RESUMO
We present the case of a 36-year-old female who was diagnosed at birth with CHI that caused severe hypoglycaemia unresponsive to Diazoxide. Subtotal pancreatectomy was performed at the age of three weeks. Later, histological analysis of her pancreas in a research setting revealed a focal form of CHI. Genetic testing was not available at that time. The patient developed pancreatic exocrine deficiency and insulin-dependent diabetes at the age of 9 years. In 2016, a genetic test revealed a missense heterozygous variant in the ABCC8 gene inherited from her father and classified as having a recessive inheritance. The geneticist concluded that the risk of CHI for her offspring would be low (1/600), making pregnancy favourable. As there was no consanguinity in the family, testing the future father was deemed unnecessary (carrier frequency 1/150 in the general population). The pregnancy occurred spontaneously in 2020 and at a gestational age of 28 weeks, the mother went into premature labour. An emergency C-section was performed in April 2021 resulting in the birth of bichorial bi-amniotic male twins. Following birth, both newborns experienced persistent severe hypoglycaemia which required glucagon treatment and intravenous glucose infusion initially, followed by Diazoxide from day 51 after birth, without satisfactory response. Continuous intravenous Octreotide treatment was introduced on day 72. Due to the recurrence of hypoglycaemia episodes despite reaching maximum doses of Octreotide, from day 92 the treatment was switched to Pasireotide. Genetic tests revealed the same genotypes for both infants: the exon 39 missense variant (c.4716C>A; p.Ser1572Arg) inherited from their mother and a truncating variant in exon 28 (c.3550del; p.Val1184*), inherited from their asymptomatic father. As a result of inheriting two recessive variants of the ABCC8 gene, the children were diagnosed with a diffuse form of CHI, consistent with the diazoxide-unresponsive presentation. This situation is very rare outside consanguinity. This case emphasises the significance of genetic counselling for individuals with a history of rare diseases outside the context of consanguinity, as there is a potential risk of recurrence. Prenatal diagnosis can lead to better outcomes for affected neonates, as well as help families make informed decisions about future pregnancies.
Assuntos
Hiperinsulinismo Congênito , Humanos , Feminino , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/tratamento farmacológico , Gravidez , Adulto , Recém-Nascido , Receptores de Sulfonilureias/genética , Masculino , Gêmeos Dizigóticos/genéticaRESUMO
BACKGROUND: ABCC8 variants can cause hyperinsulinemia by activating or deactivating gene expression. This study used targeted exon sequencing to investigate genetic variants of ABCC8 and the associated phenotypic features in Chinese patients with hyperinsulinemic hypoglycemia (HH). METHODS: We enrolled eight Chinese children with HH and analyzed their clinical characteristics, laboratory results, and genetic variations. RESULTS: The age at presentation among the patients ranged from neonates to 0.6 years old, and the age at diagnosis ranged from 1 month to 5 years, with an average of 1.3 ± 0.7 years. Among these patients, three presented with seizures, and five with hypoglycemia. One patient (Patient 7) also had microcephaly. All eight patients exhibited ABCC8 abnormalities, including six missense mutations (c. 2521 C > G, c. 3784G > A, c. 4478G > A, c. 4532T > C, c. 2669T > C, and c. 331G > A), two deletion-insertion mutations (c. 3126_3129delinsTC and c. 3124_3126delins13), and one splicing mutation (c. 1332 + 2T > C). Two of these mutations (c. 3126_3129delinsTC and c. 4532T > C) are novel. Six variations were paternal, two were maternal, and one was de novo. Three patients responded to diazoxide and one patient responded to octreotide treatment. All there patients had diazoxide withdrawal with age. Two patients (patients 3 and 7) were unresponsive to both diazoxide and octreotide and had mental retardation. CONCLUSIONS: Gene analysis can aid in the classification, treatment, and prognosis of children with HH. In this study, the identification of seven known and two novel variants in the ABCC8 gene further enriched the variation spectrum of the gene.
Assuntos
Hiperinsulinismo Congênito , Recém-Nascido , Criança , Humanos , Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/diagnóstico , Diazóxido/uso terapêutico , Octreotida/uso terapêutico , Mutação , China/epidemiologia , Receptores de Sulfonilureias/genéticaRESUMO
CONTEXT: Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion causing hypoglycemia and consequent brain damage. Dasiglucagon is a glucagon analogue under investigation to treat CHI. OBJECTIVE: To evaluate the efficacy and safety of dasiglucagon delivered via continuous subcutaneous infusion to children with CHI and persistent hypoglycemia as add-on to standard of care (SoC). METHODS: In this open-label trial, patients were randomized 1:1 to SoC or SoC + dasiglucagon (10-70â µg/h) for 4 weeks. In the following 4 weeks, all patients received dasiglucagon + SoC. Hypoglycemia was assessed by self-monitored plasma glucose (SMPG) and blinded continuous glucose monitoring (CGM). Primary endpoint was average number of SMPG-detected hypoglycemia episodes/week (SMPG <3.9â mmol/L) during Weeks 2 to 4. RESULTS: Thirty-two patients (0.6-10.9 years) were randomly assigned to dasiglucagon + SoC (n = 16) or SoC (n = 16). The rate of SMPG-detected hypoglycemia decreased from baseline in both groups, but with no statistically significant difference during Weeks 2 to 4 (event rate ratio: 0.85 [0.54; 1.36], P = .5028). However, dasiglucagon administration resulted in a 43% reduction in CGM-detected hypoglycemia (<3.9â mmol/L) vs SoC alone during Weeks 2 to 4 (post hoc analysis; event rate ratio: 0.57 [0.39; 0.83], P = .0029). Dasiglucagon enabled reductions (of 37% to 61%) in all other measures of hypoglycemia assessed by CGM vs SoC alone including extent and percent time in hypoglycemia (post hoc analyses). Dasiglucagon appeared safe and well tolerated. Skin and gastrointestinal events were more frequent with dasiglucagon + SoC than SoC only. CONCLUSION: Clinically meaningful reductions in all CGM-recorded measures of hypoglycemia support using dasiglucagon as a potential treatment for CHI.
Assuntos
Hiperinsulinismo Congênito , Diabetes Mellitus Tipo 1 , Glucagon/análogos & derivados , Lactente , Criança , Humanos , Glucagon/uso terapêutico , Glicemia , Automonitorização da Glicemia , Hiperinsulinismo Congênito/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/efeitos adversosRESUMO
OBJECTIVE: Congenital hyperinsulinism (CHI) is a heterogeneous genetic disease characterized by increased insulin secretion and causes persistent hypoglycemia in neonates and infants due to dysregulation of insulin secretion by pancreatic ß cells. Babies with severe hypoglycemia and for whom medical treatment has been ineffective usually require surgical treatment with near-total pancreatectomy. To evaluate the clinical and surgical aspects affecting survival outcomes in babies diagnosed with CHI in a single tertiary care center. METHODS: Retrospective Cohort study involving a single university tertiary center for the treatment of CHI. The authors study the demographics, clinical, laboratory, and surgical outcomes of this casuistic. RESULTS: 61 % were female, 39 % male, Birth weight: 3576 g (±313); Age of onset of symptoms: from the 2nd hour of life to 28 days; Time between diagnosis and surgery ranged between 10 and 60 days; Medical clinical treatment, all patients received glucose solution with a continuous glucose infusion and diazoxide. 81 % of the patients used corticosteroids, 77 %. thiazide, 72 % octreotide, 27 % nifedipine; Neurological sequelae during development and growth: 54 % had some degree of delay in neuropsychomotor development, 27 % obesity. Surgery was performed open in 6 and 12 minimally invasive surgery (MIS). HISTOPATHOLOGY: 2 focal and 16 diffuse, Length of stay (days) was lower in MIS (p < 0.05). Survival was 100 %. CONCLUSIONS: CHI is a rare and difficult-to-manage tumor that must be performed in a multidisciplinary and tertiary center. Most surgical results are good and the laparoscopic approach to disease has been the best choice for patients.
Assuntos
Hiperinsulinismo Congênito , Lactente , Recém-Nascido , Humanos , Masculino , Feminino , Estudos Retrospectivos , Brasil , Hiperinsulinismo Congênito/cirurgia , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/tratamento farmacológico , Glucose/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: Transient hyperinsulinism (THI) is the most common form of recurrent hypoglycaemia in neonates beyond the first week of life. Although self-resolving, treatment can be required. Consensus guidelines recommend the lower end of the diazoxide 5-15 mg/kg/day range in THI to reduce the risk of adverse events. We sought to determine if doses <5 mg/kg/day of diazoxide can be effective in THI. DESIGN, PATIENTS, MEASURMENTS: Infants with THI (duration <6 months) were treated with low-dose diazoxide from October 2015 to February 2021. Dosing was based on weight at diazoxide start: 2 mg/kg/day in infants 1000-2000 g (cohort 1), 3 mg/kg/day in those 2000-3500 g (cohort 2) and 5 mg/kg/day in those >3500 g. RESULTS: A total of 73 infants with THI (77% male, 33% preterm, 52% small-for-gestational age) were commenced on diazoxide at a median age of 11 days (range 3-43) for a median duration of 4 months (0.3-6.8), with no difference between cohorts. The mean effective diazoxide dose was 3 mg/kg/day (range 1.5-10); 35% (26/73) required an increase from their starting dose, including 60% (9/15) of cohort 1. There was no association between perinatal stress risk factors or treatment-related characteristics and dose increase. Adverse events occurred in 13 patients (18%); oedema (12%) and hyponatraemia (5%) were the most common. Two infants developed suspected necrotising enterocolitis (NEC); none had pulmonary hypertension. CONCLUSION: Diazoxide doses <5 mg/kg/day are effective in THI. While the nature of the association between diazoxide and NEC was unclear, other adverse events were mild. We suggest considering starting doses as low as 2-3 mg/kg/day in THI to balance the side effect risk while maintaining euglycaemia.
Assuntos
Hiperinsulinismo Congênito , Hiperinsulinismo , Hipoglicemia , Lactente , Feminino , Recém-Nascido , Humanos , Masculino , Diazóxido/efeitos adversos , Hipoglicemia/tratamento farmacológico , Recém-Nascido Pequeno para a Idade Gestacional , Fatores de Risco , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo Congênito/tratamento farmacológicoRESUMO
This clinical review will give doctors who work with children and neonates an introduction to the diagnosis and treatment of congenital hyperinsulinism, the most common cause of persistent neonatal hypoglycaemia. The condition is a rare monogenic disorder characterised by elevated insulin secretion and is a result of mutations in genes that regulate insulin secretion from pancreatic beta cells. The anabolic effect of insulin induces systemic glucose uptake and inhibits gluconeogenesis, glycogenolysis, ketogenesis and lipolysis. Low levels of glucose and ketone bodies in the blood are harmful to the central nervous system and can lead to brain damage or death. Early diagnosis and treatment of congenital hyperinsulinism are therefore crucial for a good prognosis.
Assuntos
Hiperinsulinismo Congênito , Criança , Recém-Nascido , Humanos , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/genética , Corpos Cetônicos , InsulinaRESUMO
OBJECTIVES: Unrecognized hypoglycemia, especially in the neonatal population, is a significant cause of morbidity and poor neurologic outcomes. Children with congenital hyperinsulinism (HI) are at risk of hypoglycemia and point of care testing (POCT) is the standard of care. Studies have shown that continuous glucose monitoring (CGM) improves glycemic control and reduces the frequency of hypoglycemia among children with type 1 diabetes. There is limited experience with the use of CGM in children with HI. To assess the glycemic pattern of children with HI on stable therapy and evaluate the frequency of undetected hypoglycemia using Dexcom G6® CGM. METHODS: A cross-sectional, observational pilot study was done in 10 children, ages 3 months to 17 years. Each child had a clinical or genetic diagnosis of HI on stable medical therapy. Participants were asked to continue their usual POCT blood glucose monitoring, as well as wear a blinded Dexcom G6® CGM during a 20-day study period with the potential of unblinding if there was severe hypoglycemia detected during the study trial. RESULTS: During the study period, 26 hypoglycemic events were noted by CGM in 60â¯% of the participants with 45â¯% occurring between 0600 and 0800. CONCLUSIONS: CGM can help detect hypoglycemia and blood glucose trends during a time when there is usually no POCT, which can guide medical management. 30â¯% of our population had a dose adjustment in their medications. This study was limited by population size.
Assuntos
Hiperinsulinismo Congênito , Diabetes Mellitus Tipo 1 , Criança , Recém-Nascido , Humanos , Glicemia , Automonitorização da Glicemia , Estudos Transversais , Hipoglicemiantes/efeitos adversos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/tratamento farmacológicoRESUMO
Objective: Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations. Methods: We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (KATP) channel variants were assessed using patch clamp recording and Western blot. Results: Nine of 13 (69%) patients with ten different pathogenic variants (7 in ABCC8, 2 in KCNJ11 and 1 in GCK) were identified by the combined sequencing. The variant ABCC8 p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F KATP channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C KATP channels were defective in trafficking. One patient had a de novo dominant mutation in the GCK gene (p.I211F), and WES revealed mosaicism of this variant from another patient. Conclusion: Pathogenic variants in KATP channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the ABCC8 gene is highly suggestive of a founder effect. The I211F mutation in the GCK gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) KATP channels are also associated with the diazoxide-unresponsive phenotype.
Assuntos
Hiperinsulinismo Congênito , Canais de Potássio Corretores do Fluxo de Internalização , Humanos , Criança , Diazóxido/uso terapêutico , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Sulfonilureias/genética , Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/genética , Estudos de Associação Genética , Trifosfato de AdenosinaRESUMO
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.
Assuntos
Hiperinsulinismo Congênito , Diazóxido , Lactente , Recém-Nascido , Humanos , Diazóxido/uso terapêutico , Estudos Retrospectivos , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/genética , Sirolimo/efeitos adversos , MutaçãoRESUMO
Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic ß-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the ß-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism. ARTICLE HIGHLIGHTS: Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.
Assuntos
Hiperinsulinismo Congênito , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hiperinsulinismo , Animais , Camundongos , Anticorpos/uso terapêutico , Glicemia , Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/genética , Diazóxido/farmacologia , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Hiperinsulinismo/imunologia , Hiperinsulinismo/terapia , Mutação , Receptores de Sulfonilureias/genéticaRESUMO
The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in neonates. Inactivating mutations in the genes encoding KATP channel (ABCC8 and KCNJ11) as well as HNF4A, HNF1A, HADH, UCP2, and activating mutations in GLUD1, GCK, and SLC16A1 have been identified as causal. A 3-month-old male infant presenting tonic-clonic seizures and hyperinsulinemia was clinically assessed and subjected to genetic analysis. Besides the index patient, his parents were clinically investigated, and a detailed family history was also recorded. The laboratory investigations and the genetic test results of the parents were compared with the index patient. The biochemical and hormonal profile of the patient confirmed his suffering from CHI and did not respond to diazoxide treatment. The genetic testing revealed that the subject harbored a novel homozygous missense mutation in the KCNJ11 gene, (c.107T>A, p.Val36Glu.). The bioinformatic analysis revealed that valine is highly conserved and predicted that the variant allele (p.Val36Glu) is likely pathogenic and causal for CHI. Parents were heterozygous carriers and did not report any abnormal metabolic profile. Identification of such mutations is critical and likely to change the therapeutic interventions for such patients in the future.
Assuntos
Hiperinsulinismo Congênito , Humanos , Lactente , Masculino , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido/uso terapêutico , Heterozigoto , Insulina/genética , Mutação , Receptores de Sulfonilureias/genéticaRESUMO
OBJECTIVES: CHI is a relevant cause of persistent and severe hypoglycemia and the ABCC8 gene mutation is one of most common cause of the disease. Two main types of CHI have been described, diffuse and focal form. Octreotide is a medication utilized in case of diazoxide-unresponsive forms of CHI. For those CHI focal forms where is decided either to manage medically or until resolutive surgery is completed, octreotide can be administered as subcutaneous injection or as continuous subcutaneous infusion via insulin pump. However, it is unclear how to adjust the drug's daily basal pattern when a pump is used. CASE PRESENTATION: We present a case of an infant with a diazoxide-unresponsive focal form of CHI, due to ABCC8 mutation ABCC8, treated with octreotide. To better evaluate the glycemic trend, a CGM was placed. In order to achieve a better personalization of the therapy we utilized an insulin pump for octreotide administration. CONCLUSIONS: The adoption of the CGM and insulin pump, allowed a better personalization of the therapy and a reduction of acute carbohydrate intake, promoting a good auxological growth before resolutive surgery. What is new? Octreotide administered with an insulin pump in patient with CHI allows a wide modulation of the daily therapy. The CGM allows a continuous and a less painful control of the glycemic trend in a patient with CHI. Different basal rates, given via insulin pump may allow a better personalization of the therapy. Prevention of hypoglycemia reduces the acute introduction of carbohydrates, promoting normal growth..
Assuntos
Hiperinsulinismo Congênito , Diazóxido , Octreotida , Humanos , Masculino , Lactente , Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido/administração & dosagem , Diazóxido/uso terapêutico , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Automonitorização da Glicemia , Resultado do Tratamento , Insulina/uso terapêuticoRESUMO
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy/childhood and is a serious condition associated with severe recurrent attacks of hypoglycemia due to dysregulated insulin secretion. Timely diagnosis and effective treatment are crucial to prevent severe hypoglycemia that may lead to life-long neurological complications. In pancreatic ß-cells, adenosine triphosphate (ATP)-sensitive K+ (KATP) channels are a central regulator of insulin secretion vital for glucose homeostasis. Genetic defects that lead to loss of expression or function of KATP channels are the most common cause of HI (KATP-HI). Much progress has been made in our understanding of the molecular genetics and pathophysiology of KATP-HI in the past decades; however, treatment remains challenging, in particular for patients with diffuse disease who do not respond to the KATP channel activator diazoxide. In this review, we discuss current approaches and limitations on the diagnosis and treatment of KATP-HI, and offer perspectives on alternative therapeutic strategies.
Assuntos
Trifosfato de Adenosina , Hiperinsulinismo Congênito , Humanos , Criança , Receptores de Sulfonilureias/genética , Trifosfato de Adenosina/metabolismo , Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/metabolismo , Mutação , Secreção de InsulinaRESUMO
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.
Assuntos
Hiperinsulinismo Congênito , Epilepsia Resistente a Medicamentos , Epilepsia , Hiperinsulinismo , Criança , Humanos , Peru , Diazóxido/uso terapêutico , Glutamato Desidrogenase/genética , Hiperinsulinismo/complicações , Hiperinsulinismo/genética , Hiperinsulinismo/diagnóstico , Hiperinsulinismo Congênito/complicações , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/tratamento farmacológico , Epilepsia/tratamento farmacológico , Epilepsia/genética , MutaçãoRESUMO
OBJECTIVES: To evaluate and present the data regarding clinical, laboratory, radiological and the results of molecular genetic analysis of patients with hyperinsulinemic hypoglycemia in our clinics. METHODS: A total of 9 patients with CHI followed at Istanbul Medipol University. Data related to gender, age at presentation, birth weight, gestational age, consanguinity, glucose and insulin levels at diagnosis, treatment modalities, response to treatment, the results of genetic analysis and radiological evaluation were gathered from the files. RESULTS: The oldest age at presentation was 6 months. KATP channel mutation was detected in 55% (n: 5). Diazoxide unresponsiveness was seen in 55% (n: 5). Octreotide was effective in 3 of them. 18F-DOPA PET performed in 4 diazoxide unresponsive patients revealed focal lesion in 3 of them. Spontaneous remission rate was 66% (n:6). All the patients with normal genetic result achieved spontaneous remission. Spontaneous remission was even noted in diazoxide unresponsive patients and in patients with focal lesion on 18F-DOPA PET. CONCLUSIONS: Clinical presentation of patients with congenital hypereinsulinism is heterogeneous. Spontaneous remission rate is quite high even in patients with severe clinical presentation. It is important to develop methods that can predict which patients will have spontaneous remission. Reporting the clinical and laboratory data of each patient is important and will help to guide the management of patients with hyperinsulinemic hypoglycemia.
Assuntos
Hiperinsulinismo Congênito , Canais de Potássio Corretores do Fluxo de Internalização , Humanos , Criança , Lactente , Canais de Potássio Corretores do Fluxo de Internalização/genética , Diazóxido/uso terapêutico , Remissão Espontânea , Receptores de Sulfonilureias/genética , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/tratamento farmacológicoRESUMO
Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates, infants, and children. Since the first case descriptions in the 1950s, the field has advanced significantly. It was the development of the insulin radioimmunoassay by Yalow and Berson a decade later that made it possible to demonstrate that this form of persistent hypoglycemia was caused by insulin, and a few years later, Drash described the successful treatment of children with hyperinsulinism with the antihypertensive diazoxide, which until today remains the only approved treatment for hyperinsulinism. In the mid 1970s, Baker and Stanley described that hyperinsulinism can be recognized by inappropriate responses of metabolic fuels and hormones during the course of a provocative fasting challenge. Later, advances in molecular genetics led to the discovery of the different genetic subtypes of hyperinsulinism. One of the most impactful discoveries in the field was the recognition of the focal form of hyperinsulinism and the development of 18F-DOPA PET for the localization of focal lesions before surgery which has resulted in the possibility of cure for children with focal disease. However, treatment options for children with nonfocal diazoxide-unresponsive hyperinsulinism have continued to be limited. New drug development programs for hyperinsulinism promise to change this in the next few years. Unfortunately, despite all these advances, children with hyperinsulinism around the world continue to experience neurological sequelae at high rates, highlighting the importance of early diagnosis and effective treatment.
Assuntos
Hiperinsulinismo Congênito , Criança , Humanos , Lactente , Recém-Nascido , Anti-Hipertensivos , Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/genética , Diazóxido/uso terapêutico , InsulinaRESUMO
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 KCNJ11 mutation was made. He was started on tablet sirolimus, after which the child was off all other medication and was euglycaemic. However, he developed bilateral pneumonia leading to acute respiratory distress syndrome with refractory shock. Our case highlights the response to sirolimus in a case of congenital hyperinsulinaemia (CHI) due to KCNJ11 mutation and severe adverse event thereafter.