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.

Wolcott-Rallison syndrome is a rare autosomal recessive disease characterized by neonatal diabetes mellitus in combination with osteodysplasia and liver failure. This disease is the most common cause of neonatal diabetes mellitus in consanguineous families. Wolcott-Rallison syndrome is associated with mutations in the EIF2AK3, the gene encoding a transmembrane enzyme PERK (pancreatic endoplasmic reticulum kinase) which inhibits the synthesis of proteins in the event of misfolding in the endoplasmic reticulum. In addition to the core symptoms patients may develop multisystemic clinical manifestation including acute renal and liver failure, short stature, exocrine pancreatic insufficiency, neuro-motor deficit, hypothyroidism, anemia, neutropenia, recurrent hypoglycemia. The disease is characterized by high mortality, more than 50% of patients die from fulminant liver failure. The awareness of Wolcott-Rallison syndrome is extremely low due to the rarity of detection, however in view of the severity of the disease and the unfavorable prognosis patients with this syndrome require timely diagnosis and care of well-organized team of specialists.

рожденный гиперинсулинизм (ВГИ) является частой причиной гипогликемии у детей. По данным гистологического исследования, заболевание подразделяют на диффузную, фокальную и атипичную формы. Хирургическая тактика ле-чения зависит от формы ВГИ: при фокальной форме выполняют резекцию патологической области поджелудочной железы с последующим полным выздоровлени-ем пациента, при диффузной форме с фармакорезистентным течением проводят ре-зекцию 95-98% поджелудочной железы, что приводит к развитию сахарного диабета и экзокринной панкреатической недостаточности. Дифференциальная диагностика фо-кальной и диффузной форм по клиническим и рентгенологическим признакам невоз-можна. ПЭТ/КТ с 18 F-ДОФА является «золотым стандартом» дифференциальной диагно-стики диффузной и фокальной форм заболевания. Настоящая статья является обзором литературных данных за последние 10 лет и посвящена методологическим основам и оценке информативности ПЭТ/КТ с 18 F-ДОФА у детей с ВГИ. ongenital hyperinsulinism is the most common cause of hypoglycemia in children. Congenital hyperinsulinism is divided into diffuse, focal and atypical forms. The surgical management for each form of congenital hyperinsulinism is crucially different. Focal form of congenital hyperinsulinism is cured by selective resection of the pathologic area leading to patient`s recovery. Medically unresponsive diffuse form of congenital hyperinsulinism requires the removal of 95-98% of pancreatic tissue, which may result in diabetes mellitus and exocrine pancreas insufficiency. Differential diagnosis of focal and diffuse forms according to clinical and radiological signs is impossible. Conducting with PET/CT with 18 F-DOPA is currently the "gold standard" of differential diagnosis between diffuse and focal forms of the disease. This article is a review of scientific papers for last 10 years and dedicated of methodology and diagnostic accuracy of PET/CT with 18 F-DOPA in children with congenital hyperinsulinism.

BACKGROUND: Children with congenital hyperinsulinism (CHI), a severe orphan disease, are still one of the most demanding patients in the endocrinology practice. The use of first- and second-line drugs is not always effective and has a number of restrictions. Lanreotide — long-acting somatostatin — represents an alternative insulinostatic therapy. The main advantage of lanreotide is stable concentration of the drug in the blood that enables minimizing the number of injections. However, the experience of using lanreotide in the treatment of CHI is limited to small groups of patients. There is also a problem of the absence of a standardized regimen in clinical practice; and the calculator for evaluating the initial effective drug dose is needed.AIM of the study is to evaluate the effectiveness and safety of lanreotide therapy in the treatment of CHI in children.MATERIALS AND METHODS: An open single-center observational study was conducted on the basis of Endocrinology Research Centre. The study included diazoxide-unresponsive pediatric patients with CHI who were initially treated with octreotide in different modes: multiple daily subcutaneous injections or continuous subcutaneous infusion via pumps. The indicators of the effectiveness and safety of the lanreotide therapy were evaluated shortly after the first injection and lately on a regular visit after further injections.RESULTS: The study group included 12 patients. Persistent euglycaemia was achieved in 67% of the subjects (8/12). Complete effectiveness of the therapy was observed in 8/12 patients (67%), partial — in 3/12 (25%), and lack of effectiveness — in 1/12 of the patient (8%). The age of the patients at the time of lanreotide administration was 6 months (5; 15). According to the study, the most effective dose of lanreotide is 3.5-5.5 mg/ kg/ month. There were no significant side effects observed.CONCLUSIONS: The use of lanreotide in patients with diazoxide-resistant congenital hyperinsulinism was effective and safe in the vast majority of the patients. Moreover, we were able to calculate the effective dosage of lanreotide in CHI patients which fulfilled the clinical demand.

Objective The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY). Design We characterised an international multi-centre paediatric cohort of patients with HNF4A or HNF1A mutations presenting with HH over a 25-year period (1995-2020). Methods Clinical and genetic analysis data from five centres were obtained. Diazoxide-responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis. Results A total of 34 patients (70.6% female, n=24) with a mean age of 7.1 years (SD 6.4) were included. A total of 21 different heterozygous HNF4A mutations were identified in 29 patients (four novel). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n=33) developed hypoglycaemia by day two of life. The mean birth weight was 3.8kg (SD 0.8), with most infants macrosomic (n=21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (IQR 0.2-6.8). Nine patients (n=9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR 9.0-13.9). Of patients with inherited mutations (n=25, 73.5%), a family history of diabetes was present in 22 (88.0%). Conclusions We build on knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1A mutations, and illustrate the heterogeneity of this condition.