C-peptide are detected against the background of hypoglycemia, the first thing to think about is congenital hyperinsulinism.