Genetics and Natural History of Non-pancreatectomized Patients With Congenital Hyperinsulinism Due to Variants in ABCC8.

CONTEXT: Patients with congenital hyperinsulinism due to ABCC8 variants generally present severe hypoglycemia and those who do not respond to medical treatment typically undergo pancreatectomy. Few data exist on the natural history of non-pancreatectomized patients. OBJECTIVE: This work aims to describe the genetic characteristics and natural history in a cohort of non-pancreatectomized patients with congenital hyperinsulinism due to variants in the ABCC8 gene. METHODS: Ambispective study of patients with congenital hyperinsulinism with pathogenic or likely pathogenic variants in ABCC8 treated in the last 48 years and who were not pancreatectomized. Continuous glucose monitoring (CGM) has been periodically performed in all patients since 2003. An oral glucose tolerance test was performed if hyperglycemia was detected in the CGM. RESULTS: Eighteen non-pancreatectomized patients with ABCC8 variants were included. Seven (38.9%) patients were heterozygous, 8 (44.4%) compound heterozygous, 2 (11.1%) homozygous, and 1 patient carried 2 variants with incomplete familial segregation studies. Seventeen patients were followed up and 12 (70.6%) of them evolved to spontaneous resolution (median age 6.0 ± 4 years; range, 1-14). Five of these 12 patients (41.7%) subsequently progressed to diabetes with insufficient insulin secretion. Evolution to diabetes was more frequent in patients with biallelic variants in the ABCC8 gene. CONCLUSION: The high remission rate observed in our cohort makes conservative medical treatment a reliable strategy for the management of patients with congenital hyperinsulinism due to ABCC8 variants. In addition, a periodic follow-up of glucose metabolism after remission is recommended, as a significant proportion of patients evolved to impaired glucose tolerance or diabetes (biphasic phenotype).

Hyperinsulinism-hyperammonemia syndrome in two Peruvian children with refractory epilepsy.

OBJECTIVES: Congenital hyperinsulinism (HI) is a heterogeneous clinical disorder with great variability in its clinical phenotype, and to date, pathogenic variants in 23 genes have been recognized.  Hyperinsulinism-hyperammonemia syndrome (HI/HA) is the second most frequent cause of this disease that shows an autosomal dominant pattern and is caused by an activating mutation of the GLUD1 gene, which responds favorably to the use of diazoxide. HI/HA syndrome presents with fasting hypoglycemia; postprandial hypoglycemia, especially in those with a high protein content (leucine); and persistent mild hyperammonemia. Neurological abnormalities, in the form of epilepsy or neurodevelopmental delay, are observed in a high percentage of patients; therefore, timely diagnosis is crucial for proper management. CASE PRESENTATION: We report the clinical presentation of two Peruvian children that presented with epilepsy whose genetic analysis revealed a missense mutation in the GLUD1 gene, one within exon 11, at 22% mosaicism; and another within exon 7, as well as their response to diazoxide therapy. To the best of our knowledge, these are the first two cases of HI/HA syndrome reported in Peru. CONCLUSIONS: HI/HA syndrome went unnoticed, because hypoglycemia was missed and were considered partially controlled epilepsies. A failure to recognize hypoglycemic seizures will delay diagnosis and adequate treatment, so a proper investigation could avoid irreversible neurological damage.

[Congenital hyperinsulinism as a part of Kabuki syndrome].

Kabuki syndrome is a rare hereditary disease characterized by distinctive facial features, skeletal abnormalities, mental retardation, developmental delay, and anomalies in multiple organ systems development.Congenital hyperinsulinism is a rare manifestation of his Kabuki syndrome. However, early diagnosis is crucial to prevent neurological complications of hypoglycemia.There are 2 types of Kabuki Syndrome depending on severity of symptoms. Kabuki syndrome Type 1 is associated with heterozygous mutations in gene KMT2D. Kabuki syndrome Type 2 is inherited in an X-linked manner. It's associated with heterozygous mutations in gene KDM6A and characterized by more severe course of the disease.This paper presents 2 cases of children with congenital hyperinsulinism as the feature of Kabuki syndrome Type 1 and Type 2.

Diagnosis, treatment and genetic analysis of two cases of congenital hyperinsulinemic hypoglycemia caused by GCK gene mutation.

Congenital hyperinsulinemia (CHI) is a heterogeneous disorder characterized by persistent hypoglycemia due to inappropriate insulin secretion. A total of 15 gene mutations have already been reported to be associated with CHI. Among them, CHI caused by the GCK mutation is named GCK-CHI, which is considered to be a rare form of CHI. Here, we reported two cases of GCK-CHI diagnosed by genetic testing and summarized the clinical characteristics. In patients with recurrent or persistent hypoglycemia, CHI should be taken into consideration. Genetic testing should be perfomed in these patients to avoid misdiagnosis and provide accurate intervention, thus to improve prognosis.

Somatostatin receptors in congenital hyperinsulinism: Biology to bedside.

Congenital hyperinsulinism (CHI), although a rare disease, is an important cause of severe hypoglycemia in early infancy and childhood, causing preventable morbidity and mortality. Prompt diagnosis and appropriate treatment is necessary to prevent hypoglycaemia mediated brain damage. At present, the medical treatment of CHI is limited to diazoxide as first line and synthetic somatostatin receptor ligands (SRLs) as second line options; therefore understanding somatostatin biology and treatment perspectives is important. Under healthy conditions, somatostatin secreted from pancreatic islet δ-cells reduces insulin release through somatostatin receptor induced cAMP-mediated downregulation and paracrine inhibition of ß- cells. Several SRLs with extended duration of action are now commercially available and are being used off-label in CHI patients. Efficacy remains variable with the present generation of SRLs, with treatment effect often being compromised by loss of initial response and adverse effects such as bowel ischaemia and hepatobiliary dysfunction. In this review we have addressed the biology of the somatostatin system contexualised to CHI. We have discussed the clinical use, limitations, and complications of somatostatin agonists and new and emerging therapies for CHI.

Case report: A particularly rare case of endogenous hyperinsulinemic hypoglycemia complicated with pregnancy treated with short-acting somatostatin analog injections.

Hyperinsulinemic hypoglycemia is a rare disease, and only two cases complicated with pregnancy were published previously when our patient became pregnant. We introduce a successful management of a pregnancy in a patient with endogenous hyperinsulinemic hypoglycemia, a condition also known as non-insulinoma pancreatogenous hypoglycemia syndrome or formerly as nesidioblastosis. A 29-year-old female patient was treated with endogenous hyperinsulinemic hypoglycemia since the age of 4 months, taking daily 3 × 75 mg diazoxide, which adds up to 225 mg per day. Adequate glycemic control could be achieved with this therapy. Genetic testing and various imaging examinations were carried out earlier to specify the disease and to exclude focal forms. The patient came to the clinic with a positive pregnancy test and consequential hypoglycemic episodes. Hospital admission was needed to correct the metabolic condition. Although the patient was informed about the potential risks, she decided to carry out the pregnancy. According to the quite limited literature, somatostatin analogs are the only therapy used previously during pregnancy in hyperinsulinemic hypoglycemic patients. One publication reported normal pregnancy outcomes, but in another case, restricted fetal growth was observed. In our case, we stopped diazoxide and parallelly introduced short-acting somatostatin analog octreotide in the therapy, and further dietetic changes were proposed. In addition to daily regular self-blood glucose monitoring, regular gynecological controls were carried out monthly, and healthy fetal development was confirmed. The patient gave birth to her first child, a well-developed female neonate, in the 38th week, by a cesarean section.

Case Report: Neurodevelopmental Outcome in a Small-for-Gestational-Age Infant With Symptomatic Hyperinsulinemic Hypoglycemia, Gaze Preference, and Infantile Spasms.

Recurrent and profound hypoglycemia is a leading cause of neonatal brain injury. Small-for-gestational-age infants are at risk of hypoglycemia due to substrate deficiency and hyperinsulinism. Inappropriate insulin secretion by the ß-cells of the pancreas results in hypoglycemia, neuronal energy deprivation, and parieto-occipital brain injury. Hypoglycemic neuronal injury is increasingly being identified as a trigger for infantile spasms, even though the underlying pathophysiological mechanisms remain elusive. A term, small-for-gestational-age male infant developed severe symptomatic hypoglycemia on day 3 of life. He required a high glucose infusion rate (14 mg/kg/min) to maintain normoglycemia. Critical blood samples showed inappropriate insulin levels while hypoglycemic and hypoketonemic, consistent with a diagnosis of hyperinsulinemic hypoglycemia. Blood glucose levels normalized with a diazoxide dose of 5 mg/kg/day. Gradually, glucose infusion was weaned with increasing oral feeds while maintaining prefeed capillary blood glucose levels. While at home, his glucose profile remained stable on the self-weaning dose of diazoxide. He passed a resolution fasting study at 4 months of age after weaning off diazoxide. He developed left gaze preference at 2.5 months of age while on treatment for hyperinsulinemic hypoglycemia but developed infantile spasms at 5 months that was confirmed with an electroencephalogram (EEG). Gaze preference may be epileptic, even in the absence of seizures. Spasms were well controlled with high-dose prednisolone therapy. At the age of 6 years, he has a mild fine motor delay and learning disabilities. Early diagnosis and treatment of infantile spasms have a better prognosis. Identifying gaze preference as a predating sign of occipital lobe epilepsy, EEG monitoring, and, if required, treatment could have possibly averted the genesis of infantile spasms.

Increased referrals for congenital hyperinsulinism genetic testing in children with trisomy 21 reflects the high burden of non-genetic risk factors in this group.

BACKGROUND: Hyperinsulinism results from inappropriate insulin secretion during hypoglycaemia. Down syndrome is causally linked to a number of endocrine disorders including Type 1 diabetes and neonatal diabetes. We noted a high number of individuals with Down syndrome referred for hyperinsulinism genetic testing, and therefore aimed to investigate whether the prevalence of Down syndrome was increased in our hyperinsulinism cohort compared to the population. METHODS: We identified individuals with Down syndrome referred for hyperinsulinism genetic testing to the Exeter Genomics Laboratory between 2008 and 2020. We sequenced the known hyperinsulinism genes in all individuals and investigated their clinical features. RESULTS: We identified 11 individuals with Down syndrome in a cohort of 2011 patients referred for genetic testing for hyperinsulinism. This represents an increased prevalence compared to the population (2.5/2011 expected vs. 11/2011 observed, p = 6.8 × 10-5 ). A pathogenic ABCC8 mutation was identified in one of the 11 individuals. Of the remaining 10 individuals, five had non-genetic risk factors for hyperinsulinism resulting from the Down syndrome phenotype: intrauterine growth restriction, prematurity, gastric/oesophageal surgery, and asparaginase treatment for leukaemia. For five individuals no risk factors for hypoglycaemia were reported although two of these individuals had transient hyperinsulinism and one was lost to follow-up. CONCLUSIONS: Down syndrome is more common in patients with hyperinsulinism than in the population. This is likely due to an increased burden of non-genetic risk factors resulting from the Down syndrome phenotype. Down syndrome should not preclude genetic testing as coincidental monogenic hyperinsulinism and Down syndrome is possible.

Hyperinsulinemic hypoglycemia in growth restricted convalescent preterm neonates: clinical characteristics and impediments to early diagnosis.

OBJECTIVES: Describe clinical characteristics, course, and risk factors for hyper-insulinemic hypoglycemia (HIH) in preterm infants and identify impediments to early diagnosis. METHODS: Electronic records of infant-mother dyads were used to describe clinical characteristics, lab parameters, and course of HIH. RESULTS: All eight patients (gestational ages 26w0d-29w3d) had intrauterine growth restriction (IUGR) due to placental insufficiency, (4/8) were small for gestational age. All maintained normal glucose levels with glucose infusion during the first 48 h six of eight patients had cholestasis despite being on parenteral nutrition for short time (average 17 days). Four of eight patients were treated with diazoxide (average 22 days). Four of eight patients who recovered spontaneously (average 49 days after diagnosis) responded to continuous feeds and hydrocortisone for other clinical indications. CONCLUSIONS: In IUGR preterms, HIH is asymptomatic, may be prolonged, requiring diazoxide treatment. Transient cholestasis is seen in majority of patients. Euglycemia should be demonstrated on bolus gavage feeds, off glucocorticoids before discontinuing blood glucose monitoring.

The coincidence of two rare diseases with opposite metabolic phenotype: a child with congenital hyperinsulinism and Bloom syndrome.

OBJECTIVES: Congenital hyperinsulinism (CHI) is a group of rare genetic disorders characterized by insulin overproduction. CHI causes life-threatening hypoglycemia in neonates and infants. Bloom syndrome is a rare autosomal recessive disorder caused by mutations in the BLM gene resulting in genetic instability and an elevated rate of spontaneous sister chromatid exchanges. It leads to insulin resistance, early-onset diabetes, dyslipidemia, growth delay, immune deficiency and cancer predisposition. Recent studies demonstrate that the BLM gene is highly expressed in pancreatic islet cells and its mutations can alter the expression of other genes which are associated with apoptosis control and cell proliferation. CASE PRESENTATION: A 5-month-old female patient from consanguineous parents presented with drug-resistant CHI and dysmorphic features. Genetic testing revealed a homozygous mutation in the KCNJ11 gene and an additional homozygous mutation in the BLM gene. While 18F-DOPA PET scan images were consistent with a focal CHI form and intraoperative frozen-section histopathology was consistent with diffuse CHI form, postoperative histopathological examination revealed features of an atypical form. CONCLUSIONS: In our case, the patient carries two distinct diseases with opposite metabolic phenotypes.

Continuous Glucose Monitoring in the Management of Neonates With Persistent Hypoglycemia and Congenital Hyperinsulinism.

BACKGROUND: Persistent hypoglycemia is common in the newborn and is associated with poor neurodevelopmental outcome. Adequate monitoring is critical in prevention, but is dependent on frequent, often hourly blood sampling. Continuous glucose monitoring (CGM) is increasingly being used in children with type 1 diabetes mellitus, but use in neonatology remains limited. We aimed to introduce real-time CGM to provide insights into patterns of dysglycemia and to support the management of persistent neonatal hypoglycemia. METHODS: This is a single-center retrospective study of real-time CGM use over a 4-year period in babies with persistent hypoglycemia. RESULTS: CGMs were inserted in 14 babies: 8 term and 6 preterm infants, 9 with evidence of congenital hyperinsulinism (CHI). A total of 224 days of data was collected demonstrating marked fluctuations in glucose levels in babies with CHI, with a higher sensor glucose SD (1.52 ±â€…0.79 mmol/L vs 0.77 ±â€…0.22 mmol/L) in infants with CHI compared with preterm infants. A total of 1254 paired glucose values (CGM and blood) were compared and gave a mean absolute relative difference of 11%. CONCLUSION: CGM highlighted the challenges of preventing hypoglycemia in these babies when using intermittent blood glucose levels alone, and the potential application of CGM as an adjunct to clinical care.

Epileptic phenotype in late-onset hyperinsulinemic hypoglycemia successfully treated by diazoxide.

OBJECTIVES: Serious hyperinsulinemic hypoglycemia (HH) is generally the main initial symptom of hyperinsulinism. Epilepsy, without any overt feature of hypoglycemia, might be a very rare initial presentation of late-onset isolated hyperinsulinism. CASE PRESENTATION: We describe a case of late-onset HH in a 15-year-old boy with a history of idiopathic generalized epilepsy, now named genetic generalized epilepsy (IGE/GGE), beginning with a tonic-clonic seizure at the age of 11 years. Subsequently, absences with rare eyelid myoclonia were recorded on electroencephalogram (EEG), followed by episodes of impaired consciousness with facial myoclonia. Neurological status was normal except attention-deficit hyperactivity disorder (ADHD). At the age of 15 years, an episode of slight alteration of consciousness with neurovegetative signs could be recorded, which did not correspond to an absence status. Hypoglycemia due to hyperinsulinism was documented (clinically, biologically, and genetically). Diazoxide treatment resolved the glycopenic symptoms, the non-hypoglycemic seizures and normalized brain electrical activity allowing complete withdrawal of antiepileptic medication. CONCLUSIONS: Epilepsy can be a very rare initial feature of HH starting in childhood. The occurrence of atypical features in the context of GGE as "absence statuses" with unusual vegetative symptoms and facial myoclonia might be suggestive for HH. Careful assessment and specific treatment are necessary to prevent hyperinsulinism related brain damage. Our case showed that diazoxide might also resolve seizures and normalize EEG.

Hyperinsulinaemic hypoglycaemia in non-anaesthetized Göttingen minipigs induces a counter-regulatory endocrine response and electrocardiographic changes.

The potentially fatal cardiovascular effects of hypoglycaemia are not well understood and large animal models of the counter-regulatory responses and cardiovascular consequences of insulin-induced hypoglycaemia are needed to understand the mechanisms in humans. The aim of this study was to develop a human-like minipig model of hypoglycaemia including healthy and diabetic pigs to investigate endocrine, electrocardiographic and platelet effects. Hypoglycaemia was induced using a hyperinsulinaemic, hypoglycaemic clamp and an insulin bolus protocol. Plasma glucose, glucagon, C-peptide, insulin, epinephrine and platelet aggregation responses were measured before, during and after hypoglycaemia. Continuous electrocardiographic recordings were obtained. Hypoglycaemia at a plasma glucose concentration of 0.8-1.0 mM in the clamp induced 25-fold increase in epinephrine and sixfold and threefold increase in glucagon for healthy and diabetic pigs, respectively. The hypoglycaemic clamp induced QTc-interval prolongation and increase in cardiac arrhythmias. In the bolus approach, the non-diabetic group reached plasma glucose target of 1.5 mM and QTc-interval was prolonged after insulin injection, but before glucose nadir. The diabetic group did not reach hypoglycaemic target, but still demonstrated QTc-interval prolongation. These results demonstrate effects of hyperinsulinaemic hypoglycaemia closely resembling human physiology, indicating the minipig as a translational animal model of counter-regulatory endocrine and myocardial effects of hypoglycaemia.

Clinical characteristics, outcome, and predictors of neurological sequelae of persistent congenital hyperinsulinism: A single tertiary center experience.

AIM: Congenital hyperinsulinism (CHI) is a heterogeneous disease with variable genetic etiology, histopathology, and clinical phenotype. This study aims to describe the clinical characteristics of persistent CHI and evaluate long-term neurological outcome and its risk factors in a cohort of Egyptian children. METHODS: Clinical, genetic, and biochemical data of 42 patients with CHI were collected. Patients were invited for neurological assessment, electroencephalogram, and magnetic resonance imaging of the brain. RESULTS: ABCC8 mutation was found in (61%) of cases who underwent genetic testing (17/28). Five cases with homozygous biparental ABCC8 mutation responded to combined diazoxide and octreotide without needing surgery. Seven out of twenty-one patients who had pancreatectomy (33%) developed diabetes after a median period of 4.8 (range:1-10) years following surgery. Fifty-five percent of our patients had neurodevelopmental impairment at follow-up. Logistic regression analysis has shown that delayed referral to tertiary centre for more than 8 days, delayed diagnosis of CHI for more than 14 days and hospital admission for more than 30 days, are significant predictors of unfavorable neurological sequelae in CHI; (OR = 12.7 [2.56], p = 0.001), (OR = 12.7 [2.9-56], p = 0.001), and (OR = 3.8 [0.14.5], p = 0.043), respectively. CONCLUSIONS: ABCC8 mutation was the commonest genetic mutation underlying CHI in this study group. CHI cases with biparental homozygous ABCC8 mutation may show response to combined octreotide and diazoxide therapy. More than half of our patients had neurodevelopmental impairment at follow-up. Delayed referral to expert centre, delayed diagnosis and longer hospital stay are significant predictors of neurological disability in CHI cases.

Conjugated hyperbilirubinemia among infants with hyperinsulinemic hypoglycemia.

From clinical practice, we noted that a subset of neonates with hyperinsulinism develop conjugated hyperbilirubinemia. A relationship between these two conditions has not been previously described. We aimed to assess the incidence of cholestasis in a cohort of neonates with hyperinsulinism and describe their clinical characteristics. In a retrospective cohort of 63 neonates with hyperinsulinism, 48% developed cholestasis (conjugated bilirubin > 17 µmol/L) with a median maximum conjugated bilirubin of 81 [21 to 191] µmol/L. A history of fetal distress (RR 2.3 [1.24-4.45], p < 0.01) and prematurity (RR 2.0 [1.23-3.26], p <0.01) was associated with the development of cholestasis, but not parental nutrition or other pharmacological treatments. An underlying etiology for the cholestasis was only found in 1 patient, and in all cases the cholestasis spontaneously improved.Conclusions: A significant percentage of infants with hyperinsulinism develop idiopathic, spontaneously resolving, conjugated hyperbilirubinemia. The association with a history of fetal distress potentially suggests that intrauterine factors leading to hyperinsulinism may also predispose towards conjugated hyperbilirubinemia. While the presence of neonatal cholestatic jaundice warrants timely investigations to exclude important underling etiologies, if validated, these findings may support a less invasive diagnostic workup of conjugated hyperbilirubinemia in infants with co-existent hyperinsulinism. What is Known: • Hyperinsulinism and conjugated hyperbilirubinemia are two common presentations in neonates. • A clinical association between the two conditions has not been described. What is New: • A significant proportion of infants with hyperinsulinism develop idiopathic, spontaneously resolving conjugated hyperbilirubinemia. • Increased risk for cholestasis in this patient population is associated with fetal distress and prematurity but not parental nutrition.

Familial hyperinsulinaemic hypoglycaemia with epileptic syndrome, cognitive impairment and detected mutation of the ABCC 8 (SUR1) gene: a case report.

Hyperinsulinaemic hypoglycaemia (HH) occurs as a consequence of unregulated insulin secretion from pancreatic beta cells. It is the most common cause of severe and prolonged hypoglycemia in newborns. HH is a major risk factor for brain damage and subsequent neurological disability, which is why the identification, rapid diagnosis, and timely treatment of patients with HH are essential for the prevention of brain damage. The present case gives a brief description of a patient with congenital HH with an established mutation in the ABCC8 gene encoding the SUR1 subunit of the K-ATP channel. The genealogical tree, the clinical picture, the diagnostic cascade, the neurological consequences and their development in dynamics are considered, with special emphasis on the epileptic syndrome and mental status. Advances in molecular genetics, radiological imaging techniques, conservative treatment, or laparoscopic surgery may completely change the clinical approach to children with severe congenital forms of HH.

Diagnosis of congenital Hyperinsulinism can occur not only in infancy but also in later age: a new flow chart from a single center experience.

BACKGROUND: Congenital Hyperinsulinism typically occurs with a neonatal hypoglycemia but can appear even in childhood or in adolescence with different types of glucose metabolism derangements. Current diagnostic algorithms don't take into account cases with a late presentation. PATIENTS AND METHODS: Clinical and laboratory data of twenty-two subjects diagnosed at Federico II University of Naples have been described: patients have been divided according to the molecular defect into channel defects, metabolic defects and unidentified molecular defects. A particular focus has been made on three cases with a late presentation. RESULTS AND CONCLUSIONS: Late presentation cases may not be identified by previous diagnostic algorithms. Consequently, it seems appropriate to design a new flow-chart starting from the age of presentation, also considering that late presentation cases can show glucose metabolism derangements other than hypoglycaemic crises such as diabetes, glucose intolerance, postprandial hypoglycaemia and gestational diabetes.

Mutations in PMM2 gene in four unrelated Spanish families with polycystic kidney disease and hyperinsulinemic hypoglycemia.

Objectives Hyperinsulinemic hypoglucemia (HH) is characterized by a dysregulation of insulin secretion from pancreatic ß cells. Congenital hyperinsulinism has been associated with specific genes in monogenic forms and also with other diseases with a yet unknown genetic cause. In 2017, Rubio Cabezas et al. described the association of HH and autosomal recessive polycystic kidney disease (ARPKD) with a promoter mutation in the PMM2 gene. They found that all the patients carried a promoter mutation (c-167G>T) in PMM2, either homozygous or in trans with a second PMM2 coding mutation. Methods We performed the study of the PMM2 gene in six patients from four unrelated families, previously diagnosed with ARPKD and HH. Results All these patients had in common the heterozygous variant c-167G>T in the promoter region for PMM2. Additionally, each patient carried a compound heterozygote for a second missense mutation in this gene (p.Arg141His, p.Asp148Asn or p.Phe157Ser), previously reported as pathogenic for congenital disorder of glycosylation type Ia, with an autosomal recessive inheritance pattern. Unlike the previous published article, two of our patients showed altered type 1 pattern and one of them with rectal bleeding that could be a sign of PMM2-congenital disorders of glycosylation. Conclusion We propose the study of this gene when carrying out the diagnosis of patients with HH, especially in the neonatal period and when a recessive polycystic kidney disease without alterations in PKDH1 is diagnosed.

Delayed Resolution of Feeding Problems in Patients With Congenital Hyperinsulinism.

Background: Congenital Hyperinsulinism (CHI) is the most common cause of recurrent and severe hypoglycaemia in childhood. Feeding problems occur frequently in severe CHI but long-term persistence and rates of resolution have not been described. Methods: All patients with CHI admitted to a specialist center during 2015-2016 were assessed for feeding problems at hospital admission and for three years following discharge, through a combination of specialist speech and language therapy review and parent-report at clinical contact. Results: Twenty-five patients (18% of all patients admitted) with CHI were prospectively identified to have feeding problems related to sucking (n = 6), swallowing (n = 2), vomiting (n = 20), and feed aversion (n = 17) at the time of diagnosis. Sixteen (64%) patients required feeding support by nasogastric/gastrostomy tubes at diagnosis; tube feeding reduced to 4 (16%) patients by one year and 3 (12%) patients by three years. Feed aversion resolved slowly with mean time to resolution of 240 days after discharge; in 15 patients followed up for three years, 6 (24%) continued to report aversion. The mean time (days) to resolution of feeding problems was lower in those who underwent lesionectomy (n = 4) than in those who did not (30 vs. 590, p = 0.009) and significance persisted after adjustment for associated factors (p = 0.015). Conclusion: Feeding problems, particularly feed aversion, are frequent in patients with CHI and require support over several years. By contrast, feeding problems resolve rapidly in patients with focal CHI undergoing curative lesionectomy, suggesting the association of feeding problems with hyperinsulinism.