Congenital Hyperinsulinemic Hypoglycemia Research Articles

Hyperinsulinemia in Sotos Syndrome with a de novo NSD1 Deletion.

Sotos syndrome belongs to the group of diseases characterised by features such as facial dysmorphism, intellectual disability, hypotonia and overgrowth. Usually, Sotos syndrome is caused by heterozygous mutations in the NSD1 gene at chromosome 5q35 or by large genomic deletions of the same region. Genotype-phenotype correlations have mainly been reported as an association of significant or major abnormalities and presence of 5q35 deletions rather than intragenic deletions or point mutations in NSD1. The congenital hyperinsulinaemic hypoglycaemia (CHI) has been described as an uncommon feature in the presentation of Sotos syndrome. Most of the patients with Sotos syndrome and transient CHI were carriers of 5q35 deletions while persistent CHI has been recently reported in individuals with point mutations or small NSD1 deletions. We report the clinical features and medical treatment in a new-born child with Sotos syndrome and CHI that was present for almost two years. Genetic cause of Sotos syndrome in this case was a novel, large genomic deletion encompassing 24 OMIM genes including the entire NSD1 gene and 6 other Morbid genes. Our report shows challenges in diagnostics and management of this rare genetic condition. We propose, that in neonatal diagnostics, the phenotypic spectrum of Sotos syndrome should include CHI as a characteristic feature and molecular genetic testing should be done by whole genome analysis.

Hypoglycemia in Children Referred to a Tertiary Care Pediatric Endocrine Clinic: Age-Dependent Etiological Variations

Introduction: Diagnosing hypoglycemia in infants and children presents significant challenges. Our objective was to elucidate the diagnoses and clinical features of children with hypoglycemia referred to a pediatric endocrine tertiary clinic. Methods: This was a retrospective study of 154 children (0–18 years old) presenting with hypoglycemia, during 1992–2018. Results: The cohort was divided by clinical diagnosis into six groups: ketotic hypoglycemia (n = 45, 29.2%), congenital hyperinsulinemic hypoglycemia (n = 35, 22.7%), transient hyperinsulinemic hypoglycemia (n = 28, 18.2%), metabolic disorder (n = 14, 9.1%), systemic disease/syndrome (n = 15, 9.7%), and hormone deficiencies (n = 8, 5.2%). Two patients had insulinoma, and in 7 (4.5%), no diagnosis was elucidated. At diagnosis, 58 (37.7%) were Conclusions: Hypoglycemia etiology in children is heterogeneous and varies by age. Any hypoglycemia measured in a child should be seriously evaluated as 7% are asymptomatic. Workup should be tailored based on age, and clinical, biochemical, and imaging findings. Despite extensive workup, in a significant number of patients the mechanism underlying pediatric hypoglycemia remains an enigma. This emphasizes the unmet needs and challenges in studying pediatric hypoglycemia.

Focal congenital hyperinsulinism

In congenital hyperinsulinemic hypoglycemia - the most common cause of persistent hypoglycemia in infancy - a focal lesion can be identified in 50% of the cases. With appropriate medical care based upon early diagnosis, these patients can be cured by the resection of the lesion rendering unnecessary long time medical care, and avoiding serious brain damage from recurrent hypoglycemic episodes. Genetic testing and 18F-fluoro-dihydroxyphenylalanine PET/CT imaging are essential for determining the best possible treatment. We report 2 cases of focal congenital hyperinsulinism - both male infants: 22 and 2 months of age - treated successfully with enucleation of the pancreas lesion (Semmelweis University, Budapest). Both patients had the pathognomonic mutation of the ABCC8 gene of the ATP-sensitive potassium channel. Radiologic imaging and histology confirmed the diagnosis, and after the operation, pharmacological treatment was terminated in both cases. During the follow-up period (5 and 1.5 years, respectively) they are euglycemic, with no morbidities attributed to the operation. We believe that these two operations for focal hyperinsulinism - diagnosed and localised by the above detailed genetic and specific radiological testing - were the first of their kind in Hungary. Based on the acquired experience, every necessary examination can be achieved in our country to improve patient care, reduce morbidity and medical costs. Orv Hetil. 2023; 164(47): 1877-1884.

Evaluation and management of neonatal onset hyperinsulinemic hypoglycemia: a single neonatal center experience

Objectives To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH). Methods This retrospective cohort study included infants >34 weeks of gestation at birth who were born in our hospital between 2018 and 2021, diagnosed with HH, and required diazoxide within the first 28 days of life. The baseline clinical characteristics, age at the time of diagnosis and treatment options in diazoxide resistance cases were recorded. Genetic mutation analysis, if performed, was also included. Results A total of 32 infants diagnosed with neonatal HH were followed up. Among the cohort, 25 infants were classified as having transient form of HH and seven infants were classified as having congenital hyperinsulinemic hypoglycemia (CHI). Thirty-one percent of the infants had no risk factors. The median birth weight was significantly higher in the CHI group, whereas no differences were found in other baseline characteristics. Patients diagnosed with CHI required higher glucose infusion rate, higher doses, and longer duration of diazoxide treatment than those in the transient HH group. Eight patients were resistant to diazoxide, and six of them required treatment with octreotide and finally sirolimus. Sirolimus prevented the need of pancreatectomy in five of six patients without causing major side effects. Homozygous mutations in the ABCC8 gene were found in four patients with CHI. Conclusions The risk of persistent neonatal hyperinsulinism should be considered in hypoglycemic neonates particularly located in regions with high rates of consanguinity. Our study demonstrated sirolimus as an effective treatment option in avoiding pancreatectomy in severe cases.

SAT157 Management Of Spontaneous Hypoglycemia In Dialysis-dependent Chronic Kidney Disease Using Diazoxide

Abstract Disclosure: A. Schledwitz: None. S.S. Habbsa: None. F. Sotomayor Villanueva: None. Y. Kim: None. Background: Patients with end-stage renal disease (ESRD) are at increased risk of spontaneous hypoglycemia due to decreased renal insulin clearance. Due to its inhibitory effect on pancreatic beta cell insulin secretion, oral diazoxide has been used to treat hypoglycemia due to insulinoma or congenital hyperinsulinemic hypoglycemia, but few cases detail the use of diazoxide in the ESRD population. Here, we present 4 cases of spontaneous hyperinsulinemic hypoglycemia in ESRD successfully treated with diazoxide. Clinical Cases: A 66-year-old man with ESRD presented with altered mental status secondary to severe hypoglycemia despite continuous IV 20% dextrose. Labs revealed glucose 50 mg/dL, insulin 7 (0-3 mcIU/mL), C-peptide 7.8 (0-0.6 ng/mL), proinsulin 35.7 (0-5 pmol/L), beta-hydroxybutyrate [bOH] 0.4 (0-2.7 mg/dL), negative sulfonylurea panel, normal cosyntropin stimulation test and undetectable insulin antibodies, without radiographic evidence of insulinoma. He was started on diazoxide 50 mg TID and remained euglycemic for the remainder of his course. On similar readmission 3 months later, he was restarted on diazoxide with resolution of hypoglycemia within 1 day. A 66-year-old male with ESRD and T1DM treated with pancreas transplant presented with toe gangrene and persistent hypoglycemia. Fasting labs revealed insulin 4, C-peptide 4.5, proinsulin 4.5, and bOH 4.5, without radiographic evidence of insulinoma. He maintained euglycemia 4 days after diazoxide 70 mg BID was started. A 67-year-old male with T2DM and ESRD was admitted for osteomyelitis and 2 years of episodic symptomatic hypoglycemia despite dietary adjustments. Labs showed glucose 59, insulin 7, C-peptide 5.2, proinsulin 7.5, bOH 0.04, and unremarkable imaging. Within 1 day of starting diazoxide 100 mg daily, his blood glucose stabilized, and he was discharged. Finally, a 42-year-old male with ESRD presented with 4 years of persistent episodic hypoglycemia, now refractory to continuous IV dextrose. He was found to have glucose 64, insulin 15, C-peptide 11.5, proinsulin 29, and bOH 0.1, with imaging revealing bulky pancreas without a discrete mass. His hypoglycemic episodes resolved within 1 day of starting diazoxide 100 mg daily. He was readmitted 3 months later for catheter site infection and had no episodes of hypoglycemia with continuation of diazoxide. Conclusion: Diazoxide may be a viable option for the treatment of refractory spontaneous hypoglycemia in patients with dialysis dependent ESRD. Presentation: Saturday, June 17, 2023

SAT163 Title: Adult-onset Hyperinsulinemic Hypoglycemia Due To An Activating Mutation In Glucokinase

Abstract Disclosure: S. Vaid: None. R. Ghosh: None. H. Elenius: None. C. Cochran: None. R. Chang: None. N. Nilubol: None. R. Muniyappa: None. Introduction: Glucokinase (GK), the key β-cell glucose sensor, determines the threshold for glucose-stimulated insulin secretion. Activating mutations of GK are infrequent causes (prevalence of 1.2%) of congenital hyperinsulinemic hypoglycemia (HH). Adult-onset of severe hypoglycemia due to GK-HH is extremely rare. Clinical Case: A 26-year-old well-nourished female (BMI, 27 kg/m2) with a recent history of dizziness, tremulousness, fatigue, sweating, and hunger, associated with weight gain presented for further workup. Hypoglycemia was noted, and Whipple's triad was confirmed. She had no family history of endocrine disease or hypoglycemia. Supervised fasting promptly produced symptomatic hypoglycemia with hyperinsulinemia. Laboratory studies revealed a low glucose level at 44 mg/dL; a plasma insulin level at 93 μIU/mL (<3 μIU/ml); a C-peptide level at 8.1 ng/mL (<0.6 ng/mL); pro-insulin at 266 pmol/L (<5 pmol/L); and beta-hydroxybutyrate <2.7 mmol/L. IGF2/IGF-1 ratio was 3.1 (<10) and renal and liver function was normal. Interestingly, a mixed meal also provoked significant hypoglycemia within an hour of consumption of a meal. Urine for sulfonylurea screen was negative, and so were anti-insulin antibodies. Imaging of the pancreas with computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound revealed a 1.2x0.8cm nodule on the superior margin of the body of the pancreas. 68Ga-DOTATATE​​ PET/CT (targeting somatostatin receptors) showed mild uptake coinciding with the nodule on the CT scan. Arteriography with calcium stimulation and venous sampling (ASVS) was non-localizing. The patient subsequently underwent laparoscopic exploration with intraoperative ultrasound (IOUS) of the pancreas followed by the enucleation of the pancreatic nodule. Histopathology of the nodule revealed a normal pancreatic tissue with no evidence of a neuroendocrine tumor. Change to multiple small meals, addition of cornstarch to diet, continuous blood glucose monitoring (CGM), diazoxide (70 mg oral, three times a day), and monthly octreotide LAR (30 mg) has allowed the patient to avoid hypoglycemia. Genetic testing by analysis of the genes known to cause hypoglycemia revealed a heterozygous GCK variant [c.1367C>T (p.Ala456Val), which was predicted to be a pathological mutation. This mutation is known to increase affinity for glucose, which leads to exaggerated insulin secretion. Conclusion: Our study highlights that in adults with non-insulinoma pancreatogenous hypoglycemia, genetic causes of HH should be considered in the differential diagnosis. Presentation: Saturday, June 17, 2023

Hyperinsulinemic Hypoglycemia in Childhood

Hyperinsulinemic Hypoglycemia (HH) is the most common cause of permanent hypoglycemia, especially in the neonatal period. Childhood HH is mostly related to genes encoding proteins in the insulin secretion pathways, and may also be seen in syndromes such as Beckwidth Wiedemann, Kabuki, and Turner. The majority of congenital HH cases are the result of KATP channel gene defect. Most of these cases are unresponsive to diazoxide treatment. In this review, recent genetic studies and recent updates in treatment options in childhood HH are reviewed.

Glucokinase and glucokinase activator

Abstract Glucokinase (GK) plays a pivotal role in glucose homeostasis as the glucose sensor in the pancreas and liver. Loss of function of GK results in hyperglycemia, and gain of function causes congenital hyperinsulinemic hypoglycemia. We speculate that the progressive loss of GK at both messenger RNA (mRNA) and protein levels in the islets and liver would be the key mechanism for Type 2 diabetes (T2D) pathogenesis. The development of GK activator (GKA) as an anti-diabetic drug has been endeavored for several decades. The failure of the early development of GKAs is due to the limitation of understanding the mode of GKA action. The success of dorzagliatin in the treatment of T2D has brought new hope for GK in setting a good model for repairing the underlying defects in the pancreatic islets and liver of T2D patients.

Two Sri Lankan siblings with diazoxide responsive congenital hyperinsulinaemic hypoglycaemia due to a rare mutation in the <em>ABCC8</em> gene

No abstract available Sri Lanka Journal of Child Health, 2023: 52(2): 231-235

Expert consensus on the diagnosis and treatment of congenital hyperinsulinemic hypoglycemia(2022)

先天性高胰岛素血症是导致儿童（尤其是新生儿）持续性高胰岛素血症性低血糖的一组遗传异质性疾病。病因复杂，临床表现谱广，神经发育障碍发生的风险性高使其早期诊治至关重要。在综合国内外学科进展的基础上，经广泛征求专家意见，特制定先天性高胰岛素血症性低血糖诊治专家共识（2022），旨在指导临床实践，提高我国儿科医师对该病的诊治水平，改善患儿预后。.

A case of diazoxide unresponsive congenital hyperinsulinemic hypoglycemia with missense mutation in ABCC8 gene

Hypersecretion of insulin by pancreatic ß-cells causes hypoglycemia called congenital hyperinsulinism (CHI). It can inhibit brain development in infants. It is associated with mutations in the ABCC8 or KCNJ11 genes encoding for the SUR1 and KIR 6 (subunits of the ATP-sensitive potassium (KATP channel) a rare genetic disorder. It has an incidence rate of 1 in 50,000 in general populations and 1 in 2000 in areas with a higher rate of consanguinity. Here, we report a case of hyperinsulinemic hypoglycemia with ABCC8 gene mutation in a late preterm female infant who developed late-onset hypoglycemia. The infant developed hypoglycemic seizures on day 3 of life and her metabolic workup revealed hyperinsulinemia. A high glucose infusion rate and enteral feeding could not maintain the infant's serum glucose level. PET scan showed no abnormal somatostatin receptor avid lesion in pancreatic parenchyma. Hence genetic workup was done which showed a missense mutation in the ABCC8 gene which was c.4154C>G/p.Ser1385Cys. Over 9 months of follow-up, the infant is treated with octreotide and diazoxide, hasn't had any hypoglycemic events and has normal growth and psychomotor development for her age.

Congenital Hyperinsulinaemic Hypoglycaemia-A Review and Case Presentation.

Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of persistent hypoglycaemia in infants and children with incidence estimated at 1 per 50,000 live births. Congenital hyperinsulinism (CHI) is symptomatic mostly in early infancy and the neonatal period. Symptoms range from ones that are unspecific, such as poor feeding, lethargy, irritability, apnoea and hypothermia, to more serious symptoms, such as seizures and coma. During clinical examination, newborns present cardiomyopathy and hepatomegaly. The diagnosis of CHI is based on plasma glucose levels <54 mg/dL with detectable serum insulin and C-peptide, accompanied by suppressed or low serum ketone bodies and free fatty acids. The gold standard in determining the form of HH is fluorine-18-dihydroxyphenyloalanine PET ((18)F-DOPA PET). The first-line treatment of CHI is diazoxide, although patients with homozygous or compound heterozygous recessive mutations responsible for diffuse forms of CHI remain resistant to this therapy. The second-line drug is the somatostatin analogue octreotide. Other therapeutic options include lanreotide, glucagon, acarbose, sirolimus and everolimus. Surgery is required in cases unresponsive to pharmacological treatment. Focal lesionectomy or near-total pancreatectomy is performed in focal and diffuse forms of CHI, respectively. To prove how difficult the diagnosis and management of CHI is, we present a case of a patient admitted to our hospital.

Incidence and prevalence of 121 rare diseases in China: Current status and challenges: 2022 revision.

The current study updated data on the incidence and prevalence of 121 rare diseases listed in China's First List of Rare Diseases to provide rationales and references for the development and promotion of rare-disease-related policies. The National Health Commission of the People's Republic of China issued the Rare Disease Diagnosis and Treatment Guide (2019) (denoted here as China's Rare Disease Diagnosis and Treatment Guide). Then 121 diseases were registered with the national rare disease diagnosis and treatment network. The incidence/prevalence of 121 rare diseases varied from country to country. Data are available for a total of 76 rare diseases (76 of 121 rare diseases, 62.81%) in China, including data on the incidence of 23 rare diseases (19.01%) and data on the prevalence of 66 (54.55%). There are data on the incidence/prevalence of 112 rare diseases (112 of 121 rare diseases, 92.56%) at the global level, including data on the incidence of 86 rare diseases (71.07%) and data on the prevalence of 91 (75.21%). On average, the incidence of progressive muscular dystrophies, hyperphenylalaninemia, citrullinemia, and methylmalonic acidemia is over 1/10,000 in China. The prevalence of coronary artery ectasia, congenital scoliosis, retinitis pigmentosa, severe congenital neutropenia, congenital hyperinsulinemic hypoglycemia, and osteogenesis imperfecta is over 1/10,000 in China. All of these figures are beyond the cut-off of 1/10,000 according to the 2021 definition of rare diseases in China. As registration and investigation of rare diseases continues, the spectrum of rare diseases in some provinces is expanding. Diseases such as idiopathic pulmonary arterial hypertension, hepatolenticular degeneration, hemophilia, amyotrophic lateral sclerosis, idiopathic pulmonary fibrosis, and multiple sclerosis are relatively prevalent in some regions and cities of China. Registration efforts promote the correction of incidence/prevalence data, development of orphan drugs, coverage by medical insurance, and development of clinical and diagnostic pathways.

Generation of the human induced pluripotent stem cell line (IBKMOLi002-A) from PBMCs of a patient carrying the heterozygous L271H mutation of the voltage-gated calcium channel subunit Cav1.3-encoding CACNA1D gene

Congenital hyperinsulinemic hypoglycemia (HH) is the most frequent cause of persistent and recurrent hypoglycemia. Peripheral mononuclear blood cells (PBMCs) from a patient diagnosed with HH, alongside autism-spectrum-disorder (ASD), carrying a heterozygous c.812 T>A (L271H) mutation in the voltage-gated calcium channel subunit Cav1.3-encoding gene CACNA1D, were reprogrammed into induced pluripotent stem cells (iPSC). The CACNA1D L271H iPSC (IBKMOLi002-A) exhibit a normal karyotype, high expression of pluripotency-associated markers and the capacity to differentiate into cells of all three germ layers. We provide a novel patient-specific iPSC line, allowing to study HH, ASD, the associated neurodevelopmental disorder as well as CACNA1D-associated channelopathies in general.

Biallelic DNAJC3 variants in a neuroendocrine developmental disorder with insulin dysregulation.

DNAJC3, a co-chaperone of BiP, is a member of the heat shock protein family. These proteins are produced in the endoplasmic reticulum (ER) to counter cell stress resulting from healthy functional protein processing. Dysregulation of unfolded proteins within the ER is implicated as a mechanism of genetic disease. Examples include Marinesco-Sjogren and Wolcott-Rallison syndromes that share similar clinical features, manifesting neurodegenerative disease and endocrine dysfunction. Recently, loss of function mutations in DNAJC3 was associated with syndromic diabetes mellitus in three families. The full phenotype included neurodegeneration, ataxia, deafness, neuropathy, adolescent-onset diabetes mellitus, growth hormone deficiency and hypothyroidism. A subsequent report of two unrelated individuals extended the phenotype to include early-onset hyperinsulinaemic hypoglycaemia. Here, we describe two siblings that recapitulate this extended phenotype in association with a homozygous novel mutation in the final exon of DNAJC3 [c.1367_1370delAGAA (p.Lys456SerfsTer85)] resulting in protein elongation predicted to abrogate the functional J domain. This report confirms DNAJC3 as a cause of syndromic congenital hyperinsulinaemic hypoglycaemia. Currently, PanelApp only includes this gene on diabetes mellitus panels. We propose DNAJC3 should be promoted from a red to a green gene on a wider number of panels to improve the diagnosis of this rare condition.

50 Years Ago in TheJournalofPediatrics: Advances in the Understanding of Congenital Hyperinsulinemic Hypoglycemia

50 Years Ago in TheJournalofPediatrics: Advances in the Understanding of Congenital Hyperinsulinemic Hypoglycemia

Clinical, Genetic Features and Treatment Results in Patients with Congenital Hyperinsulinemic Hypoglycemia: A Single Center Experience

Clinical, Genetic Features and Treatment Results in Patients with Congenital Hyperinsulinemic Hypoglycemia: A Single Center Experience

Altered Serum Amino Acid and Acylcarnitine Profiles in Hyperinsulinemic Hypoglycemia and Ketotic Hypoglycemia.

BackgroundIn addition to inborn metabolic disorders, altered metabolic profiles were reported to be associated with the risk and prognosis of some non-metabolic diseases, while as a rare metabolic disease, the overall secondary metabolic spectrum in congenital hyperinsulinemic hypoglycemia (HH) is largely undetermined. Therefore, we investigated metabolic profiles in HH patients and used ketotic hypoglycemia (KH) patients as a control cohort to unveil their distinct metabolic features.MethodsA total of 97 hypoglycemia children, including 74 with hyperinsulinemic hypoglycemia and 23 with ketotic hypoglycemia, and 170 euglycemia control subjects were studied retrospectively. Clinical and biochemical data were collected. The normoglycemic spectra of amino acids and acylcarnitines were determined by liquid chromatography tandem mass spectrometry. The serum insulin and fatty acid concentrations during standardized fasting tests in hypoglycemia patients were also collected. Receiver operating characteristic curve analysis was performed to screen potential biomarkers.ResultsAmong the normoglycemic spectra of amino acids, blood valine (p < 0.001), arginine (p < 0.001), threonine (p = 0.001), glutamate (p = 0.002), methionine (p = 0.005), ornithine (p = 0.008), leucine (p = 0.014), alanine (p = 0.017), proline (p = 0.031), citrulline (p = 0.042), aspartate (p = 0.046), and glycine (p = 0.048) levels differed significantly among the three groups. Significantly decreased levels of long- (C14:1, p < 0.001; C18, p < 0.001), medium- (C8, p < 0.001; C10, p < 0.001; C10:1, p < 0.001), and short-chain (C4-OH, p < 0.001; C5OH, p < 0.001) acylcarnitines were found in the hyperinsulinemic hypoglycemia group. Hyperinsulinemic hypoglycemia children with focal lesions and diffuse lesions had similar amino acid and acylcarnitine spectra. C10:1 < 0.09 μmol/L, threonine > 35 μmol/L, and threonine/C10:1 > 440 showed sensitivities of 81.1, 66.2, and 81.1% and specificities of 72.7, 78.3, and 81.8%, respectively, in distinguishing HH from KH.ConclusionsWe found significantly different altered serum amino acid and acylcarnitine profiles at normoglycemia, especially decreased C10:1 and increased threonine levels, between HH and KH children, which may reflect the insulin ketogenesis inhibition effect in HH patients; however, the detailed mechanisms and physiological roles remain to be studied in the future.

Experience with Real-Time Continuous Glucose Monitoring in Newborns with Congenital Hyperinsulinemic Hypoglycemia

Effective treatment and close monitoring of hypoglycemia in children with congenital hyperinsulinemic hypoglycemia (CHH) is vital to prevent brain damage. The current use of capillary sampling schedules does not provide a comprehensive assessment of glycemic status and fails to detect asymptomatic hypoglycemia episodes. To investigate the efficacy and accuracy of a real-time continuous glucose monitoring system (RT-CGMS) in neonates with CHH. A sensor connected to RT-CGMS was inserted into the newborn patients and maintained for at least 6 days during their stay in the hospital. We compared the readings of CGMS with capillary blood glucose values using Bland-Altman analysis. A total of 110 blood glucose values were compared to readings from the CGMS. All results were calculated and plotted for CGMS values at 0-4, 5-9, 10-14, 15-19, 20-24, and 25-29 min after capillary blood glucose sampling. CGMS readings were highly correlated with blood glucose values, especially during normoglycemia. In case of hypoglycemia, the mean difference between the CGMS and capillary glucose values was higher. Although the false positive rate for hypoglycemia was relatively high in CGMS, RT-CGMS may show some episodes of hypoglycemia earlier than blood measurement. RT-CGMS is accurate during normoglycemia, and it can reduce the number of capillary blood samples in children with CHH.

Diagnosis and management of hyperinsulinaemic hypoglycaemia

Hyperinsulinaemic hypoglycaemia (HH) is a heterogeneous condition with dysregulated insulin secretion which persists in the presence of low blood glucose levels. It is the most common cause of severe and persistent hypoglycaemia in neonates and children. Recent advances in genetics have linked congenital HH to mutations in 14 different genes that play a key role in regulating insulin secretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, PPM2, CACNA1D, FOXA2). Histologically, congenital HH can be divided into 3 types: diffuse, focal and atypical. Due to the biochemical basis of this condition, it is essential to diagnose and treat HH promptly in order to avoid the irreversible hypoglycaemic brain damage. Recent advances in the field of HH include new rapid molecular genetic testing, novel imaging methods (18F-DOPA PET/CT), novel medical therapy (long-acting octreotide formulations, mTOR inhibitors, GLP-1 receptor antagonists) and surgical approach (laparoscopic surgery). The review article summarizes the current diagnostic methods and management strategies for HH in children.