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Necrolytic migratory erythema is a rare side effect of glucagon therapy. Typically the rash spreads with a red irregular border and starts to disappear within 1-2 days of stopping treatment. CHI, congenital hyperinsulinism; CT, computed tomography; SSRA, somatostatin receptor analogue; PET, positron-emission tomography.
Source publication
Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive and dysregulated insulin secretion (hyperinsulinism) from disordered pancreatic β cells can often lead to irreversible brain damage with lifelong neurodisability. Although congenit...
Context in source publication
Context 1
... of native glucagon in slow-moving solutions rendering treatment unsafe and ineffective. Newer glucagon formulations that are soluble and stable in saline may provide long-term treatment options [32]. While glucagon is generally effective in CHI, rare side effects need to be monitored, including the possibility of necrolytic migratory erythema (Fig. ...
Citations
... The Arg598Ter variant has been reported in over 10 individuals with congenital hyperinsulinism [19,20]. Approximately 0.006% of African Americans are healthy heterozygous carriers for this single nucleotide polymorphism (SNP) with National Center for Biotechnology Information (NCBI) dbSNP ID rs13932856 [21], according to The Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org, ...
... In the case of the ABCC8 gene, a genetic heterogeneity correlated with the phenotypic variability is described with over 890 variants in ABCC8 annotated as disease-causing mutations (DCM) in the HGMD Professional variant database, including both missense and truncating variants (nonsense, frameshift, variants affecting splicing, gross deletions). Of these, over 400 are associated with HH, and at least 14 mutations have been associated with permanent neonatal diabetes mellitus (PNDM) [19,32]. ...
... Sporadic forms of HH are associated with moderate/severe episodes of hypoglycemia and hyperinsulinism evident from the first days of life and usually have a poor response to treatment, but the prognosis improves after partial pancreatectomy [19]. ...
Congenital hyperinsulinism (CHI) is a rare disorder of glucose metabolism and is the most common cause of severe and persistent hypoglycemia (hyperinsulinemic hypoglycemia, HH) in the neonatal period and childhood. Most cases are caused by mutations in the ABCC8 and KCNJ11 genes that encode the ATP-sensitive potassium channel (KATP). We present the correlation between genetic heterogeneity and the variable phenotype in patients with early-onset HH caused by ABCC8 gene mutations. In the first patient, who presented persistent severe hypoglycemia since the first day of life, molecular genetic testing revealed the presence of a homozygous mutation in the ABCC8 gene [deletion in the ABCC8 gene c.(2390+1_2391-1)_(3329+1_3330-1)del] that correlated with a diffuse form of hyperinsulinism (the parents being healthy heterozygous carriers). In the second patient, the onset was on the third day of life with severe hypoglycemia, and genetic testing identified a heterozygous mutation in the ABCC8 gene c.1792C>T (p.Arg598*) inherited on the paternal line, which led to the diagnosis of the focal form of hyperinsulinism. To locate the focal lesions, (18)F-DOPA (3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine) positron emission tomography/computed tomography (PET/CT) was recommended (an investigation that cannot be carried out in the country), but the parents refused to carry out the investigation abroad. In this case, early surgical treatment could have been curative. In addition, the second child also presented secondary adrenal insufficiency requiring replacement therapy. At the same time, she developed early recurrent seizures that required antiepileptic treatment. We emphasize the importance of molecular genetic testing for diagnosis, management and genetic counseling in patients with HH.
... Persistent CHI continues for a longer period than the transient form. The incidence of persistent CHI in Japan is one in 35,400 neonates (1,2). Underlying genetic causes are identifiable in 45-79% of children with persistent CHI (3,4). ...
Patients with diffuse congenital hyperinsulinism (CHI) refractory to drug therapy require subtotal or near-total pancreatectomy. Although almost all patients develop diabetes postoperatively, the clinical course and timing of insulin therapy remain unclear. A 7-yr-old girl presented with recurrent hypoglycemia shortly after birth and a relatively elevated insulin level, which confirmed the diagnosis of CHI. Genetic analysis revealed compound heterozygous ATP-binding cassette, Subfamily C, Member 8 pathogenic variants and diffuse CHI was suspected. Because her condition was refractory to diazoxide and octreotide, she underwent a subtotal pancreatectomy at the age of 4 mo. The drug therapy was discontinued. Although an oral glucose tolerance test at the age of 2 yr showed hyperglycemia after loading, continuous glucose monitoring (CGM) revealed that her daily glucose trends were almost within the 70–180 mg/dL range, and mild hypoglycemia appeared during the daytime. After the age of 6 yr, CGM showed an elevation in glucose trends from midnight to early morning, suggesting that insulin secretion was attenuated and hepatic glucose production was insufficiently suppressed. Insulin therapy was initiated at the age of 7 yr. These results indicate that CGM can be useful for making treatment decisions.
... The Arg598Ter variant has been reported in over 10 individuals with congenital hyperinsulinism [16,17] 8 In vitro functional studies provided evidence that the Arg598Ter variant may slightly affect protein function [21,23].This variant causes a premature stop codon at position 598, leading to a truncated or absent protein. Paternally-inherited loss-of-function (LOF) ABCC8 mutations represent a known mechanism in autosomal recessive hyperinsulinemic hypoglycemia [24,25]. ...
... In the case of the ABCC8 gene, a genetic heterogeneity correlated with the phenotypic variability is described, being reported over 890 variants in ABCC8 annotated as disease-causing mutation (DCM) in the HGMD Professional variant database, including both missense and truncating variants (nonsense, frameshift, variants affecting splicing, gross deletions). Of these, over 400 are associated with hyperinsulinemic hypoglycemia and at least 14 mutations have been associated with permanent neonatal diabetes mellitus (PNDM) [16,27]. ...
Congenital hyperinsulinism (CHI) is a rare disorder of glucose metabolism and is the most common cause of severe and persistent hypoglycemia (hyperinsulinemic hypoglycemia, HH) in the neonatal period and childhood. Most cases are caused by mutations in the ABCC8 and KCNJ11 genes that encode the ATP-sensitive potassium channel (KATP). We present the correlation between genetic heterogeneity and the variable phenotype in patients with early-onset hyperinsulinemic hypoglycemia caused by ABCC8 gene mutations. In the first patients, which presented persistent severe hypoglycemia since the first day of life, molecular genetic testing revealed the presence of a homozygous mutation in the ABCC8 gene [deletion in the ABCC8 gene c.(2390+1_2391-1)_(3329+1_3330- 1)del] correlated with a diffuse form of hyperinsulinism (the parents being healthy heterozygous carriers). In the second patient, the onset was on the third day of life with severe hypoglycemia, and genetic testing identified a heterozygous mutation in the ABCC8 gene c.1792C>T (p.Arg598*) inherited on the paternal line, which led to the diagnosis of focal form of hyperinsulinism. To locate the focal lesions, (18)F-DOPA (3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine) PET/CT was recommended (an investigation that cannot be carried out in the country), but the parents refused to carry out the investigation abroad. In this case, early surgical treatment could have been curative. In addition, the second child also presented secondary adrenal insufficiency requiring replacement therapy. At the same time, she developed early recurrent seizures that required antiepileptic treatment. We emphasize the importance and of molecular genetic testing for diagnosis, management and genetic counseling in patients with HH.
... There is evidence that untreated, or inadequately treated, early life hypoglycaemia may cause later life neurological injury (1). This is particularly prominent when both glucose and alternative brain fuel sources are simultaneously suppressed, such as in patients with congenital hyperinsulinism (2), irrespective of the permanence of disease (3). ...
Introduction
Neonatal and early-life hypoglycaemia, is a frequent finding but is often non-specific and asymptomatic, making detection and diagnosis challenging. Hypoglycaemia-induced cerebral injury can be identified by magnetic resonance imaging (MRI) changes in cerebral white matter, occipital lobes, and posterior parietotemporal regions. It is unknown if children may have hypoglycaemic brain injury secondary to unrecognised hypoglycaemia in early life. We have examined retrospective radiological findings of likely brain injury by neuroimaging to investigate the existence of previous missed hypoglycaemic events.
Methods
Retrospective MRI data in children in a single tertiary centre, over a ten-year period was reviewed to identify potential cases of unrecognised early-life hypoglycaemia. A detailed search from an electronic radiology repository involved the term “hypoglycaemia’’ from text-based reports. The initial report was used for those who required serial scanning. Images specific to relevant reports were further reviewed by a designated paediatric neuroradiologist to confirm likely hypoglycaemia induced brain injury. Medical records of those children were subsequently reviewed to assess if the hypoglycaemia had been diagnosed prior to imaging.
Results
A total of 107 MR imaging reports were identified for review, and 52 (48.5%) showed typical features strongly suggestive of hypoglycaemic brain injury. Medical note review confirmed no documented clinical information of hypoglycaemia prior to imaging in 22 (42%) patients, raising the likelihood of missed hypoglycaemic events resulting in brain injury.
Conclusions
We have identified the existence of unrecognised childhood hypoglycaemia through neuroimaging review. This study highlights the need for heightened awareness of early life hypoglycaemia to prevent adverse neurological outcomes later in childhood.
... 7 Consequently, the biochemical profile resembles hyperinsulinism with suppressed free fatty acids and ketones. 13 However, insulin levels are undetectable due to negative feedback from the constitutively active signaling cascade. 14 Despite variable clinical features, our patient's presentation overlaps considerably with previous reports, including growth parameters reflective of excess insulin action. ...
... Consistent with previous reports, 5,7 diazoxide and octreotide were ineffective in our patient as these agents target upstream insulin release, as opposed to downstream signaling. 13 Due to its action on this pathway, sirolimus was trialed in a sibling pair with activating AKT2 mutations. The frequency of hypoglycemic episodes and carbohydrate need were reduced; however, overnight fasting was extended only up to 4 h. 5 Although no serious adverse effects occurred, use of sirolimus in congenital hyperinsulinism and PIK3CA-related overgrowth spectrum has been associated with severe infectious and hematologic complications, including sepsis and anemia requiring blood transfusion. ...
Key Clinical Message
The gain‐of‐function AKT2 c.49G>A variant causes hypoketotic hypoglycemia with variable associated features. Due to lack of effective medications, treatment is primarily supportive. This report suggests waxy maize heat is a viable treatment option.
Abstract
The serine–threonine kinase AKT2 is a critical mediator of insulin's anabolic effects, particularly cellular glucose uptake. The gain‐of‐function c.49G>A, p.(Glu17Lys) AKT2 variant results in hypoketotic hypoglycemia with suppressed insulin and free fatty acid levels due to constitutive activation of the insulin signaling cascade. Although biochemical similarities exist among the eight individuals identified to date, the associated phenotype varies considerably. Treatment of these patients remains challenging, consisting primarily of frequent feeds with uncooked cornstarch. We describe a female with hemihypertrophy, developmental delay, and dysmorphic features who presented to our center with hypoglycemic seizures at age 6 months. Critical sample revealed hypoketotic hypoglycemia, undetectable insulin, and suppressed free fatty acids. Molecular testing confirmed a pathogenic c.49G>A, p.(Glu17Lys) AKT2 mutation. Glycemic control was initially difficult to establish, with recurrent hypoglycemia despite high glucose infusion rates. Following in‐hospital administration of waxy maize heat‐modified starch at age 4‐years, she remained euglycemic overnight, despite a previous report showing no benefit compared to uncooked cornstarch in an infant with the same mutation. Our report suggests waxy maize heat‐modified starch is a viable treatment option for patients with activating c.49G>A AKT2 mutations and provides further evidence of a broad phenotypic spectrum.
... There were three forms of HH, namely, sporadic, autosomal recessive, and autosomal dominant [12]. Patients with sporadic forms usually have no family history, present with moderate/severe episode of hypoglycemia/ hyperinsulinemia in the first days to weeks of life, and generally respond poorly to medical management but have excellent prognosis after partial or > 95% pancreatectomy [16]. Patients with the recessive form usually have severe clinical presentation in infancy, with symptoms and signs secondary to hypoglycemia and hyperinsulinemia. ...
... Patients with the recessive form usually have severe clinical presentation in infancy, with symptoms and signs secondary to hypoglycemia and hyperinsulinemia. These patients frequently do not respond to medical management and require surgical intervention in the form of near-total pancreatectomy [16]. Autosomal dominant HH patients usually have a relatively mild clinical presentation than the autosomal recessive form, usually onset at 6-9 months of age or later, and are quite responsive to medical therapy with diazoxide [17]. ...
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.
... This study demonstrates that mice treated with LPS alone also suffer from severe hypoglycemia. The possible causes of hypoglycemia are insufficient intestinal glucose absorption, congenital hyperinsulinism, increased insulin sensitivity, and hindered gluconeogenesis (Shah et al. 2017;Banerjee et al. 2019). In the case of mice fasting overnight and glycogen depletion, the gluconeogenic substrate sodium pyruvate was used to further study the effect of LPS on gluco-neogenesis. ...
Lipopolysaccharide (LPS) results in a lethal hypoglycemic response. However, the main molecular mechanism involved in LPS-induced glucose metabolism disorder is poorly understood. This study intends to investigate the signaling pathways involved in LPS-induced hypoglycemia and potential efficacy of extracellular signal-regulated kinase (ERK) inhibitor SCH772984. The effects of LPS and SCH772984 on gluconeogenesis, glucose absorption, and glycogenolysis were evaluated by pyruvate tolerance test, oral glucose tolerance test, and glucagon test, respectively. After a single intraperitoneal injection of 0.5 mg/kg LPS, the mice’s blood glucose levels and gluconeogenesis ability were significantly lower than that of control group. Besides, mRNA and protein expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) decreased significantly after LPS treatment. LPS induced the phosphorylation of ERK1/2, MEK1/2 (mitogen-activated protein kinase), and Foxo1 while inhibited Foxo1 expression in the nucleus, indicating an important role of the MEK/ERK/Foxo1 signaling in the inhibition of gluconeogenesis by LPS. Furthermore, SCH772984 elevated blood glucose, increased the G6Pase and PEPCK expression, and inhibited pERK1/2 and pFoxo1 expression in LPS-induced mice. In summary, LPS inhibited gluconeogenesis and induced hypoglycemia through the MEK/ERK/Foxo1 signal pathway, and ERK inhibitor could effectively reverse decreased blood glucose in mice with LPS treatment. These findings provide a novel therapeutic target for LPS-induced hypoglycemia.
... CHI commonly presents in the neonatal period, with initial investigations and management initiated by general paediatric or neonatal teams. While a number of published reviews have summarised broad management principles and strategies and an international consensus guideline is due for publication, there is no clinical practice collaborative consensus that underpins the shared network treatment of CHI (9)(10)(11). This group has aimed to collaborate and harmonise current best practice to produce a working guideline for the management of CHI in the UK, with a focus on practical aspects including diet, medication changes and monitoring. ...
... Hypoglycaemia occurs when blood glucose is low, ie less than the normal range (4.0 and 6.0 mmol/L) (12). As patients with CHI have greater risk of neuronal injury and neurodevelopmental sequelae due to severe hypoglycaemia and the absence of ketone production, it is pragmatic to keep glucose levels close to the normal cut-off of 4.0 mmol/L as possible rather than risk possible neuronal injury with lower levels (9). ...
... GIR, a practical measure of glucose requirement, can be calculated from the rate of infusion, concentration of dextrose and body weight [mg/kg/min) = (Fluid rate (ml/hr) X % Dextrose)/(Weight (kg) X 6)] or by using online calculators (20,21). A normal GIR in the neonatal period is 4-6 mg/kg/min; rates exceeding 8 mg/kg/min suggest the diagnosis of CHI (9,17). ...
Congenital hyperinsulinism (CHI) is a condition characterised by severe and recurrent hypoglycaemia in infants and young children caused by inappropriate insulin over-secretion. CHI is of heterogeneous aetiology with a significant genetic component and is often unresponsive to standard medical therapy options. The treatment of CHI can be multifaceted and complex, requiring multidisciplinary input. It is important to manage hypoglycaemia in CHI promptly as the risk of long-term neurodisability arising from neuroglycopaenia is high. The UK CHI consensus on the practice and management of CHI was developed to optimise and harmonise clinical management of patients in centres specialising in CHI as well as in non-specialist centres engaged in collaborative, networked models of care. Using current best practice and a consensus approach, it provides guidance and practical advice in the domains of diagnosis, clinical assessment and treatment to mitigate hypoglycaemia risk and improve long term outcomes for health and well-being.
... According to an algorithm, genetic testing is recommended only for patients who are diazoxide unresponsive, need high diazoxide dose for prolonged periods of time, or in patients who continue on medication after 6 months [27]. A comprehensive study conducted in Finland focusing on the genetic characterization of persistent HH cases did not identify any carriers of pathogenic variants among patients with THI [7]. ...
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.
... Entre sus causas más frecuentes están el hiperinsulinismo, el déficit de hormonas contrarreguladoras y los errores innatos del metabolismo (2,7,11). El hiperinsulinismo es la principal causa de hipoglucemia persistente, pues hay una alteración en la secreción de la insulina, al igual que en las hormonas contrarreguladoras de la glucosa, por lo que se inhibe la lipólisis y las cetonas, que son vías alternas para mantener la función neuronal (12). ...
... El uso de diazóxido se ha asociado con ciertos efectos adversos, como retención de líquidos, descompensación respiratoria, hipertensión pulmonar y enterocolitis necrotizante. Suele ser eficaz en niños en quienes los canales potasio (adenosina-trifosfato) estén intactos; es ineficaz si los canales están alterados, por ejemplo, en las mutaciones en ABCC8/ KCNJ11 (12). Los endocrinólogos pediátricos recomiendan el tratamiento de la hipoglucemia con hiperinsulinismo con diazóxido para prevenir las consecuencias a largo plazo en el desarrollo neurológico de la hipoglucemia persistente (20). ...
... Adicionalmente, se describe el uso de los esteroides sistémicos, los cuales estimulan la gluconeogénesis a partir de proteínas(2,7,9). Se ha implementado la hidrocortisona a dosis de 5 mg/kg/día, teniendo en cuenta las posibles complicaciones, como alteración del eje de cortisol; de ahí que su descenso deba ser gradual y estar reservado para ciertas patologías, como insuficiencia suprarrenal(9).Se recomienda el tratamiento de la hipoglucemia persistente por hiperinsulinismo con diazóxido, para prevenir las consecuencias a largo plazo en el desarrollo neurológico(12). Es el fármaco de primera línea ...
Objetivo: Caracterizar a los pacientes con hipoglucemia persistente atendidos del 1 de enero del 2016 hasta el 31 de diciembre del 2021 en la unidad neonatal del Hospital Universitario San Ignacio (Colombia). Metodología: Estudio descriptivo de cohorte histórica. Resultados: De 6452 recién nacidos hospitalizados en la unidad de recién nacidos del Hospital San Ignacio, 390 (6%) tuvieron diagnóstico de hipoglucemia. De estos últimos pacientes, 17 (4,3% del total) tenían hipoglucemia persistente. La incidencia acumulada por año estuvo entre el 2% y el 11%. En el mismo periodo, por cada 1000 egresos hospitalarios en la unidad de recién nacidos, entre 1 y 7 pacientes tuvieron diagnóstico de hipoglucemia persistente. Conclusiones: La hipoglucemia persistente es una entidad poco frecuente; sin embargo, siempre debe tenerse en cuenta cuando se diagnostique hipoglucemia neonatal; adicionalmente, debe realizarse una muestra crítica en el periodo de hipoglucemia para establecer la etiología y ofrecer un tratamiento adecuado.
