Genetic variants of ABCC8 and clinical manifestations in eight Chinese children with hyperinsulinemic hypoglycemia.

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.

Congenital hyperinsulinism. / Medfødt hyperinsulinisme.

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.

[Focal congenital hyperinsulinism]. / Focalis congenitalis hyperinsulinismus.

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

The use of CGM to identify hypoglycemia and glycemic patterns in congenital hyperinsulinism.

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 60 % of the participants with 45 % 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. 30 % of our population had a dose adjustment in their medications. This study was limited by population size.

Standardised practices in the networked management of congenital hyperinsulinism: a UK national collaborative consensus.

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.

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

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

Syndromic forms of congenital hyperinsulinism.

Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic ß-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.

Bridging the gaps: recent advances in diagnosis, care, and outcomes in congenital hyperinsulinism.

PURPOSE OF REVIEW: To highlight advances in congenital hyperinsulinism (HI), including newly described molecular mechanisms of disease, novel therapeutic interventions, and improved understanding of long-term outcomes. RECENT FINDINGS: Important advances have been made elucidating the molecular mechanisms responsible for HI. Non-coding variants in HK1 have been found to cause aberrant hexokinase expression. Inactivating mutations in SLC25A36 have been identified in children with features of the hyperinsulinism hyperammonemia syndrome. Low-level mosaic mutations in known HI genes have been detected in cases of 'genetic testing negative' HI. Identification and localization of focal HI lesions remains a priority, since focal HI can be cured with surgery. Use of 68 Ga-NODAGA-exendin-4 PET has been proposed to localize focal lesions. Additional studies are needed before this technique replaces 18 F-DOPA PET as standard of care. Treatment options for children with diffuse HI remain limited. The long-acting somatostatin analog, lanreotide, was shown to significantly improve glycemic control in a large series of children with HI. New therapies are under development, with promising preliminary results. Long-term quality of life and neurodevelopmental outcomes remain suboptimal. SUMMARY: Advanced genetic and epigenomic analytic techniques have uncovered novel molecular mechanisms of HI. Development of new drugs holds promise to improve long-term outcomes for individuals with HI.

Glutamate dehydrogenase hyperinsulinism: mechanisms, diagnosis, and treatment.

Congenital hyperinsulinism (CHI) is a genetically heterogeneous disease, in which intractable, persistent hypoglycemia is induced by excessive insulin secretion and increased serum insulin concentration. To date,15 genes have been found to be associated with the pathogenesis of CHI. Glutamate dehydrogenase hyperinsulinism (GDH-HI) is the second most common type of CHI and is caused by mutations in the glutamate dehydrogenase 1 gene. The objective of this review is to summarize the genetic mechanisms, diagnosis and treatment progress of GDH-HI. Early diagnosis and treatment are extremely important to prevent long-term neurological complications in children with GDH-HI.

Congenital Hyperinsulinism and Maple Syrup Urine Disease: A Challenging Combination

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy. CHI is a challenging disease to diagnose and manage. Moreover, complicating the course of the disease with another metabolic disease, in this case maple syrup urine disease (MSUD), adds more challenges to the already complex management. We report a term neonate who developed symptomatic, non-ketotic hypoglycemia with a blood glucose (BG) level of 1.9 mmol/L at 21-hours of life. A critical sample at that time showed high serum insulin and C-peptide levels confirming the diagnosis of CHI. Tandem mass spectrometry done at the same time was suggestive of MSUD which was confirmed by high performance liquid chromatography. The diagnosis of both conditions was subsequently confirmed by molecular genetic testing. His hypoglycemia was managed with high glucose infusion with medical therapy for CHI and branched chain amino acids (BCAA) restricted medical formula. At the age of four months, a near-total pancreatectomy was done, due to the failure of conventional therapy. Throughout his complicated course, he required meticulous monitoring of his BG and modified plasma amino acid profile aiming to maintain the BG at ≥3.9 mmol/L and levels of the three BCAAs at the disease therapeutic targets for his age. The patient is currently 29 months old and has normal growth and development. This patient is perhaps the only known case of the co-occurrence of CHI with MSUD. Both hypoglycemia and leucine encephalopathy can result in death or permanent neurological damage. The management of CHI and MSUD in combination is very challenging.

Hyperinsulinemic Hypoglycemia Diagnosed in Childhood Can Be Monogenic.

CONTEXT: Congenital hyperinsulinism (HI) is characterized by inappropriate insulin secretion despite low blood glucose. Persistent HI is often monogenic, with the majority of cases diagnosed in infancy. Less is known about the contribution of monogenic forms of disease in those presenting in childhood. OBJECTIVE: We investigated the likelihood of finding a genetic cause in childhood-onset HI and explored potential factors leading to later age at presentation of disease. METHODS: We screened known disease-causing genes in 1848 individuals with HI, referred for genetic testing as part of routine clinical care. Individuals were classified as infancy-onset (diagnosed with HI < 12 months of age) or childhood-onset (diagnosed at age 1-16 years). We assessed clinical characteristics and the genotypes of individuals with monogenic HI diagnosed in childhood to gain insights into the later age at diagnosis of HI in these children. RESULTS: We identified the monogenic cause in 24% (n = 42/173) of the childhood-onset HI cohort; this was significantly lower than the proportion of genetic diagnoses in infancy-onset cases (74.5% [n = 1248/1675], P < 0.00001). Most (75%) individuals with genetically confirmed childhood-onset HI were diagnosed before 2.7 years, suggesting these cases represent the tail end of the normal distribution in age at diagnosis. This is supported by the finding that 81% of the variants identified in the childhood-onset cohort were detected in those diagnosed in infancy. CONCLUSION: We have shown that monogenic HI is an important cause of hyperinsulinism presenting outside of infancy. Genetic testing should be considered in children with persistent hyperinsulinism, regardless of age at diagnosis.

Clinical and laboratory evaluation of children with congenital hyperinsulinism: a single center experience.

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.

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.

The hypoglycaemia error grid: A UK-wide consensus on CGM accuracy assessment in hyperinsulinism.

Objective: Continuous Glucose Monitoring (CGM) is gaining in popularity for patients with paediatric hypoglycaemia disorders such as Congenital Hyperinsulinism (CHI), but no standard measures of accuracy or associated clinical risk are available. The small number of prior assessments of CGM accuracy in CHI have thus been incomplete. We aimed to develop a novel Hypoglycaemia Error Grid (HEG) for CGM assessment for those with CHI based on expert consensus opinion applied to a large paired (CGM/blood glucose) dataset. Design and methods: Paediatric endocrinology consultants regularly managing CHI in the two UK centres of excellence were asked to complete a questionnaire regarding glucose cutoffs and associated anticipated risks of CGM errors in a hypothetical model. Collated information was utilised to mathematically generate the HEG which was then approved by expert, consensus opinion. Ten patients with CHI underwent 12 weeks of monitoring with a Dexcom G6 CGM and self-monitored blood glucose (SMBG) with a Contour Next One glucometer to test application of the HEG and provide an assessment of accuracy for those with CHI. Results: CGM performance was suboptimal, based on 1441 paired values of CGM and SMBG showing Mean Absolute Relative Difference (MARD) of 19.3% and hypoglycaemia (glucose <3.5mmol/L (63mg/dL)) sensitivity of only 45%. The HEG provided clinical context to CGM errors with 15% classified as moderate risk by expert consensus when data was restricted to that of practical use. This provides a contrasting risk profile from existing diabetes error grids, reinforcing its utility in the clinical assessment of CGM accuracy in hypoglycaemia. Conclusions: The Hypoglycaemia Error Grid, based on UK expert consensus opinion has demonstrated inadequate accuracy of CGM to recommend as a standalone tool for routine clinical use. However, suboptimal accuracy of CGM relative to SMBG does not detract from alternative uses of CGM in this patient group, such as use as a digital phenotyping tool. The HEG is freely available on GitHub for use by other researchers to assess accuracy in their patient populations and validate these findings.

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.

Response to sirolimus in a case of diffuse congenital hyperinsulinaemic hypoglycaemia due to homozygous KCNJ11 mutation.

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.

Families' Experiences of Continuous Glucose Monitoring in the Management of Congenital Hyperinsulinism: A Thematic Analysis.

Background and Aims: In patients with congenital hyperinsulinism (CHI), recurrent hypoglycaemia can lead to longstanding neurological impairments. At present, glycaemic monitoring is with intermittent fingerprick blood glucose testing but this lacks utility to identify patterns and misses hypoglycaemic episodes between tests. Although continuous glucose monitoring (CGM) is well established in type 1 diabetes, its use has only been described in small studies in patients with CHI. In such studies, medical perspectives have been provided without fully considering the views of families using CGM. In this qualitative study, we aimed to explore families' experiences of using CGM in order to inform future clinical strategies for the management of CHI. Methods: Ten patients with CHI in a specialist centre used CGM for twelve weeks. All were invited to participate. Semi-structured interviews were conducted with nine families in whom patient ages ranged between two and seventeen years. Transcripts of the audio-recorded interviews were analysed using an inductive thematic analysis method. Results: Analysis revealed five core themes: CGM's function as an educational tool; behavioural changes; positive experiences; negative experiences; and design improvements. Close monitoring and retrospective analysis of glucose trends allowed for enhanced understanding of factors that influenced glucose levels at various times of the day. Parents noted more hypoglycaemic episodes than previously encountered through fingerprick tests; this new knowledge prompted modification of daily routines to prevent and improve the management of hypoglycaemia. CGM use was viewed favourably as offering parental reassurance, reduced fingerprick tests and predictive warnings. However, families also reported unfavourable aspects of alarms and questionable accuracy at low glucose levels. Adolescents were frustrated by the short proximity range for data transmission resulting in the need to always carry a separate receiver. Overall, families were positive about the use of CGM but expected application to be tailored to their child's medical condition. Conclusions: Patients and families with CHI using CGM noticed trends in glucose levels which motivated behavioural changes to reduce hypoglycaemia with advantages outweighing disadvantages. They expected CHI-specific modifications to enhance utility. Future design of CGM should incorporate end users' opinions and experiences for optimal glycaemic monitoring of CHI.

Congenital Hyperinsulinism: Current Laboratory-Based Approaches to the Genetic Diagnosis of a Heterogeneous Disease.

Congenital hyperinsulinism is characterised by the inappropriate release of insulin during hypoglycaemia. This potentially life-threatening disorder can occur in isolation, or present as a feature of syndromic disease. Establishing the underlying aetiology of the hyperinsulinism is critical for guiding medical management of this condition especially in children with diazoxide-unresponsive hyperinsulinism where the underlying genetics determines whether focal or diffuse pancreatic disease is present. Disease-causing single nucleotide variants affecting over 30 genes are known to cause persistent hyperinsulinism with mutations in the KATP channel genes (ABCC8 and KCNJ11) most commonly identified in children with severe persistent disease. Defects in methylation, changes in chromosome number, and large deletions and duplications disrupting multiple genes are also well described in congenital hyperinsulinism, further highlighting the genetic heterogeneity of this condition. Next-generation sequencing has revolutionised the approach to genetic testing for congenital hyperinsulinism with targeted gene panels, exome, and genome sequencing being highly sensitive methods for the analysis of multiple disease genes in a single reaction. It should though be recognised that limitations remain with next-generation sequencing with no single application able to detect all reported forms of genetic variation. This is an important consideration for hyperinsulinism genetic testing as comprehensive screening may require multiple investigations.

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.