[Congenital hyperinsulinism : contributions of chemistry, therapeutic response, genetics and imaging]. / Hyperinsulinisme congénital : apports de la biologie, de la réponse thérapeutique, de la génétique et de l'imagerie.

Congenital hyperinsulinism is the most common cause of recurrent hypoglycemia in newborns and children. Early diagnosis and rapid management are essential to avoid hypoglycaemic brain injury and later neurological complications. Management of those patients involves biological evaluation, molecular genetics, imaging techniques and surgical advances. We report the case of a newborn with recurrent hypoglycemia due to congenital hyperinsulinism (CHI) caused by a new variant in the ABCC8 gene. Fluorine 18-L-3,4 Dihydroxyphenylalanine Positron Emission Tomography (18F-DOPA PET/CT scan) reported a focal lesion at the isthmus of the pancreas which has been removed by laparoscopic surgery with a complete recovery for the patient.

L'hyperinsulinisme congénital est la cause la plus fréquente d'hypoglycémies récidivantes chez le nouveau-né et l'enfant. Un diagnostic et une prise en charge précoces sont primordiaux pour éviter les conséquences potentielles sur le développement neurologique. Ces derniers reposent sur la conjonction d'éléments biologiques, génétiques et d'imagerie. Nous rapportons le cas d'un nouveau-né présentant des hypoglycémies récidivantes. La mise au point mettra en évidence un hyperinsulinisme congénital (CHI) lié à un variant non encore décrit au sein du gène ABCC8. L'imagerie par Fluorine 18-L-3,4 Dihydroxyphenylalanine Positron Emission Tomography/Computed Tomography-scanner (18F-DOPA PET/CT scan) a mis en évidence une forme focale de l'hyperinsulinisme justifiant une prise en charge chirurgicale amenant à une guérison complète et à l'arrêt de tout traitement médicamenteux.

Congenital hyperinsulinism: localization of a focal lesion with 18F-FDOPA positron emission tomography.

Hyperinsulinemic hypoglycemia of infancy, also known as congenital hyperinsulinism, is a group of disorders characterized by dysregulated insulin release. Neonates with severe, persistent hyperinsulinemic hypoglycemia who are unresponsive to medical therapy require pancreatectomy to prevent brain damage from hypoglycemia. To date, multiple genetic mutations and syndromes and several unique histopathological entities have been identified in children with hyperinsulinism. Histopathology is characterized as diffuse, focal or atypical. Surgical resection of a focal lesion results in a cure in up to 97% of these children. Imaging with 6-fluoro-(18F)-L-3,4-dihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET) is the test of choice for identifying and localizing a focal lesion and has proved to be an invaluable guide for surgical resection. Genetic evaluation is essential for determining who will benefit from PET imaging. This article provides an approach to determine who should be imaged, how to set up a protocol and how to interpret the imaging findings. The diagnosis and management of this disorder require a multidisciplinary approach to prevent brain damage from hypoglycemia.

68Ga-NODAGA-Exendin-4 PET/CT Improves the Detection of Focal Congenital Hyperinsulinism.

Surgery with curative intent can be offered to congenital hyperinsulinism (CHI) patients, provided that the lesion is focal. Radiolabeled exendin-4 specifically binds the glucagonlike peptide 1 receptor on pancreatic ß-cells. In this study, we compared the performance of 18F-DOPA PET/CT, the current standard imaging method for CHI, and PET/CT with the new tracer 68Ga-NODAGA-exendin-4 in the preoperative detection of focal CHI. Methods: Nineteen CHI patients underwent both 18F-DOPA PET/CT and 68Ga-NODAGA-exendin-4 PET/CT before surgery. The images were evaluated in 3 settings: a standard clinical reading, a masked expert reading, and a joint reading. The target (lesion)-to-nontarget (normal pancreas) ratio was determined using SUVmax Image quality was rated by pediatric surgeons in a questionnaire. Results: Fourteen of 19 patients having focal lesions underwent surgery. On the basis of clinical readings, the sensitivity of 68Ga-NODAGA-exendin-4 PET/CT (100%; 95% CI, 77%-100%) was higher than that of 18F-DOPA PET/CT (71%; 95% CI, 42%-92%). Interobserver agreement between readings was higher for 68Ga-NODAGA-exendin-4 than for 18F-DOPA PET/CT (Fleiss κ = 0.91 vs. 0.56). 68Ga-NODAGA-exendin-4 PET/CT provided significantly (P = 0.021) higher target-to-nontarget ratios (2.02 ± 0.65) than did 18F-DOPA PET/CT (1.40 ± 0.40). On a 5-point scale, pediatric surgeons rated 68Ga-NODAGA-exendin-4 PET/CT as superior to 18F-DOPA PET/CT. Conclusion: For the detection of focal CHI, 68Ga-NODAGA-exendin-4 PET/CT has higher clinical sensitivity and better interobserver correlation than 18F-DOPA PET/CT. Better contrast and image quality make 68Ga-NODAGA-exendin-4 PET/CT superior to 18F-DOPA PET/CT in surgeons' intraoperative quest for lesion localization.

[Clinical features of 123 patients with hyperinsulinemic hypoglycemia auxiliarily diagnosed by 18F-DOPA-PET CT scanning].

Objective: To summarize the clinical features and therapeutic outcomes of patients with hyperinsulinemic hypoglycemia (HH) auxiliarily diagnosed by 18F-DOPA positron emission tomography (PET) CT scanning. Methods: The clinical data of 123 patients who were diagnosed with hyperinsulinemic hypoglycemia by comprehensive clinical diagnostic procedures in the Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University between January 2016 and December 2020 were retrospectively analyzed. Clinical data such as gender, age of onset, province, concurrent serum insulin level measured during hypoglycemia, lesion type of pancreas by 18F-DOPA-PET CT scanning, genetic test results, and treatment were collected successively. The clinical features and therapeutic outcomes were compared between patients with focal and diffuse pancreatic lesions. T test, Rank sum test, and χ² test were used for comparison between groups. Results: A total of 123 patients with hyperinsulinemic hypoglycemia (72 males and 51 females), whose average age of onset was 3 days (ranging from 1 day to 4 860 days), were recruited from 24 provinces. The concurrent serum insulin level was 7.1 (0.4-303.0) mU/L during hypoglycemia. 18F-DOPA-PET CT scanning identified focal lesions in 25.2% (31/123) and diffuse lesions in 74.8% (92/123) of the patients; 64.2% (79/123) of the HH cases were found to have pathogenic gene variants, in which 88.6% (70/79) were found to have KATP channel related genes (61 in ABCC8 and 9 in KCNJ11 mutations). Thirty-seven patients (17 focal and 20 diffuse) received surgical treatment with a success rate of 67.6% (25/37). The effective rate of diazoxide for children with diffuse type was significantly higher than that of children with focal group (28.3% (26/92) vs. 9.7% (3/31), χ²=10.31, P=0.001). Conclusions: 18F-DOPA-PET CT scan can improve the success rate of surgery. Comprehensive diagnosis of the etiology of hyperinsulinemic hypoglycemia by genetic analysis and 18F-DOPA-PET CT scanning can result in better treatment and prognosis.

Retrospective analysis of 23 Chinese children with congenital hyperinsulinism undergoing pancreatectomy.

INTRODUCTION: The aim of the study was to discuss therapeutic effect and prognosis of pancreatectomy in the treatment of congenital hyperinsulinism (CHI). MATERIAL AND METHODS: A total of 23 Chinese children with CHI, who had undergone pancreatectomy, were selected as the study objects. The clinical data, the results of the ¹8Fluoro-L-3-4 dihydroxyphenylalanine positron emission tomography/computerized tomography (¹8F-DOPA PET/CT) scanning, and the diagnosis, treatment, and follow-up were analysed retrospectively. RESULTS: Among the 23 cases, 14 patients were diagnosed with focal-type CHI via a ¹8F-DOPA PET/CT scan prior to the operation, with the lesions removed via partial pancreatectomy. After the operation, ten patients (71%) had normal blood glucose levels, while frequent feeding was required in four patients (29%) to control the hypoglycaemia. Three cases were diagnosed as diffuse-type CHI via preoperative scanning, two of which were treated by subtotal pancreatectomy. The other case was treated by near-total pancreatectomy, and the blood glucose level was normal following the operation. The remaining six cases were not diagnosed via the pancreatic scanning prior to the operation due to the limitation of certain conditions. Here, pancreatectomy was performed directly due to severe hypoglycaemia. CONCLUSIONS: ¹8F-DOPA PET/CT scanning was a reliable method for determining the histological type and localizing the lesion before the operation. Partial pancreatectomy for focal-type CHI had a high cure rate.

Neuroblastoma Shown on 18F-DOPA PET/CT Performed to Evaluate Congenital Hyperinsulinism.

ABSTRACT: 18F-DOPA PET/CT was performed to evaluate congenital hyperinsulinism in a 55-day-old boy with hypoglycemia. The images revealed not only a focal 18F-DOPA-avid lesion in the pancreas but also in a left thoracic paraspinal neuroblastoma.

Intraoperative ultrasound imaging in the surgical treatment of congenital hyperinsulinism: prospective, blinded study.

BACKGROUND: In congenital hyperinsulinism (CHI), preoperative prediction of the histological subtype (focal, diffuse, or atypical) relies on genetics and 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine (18F-DOPA) PET-CT. The scan also guides the localization of a potential focal lesion along with perioperative frozen sections. Intraoperative decision-making is still challenging. This study aimed to describe the characteristics and potential clinical impact of intraoperative ultrasound imaging (IOUS) during CHI surgery. METHODS: This was a prospective, observational study undertaken at an expert centre over a 2-year interval. IOUS was performed blinded to preoperative diagnostic test results (genetics and 18F-DOPA PET-CT), followed by unblinding and continued IOUS during pancreatic resection. Characteristics and clinical impact were assessed using predefined criteria. RESULTS: Eighteen consecutive, surgically treated patients with CHI, with a median age of 5.5 months, were included (focal 12, diffuse 3, atypical 3). Focal lesions presented as predominantly hypoechoic, oval lesions with demarcated or blurred margins. Patients with diffuse and atypical disease had varying echogenicity featuring stranding and non-shadowing hyperechoic foci in three of six, whereas these characteristics were absent from those with focal lesions. The blinded IOUS-based subclassification was correct in 17 of 18 patients; one diffuse lesion was misclassified as focal. IOUS had an impact on the surgical approach in most patients with focal lesions (9 of 12), and in those with diffuse (2 of 3) and atypical (2 of 3) disease when the resection site was close to the bile or pancreatic duct. CONCLUSION: Uniform IOUS characteristics made all focal lesions identifiable. IOUS had a clinical impact in 13 of 18 patients by being a useful real-time supplementary modality in terms of localizing focal lesions, reducing the need for frozen sections, and preserving healthy tissue and delicate structures.

Visual interpretation, not SUV ratios, is the ideal method to interpret 18F-DOPA PET scans to aid in the cure of patients with focal congenital hyperinsulinism.

INTRODUCTION: Congenital hyperinsulinism is characterized by abnormal regulation of insulin secretion from the pancreas causing profound hypoketotic hypoglycemia and is the leading cause of persistent hypoglycemia in infants and children. The main objective of this study is to highlight the different mechanisms to interpret the 18F-DOPA PET scans and how this can influence outcomes. MATERIALS AND METHODS: After 18F-Fluoro-L-DOPA was injected intravenously into 50 subjects' arm at a dose of 2.96-5.92 MBq/kg, three to four single-bed position PET scans were acquired at 20, 30, 40 and 50-minute post injection. The radiologist interpreted the scans for focal and diffuse hyperinsulinism using a visual interpretation method, as well as determining the Standard Uptake Value ratios with varying cut-offs. RESULTS: Visual interpretation had the combination of the best sensitivity and positive prediction values. CONCLUSIONS: In patients with focal disease, SUV ratios are not as accurate in identifying the focal lesion as visual inspection, and cases of focal disease may be missed by those relying on SUV ratios, thereby denying the patients a chance of cure. We recommend treating patients with diazoxide-resistant hyperinsulinism in centers with dedicated multidisciplinary team comprising of at least a pediatric endocrinologist with a special interest in hyperinsulinism, a radiologist experienced in interpretation of 18F-Fluoro-L-DOPA PET/CT scans, a histopathologist with experience in frozen section analysis of the pancreas and a pancreatic surgeon experienced in partial pancreatectomies in patients with hyperinsulinism.

Non-18F-Fluorodeoxyglucos PET Tracers in Pediatric Disease.

18F-fluorodeoxyglucose (FDG) PET/computed tomography (CT) is an efficient method of diagnosing, staging, treatment evaluation, and recurrence monitoring of pediatric diseases. FDG has some limitations, but other PET/CT tracers have shown promising roles in evaluation of pathologies in pediatric patients. FDG is the most commonly used PET tracer but can accumulate in different types of infection and inflammation. In recent years, more non-FDG tracers have shown utility in evaluating pediatric disease. This article reviews currently available literature on the clinical application of non-FDG PET tracers in the application in the pediatric population.

18-F-L 3,4-Dihydroxyphenylalanine PET/Computed Tomography in the Management of Congenital Hyperinsulinism.

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in neonates and infants. Several genetic mutations have been identified and are associated with 2 distinct histopathologic forms of disease: diffuse and focal. Targeted clinical evaluation to distinguish medically treatable disease from disease requiring surgical management can prevent life-threatening complications. Detection and localization of a surgically curable focal lesion using PET imaging with 18-F-L 3,4-dihydroxyphenylalanine ([18F]-FDOPA) has become standard of care. This article provides guidelines for the selection of patients who can benefit from [18F]-FDOPA-PET/computed tomography and protocols and tips used to diagnose a focal lesion of HI.

The role of 18F-DOPA PET/CT in the diagnosis of the congenital focal form of hyperinsulinism in children. / Papel de la PET/TC con 18F-DOPA en el diagnóstico de la forma congénita focal del hiperinsulinismo en niños.

BACKGROUND: Congenital hyperinsulinism (CHI) is a neuroendocrine disease with focal or diffuse abnormalities in pancreas. While drug-resistant diffuse forms require near-total pancreatectomy or prolonged pharmacotherapy, focal CHI may be treated by targeted surgical resection. We evaluated the usefulness of 18F-DOPA PET/CT to identify the focal pancreatic form. SUBJECTS AND METHODS: Nineteen children (11 boys, 8 girls, aged 2-54 months) with clinical signs of neonatal CHI and positive genetic examinations were enrolled in the study. After i.v. administration of 18F-DOPA, early PET and late PET/CT acquisition covering one-bed length over thoraco-abdominal region were performed. Both acquisitions were done in dynamic mode to allow exclusion of frames with motion artefacts. Standardized uptake values were adjusted to bodyweight (SUVbw). The finding was considered as focal when the ratio of SUVbwmax between the suspicious region and the rest of pancreas was greater than 1.2. RESULTS: Focal forms were recorded in 10/19 children and 4 of them underwent surgical resection with complete recovery. Focal uptake was significantly higher than the uptake in the normal pancreatic tissue (p=0.0059). Focal and diffuse forms of CHI did not differ significantly in normal pancreatic tissue uptake. We found no advantage in the measurement of SUVbwmean ratio compared to SUVbwmax ratio (p=0.50). CONCLUSION: 18F-DOPA PET/CT is a useful tool for the localization of focal CHI and planning of surgical treatment.

Congenital hyperinsulinism: characterization of patients treated in a pediatric university hospital in Colombia.

Background: Congenital hyperinsulinism is a disease of the glucose metabolism, relevant in pediatric endocrinology because of the elevated production of insulin according to blood glucose level, which leads to persistent severe hypoglycemia. This condition can produce important neurological sequelae in the patient due to the irreversible damage that occurs in the neuron caused by the exposure to hypoglycemia for short periods of time. Congenital hyperinsulinism diagnosis is not simple and it requires a high index of suspicion. The treatment should be established sequentially, in several steps, noticing the response to each possible medication used. If the pharmacological management fails, surgical procedures are required occasionally. Case series report: Seven cases of congenital hyperinsulinism diagnosed in the last seven years at the Instituto Roosevelt in Bogotá, Colombia are presented. In this country, the radiotracer used internationally during positron emission tomography/computed tomography (PET/CT) is not available. However, was possible to use an alternative radiotracer in one of the cases, which led to an adequate diagnosis and a successful surgical treatment. Conclusions: Congenital hyperinsulinism is a complex clinical condition, which requires proper diagnosis and treatment, with the aim of avoiding any neurological damage caused by persistent hypoglycemia. PET/CT can be used with an appropriate radiotracer for a timely diagnosis and to provide the best available therapeutic option.

Introducción: El hiperinsulinismo congénito es una enfermedad del metabolismo de la glucosa, fundamental en la endocrinología pediátrica, ya que se refiere a la producción de mayor cantidad de insulina de la necesaria según la glucemia, lo cual produce hipoglucemias graves persistentes. Esta alteración puede tener importantes secuelas neurológicas debido al daño irreversible que se produce en la neurona por la exposición a la hipoglucemia por cortos periodos de tiempo. Su diagnóstico no es sencillo y requiere un alto índice de sospecha. El tratamiento se establece de manera secuencial, en varias etapas, observando la respuesta a cada uno de los posibles medicamentos empleados. En caso de que falle el manejo farmacológico, se requieren procedimientos quirúrgicos. Serie de casos: Se presentan siete casos de hiperinsulinismo congénito que fueron diagnosticados en los últimos 7 años en el Instituto Roosevelt en Bogotá, Colombia. En este país, el radiotrazador empleado usualmente durante la tomografía por emisión de positrones (PET/TC) no se encuentra disponible. Sin embargo, en uno de los casos descritos fue posible emplear otro radiotrazador alternativo que permitió un adecuado diagnóstico y un tratamiento quirúrgico exitoso. Conclusiones: El hiperinsulinismo congénito es una condición clínica compleja que amerita un correcto diagnóstico y un apropiado manejo, con el objetivo de evitar el daño neurológico que producen las hipoglucemias persistentes. Es posible emplear PET/TC con un radiotrazador adecuado para realizar un diagnóstico oportuno y proporcionar la mejor opción terapéutica disponible.

Hiperinsulinismo congénito: caracterización de pacientes atendidos en un hospital universitario pediátrico en Colombia / Congenital hyperinsulinism: characterization of patients treated in a pediatric university hospital in Colombia

Resumen Introducción: El hiperinsulinismo congénito es una enfermedad del metabolismo de la glucosa, fundamental en la endocrinología pediátrica, ya que se refiere a la producción de mayor cantidad de insulina de la necesaria según la glucemia, lo cual produce hipoglucemias graves persistentes. Esta alteración puede tener importantes secuelas neurológicas debido al daño irreversible que se produce en la neurona por la exposición a la hipoglucemia por cortos periodos de tiempo. Su diagnóstico no es sencillo y requiere un alto índice de sospecha. El tratamiento se establece de manera secuencial, en varias etapas, observando la respuesta a cada uno de los posibles medicamentos empleados. En caso de que falle el manejo farmacológico, se requieren procedimientos quirúrgicos. Serie de casos: Se presentan siete casos de hiperinsulinismo congénito que fueron diagnosticados en los últimos 7 años en el Instituto Roosevelt en Bogotá, Colombia. En este país, el radiotrazador empleado usualmente durante la tomografía por emisión de positrones (PET/TC) no se encuentra disponible. Sin embargo, en uno de los casos descritos fue posible emplear otro radiotrazador alternativo que permitió un adecuado diagnóstico y un tratamiento quirúrgico exitoso. Conclusiones: El hiperinsulinismo congénito es una condición clínica compleja que amerita un correcto diagnóstico y un apropiado manejo, con el objetivo de evitar el daño neurológico que producen las hipoglucemias persistentes. Es posible emplear PET/TC con un radiotrazador adecuado para realizar un diagnóstico oportuno y proporcionar la mejor opción terapéutica disponible.

Abstract Background: Congenital hyperinsulinism is a disease of the glucose metabolism, relevant in pediatric endocrinology because of the elevated production of insulin according to blood glucose level, which leads to persistent severe hypoglycemia. This condition can produce important neurological sequelae in the patient due to the irreversible damage that occurs in the neuron caused by the exposure to hypoglycemia for short periods of time. Congenital hyperinsulinism diagnosis is not simple and it requires a high index of suspicion. The treatment should be established sequentially, in several steps, noticing the response to each possible medication used. If the pharmacological management fails, surgical procedures are required occasionally. Case series report: Seven cases of congenital hyperinsulinism diagnosed in the last seven years at the Instituto Roosevelt in Bogotá, Colombia are presented. In this country, the radiotracer used internationally during positron emission tomography/computed tomography (PET/CT) is not available. However, was possible to use an alternative radiotracer in one of the cases, which led to an adequate diagnosis and a successful surgical treatment. Conclusions: Congenital hyperinsulinism is a complex clinical condition, which requires proper diagnosis and treatment, with the aim of avoiding any neurological damage caused by persistent hypoglycemia. PET/CT can be used with an appropriate radiotracer for a timely diagnosis and to provide the best available therapeutic option.

Genotype and phenotype analysis of a cohort of patients with congenital hyperinsulinism based on DOPA-PET CT scanning.

Congenital hyperinsulinism (CHI) is a clinically, genetically, and morphologically heterogeneous disorder. 18F DOPA-PET CT scanning greatly improves its clinical outcome. Here, we presented the first Chinese 18F DOPA-PET CT scanning-based CHI cohort highlighting the variable ethic clinical phenotypes and genotypes. Fifty CHI patients were recruited. Median age at presentation was 2 days. Median fasting time was 2 h. Mean insulin level was 25.6 µIU/ml. Fifty-two percent of patients were diazoxide-unresponsive with significantly shorter fasting tolerance time and higher serum insulin level compared with the responsive patients. Seventy-four percent of patients experienced at least one adverse drug reaction. Tremendously increased focal lesions (32%) were detected and 75% of them were cured through surgery. Thirty-one nucleotide sequence changes were identified in 48% patients. Four novel variants (Q608X, Q1347X, Q289X, F1489S) in ABCC8 gene and 2 novel variants (G132A, V138E) in KCNJ11 gene were detected. Of the variants, 87.1% harbored in ABCC and KCNJ11 genes. T1042Qfs*75 in ABCC8 gene was the most common mutation.Conclusion: Highly increased portion of focal lesion was presented in Chinese CHI patients compared with that of the previous reports. Intolerance to diazoxide was much more evident in Chinese or East Asian than other populations. Certain hotspot mutations harbored in Chinese CHI patients. What is Known: • 18F DOPA-PET CT scanning can provide informative guidance for surgical procedure when medical therapy is not well responded in CHI patients. What is New: • Intolerance to diazoxide is much more evident in Chinese and East Asian CHI patients compared with the other ethnic populations. • Novel mutations were detected in ABCC8 and KCNJ11 gene. Hotspot mutations such as T1042Qfs*75, I1511K, E501K, G111R in ABCC8 gene, and R34H in KCNJ11 gene are predominantly responsible for Chinese CHI patients.

Surgical treatment of congenital hyperinsulinism: Results from 500 pancreatectomies in neonates and children.

BACKGROUND: Congenital Hyperinsulinism (HI) causes severe hypoglycemia in neonates and children. We reviewed our experience with pancreatectomy for the various types of HI. METHODS: From 1998 to 2018, 500 patients with HI underwent pancreatectomy: 246 for focal HI, 202 for diffuse HI, 37 for atypical HI (16 for Localized Islet Nuclear Enlargement [LINE], 21 for Beckwith-Wiedemann Syndrome), and 15 for insulinoma. Focal HI neonates were treated with partial pancreatectomy. Patients with diffuse HI who failed medical management underwent near-total (98%) pancreatectomy. Atypical HI patients had pancreatectomies tailored to the PET scan and biopsy findings. RESULTS: The vast majority of pancreatectomies for focal HI were < 50%, and many were 2%-10%. 97% of focal HI patients are cured. For diffuse disease patients, 31% were euglycemic, 20% were hyperglycemic, and 49% required treatment for hypoglycemia; the incidence of diabetes increased with long-term follow-up. All 15 insulinoma patients were cured. CONCLUSIONS: Our approach to patients with focal HI can distinguish focal from diffuse HI, localize focal lesions, and permit partial pancreatectomy with cure in almost all focal patients. Surgery does not cure diffuse disease but can help prevent severe hypoglycemia and brain damage. Surgery can be curative for insulinoma and for some cases of atypical HI. LEVEL OF EVIDENCE: Level IV.

[Clinical, genetic, and radionuclide characteristics of the focal form of congenital hyperinsulinism].

BACKGROUND: Congenital hyperinsulinism (CHI) is a severe disease with a high risk of complications including neurological deficit. Persistent hypoglycemia in patients with focal form of CHI can not be managed with medical treatment in 96.4% of cases, what subsequently leads to surgical treatment. Currently, there is a lack of information regarding patients with focal form of CHI. This study is aimed at finding better approaches for diagnosis and treatment of patients with focal form of CHI. AIMS: To study clinical, genetic and PET/CT findings of the focal form of CHI in Russian group of patients. MATERIALS AND METHODS: The observational research included all patients with a histologically confirmed focal form of CHI, who were admitted to Endocrinology Research Centre during the period from January 2008 to January 2019. A statistical analysis of clinical data, genotype, and positron emission tomography (PET) with 18F-dihydroxyphenylalanine (18F-DOPA) was performed. The median follow-up was 18 months. RESULTS: The study included 31 patients with focal CHI (14 boys, 45.2%). All patients had a neonatal presentation of the disease and demanded high levels of continuous glucose infusion to maintain euglycemia. The difference between the age of hypoglycemia presentation and the age of diagnosis ranged from 1 day to 3.9 months. In all cases, diazoxide was found to be ineffective. However, in 9 patients, it was possible to withdraw continuous glucose infusion and maintain euglycemia using octreotide in the preoperative period. A molecular genetic study allowed us to detect diverse pathogenic variants in ABCC8 and KCNJ11 genes in 30 patients. According to PET data with 18F-DOPA, the pancreatic index (PI) varied widely from 1.16 to 3.59. After partial resection of the pancreatic region with insulin hypersecretion, all patients showed complete recovery. CONCLUSIONS: The focal form of CHI is a severe condition with high prevalence of neurological complications. For preoperative diagnosis of the morphological form of the disease, it is necessary to conduct genetic analysis and radionuclide studies. Solely evaluation of mathematical parameters in 18F-DOPA PET without taking into account the visual data and the results of genetic analysis does not allow establishing the robust diagnosis. Timely diagnosis, identification of risk factors, and prevention of complications of persistent hypoglycemia are important tasks for clinicians.

The Use of a Long-Acting Somatostatin Analogue (Lanreotide) in Three Children with Focal Forms of Congenital Hyperinsulinaemic Hypoglycaemia.

BACKGROUND: A long-acting somatostatin analogue (lanreotide) is used in the management of a diazoxide-unresponsive diffuse form of congenital hyperinsulinism (CHI). However, no reports of its use in patients with the focal form of CHI exist. Case 1: A 1-month-old boy diagnosed with diazoxide-unresponsive CHI due to a paternal heterozygous ABCC8 gene mutation showed partial response to octreotide. 18F-DOPA-PET/CT scan revealed a focal lesion in the pancreatic head. Surgical removal of the lesion was unsuccessful. He was switched to monthly lanreotide treatment at the age of 11 months, which stabilised his blood glucose over a 12-month period. Case 2: A 1-month-old boy with diazoxide-unresponsive CHI due to a paternal heterozygous KCNJ11 gene mutation was partially responsive to octreotide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. Over 6 months, he underwent 3 lesionectomies and afterwards responded to octreotide. At the age of 9 months, treatment was switched to monthly lanreotide. Currently, he is aged 3, with stable glycaemia, and improved fasting tolerance. Case 3: A 3-week-old girl with a paternal heterozygous ABCC8 gene mutation was unresponsive to diazoxide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. She responded to octreotide, and her parents preferred to avoid pancreatic surgery. At the age of 20 months, treatment was switched to monthly lanreotide, resulting in euglycaemia over the last 7 months. CONCLUSION: CHI patients with focal pancreatic head lesions are challenging, especially if not surgically amenable. Conservative treatment is preferable, and lanreotide might be an option. The therapeutic impact of lanreotide treatment in patients with the focal forms of CHI should be confirmed in prospective studies with close monitoring of the side effects.