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      Clinical practice guidelines for congenital hyperinsulinism

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          Abstract.

          Congenital hyperinsulinism is a rare condition, and following recent advances in diagnosis and treatment, it was considered necessary to formulate evidence-based clinical practice guidelines reflecting the most recent progress, to guide the practice of neonatologists, pediatric endocrinologists, general pediatricians, and pediatric surgeons. These guidelines cover a range of aspects, including general features of congenital hyperinsulinism, diagnostic criteria and tools for diagnosis, first- and second-line medical treatment, criteria for and details of surgical treatment, and future perspectives. These guidelines were generated as a collaborative effort between The Japanese Society for Pediatric Endocrinology and The Japanese Society of Pediatric Surgeons, and followed the official procedures of guideline generation to identify important clinical questions, perform a systematic literature review (April 2016), assess the evidence level of each paper, formulate the guidelines, and obtain public comments.

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          Most cited references115

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          Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children.

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            Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.

            Hypoglycemia due to congenital hyperinsulinism (HI) is caused by mutations in 9 genes. Our objective was to correlate genotype with phenotype in 417 children with HI. Mutation analysis was carried out for the ATP-sensitive potassium (KATP) channel genes (ABCC8 and KCNJ11), GLUD1, and GCK with supplemental screening of rarer genes, HADH, UCP2, HNF4A, HNF1A, and SLC16A1. Mutations were identified in 91% (272 of 298) of diazoxide-unresponsive probands (ABCC8, KCNJ11, and GCK), and in 47% (56 of 118) of diazoxide-responsive probands (ABCC8, KCNJ11, GLUD1, HADH, UCP2, HNF4A, and HNF1A). In diazoxide-unresponsive diffuse probands, 89% (109 of 122) carried KATP mutations; 2% (2 of 122) had GCK mutations. In mutation-positive diazoxide-responsive probands, 42% were GLUD1, 41% were dominant KATP mutations, and 16% were in rare genes (HADH, UCP2, HNF4A, and HNF1A). Of the 183 unique KATP mutations, 70% were novel at the time of identification. Focal HI accounted for 53% (149 of 282) of diazoxide-unresponsive probands; monoallelic recessive KATP mutations were detectable in 97% (145 of 149) of these cases (maternal transmission excluded in all cases tested). The presence of a monoallelic recessive KATP mutation predicted focal HI with 97% sensitivity and 90% specificity. Genotype to phenotype correlations were most successful in children with GLUD1, GCK, and recessive KATP mutations. Correlations were complicated by the high frequency of novel missense KATP mutations that were uncharacterized, because such defects might be either recessive or dominant and, if dominant, be either responsive or unresponsive to diazoxide. Accurate and timely prediction of phenotype based on genotype is critical to limit exposure to persistent hypoglycemia in infants and children with congenital HI.
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              Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia.

              There has been considerable debate over whether asymptomatic neonatal hypoglycaemia results in neurological damage. In a detailed multicentre study of 661 preterm infants hypoglycaemia was found to be common. Moderate hypoglycaemia (plasma glucose concentration less than 2.6 mmol/l) occurred in 433 of the infants and in 104 was found on three to 30 separate days. There was considerable variation among the centres, implying differences in decisions to intervene. The number of days on which moderate hypoglycaemia occurred was strongly related to reduced mental and motor development scores at 18 months (corrected age), even after adjustment for a wide range of factors known to influence development. When hypoglycaemia was recorded on five or more separate days adjusted mental and motor developmental scores at 18 months (corrected age) were significantly reduced by 14 and 13 points respectively, and the incidence of neurodevelopmental impairment (cerebral palsy or developmental delay) was increased by a factor of 3.5 (95% confidence interval 1.3 to 9.4). These data suggest that, contrary to general belief, moderate hypoglycaemia may have serious neurodevelopmental consequences, and reappraisal of current management is urgently required.
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                Author and article information

                Journal
                Clin Pediatr Endocrinol
                Clin Pediatr Endocrinol
                CPE
                Clinical Pediatric Endocrinology
                The Japanese Society for Pediatric Endocrinology
                0918-5739
                1347-7358
                27 July 2017
                2017
                : 26
                : 3
                : 127-152
                Affiliations
                [1 ] Division of Pediatric Endocrinology and Metabolism, Children’s Medical Center, Osaka City General Hospital, Osaka, Japan
                [2 ] Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan
                [3 ] Department of Pediatrics, Keio University, Tokyo, Japan
                [4 ] Department of Endocrinology and Metabolism, Kanagawa Children’s Medical Center, Kanagawa, Japan
                [5 ] Department of Pediatrics, St. Marianna University School of Medicine, Kanagawa, Japan
                [6 ] Division of Endocrinology, Chiba Children’s Hospital, Chiba, Japan
                [7 ] Department of Pediatric Gastroenterology, Nutrition and Endocrinology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan
                [8 ] Department of Pediatric Surgery, Nara Hospital, Kindai University Faculty of Medicine, Nara, Japan
                [9 ] Department of Pediatric Surgery, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
                [10 ] Department of Surgery, National Center for Child Health and Development, Tokyo, Japan
                [11 ] Division of Pediatric Surgery, St. Marianna University School of Medicine, Kanagawa, Japan
                [12 ] Department of Surgery, Kanagawa Children’s Medical Center, Kanagawa, Japan
                [13 ] Department of Pediatric Surgery, Tohoku University, Miyagi, Japan
                Author notes
                Corresponding author: Tohru Yorifuji, MD, PhD, Division of Pediatric Endocrinology and Metabolism, Children’s Medical Center, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima, Osaka, Osaka 534-0021, Japan
                Article
                2017-0008
                10.1297/cpe.26.127
                5537210
                28804205
                5623f3f7-f9ff-4b81-a6df-2a53860d0080
                2017©The Japanese Society for Pediatric Endocrinology

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License.

                History
                : 21 February 2017
                : 08 March 2017
                Categories
                Original Article

                congenital hyperinsulinism,hypoglycemia,guidelines
                congenital hyperinsulinism, hypoglycemia, guidelines

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