sirolimus and Congenital-Hyperinsulinism

Hyperinsulinemic hypoglycemia (HI) is the most common cause of hypoglycemia in children. Impairment of cellular pathways involved in insulin secretion from pancreatic β-cells, broadly classified as channelopathies and metabolopathies, have been discovered in the past two decades. The increasing use of NGS target panels, combined with clinical, biochemical and imaging findings allows differentiating the diagnostic management of children with focal forms, surgically curable, from those with diffuse forms, more conservatively treated with pharmacological and nutritional interventions. Specific approaches according to the subtype of HI have been established and novel therapies are currently under investigation. Despite diagnostic and therapeutic advances, HI remains an important cause of morbidity in children, still accounting for 26-44% of permanent intellectual disabilities, especially in neonatal-onset patients. Initial insult from recurrent hypoglycemia in early life greatly contributes to the poor outcomes. Therefore, patients need to be rapidly identified and treated aggressively, and require at follow-up a complex and regular monitoring, managed by a multidisciplinary HI team. This review gives an overview on the more recent diagnostic and therapeutic tools, on the novel drug and nutritional therapies, and on the long-term neurological outcomes.

Topics: Adenosine Triphosphate; Animals; Child; Child, Preschool; Congenital Hyperinsulinism; Diet, Ketogenic; Galactose; Glucagon; Humans; Hypoglycemia; Infant; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Nervous System Diseases; Peptide Fragments; Potassium Channels; Receptor, Insulin; Sirolimus; Somatostatin; Treatment Outcome

In hyperinsulinemic hypoglycemia (HH) there is dysregulation of insulin secretion from pancreatic β-cells. Insulin secretion becomes inappropriate for the level of blood glucose leading to severe hypoglycemia. HH is associated with a high risk of brain injury because insulin inhibits lipolysis and ketogenesis thus preventing the generation of alternative brain substrates (such as ketone bodies). Hence HH must be diagnosed as soon as possible and the management instituted appropriately to prevent brain damage. This article reviews the mechanisms of glucose physiology in the newborn, the mechanisms of insulin secretion, the etiologic types of HH, and its management.

Topics: Blood Glucose; Brain Diseases; Congenital Hyperinsulinism; Diagnostic Imaging; Genetic Testing; Humans; Immunosuppressive Agents; Infant, Newborn; Insulin; Insulin Secretion; Insulin-Secreting Cells; Pancreatectomy; Receptors, Glucagon; Sirolimus

To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH).. 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.. 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. 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.

Topics: Congenital Hyperinsulinism; Diazoxide; Humans; Infant; Infant, Newborn; Mutation; Retrospective Studies; Sirolimus

We present a case of a male neonate with refractory and persistent neonatal hypoglycaemia not responding to octreotide. On evaluation for hypoglycaemia, his cortisol was within the reference range while the serum insulin concentrations were high. Gallium-68 dotatate scan (GA-68 DOTA) showed diffuse pancreatic involvement. Genetic diagnosis of congenital hyperinsulinaemic hypoglycaemia due to

Topics: Child; Congenital Hyperinsulinism; Gallium Radioisotopes; Humans; Infant, Newborn; Male; Mutation; Sirolimus

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in neonates and infants. Medical treatment includes the use of high concentrations of glucose and combinations of diazoxide, octreotide and glucagon. We report our experience of using sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in the treatment of CHI in seven newborns who are poorly responding to standard medical therapy. Majority (87%) of infants achieved euglycaemia using a combination of oral feeding and the addition of sirolimus to standard medical treatment. One infant who failed to achieve euglycaemia even after surgery managed successfully with sirolimus. Diagnosis was confirmed by genetics evaluation; in three infants, novel mutations were detected. Outcome and long-term follow-up of all cases are described.Conclusion: Sirolimus can be considered in treatment of CHI refractory to standard medical treatment or in cases unresponsive to surgical treatment. What is Known: • Congenital hyperinsulinism (CHI) or persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) associated with mutations such as the ABBC8 or KCNJ gene known to cause hypoglycaemia refractory to standard medical treatment such as diazoxide and octreotide and may need subtotal pancreatectomy (STP). • Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, was recently reported to be useful for refractory CHI cases with variable efficacy. What is New: • Our case series describes efficacy and safety of sirolimus in seven genetically proven refractory CHI cases with mainly neonatal presentation. All patients' follow-ups are described. • Out of seven infants, six infants responded well to sirolimus, and among these one infant who failed to respond to surgery (STP) also successfully managed with sirolimus. • It highlights the right patient selection and right dose to successfully manage these cases without much adverse effects.

Topics: Congenital Hyperinsulinism; Diazoxide; Glucose; Humans; Hyperinsulinism; Infant; Infant, Newborn; Mutation; Sirolimus

Topics: Child, Preschool; Congenital Hyperinsulinism; Follow-Up Studies; Humans; Male; Pancreatectomy; Protein Kinase Inhibitors; Severity of Illness Index; Sirolimus; Sulfonylurea Receptors

To report the genotype-phenotype characteristics, demographic features and clinical outcome of Omani patients with congenital hyperinsulinism (CHI). Methods: We retrospectively analyzed the clinical, biochemical, genotypical, phenotypical characteristics and outcomes of  children with CHI who were presented to the pediatric endocrine team in the Royal Hospital, Muscat, Oman between January 2007 and December 2016. Results: Analysis of 25 patients with CHI genetically revealed homozygous mutation in ABCC8 in 23 (92%) patients and 2 patients (8%) with compound heterozygous mutation in ABCC8. Fifteen (60%) patients underwent subtotal pancreatectomy as medical therapy failed and 2 (8%) patients showed response to medical therapy. Three patients expired during the neonatal period, 2 had cardiomyopathy and sepsis, and one had sepsis and severe metabolic acidosis. Out of the 15 patients who underwent pancreatectomy, 6 developed diabetes mellitus, 6 continued to have hypoglycemia and required medical therapy and one had pancreatic exocrine dysfunction post-pancreatectomy, following up with gastroenterology clinic and was placed on pancreatic enzyme supplements, while 2 patients continued to have hypoglycemia and both had abdominal MRI and 18-F-fluoro-L-DOPA positron emission tomography scan (PET-scan), that showed  persistent of the disease and started on medical therapy. Conclusion:  Mutation in ABCC8 is the most common cause of CHI and reflects the early age of presentation. There is a need for early diagnosis and appropriate therapeutic strategy.

Topics: Apnea; Child, Preschool; Congenital Hyperinsulinism; Diabetes Mellitus; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Female; Gastrointestinal Agents; Heterozygote; Homozygote; Humans; Hypoglycemia; Infant; Infant, Newborn; Lethargy; Male; Mutation; Octreotide; Oman; Pancreatectomy; Peptides, Cyclic; Postoperative Complications; Retrospective Studies; Seizures; Sirolimus; Somatostatin; Sulfonylurea Receptors; Treatment Outcome

Congenital hyperinsulinism results in refractory hypoglycemia. If a therapy with diazoxide has been unresponsive this has been treated by subtotal pancreatectomy in the past. This therapeutic option poses an increased risk of developing diabetes at a later stage. There have been a few case reports on the use of sirolimus in such situations in the recent past.. Our patient was started on sirolimus very early, on day 29 of life and at the age of 14 months is doing well on sirolimus therapy. His growth and development have been good and he has not had any major complications so far. Genetic testing showed a novel KCNJ11 homozygous mutation on next generation sequencing and the parents were heterozygous carriers.. We report the successful use of sirolimus in the management of diazoxide unresponsive congenital hyperinsulinism with diffuse pancreatic involvement. We believe this is the youngest patient to be initiated on sirolimus so far.

Topics: Congenital Hyperinsulinism; Homozygote; Humans; Immunosuppressive Agents; Infant; Male; Mutation; Potassium Channels, Inwardly Rectifying; Prognosis; Sirolimus

Sirolimus has been reported to be effective in the treatment of the diffuse form of congenital hyperinsulinism (CHI), unresponsive to diazoxide and octreotide, without causing severe side effects. Two newborns with CHI due to homozygous ABCC8 gene mutations were started on sirolimus aged 21 and 17 days, due to lack of response to medical treatment. A good response to sirolimus was observed. At follow-up after ten and two months of treatment, liver enzymes were found to be increased [serum sirolimus level 1.4 ng/mL (normal range: 5-15), aspartate aminotransferase (AST): 298U/L, alanine aminotransferase (ALT): 302U/L and serum sirolimus level: 9.9 ng/mL, AST: 261U/L, ALT: 275U/L, respectively]. In Case 1, discontinuation of the drug resulted in normalization of liver enzymes within three days. Two days after normalization, sirolimus was restarted at a lower dose, which resulted in a repeated increase in transferases. In Case 2, a reduction of sirolimus dose caused normalization of liver enzymes within ten days. When the dose was increased, enzymes increased within three days. Sirolimus was discontinued in both cases.\ The rapid normalization of liver enzyme levels after sirolimus withdrawal or dose reduction; elevation of transaminases after restart or dose increase and rapid normalization after sirolimus withdrawal were findings strongly suggestive of sirolimus-induced hepatitis.\ To the best of our knowledge, this is the first report of sirolimus-induced hepatitis in CHI. Sirolimus is a promising drug for CHI patients who are unresponsive to medical treatment, but physicians should be vigilant for adverse effects on liver function.

Topics: Chemical and Drug Induced Liver Injury; Congenital Hyperinsulinism; Female; Humans; Immunosuppressive Agents; Infant, Newborn; Sirolimus; Sulfonylurea Receptors

We have recently published on the limited effectiveness of sirolimus as a treatment option for hypoglycaemia as a consequence of hyperinsulinism. Our data oppose the view that mTOR inhibitors provide new opportunities for the treatment of patients with hyperinsulinism. We are not convinced by the argument that any benefit for some patients outweighs the potential and later long-term problems that accompany mTOR inhibition in the neonate. We also express the opinion that caution must be taken when repurposing/repositioning therapies in the field of rare disease.

Topics: Animals; Congenital Hyperinsulinism; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Sirolimus; TOR Serine-Threonine Kinases

Congenital hyperinsulinism (CHI) is a major cause of persistent hypoglycemia and brain damage. Therapeutic strategies to avoid near total pancreatectomy in patients who are unresponsive to maximum doses of diazoxide and octreotide remain to be identified, although sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used successfully to treat diffuse type CHI.. We used sirolimus to treat three infants with diffuse CHI. Diagnosis was confirmed clinically, biochemically and by genetic testing. Homozygous mutations in KCNJ11, ABCC8 and KCNJ11 were identified in infants 1, 2 and 3, respectively. Each infant had received the therapy for at least 2 months with close monitoring of glycemic response, serum insulin and C-peptide. None of the infants responded to the therapy.. We conclude that sirolimus is less effective in the treatment of diffuse CHI in patients with severe mutations in the homozygous state compared with those with the mutations in the heterozygous.

Topics: Blood Glucose; Congenital Hyperinsulinism; Female; Humans; Infant; Male; Mutation; Potassium Channels, Inwardly Rectifying; Sirolimus; Sulfonylurea Receptors; Treatment Outcome

Sirolimus (mTOR inhibitor) is proven to be effective in children with congenital hyperinsulinism (CHI). Studies in animals suggest that sirolimus may have diabetogenic actions. However, its role in precipitating diabetes mellitus (DM) in children with CHI has not been reported.. A 16-year-old female with CHI due to a dominant ABCC8 gene mutation was switched from diazoxide therapy to sirolimus, due to the hypertrichosis side effect of diazoxide. She developed facial cellulitis that was treated with clarithromycin and a month later, once the infection was resolved, she was found to have persistent hyperglycaemia, and was diagnosed with DM. She was unresponsive to oral sulfonylurea therapy and is currently managed with metformin. Her mother, who had the same ABCC8 mutation, developed DM at her 30s.. Patients with dominant ABCC8 gene mutations are prone to DM in adulthood, but Sirolimus therapy might increase the risk of developing diabetes at an early age, as this case illustrates.

Topics: Adolescent; Antibiotics, Antineoplastic; Biomarkers; Congenital Hyperinsulinism; Diabetes Mellitus; Female; Genes, Dominant; Humans; Mutation; Prognosis; Sirolimus; Sulfonylurea Receptors

We first introduced the concept of the mTOR pathway's involvement in congenital hyperinsulinism of infancy (CHI), based largely on morphoproteomic observations and clinical outcomes using sirolimus (rapamycin) as a therapeutic agent in infants refractory to octreotide and diazoxide treatment. Subsequent publications have verified the efficacy of such treatment in some cases but limited and variable in others. We present further evidence of a constant but variable role for the mTOR pathway in the biology of CHI and provide a strategy that allows for the short-term testing of sirolimus in individual CHI patients.

Topics: Congenital Hyperinsulinism; Diazoxide; Humans; Infant; Octreotide; Proteomics; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Almost half of the children with Beckwith-Wiedemann syndrome (BWS) will develop hyperinsulinaemic hypoglycaemia (HH). In the majority of BWS cases, HH will be transient; however, approximately in 5% of them, HH will be severe and often medically-unresponsive. Children with BWS due to paternal uniparental disomy (UPD) of chromosome 11p15 belong to this severe category and have traditionally required near-total pancreatectomy. The use of mTOR inhibitors had not been reported yet in this type of patients.. A 1-month-old female with genetically confirmed BWS due to UPD of chromosome 11p15 was admitted for management of severe HH. Blood glucose concentrations were stabilised with high intravenous dextrose concentration, glucagon and octreotide infusions as she was proven to be diazoxide unresponsive. To avoid a subtotal pancreatectomy, an mTOR inhibitor - sirolimus - was introduced. The dose of sirolimus was optimised progressively and she was able to come off intravenous fluids and glucagon therapy. She has not presented any side effects and her growth is normal after 19 months of therapy.. This is the first case reported of BWS due to UPD of chromosome 11p15 where sirolimus treatment has been effective in stabilising the blood glucose concentrations and avoiding a near-total pancreatectomy without major side effects detected.

Topics: Beckwith-Wiedemann Syndrome; Chromosomes, Human, Pair 11; Congenital Hyperinsulinism; Female; Humans; Infant; Sirolimus; Uniparental Disomy

Congenital hyperinsulinism (CHI) is the most common cause of neonatal persistent hypoglycemia caused by mutations in nine known genes. Early diagnosis and treatment are important to prevent brain injury. The clinical presentation and response to pharmacological therapy may vary depending on the underlying pathology. Genetic analysis is important in the diagnosis, treatment, patient follow-up, and prediction of recurrence risk within families. Our patient had severe hypoglycemia and seizure following birth. His diagnostic evaluations including genetic testing confirmed CHI. He was treated with a high-glucose infusion, high-dose diazoxide, nifedipine, and glucagon infusion. A novel homozygous mutation (p.F315I) in the KCNJ11 gene, leading to diazoxide-unresponsive CHI, was identified. Both parents were heterozygous for this mutation. Our patient's clinical course was complicated by severe refractory hypoglycemia; he was successfully managed with sirolimus and surgical intervention was not required. Diazoxide, nifedipine, and glucagon were discontinued gradually following sirolimus therapy. The patient was discharged at 2 months of age on low-dose octreotide and sirolimus. His outpatient clinical follow-up continues with no episodes of hypoglycemia. We present a novel homozygous p.F315I mutation in the KCNJ11 gene leading to diazoxide-unresponsive CHI in a neonate. This case illustrates the challenges associated with the diagnosis and management of CHI, as well as the successful therapy with sirolimus.

Topics: Congenital Hyperinsulinism; Consanguinity; Family Health; Female; Genetic Predisposition to Disease; Heterozygote; Homozygote; Humans; Immunosuppressive Agents; Infant, Newborn; Male; Mutation; Parents; Potassium Channels, Inwardly Rectifying; Sirolimus; Treatment Outcome

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in neonates and infants. In medically unresponsive CHI, subtotal pancreatectomy is performed to achieve euglycemia with consequent diabetes in later life. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been reported to obviate the need for pancreatectomy, but experience is limited.. We have investigated the efficacy and adverse effect profile of mTOR inhibitors in the treatment of severe CHI.. This was an observational review of 10 severe CHI patients treated with mTOR inhibitors, in France and the United Kingdom, with the intention of achieving glycemic control without pancreatectomy. Safety information was recorded.. We examined whether mTOR inhibitors achieved glycemic control, fasting tolerance, and weaning of supportive medical therapy.. mTOR inhibition achieved euglycemia, fasting tolerance, and reduced medical therapy in only three patients (30%). Triglyceride levels were elevated in five patients (50%). One child required a blood transfusion for anemia, four had stomatitis, two had sepsis, one developed varicella zoster, and two patients developed gut dysmotility in association with exocrine pancreatic insufficiency. In silico analysis of transcriptome arrays from CHI patients revealed no significant association between mTOR signaling and disease. Pancreatic tissue from two patients who did not respond to sirolimus showed no reduction in cell proliferation, further suggesting that mTOR signaling did not down-regulate proliferation in the CHI pancreas.. mTOR inhibitor treatment is associated with very limited success and must be used with caution in children with severe CHI.

Topics: Child, Preschool; Congenital Hyperinsulinism; Everolimus; Female; Humans; Immunosuppressive Agents; Infant; Male; Outcome Assessment, Health Care; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases

Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of severe and persistent hypoglycaemia in neonates. The treatment of severe diazoxide unresponsive HH involves near total pancreatectomy. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates cellular proliferation. mTOR inhibitors are used in cancer patients and recently found to be effective in the treatment of insulinoma and HH patients.. A 36 weeks large for gestational age neonate presented with severe hypoglycaemia on day 1 of life. The hypoglycaemia screen confirmed HH and genetic testing revealed compound heterozygous ABCC8 mutation, confirming diffuse disease. He was unresponsive to the maximal dose of diazoxide (15 mg/kg/day), hence needed treatment with higher concentration of intravenous glucose (25 mg/kg/min), intravenous glucagon and subcutaneous octreotide (30 μg/kg/day) infusions to maintain normoglycaemia. Sirolimus, a mTOR inhibitor, was commenced at 9 weeks of age following which he showed a marked improvement in his glycaemic control. After 4 weeks of sirolimus therapy, he was discharged home on subcutaneous octreotide injection (20 μg/kg/day) and oral sirolimus, thereby avoiding the need for a near total pancreatectomy.. We report the first case of compound heterozygous ABCC8 mutation causing severe diffuse HH that responded to therapy with a mTOR inhibitor.

Topics: Congenital Hyperinsulinism; Heterozygote; Humans; Infant, Newborn; Insulin; Male; Mutation; Sirolimus; Sulfonylurea Receptors

Hyperinsulinaemic hypoglycaemia (HH) is characterised by inappropriate insulin secretion and is the most common cause for persistent neonatal hypoglycaemia. The only treatment available for medically unresponsive hypoglycaemia is a near-total pancreatectomy. A neonate with severe HH, due to a homozygous ABCC8 mutation, was not responsive to treatment with maximal doses of diazoxide and subcutaneous daily octreotide, and underwent a near-total pancreatectomy; however, hypoglycaemia persisted. Introduction of sirolimus, an mTOR (mammalian target of rapamycin) inhibitor, obviated the requirement for glucose infusion. Euglycaemia was achieved with no significant adverse events from the drug. Sirolimus therapy was ceased at 13 months of age. No episodes of persistent hypoglycaemia were observed after cessation of sirolimus. This report demonstrates the successful use of sirolimus for persistent hypoglycaemia in the critically ill infant post pancreatectomy. Sirolimus could be considered in patients with severe HH not responsive to conventional medical and surgical therapy. However, the long-term efficacy and safety with this immunosuppressive drug in very young patients are not assured.

Topics: Congenital Hyperinsulinism; Humans; Hypoglycemia; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Pancreatectomy; Sirolimus; Treatment Outcome

Congenital hyperinsulinism (CHI) due to diffuse involvement of the pancreas is a challenging and severe illness in children. Its treatment is based on chronic therapy with diazoxide and/or octreotide, followed by partial pancreatectomy, which is often not resolutive. Sirolimus, a mammalian target of rapamycin inhibitor, was reported to be effective in treating CHI in infants. We report here the case of an 8-year-old boy affected by a severe form of CHI due to a biallelic heterozygous ABCC8 mutation who responded to sirolimus with a dramatic improvement in his glucose blood level regulation and quality of life, with no serious adverse events after 6 months of follow-up. To the best of our knowledge, this is the first report of a successful intervention in an older child. It provides a promising basis for further studies comparing sirolimus with other treatments, particularly in older children.

Topics: Child; Congenital Hyperinsulinism; Humans; Male; Remission Induction; Sirolimus

Hyperinsulinemic hypoglycemia is the most common cause of severe, persistent neonatal hypoglycemia. The treatment of hyperinsulinemic hypoglycemia that is unresponsive to diazoxide is subtotal pancreatectomy. We examined the effectiveness of the mammalian target of rapamycin (mTOR) inhibitor sirolimus in four infants with severe hyperinsulinemic hypoglycemia that had been unresponsive to maximal doses of diazoxide (20 mg per kilogram of body weight per day) and octreotide (35 μg per kilogram per day). All the patients had a clear glycemic response to sirolimus, although one patient required a small dose of octreotide to maintain normoglycemia. There were no major adverse events during 1 year of follow-up.

Topics: Blood Glucose; Congenital Hyperinsulinism; Female; Humans; Infant; Male; Mutation; Sirolimus; TOR Serine-Threonine Kinases

Topics: Congenital Hyperinsulinism; Female; Humans; Male; Sirolimus; TOR Serine-Threonine Kinases

Topics: Congenital Hyperinsulinism; Female; Humans; Male; Sirolimus; TOR Serine-Threonine Kinases