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States LJ, Davis JC, Hamel SM, Becker SA, Zhuang H. 18F-6-Fluoro-l-Dopa PET/CT Imaging of Congenital Hyperinsulinism. J Nucl Med 2021; 62:51S-56S. [PMID: 34230074 DOI: 10.2967/jnumed.120.246033] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 12/08/2020] [Indexed: 11/16/2022] Open
Abstract
Congenital hyperinsulinism is characterized by persistent hypoglycemia due to inappropriate excess secretion of insulin resulting in hyperinsulinemic hypoglycemia. The clinical course varies from mild to severe, with a significant risk for brain damage. Imaging plays a valuable role in the care of infants and children with severe hypoglycemia unresponsive to medical therapy. 18F-6-fluoro-l-dopa PET/CT is the method of choice for the detection and localization of a focal lesion of hyperinsulinism. Surgical resection of a focal lesion can lead to a cure with limited pancreatectomy. This article reviews the role of 18F-6-fluoro-l-dopa PET/CT in the management of this vulnerable population.
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Affiliation(s)
- Lisa J States
- Radiology Department, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, and
| | - J Christopher Davis
- Radiology Department, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, and
| | - Steven M Hamel
- Radiology Department, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and
| | - Susan A Becker
- Radiology Department, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and
| | - Hongming Zhuang
- Radiology Department, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, and
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2
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Garg PK, Putegnat B, Truong L, Reynolds C, Sanchez I, Nedrelow JK, Uffman J, Lokitz SJ, Nazih R, Garg S, Thornton PS. 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. PLoS One 2020; 15:e0241243. [PMID: 33108363 PMCID: PMC7591017 DOI: 10.1371/journal.pone.0241243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/11/2020] [Indexed: 11/18/2022] Open
Abstract
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.
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Affiliation(s)
- Pradeep K. Garg
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
- * E-mail:
| | - Burton Putegnat
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Lisa Truong
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Courtney Reynolds
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Irene Sanchez
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | | | - John Uffman
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Stephen J. Lokitz
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
| | - Rachid Nazih
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
| | - Sudha Garg
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
| | - Paul S. Thornton
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
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Männistö JME, Maria M, Raivo J, Kuulasmaa T, Otonkoski T, Huopio H, Laakso M. Clinical and Genetic Characterization of 153 Patients with Persistent or Transient Congenital Hyperinsulinism. J Clin Endocrinol Metab 2020; 105:5805131. [PMID: 32170320 DOI: 10.1210/clinem/dgz271] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 12/16/2019] [Indexed: 02/08/2023]
Abstract
CONTEXT Major advances have been made in the genetics and classification of congenital hyperinsulinism (CHI). OBJECTIVE To examine the genetics and clinical characteristics of patients with persistent and transient CHI. DESIGN A cross-sectional study with the register data and targeted sequencing of 104 genes affecting glucose metabolism. PATIENTS Genetic and phenotypic data were collected from 153 patients with persistent (n = 95) and transient (n = 58) CHI diagnosed between 1972 and 2015. Of these, 86 patients with persistent and 58 with transient CHI participated in the analysis of the selected 104 genes affecting glucose metabolism, including 10 CHI-associated genes, and 9 patients with persistent CHI were included because of their previously confirmed genetic diagnosis. MAIN OUTCOME MEASURES Targeted next-generation sequencing results and genotype-phenotype associations. RESULTS Five novel and 21 previously reported pathogenic or likely pathogenic variants in ABCC8, KCNJ11, GLUD1, GCK, HNF4A, and SLC16A1 genes were found in 68% (n = 65) and 0% of the patients with persistent and transient CHI, respectively. KATP channel mutations explained 82% of the mutation positive cases. CONCLUSIONS The genetic variants found in this nationwide CHI cohort are in agreement with previous studies, mutations in the KATP channel genes being the major causes of the disease. Pathogenic CHI-associated variants were not identified in patients who were both diazoxide responsive and able to discontinue medication within the first 4 months. Therefore, our results support the notion that genetic testing should be focused on patients with inadequate response or prolonged need for medication.
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Affiliation(s)
- Jonna M E Männistö
- Department of Pediatrics, University of Eastern Finland, and Kuopio University Hospital, Kuopio, Finland
| | - Maleeha Maria
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
| | - Joose Raivo
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
| | - Teemu Kuulasmaa
- Institute of Clinical Medicine, Internal Medicine, and Institute of Biomedicine, Bioinformatics Center, University of Eastern Finland, Kuopio, Finland
| | - Timo Otonkoski
- Children's Hospital, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland
| | - Hanna Huopio
- Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, and Kuopio University Hospital Kuopio, Finland
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Ni J, Ge J, Zhang M, Hussain K, Guan Y, Cheng R, Xi L, Zheng Z, Ren S, Luo F. Genotype and phenotype analysis of a cohort of patients with congenital hyperinsulinism based on DOPA-PET CT scanning. Eur J Pediatr 2019; 178:1161-1169. [PMID: 31218401 PMCID: PMC6647509 DOI: 10.1007/s00431-019-03408-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 06/04/2019] [Accepted: 06/05/2019] [Indexed: 11/24/2022]
Abstract
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.
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Affiliation(s)
- Jinwen Ni
- Department of Endocrinology and Inborn Metabolic Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102 China
| | - Jingjie Ge
- PET CT Center, Division of Nuclear Medicine, Huashan Hospital, Fudan University, 518 East Wuzhong Road, Shanghai, 200235 China
| | - Miaoying Zhang
- Department of Endocrinology and Inborn Metabolic Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102 China
| | - Khalid Hussain
- Department of Pediatrics, Division of Endocrinology, Sidra Medicine OPC, C6-340 PO Box 26999, Al Luqta Street Education City North Campus, Doha, Qatar
| | - Yihui Guan
- PET CT Center, Division of Nuclear Medicine, Huashan Hospital, Fudan University, 518 East Wuzhong Road, Shanghai, 200235 China
| | - Ruoqian Cheng
- Department of Endocrinology and Inborn Metabolic Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102 China
| | - Li Xi
- Department of Endocrinology and Inborn Metabolic Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102 China
| | - Zhangqian Zheng
- Department of Endocrinology and Inborn Metabolic Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102 China
| | - Shuhua Ren
- PET CT Center, Division of Nuclear Medicine, Huashan Hospital, Fudan University, 518 East Wuzhong Road, Shanghai, 200235 China
| | - Feihong Luo
- Department of Endocrinology and Inborn Metabolic Diseases, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
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5
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Farnaes L, Hildreth A, Sweeney NM, Clark MM, Chowdhury S, Nahas S, Cakici JA, Benson W, Kaplan RH, Kronick R, Bainbridge MN, Friedman J, Gold JJ, Ding Y, Veeraraghavan N, Dimmock D, Kingsmore SF. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. NPJ Genom Med 2018; 3:10. [PMID: 29644095 PMCID: PMC5884823 DOI: 10.1038/s41525-018-0049-4] [Citation(s) in RCA: 316] [Impact Index Per Article: 45.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 03/06/2018] [Accepted: 03/12/2018] [Indexed: 02/08/2023] Open
Abstract
Genetic disorders are a leading cause of morbidity and mortality in infants. Rapid whole-genome sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants. We report a retrospective cohort study of acutely ill inpatient infants in a regional children's hospital from July 2016-March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands also received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points. The diagnostic sensitivity of rWGS was 43% (eighteen of 42 infants) and 10% (four of 42 infants) for standard genetic tests (P = .0005). The rate of clinical utility of rWGS (31%, thirteen of 42 infants) was significantly greater than for standard genetic tests (2%, one of 42; P = .0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had a 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800,000-$2,000,000. These findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.
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Affiliation(s)
- Lauge Farnaes
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
- Department of Pediatrics, University of California San Diego, San Diego, CA USA
| | - Amber Hildreth
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
- Department of Pediatrics, University of California San Diego, San Diego, CA USA
| | - Nathaly M. Sweeney
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
- Department of Pediatrics, University of California San Diego, San Diego, CA USA
| | | | - Shimul Chowdhury
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
| | - Shareef Nahas
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
| | - Julie A. Cakici
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
| | - Wendy Benson
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
| | | | - Richard Kronick
- Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA USA
| | | | - Jennifer Friedman
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
- Department of Pediatrics, University of California San Diego, San Diego, CA USA
- Department of Neurosciences, University of California San Diego, San Diego, CA USA
| | - Jeffrey J. Gold
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
- Department of Neurosciences, University of California San Diego, San Diego, CA USA
| | - Yan Ding
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
| | | | - David Dimmock
- Rady Children’s Institute for Genomic Medicine, San Diego, CA USA
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Abstract
Hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants. Prompt recognition and treatment, independent of whether infants have transient or permanent HI, are essential to decrease risk of neurologic damage. The most common form of congenital HI is due to inactivating mutations of the β-cell ATP-sensitive potassium (KATP) channel (KATP-HI) and is typically diazoxide unresponsive. KATP-HI occurs in diffuse and focal forms. Distinguishing between the 2 forms is crucial, because pancreatectomy is curative in the focal form but palliative in the diffuse form. The 18-fluoro-L-3,4-dihydroxyphenylalanine PET scan has revolutionized HI management by allowing accurate localization of focal lesions prior to surgery.
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Affiliation(s)
- Katherine Lord
- The Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Diva D De León
- The Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA.
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7
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Lee KPK, Chen J, MacKinnon R. Molecular structure of human KATP in complex with ATP and ADP. eLife 2017; 6:32481. [PMID: 29286281 PMCID: PMC5790381 DOI: 10.7554/elife.32481] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 12/29/2017] [Indexed: 12/20/2022] Open
Abstract
In many excitable cells, KATP channels respond to intracellular adenosine nucleotides: ATP inhibits while ADP activates. We present two structures of the human pancreatic KATP channel, containing the ABC transporter SUR1 and the inward-rectifier K+ channel Kir6.2, in the presence of Mg2+ and nucleotides. These structures, referred to as quatrefoil and propeller forms, were determined by single-particle cryo-EM at 3.9 Å and 5.6 Å, respectively. In both forms, ATP occupies the inhibitory site in Kir6.2. The nucleotide-binding domains of SUR1 are dimerized with Mg2+-ATP in the degenerate site and Mg2+-ADP in the consensus site. A lasso extension forms an interface between SUR1 and Kir6.2 adjacent to the ATP site in the propeller form and is disrupted in the quatrefoil form. These structures support the role of SUR1 as an ADP sensor and highlight the lasso extension as a key regulatory element in ADP’s ability to override ATP inhibition. A hormone called insulin finely controls the amount of sugar in the blood. When the blood sugar content is high, a group of cells in the pancreas release insulin; when it is low, they stop. In these cells, the level of sugar in the blood modifies the ratio of two molecules: ATP, the body’s energy currency, and ADP, a molecule closely related to ATP. Changes in the ATP/ADP ratio are therefore a proxy of the variations in blood sugar levels. In these pancreatic cells, a membrane protein called ATP sensitive potassium channel, KATP channel for short, acts as a switch that turns on and off the production of insulin. ATP and ADP control that switch, with the two molecules having opposite effects on the channel – ATP deactivates it, ADP activates it. The changes in ATP/ADP ratio – and by extension in blood sugar levels – are therefore coupled with the release of insulin. However, how KATP channels sense the changes in the ATP/ADP ratio in these cells is still unclear. In particular, ATP levels are usually high and constant: ATP is then continuously deactivating the channels, and it is unclear how ADP ever activates them. Here, Lee et al. use a microscopy technique that can image biological molecules at the atomic scale to look at the structure of human pancreatic KATP channels. The 3D reconstruction maps show that KATP channels have binding sites for ATP but also one for ADP. This ADP site acts as a sensor that can detect even small changes in ADP levels in the cell. The maps also reveal a dynamic lasso-like structure connecting the ATP and ADP binding areas. This domain may play a vital role in allowing ADP to override ATP’s control of the channel. The presence of the ADP sensor and the lasso structure could explain how KATP channels monitor changes in the ATP/ADP ratio and can therefore control the release of insulin based on blood sugar levels. Defects in the KATP channels of the pancreas are present in genetic diseases where infants produce too much or too little insulin. Understanding the structure of these channels and how they work may help scientists to design new drugs to treat these conditions.
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Affiliation(s)
- Kenneth Pak Kin Lee
- Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
| | - Jue Chen
- Laboratory of Membrane Biology and Biophysics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
| | - Roderick MacKinnon
- Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
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8
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Jha RM, Puccio AM, Okonkwo DO, Zusman BE, Park SY, Wallisch J, Empey PE, Shutter LA, Clark RSB, Kochanek PM, Conley YP. ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI. Neurocrit Care 2017; 26:213-224. [PMID: 27677908 DOI: 10.1007/s12028-016-0309-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE. METHODS DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy. RESULTS Fourteen SNPs with minor allele frequency >0.2 were identified. Four SNPS rs2283261, rs3819521, rs2283258, and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR 2.45, p = 0.007; OR 2.95, p = 0.025; OR 3.00, p = 0.013), had higher mean (β = 3.13, p = 0.000; β = 2.95, p = 0.005; β = 3.20, p = 0.008), and peak ICP (β = 8.00, p = 0.001; β = 7.64, p = 0.007; β = 6.89, p = 0.034). The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR 0.47, p = 0.004). CONCLUSIONS This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective-potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.
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Affiliation(s)
- Ruchira M Jha
- Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA. .,Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. .,Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. .,Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. .,Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Ava M Puccio
- Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - David O Okonkwo
- Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Benjamin E Zusman
- Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Seo-Young Park
- Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jessica Wallisch
- Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.,Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Philip E Empey
- Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.,Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Lori A Shutter
- Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.,Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Robert S B Clark
- Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.,Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Anesthesiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Patrick M Kochanek
- Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.,Safar Center for Resuscitation Research, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Anesthesiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.,Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yvette P Conley
- Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.,School of Nursing, University of Pittsburgh, Pittsburgh, PA, USA.,Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA
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9
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Maiorana A, Dionisi-Vici C. Hyperinsulinemic hypoglycemia: clinical, molecular and therapeutical novelties. J Inherit Metab Dis 2017; 40:531-542. [PMID: 28656511 DOI: 10.1007/s10545-017-0059-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 05/25/2017] [Accepted: 05/29/2017] [Indexed: 01/01/2023]
Abstract
Hyperinsulinemic hypoglycemia (HI) is the most common cause of hypoglycemia in children. Impairment of cellular pathways involved in insulin secretion from pancreatic β-cells, broadly classified as channelopathies and metabolopathies, have been discovered in the past two decades. The increasing use of NGS target panels, combined with clinical, biochemical and imaging findings allows differentiating the diagnostic management of children with focal forms, surgically curable, from those with diffuse forms, more conservatively treated with pharmacological and nutritional interventions. Specific approaches according to the subtype of HI have been established and novel therapies are currently under investigation. Despite diagnostic and therapeutic advances, HI remains an important cause of morbidity in children, still accounting for 26-44% of permanent intellectual disabilities, especially in neonatal-onset patients. Initial insult from recurrent hypoglycemia in early life greatly contributes to the poor outcomes. Therefore, patients need to be rapidly identified and treated aggressively, and require at follow-up a complex and regular monitoring, managed by a multidisciplinary HI team. This review gives an overview on the more recent diagnostic and therapeutic tools, on the novel drug and nutritional therapies, and on the long-term neurological outcomes.
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Affiliation(s)
- Arianna Maiorana
- Division of Metabolic Diseases, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy.
| | - Carlo Dionisi-Vici
- Division of Metabolic Diseases, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy
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10
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Galcheva S, Iotova V, Ellard S, Flanagan SE, Halvadzhiyan I, Petrova C, Hussain K. Clinical presentation and treatment response to diazoxide in two siblings with congenital hyperinsulinism as a result of a novel compound heterozygous ABCC8 missense mutation. J Pediatr Endocrinol Metab 2017; 30:471-474. [PMID: 28328534 DOI: 10.1515/jpem-2016-0345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/30/2017] [Indexed: 11/15/2022]
Abstract
BACKGROUND Congenital hyperinsulinism (CHI) can present with considerable clinical heterogeneity which may be due to differences in the underlying genetic etiology. We present two siblings with hyperinsulinaemic hypoglycaemia (HH) and marked clinical heterogeneity caused by compound heterozygosity for the same two novel ABCC8 mutations. CASE PRESENTATION The index patient is a 3-year-old boy with hypoglycaemic episodes presenting on the first day of life. HH was diagnosed and treatment with intravenous glucose and diazoxide was initiated. Currently he has normal physical and neurological development, with occasional hypoglycaemic episodes detected following continuous fasting on treatment with diazoxide. The first-born 8-year-old sibling experienced severe postnatal hypoglycaemia, generalised seizures and severe brain damage despite diazoxide treatment. The latter was stopped at 6-months of age with no further registered hypoglycaemia. Genetic testing showed that both children were compound heterozygotes for two novel ABCC8 missense mutations p.I60N (c.179T>A) and p.G1555V (c.4664G>T). CONCLUSIONS These ABCC8 missense mutations warrant further studies mainly because of the variable clinical presentation and treatment response.
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Affiliation(s)
- Sonya Galcheva
- Department of Paediatrics, Medical University of Varna, 55 Marin Drinov street, Varna 9002
| | - Violeta Iotova
- Department of Paediatrics, Medical University of Varna, Varna
| | - Sian Ellard
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter
| | - Sarah E Flanagan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter
| | | | | | - Khalid Hussain
- Genetics and Epigenetics in Health and Disease Genetics and Genomic Medicine Programme, UCL Institute Child Health, London
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Martínez R, Fernández-Ramos C, Vela A, Velayos T, Aguayo A, Urrutia I, Rica I, Castaño L. Clinical and genetic characterization of congenital hyperinsulinism in Spain. Eur J Endocrinol 2016; 174:717-26. [PMID: 27188453 DOI: 10.1530/eje-16-0027] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 03/07/2016] [Indexed: 12/30/2022]
Abstract
CONTEXT Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease characterized by severe hypoglycemia caused by inappropriate insulin secretion by pancreatic β-cells. OBJECTIVE To characterize clinically and genetically CHI patients in Spain. DESIGN AND METHODS We included 50 patients with CHI from Spain. Clinical information was provided by the referring clinicians. Mutational analysis was carried out for KCNJ11, ABCC8, and GCK genes. The GLUD1, HNF4A, HNF1A, UCP2, and HADH genes were sequenced depending on the clinical phenotype. RESULTS We identified the genetic etiology in 28 of the 50 CHI patients tested: 21 had a mutation in KATP channel genes (42%), three in GLUD1 (6%), and four in GCK (8%). Most mutations were found in ABCC8 (20/50). Half of these patients (10/20) were homozygous or compound heterozygous, with nine being unresponsive to diazoxide treatment. The other half had heterozygous mutations in ABCC8, six of them being unresponsive to diazoxide treatment and four being responsive to diazoxide treatment. We identified 22 different mutations in the KATP channel genes, of which ten were novel. Notably, patients with ABCC8 mutations were diagnosed earlier, with lower blood glucose levels and required higher doses of diazoxide than those without a genetic diagnosis. CONCLUSIONS Genetic analysis revealed mutations in 56% of the CHI patients. ABCC8 mutations are the most frequent cause of CHI in Spain. We found ten novel mutations in the KATP channel genes. The genetic diagnosis is more likely to be achieved in patients with onset within the first week of life and in those who fail to respond to diazoxide treatment.
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Affiliation(s)
- R Martínez
- Endocrinology and Diabetes Research GroupBioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain
| | - C Fernández-Ramos
- Pediatric Endocrinology SectionBasurto University Hospital, BioCruces Health Research Institute, UPV/EHU, Bilbao, Spain
| | - A Vela
- Pediatric Endocrinology SectionCruces University Hospital, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV/EHU, Barakaldo, Spain
| | - T Velayos
- Endocrinology and Diabetes Research GroupBioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain
| | - A Aguayo
- Endocrinology and Diabetes Research GroupBioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain
| | - I Urrutia
- Endocrinology and Diabetes Research GroupBioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain
| | - I Rica
- Pediatric Endocrinology SectionCruces University Hospital, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV/EHU, Barakaldo, Spain
| | - L Castaño
- Endocrinology and Diabetes Research GroupBioCruces Health Research Institute, Cruces University Hospital, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain
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Lee CT, Liu SY, Tung YC, Chiu PC, Wu MZ, Tsai WY. Clinical characteristics and long-term outcome of Taiwanese children with congenital hyperinsulinism. J Formos Med Assoc 2016; 115:306-10. [DOI: 10.1016/j.jfma.2015.04.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 03/28/2015] [Accepted: 04/05/2015] [Indexed: 10/23/2022] Open
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Rozenkova K, Malikova J, Nessa A, Dusatkova L, Bjørkhaug L, Obermannova B, Dusatkova P, Kytnarova J, Aukrust I, Najmi LA, Rypackova B, Sumnik Z, Lebl J, Njølstad PR, Hussain K, Pruhova S. High Incidence of Heterozygous ABCC8 and HNF1A Mutations in Czech Patients With Congenital Hyperinsulinism. J Clin Endocrinol Metab 2015; 100:E1540-9. [PMID: 26431509 DOI: 10.1210/jc.2015-2763] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
CONTEXT Congenital hyperinsulinism of infancy (CHI) represents a group of heterogeneous disorders characterized by oversecretion of insulin from pancreatic β-cells causing severe hypoglycemia. OBJECTIVE We studied the distribution of genetic causes of CHI in a Czech population. METHODS Countrywide collection of patients with CHI included 40 subjects (12 females, median age of diagnosis, 1 wk [interquartile range, 1-612 wk]). We sequenced the ABCC8, KCNJ11, GLUD1, GCK, HADH, UCP2, SLC16A1, HNF4A, and HNF1A genes and investigated structural changes in the ABCC8 gene. We functionally tested novel variants in the ABCC8 gene by Rb(86+) efflux assay and novel variants in the HNF1A gene by transcriptional activation and DNA-binding tests. RESULTS We found causal mutations in 20 subjects (50%): 19 carried a heterozygous mutation while one patient was homozygous for mutation in the ABCC8 gene. Specifically, we detected 11 mutations (seven novel) in ABCC8, one novel mutation in KCNJ11, five mutations (two novel) in HNF1A, two novel mutations in HNF4A, and one in GCK. We showed a decrease of activation by diazoxide in mutant KATP channels with novel ABCC8 variants by 41-91% (median, 82%) compared with wild-type (WT) channels and reduced transcriptional activity of mutant HNF1A proteins (2.9% for p.Asn62Lysfs93* and 22% for p.Leu254Gln) accompanied by no DNA-binding ability compared with WT HNF1A. CONCLUSION We detected a higher proportion of heterozygous mutations causing CHI compared with other cohorts probably due to lack of consanguinity and inclusion of milder CHI forms. Interestingly, HNF1A gene mutations represented the second most frequent genetic cause of CHI in the Czech Republic. Based on our results we present a genetic testing strategy specific for similar populations.
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Affiliation(s)
- Klara Rozenkova
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Jana Malikova
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Azizun Nessa
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Lenka Dusatkova
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Lise Bjørkhaug
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Barbora Obermannova
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Petra Dusatkova
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Jitka Kytnarova
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Ingvild Aukrust
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Laeya A Najmi
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Blanka Rypackova
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Zdenek Sumnik
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Jan Lebl
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Pål R Njølstad
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Khalid Hussain
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
| | - Stepanka Pruhova
- Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom
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Fan ZC, Ni JW, Yang L, Hu LY, Ma SM, Mei M, Sun BJ, Wang HJ, Zhou WH. Uncovering the molecular pathogenesis of congenital hyperinsulinism by panel gene sequencing in 32 Chinese patients. Mol Genet Genomic Med 2015; 3:526-36. [PMID: 26740944 PMCID: PMC4694131 DOI: 10.1002/mgg3.162] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 06/05/2015] [Accepted: 06/09/2015] [Indexed: 01/06/2023] Open
Abstract
Congenital hyperinsulinism (CHI) has been mostly associated with mutations in seven major genes. We retrospectively reviewed a cohort of 32 patients with CHI. Extensive mutational analysis (ABCC8,KCNJ11,GCK,GLUD1,HADH,HNF4A, and UCP2) was performed on Ion torrent platform, which could analyze hundreds of genes simultaneously with ultrahigh-multiplex PCR using up to 6144 primer pairs in a single primer pool and address time-sensitive samples with single-day assays, from samples to annotated variants, to identify the genetic etiology of this disease. Thirty-seven sequence changes were identified, including in ABCC8/KCNJ11 (n = 25, 65.7%), GCK (n = 2), HNF4A (n = 3), GLUD1 (n = 2), HADH (n = 4), and UCP2 (n = 1); these mutations included 14 disease-causing mutations, eight rare SNPs, 14 common SNPs, and one novel mutation. Mutations were identified in 21 of 32 patients (65.6%). Among the patients with an identified mutation, 14 had mutations in ABCC8, one of which was combined with a GLUD1 mutation. Four patients had mutations in KCNJ11, 1 had a GCK mutation, 1 had a mutation in HADH, and two had a mutation in HNF4A. Among the 32 patients, the age at the onset of hyperinsulinemia ranged from the neonatal period to 1 year of age; five patients underwent a pancreatectomy due to intractable hyperinsulinemia. This study describes novel and previously identified mutations in patients with CHI. The spectrum of mutations in CHI patients represents an important tool for the diagnosis and prognosis of CHI patients in the Chinese population as well as for the genetic counseling of CHI families.
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Affiliation(s)
- Zi-Chuan Fan
- Department of NeonatologyChildren's Hospital of Fudan UniversityShanghaiChina; Key Laboratory of Birth DefectChildren's Hospital of Fudan UniversityShanghaiChina
| | - Jin-Wen Ni
- Department of Neonatology Children's Hospital of Fudan University Shanghai China
| | - Lin Yang
- Key Laboratory of Birth DefectChildren's Hospital of Fudan UniversityShanghaiChina; Key Laboratory of Neonatal DiseasesMinistry of HealthChildren's HospitalFudan UniversityShanghaiChina
| | - Li-Yuan Hu
- Department of Neonatology Children's Hospital of Fudan University Shanghai China
| | - Si-Min Ma
- Department of Neonatology Children's Hospital of Fudan University Shanghai China
| | - Mei Mei
- Department of Neonatology Children's Hospital of Fudan University Shanghai China
| | - Bi-Jun Sun
- Department of NeonatologyChildren's Hospital of Fudan UniversityShanghaiChina; Key Laboratory of Birth DefectChildren's Hospital of Fudan UniversityShanghaiChina
| | - Hui-Jun Wang
- Key Laboratory of Birth DefectChildren's Hospital of Fudan UniversityShanghaiChina; Key Laboratory of Neonatal DiseasesMinistry of HealthChildren's HospitalFudan UniversityShanghaiChina
| | - Wen-Hao Zhou
- Department of NeonatologyChildren's Hospital of Fudan UniversityShanghaiChina; Key Laboratory of Birth DefectChildren's Hospital of Fudan UniversityShanghaiChina; Key Laboratory of Neonatal DiseasesMinistry of HealthChildren's HospitalFudan UniversityShanghaiChina
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Arya VB, Guemes M, Nessa A, Alam S, Shah P, Gilbert C, Senniappan S, Flanagan SE, Ellard S, Hussain K. Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. Eur J Endocrinol 2014; 171:685-95. [PMID: 25201519 DOI: 10.1530/eje-14-0353] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
CONTEXT Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported. OBJECTIVE The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. DESIGN A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted. RESULTS Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 l-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography 18F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (n=8) or 18F DOPA-PET CT (n=27). Diffuse, indeterminate and focal disease was identified in 13, 1 and 21 patients respectively. Two patients with suspected diffuse disease were identified to have focal disease on histology. CONCLUSIONS Paternally inherited heterozygous ABCC8/KCNJ11 mutations can manifest as a wide spectrum of CHI with variable 18F DOPA-PET CT/histological findings and clinical outcomes. Focal disease was histologically confirmed in 24/53 (45%) of CHI patients with paternally inherited heterozygous ABCC8/KCNJ11 mutations.
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Affiliation(s)
- Ved Bhushan Arya
- Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK
| | - Maria Guemes
- Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK
| | - Azizun Nessa
- Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK
| | - Syeda Alam
- Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK
| | - Pratik Shah
- Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK
| | - Clare Gilbert
- Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK
| | - Senthil Senniappan
- Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK
| | - Sarah E Flanagan
- Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK
| | - Sian Ellard
- Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK
| | - Khalid Hussain
- Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK Developmental Endocrinology Research GroupClinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UKLondon Centre for Paediatric EndocrinologyGreat Ormond Street Hospital for Children, London WC1N 3JH, UKInstitute of Biomedical and Clinical ScienceUniversity of Exeter Medical School, Exeter EX2 5DW, UK
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Montravers F, Arnoux JB, Ribeiro MJ, Kerrou K, Nataf V, Galmiche L, Aigrain Y, Bellanné-Chantelot C, Saint-Martin C, Ohnona J, Balogova S, Huchet V, Michaud L, Talbot JN, de Lonlay P. Strengths and limitations of using 18fluorine-fluorodihydroxyphenylalanine PET/CT for congenital hyperinsulinism. Expert Rev Endocrinol Metab 2014; 9:477-485. [PMID: 30736210 DOI: 10.1586/17446651.2014.949240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
18fluorine-fluorodihydroxyphenylalanine (FDOPA) PET/CT is currently the first-line imaging technique to distinguish between focal and diffuse forms of congenital hyperinsulinism (CHI) and to accurately localize focal forms. However, this technique has a number of limitations, mainly the very small size of focal forms or inversely a very large focal form mimicking a diffuse form, and misinterpretation of physiologic uptake masking hot spots or inversely mimicking focal forms. The other limitation is the limited availability of the radiopharmaceutical. FDOPA PET/CT has no recognized competitor to date among the available morphologic and functional imaging techniques. Other potential approaches using specific tracers for positron emission tomography (PET) are discussed, using radiopharmaceuticals specific for β cell mass or targeting somatostatin receptors. These radiopharmaceuticals can be labeled with gallium-68, a PET emitter readily available in PET centers equipped with 68Ge/68Ga generators.
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Affiliation(s)
- Françoise Montravers
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Jean-Baptiste Arnoux
- b Centre de référence des maladies héréditaires du métabolisme de l'enfant, et l'adulte, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
| | - Maria-Joao Ribeiro
- c Service de médecine nucléaire, CHRU, Université François Rabelais, INSERM U930, Tours, France
| | - Khaldoun Kerrou
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Valérie Nataf
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Louise Galmiche
- d Service d'anatomo-pathologie, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
| | - Yves Aigrain
- b Centre de référence des maladies héréditaires du métabolisme de l'enfant, et l'adulte, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
| | - Christine Bellanné-Chantelot
- e Département de génétique, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Cécile Saint-Martin
- e Département de génétique, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Jessica Ohnona
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Sona Balogova
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
- f Department of nuclear medicine, Comenius University and St. Elisabeth Institute, Bratislava, Slovakia
| | - Virginie Huchet
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Laure Michaud
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Jean-Noël Talbot
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Pascale de Lonlay
- b Centre de référence des maladies héréditaires du métabolisme de l'enfant, et l'adulte, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
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Gopal-Kothandapani JS, Hussain K. Congenital hyperinsulinism: Role of fluorine-18L-3, 4 hydroxyphenylalanine positron emission tomography scanning. World J Radiol 2014; 6:252-260. [PMID: 24976928 PMCID: PMC4072812 DOI: 10.4329/wjr.v6.i6.252] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 03/19/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Congenital hyperinsulinism (CHI) is a rare but complex heterogeneous disorder caused by unregulated secretion of insulin from the β-cells of the pancreas leading to severe hypoglycaemia and neuroglycopaenia. Swift diagnosis and institution of appropriate management is crucial to prevent or minimise adverse neurodevelopmental outcome in children with CHI. Histologically there are two major subtypes of CHI, diffuse and focal disease and the management approach will significantly differ depending on the type of the lesion. Patients with medically unresponsive diffuse disease require a near total pancreatectomy, which then leads on to the development of iatrogenic diabetes mellitus and pancreatic exocrine insufficiency. However patients with focal disease only require a limited pancreatectomy to remove only the focal lesion thus providing complete cure to the patient. Hence the preoperative differentiation of the histological subtypes of CHI becomes paramount in the management of CHI. Fluorine-18L-3, 4-hydroxyphenylalanine positron emission tomography (18F-DOPA-PET) is now the gold standard for pre-operative differentiation of focal from diffuse disease and localisation of the focal lesion. The aim of this review article is to give a clinical overview of CHI, then review the role of dopamine in β-cell physiology and finally discuss the role of 18F-DOPA-PET imaging in the management of CHI.
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18
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Blomberg BA, Moghbel MC, Saboury B, Stanley CA, Alavi A. The value of radiologic interventions and (18)F-DOPA PET in diagnosing and localizing focal congenital hyperinsulinism: systematic review and meta-analysis. Mol Imaging Biol 2013; 15:97-105. [PMID: 22752652 PMCID: PMC3553406 DOI: 10.1007/s11307-012-0572-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE This systematic review and meta-analysis aimed to quantify the diagnostic performance of pancreatic venous sampling (PVS), selective pancreatic arterial calcium stimulation with hepatic venous sampling (ASVS), and (18)F-DOPA positron emission tomography (PET) in diagnosing and localizing focal congenital hyperinsulinism (CHI). PROCEDURES This systematic review and meta-analysis was conducted according to the PRISMA statement. PubMed, EMBASE, SCOPUS and Web of Science electronic databases were systematically searched from their inception to November 1, 2011. Using predefined inclusion and exclusion criteria, two blinded reviewers selected articles. Critical appraisal ranked the retrieved articles according to relevance and validity by means of the QUADAS-2 criteria. Pooled data of homogeneous study results estimated the sensitivity, specificity, likelihood ratios and diagnostic odds ratio (DOR). RESULTS (18)F-DOPA PET was superior in distinguishing focal from diffuse CHI (summary DOR, 73.2) compared to PVS (summary DOR, 23.5) and ASVS (summary DOR, 4.3). Furthermore, it localized focal CHI in the pancreas more accurately than PVS and ASVS (pooled accuracy, 0.82 vs. 0.76, and 0.64, respectively). Important limitations comprised the inclusion of studies with small sample sizes, high probability of bias and heterogeneity among their results. Studies with small sample sizes and high probability of bias tended to overestimate the diagnostic accuracy. CONCLUSIONS This systematic review and meta-analysis found evidence for the superiority of (18)F-DOPA PET in diagnosing and localizing focal CHI in patients requiring surgery for this disease.
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Affiliation(s)
- Björn A. Blomberg
- Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA USA
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA USA
- University Medical Center Utrecht, Utrecht University School of Medicine, Utrecht, The Netherlands
| | - Mateen C. Moghbel
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA USA
| | - Babak Saboury
- Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA USA
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA USA
| | - Charles A. Stanley
- Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA USA
- Division of Endocrinology, Children’s Hospital of Philadelphia, Philadelphia, PA USA
| | - Abass Alavi
- Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA USA
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA USA
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19
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Diagnostic role of 18F-dihydroxyphenylalanine positron emission tomography in patients with congenital hyperinsulinism: a meta-analysis. Nucl Med Commun 2013; 34:347-53. [PMID: 23376859 DOI: 10.1097/mnm.0b013e32835e6ac6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Studies have reported the applications of F-dihydroxyphenylalanine (F-DOPA) PET in patients with congenital hyperinsulinism (CHI). The aim of this study was to systematically review and perform a meta-analysis of published data on the diagnostic role of F-DOPA PET in patients with CHI. MATERIALS AND METHODS A comprehensive computer literature search of studies on F-DOPA PET or PET/computed tomography (CT) in patients with CHI was conducted. The pooled sensitivity and specificity of F-DOPA PET or PET/CT in patients with CHI were calculated. The area under the receiver-operating characteristic curve was calculated to measure the accuracy of F-DOPA PET or PET/CT in patients with CHI. RESULTS Ten studies comprising 181 patients with CHI were included in this meta-analysis. The pooled sensitivity of F-DOPA PET and PET/CT in detecting CHI was 88% on a per-patient-based analysis. The pooled specificity of F-DOPA PET and PET/CT in demonstrating CHI was 79%. The area under the receiver-operating characteristic curve was 0.92 on a per-patient-based analysis. CONCLUSION In patients with CHI, F-DOPA PET or PET/CT demonstrated high sensitivity and specificity. F-DOPA PET and PET/CT are accurate methods for the diagnosis of CHI. Nevertheless, possible sources of false-positive and false-negative results should be kept in mind.
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Banerjee I, Avatapalle B, Padidela R, Stevens A, Cosgrove KE, Clayton PE, Dunne MJ. Integrating genetic and imaging investigations into the clinical management of congenital hyperinsulinism. Clin Endocrinol (Oxf) 2013; 78:803-13. [PMID: 23347463 DOI: 10.1111/cen.12153] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 01/03/2013] [Accepted: 01/14/2013] [Indexed: 11/27/2022]
Abstract
Congenital Hyperinsulinism (CHI) is a rare but important cause of hypoglycaemia in infancy. CHI is a heterogeneous disease, but has a strong genetic basis; a number of genetic causes have been identified with CHI in about a third of individuals, chiefly in the genes that code for the ATP sensitive K(+) channels (KATP ) in the pancreatic β-cells. Rapid KATP channel gene testing is a critical early step in the diagnostic algorithm of CHI, with paternal heterozygosity correlating with the occurrence of focal lesions. Imaging investigations to diagnose and localize solitary pancreatic foci have evolved over the last decade with (18)F-DOPA PET-CT scanning as the current diagnostic tool of choice. Although clinical management of CHI has improved significantly with the application of genetic screening and imaging investigations, much remains to be uncovered. This includes a better understanding of the molecular mechanisms for dysregulated insulin release in those patients without known genetic mutations, and the development of biomarkers that could characterize CHI, including long-term prognosis and targeted treatment planning, i.e. 'personalised medicine'. From the perspective of pancreatic imaging, it would be important to achieve greater specificity of diagnosis not only for focal lesions but also for diffuse and atypical forms of the disease.
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Affiliation(s)
- I Banerjee
- Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, UK.
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Lord K, De León DD. Monogenic hyperinsulinemic hypoglycemia: current insights into the pathogenesis and management. INTERNATIONAL JOURNAL OF PEDIATRIC ENDOCRINOLOGY 2013; 2013:3. [PMID: 23384201 PMCID: PMC3573904 DOI: 10.1186/1687-9856-2013-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Accepted: 02/01/2013] [Indexed: 11/10/2022]
Abstract
Hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in children, which if unrecognized may lead to development delays and permanent neurologic damage. Prompt recognition and appropriate treatment of HI are essential to avoid these sequelae. Major advances have been made over the past two decades in understanding the molecular basis of hyperinsulinism and mutations in nine genes are currently known to cause HI. Inactivating KATP channel mutations cause the most common and severe type of HI, which occurs in both a focal and a diffuse form. Activating mutations of glutamate dehydrogenase (GDH) lead to hyperinsulinism/hyperammonemia syndrome, while activating mutations of glucokinase (GK), the “glucose sensor” of the beta cell, causes hyperinsulinism with a variable clinical phenotype. More recently identified genetic causes include mutations in the genes encoding short-chain 3-hydroxyacyl-CoA (SCHAD), uncoupling protein 2 (UCP2), hepatocyte nuclear factor 4-alpha (HNF-4α), hepatocyte nuclear factor 1-alpha (HNF-1α), and monocarboyxlate transporter 1 (MCT-1), which results in a very rare form of HI triggered by exercise. For a timely diagnosis, a critical sample and a glucagon stimulation test should be done when plasma glucose is < 50 mg/dL. A failure to respond to a trial of diazoxide, a KATP channel agonist, suggests a KATP defect, which frequently requires pancreatectomy. Surgery is palliative for children with diffuse KATPHI, but children with focal KATPHI are cured with a limited pancreatectomy. Therefore, distinguishing between diffuse and focal disease and localizing the focal lesion in the pancreas are crucial aspects of HI management. Since 2003, 18 F-DOPA PET scans have been used to differentiate diffuse and focal disease and localize focal lesions with higher sensitivity and specificity than more invasive interventional radiology techniques. Hyperinsulinism remains a challenging disorder, but recent advances in the understanding of its genetic basis and breakthroughs in management should lead to improved outcomes for these children.
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Affiliation(s)
- Katherine Lord
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Abramson Research Center Room 802A, Philadelphia, PA, 19104, USA.
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Laje P, States LJ, Zhuang H, Becker SA, Palladino AA, Stanley CA, Adzick NS. Accuracy of PET/CT Scan in the diagnosis of the focal form of congenital hyperinsulinism. J Pediatr Surg 2013; 48:388-93. [PMID: 23414871 PMCID: PMC3597386 DOI: 10.1016/j.jpedsurg.2012.11.025] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Accepted: 11/12/2012] [Indexed: 01/30/2023]
Abstract
PURPOSE The purpose of the study was to determine the sensitivity of the (18)fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography scan (18F-PET/CT) in the diagnosis of focal congenital hyperinsulinism (HI). METHODS A retrospective review of children with HI who underwent a preoperative 18F-PET/CT scan was performed. RESULTS Between 1/2008 and 2/2012 we performed 105 consecutive 18F-PET/CT scans on infants with HI. Fifty-three patients had focal HI. Of those fifty-three patients, eight had a preoperative 18F-PET/CT scan read as "diffuse disease". The sensitivity of the study in the diagnosis of focal HI was 85%. The location of the eight missed focal lesions was: head (3), body (2), and tail (3). The 18F-PET/CT of the missed head lesions showed homogeneous tracer uptake (n =2) or heterogeneous uptake throughout the pancreas (n=1). The 18F-PET/CT of the 2 missed body lesions and 1 missed tail lesion showed heterogeneous uptake throughout the pancreas. The 18F-PET/CT of the other 2 missed tail lesions showed lesions adjacent to and obscured by the signal of the upper renal pole, identified retrospectively by closer observation. Fifty-two of the 105 patients had diffuse HI. Two of them had 18F-PET/CT studies read as "focal disease". Therefore, the specificity of the study was 96%. Of the forty-seven 18F-PET/CT studies read as "focal disease", forty-five had true focal HI. Therefore, the positive predictive value of the study in the diagnosis of focal HI was 96%. CONCLUSION The sensitivity and specificity of 18 F-PET/CT can be affected by certain anatomic features of the pancreas, by the location of the lesion, and by the reader's experience.
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Affiliation(s)
| | | | | | | | | | | | - N. Scott Adzick
- Corresponding author. Department of Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA. Tel.: +1 215 590 2727; fax: +1 215 590 3265. (N.S. Adzick)
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Pinney SE, Ganapathy K, Bradfield J, Stokes D, Sasson A, Mackiewicz K, Boodhansingh K, Hughes N, Becker S, Givler S, Macmullen C, Monos D, Ganguly A, Hakonarson H, Stanley CA. Dominant form of congenital hyperinsulinism maps to HK1 region on 10q. Horm Res Paediatr 2013; 80:18-27. [PMID: 23859901 PMCID: PMC3876732 DOI: 10.1159/000351943] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 05/10/2013] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND/AIMS In a family with congenital hyperinsulinism (HI), first described in the 1950s by McQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI. METHODS We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing. RESULTS Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21-22, a region containing 48 genes. Three novel noncoding variants were found in hexokinase 1 (HK1) and one missense variant in the coding region of DNA2. CONCLUSION Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. HK1 is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.
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Affiliation(s)
- Sara E. Pinney
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA,Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Karthik Ganapathy
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Jonathan Bradfield
- Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - David Stokes
- Translational Core Facility, Clinical and Translational Research Center, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Ariella Sasson
- Center for Biomedical Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Katarzyna Mackiewicz
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Kara Boodhansingh
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Nkecha Hughes
- Translational Core Facility, Clinical and Translational Research Center, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Susan Becker
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Stephanie Givler
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Courtney Macmullen
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Dimitrios Monos
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA,Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Arupa Ganguly
- Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Hakon Hakonarson
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA,Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Charles A. Stanley
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA,Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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Patterson ME, Mao CS, Yeh MW, Ipp E, Cortina G, Barank D, Vasinrapee P, Pawlikowska-Haddal A, Lee WNP, Yee JK. Hyperinsulinism presenting in childhood and treatment by conservative pancreatectomy. Endocr Pract 2012; 18:e52-6. [PMID: 22548943 DOI: 10.4158/ep11232.cr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To describe the uncommon presentation of hyperinsulinism in an 8-year-old boy. METHODS We describe the patient's clinical findings, results from biochemical and imaging studies, surgical approach, and outcome. The discussion encompasses a review of literature that provided the basis for the diagnostic and surgical approach applied to this patient's case. RESULTS An obese 8.5-year-old boy initially presented with hypoglycemic seizures after initiation of dietary changes to treat obesity. Biochemical analysis indicated hyperinsulinism. Endoscopic ultrasonography showed no pancreatic lesions suggestive of insulinoma. Genetic studies identified no known mutations in the ABCC8, KCNJ11, GCK, or GLUD1 genes. Selective arterial calcium stimulation and hepatic venous sampling did not document a focal source for hyperinsulinism in the pancreas, and positron emission tomography with 18-fluoro-L-3,4-dihydroxyphenylalanine showed diffusely increased uptake in the pancreas. The patient ultimately required partial pancreatectomy because of continued hypoglycemia while taking diazoxide and octreotide. Intraoperative glucose monitoring directed the extent of surgical resection. A 45% pancreatectomy was performed, which resolved the hypoglycemia but led to impaired glucose tolerance after surgery. CONCLUSION The unusual presentation of hyperinsulinism in childhood required a personalized approach to diagnosis and surgical management using intraoperative glucose monitoring that resulted in a conservative pancreatectomy.
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Affiliation(s)
- Mary E Patterson
- Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California 90509, USA
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de Wet H, Shimomura K, Aittoniemi J, Ahmad N, Lafond M, Sansom MSP, Ashcroft FM. A universally conserved residue in the SUR1 subunit of the KATP channel is essential for translating nucleotide binding at SUR1 into channel opening. J Physiol 2012; 590:5025-36. [PMID: 22802590 PMCID: PMC3495298 DOI: 10.1113/jphysiol.2012.236075] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The sulphonylurea receptor (SUR1) subunit of the ATP-sensitive potassium (KATP) channel is a member of the ATP-binding cassette (ABC) protein family. Binding of MgADP to nucleotide-binding domain 2 (NBD2) is critical for channel activation.We identified a residue in NBD2 (G1401) that is fully conserved among ABC proteins and whose functional importance is unknown. Homology modelling places G1401 on the outer surface of the protein, distant from the nucleotide-binding site. The ATPase activity of purified SUR1-NBD2-G1410R (bound to maltose-binding protein) was slightly inhibited when compared to the wild-type protein, but its inhibition by MgADP was unchanged, indicating that MgADP binding is not altered. However, MgADP activation of channel activity was abolished. This implies that the G1401R mutation impairs the mechanism by which MgADP binding to NBD2 is translated into opening of the KATP channel pore. The location of G1401 would be consistent with interaction of this residue with the pore-forming Kir6.2 subunit. Channel activity in the presence of MgATP reflects the balance between the stimulatory (at SUR1) and inhibitory (at Kir6.2) effects of nucleotides. Mutant channels were 2.5-fold less sensitive to MgATP inhibition and not activated by MgATP. This suggests that ATP block of the channel is reduced by the SUR1 mutation. Interestingly, this effect was dependent on the functional integrity of the NBDs. These results therefore suggest that SUR1 modulates both nucleotide inhibition and activation of the KATP channel.
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Affiliation(s)
- Heidi de Wet
- Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK
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Near-total pancreatectomy for persistent hyperinsulinemic hypoglycemia of infancy (nesidioblastosis). ANNALS OF PEDIATRIC SURGERY 2012. [DOI: 10.1097/01.xps.0000412949.98148.cf] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
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Laje P, Stanley CA, Palladino AA, Becker SA, Adzick NS. Pancreatic head resection and Roux-en-Y pancreaticojejunostomy for the treatment of the focal form of congenital hyperinsulinism. J Pediatr Surg 2012; 47:130-5. [PMID: 22244405 PMCID: PMC3595012 DOI: 10.1016/j.jpedsurg.2011.10.032] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Accepted: 10/06/2011] [Indexed: 10/14/2022]
Abstract
PURPOSE To determine the outcome of patients who underwent pancreatic head resection and Roux-en-Y pancreaticojejunostomy to the remaining normal pancreatic body and tail for the treatment of a focal lesion in the pancreatic head causing congenital hyperinsulinism (HI). METHODS One hundred thirty-eight patients underwent pancreatic resection for focal HI between 1998 and 2010. Twenty-three patients in the group underwent pancreatic head resection and Roux-en-Y pancreaticojejunostomy. RESULTS There were 13 females and 10 males. Median age and weight at surgery were 8 weeks and 5.8 kg, respectively. Twenty-one patients had a near-total pancreatic head resection, and 2 patients had a pylorus-preserving Whipple procedure. The pancreaticojejunostomy anastomosis was performed with interrupted fine monofilament sutures such that the transected end of the pancreatic body was tucked within the end of the Roux-en-Y jejunal limb. Median hospital stay was 22 days. All patients were cured of HI. CONCLUSION We conclude that pancreatic head resection with Roux-en-Y pancreaticojejunostomy is a safe and effective procedure for the treatment of the HI patient with a large focal lesion in the pancreatic head that is not amenable to local resection alone.
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Affiliation(s)
| | | | | | | | - N. Scott Adzick
- Corresponding author. Tel.: +1 215 590 2727; fax: +1 215 590 4875. (N. Scott Adzick)
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Henquin JC, Nenquin M, Sempoux C, Guiot Y, Bellanné-Chantelot C, Otonkoski T, de Lonlay P, Nihoul-Fékété C, Rahier J. In vitro insulin secretion by pancreatic tissue from infants with diazoxide-resistant congenital hyperinsulinism deviates from model predictions. J Clin Invest 2011; 121:3932-42. [PMID: 21968111 DOI: 10.1172/jci58400] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Accepted: 07/13/2011] [Indexed: 01/25/2023] Open
Abstract
Congenital hyperinsulinism (CHI) is the major cause of persistent neonatal hypoglycemia. CHI most often occurs due to mutations in the ABCC8 (which encodes sulfonylurea receptor 1) or KCNJ11 (which encodes the potassium channel Kir6.2) gene, which result in a lack of functional KATP channels in pancreatic β cells. Diffuse forms of CHI (DiCHI), in which all β cells are abnormal, often require subtotal pancreatectomy, whereas focal forms (FoCHI), which are characterized by localized hyperplasia of abnormal β cells, can be cured by resection of the lesion. Here, we characterized the in vitro kinetics of insulin secretion by pancreatic fragments from 6 DiCHI patients and by focal lesion and normal adjacent pancreas from 18 FoCHI patients. Responses of normal pancreas were similar to those reported for islets from adult organ donors. Compared with normal pancreas, basal insulin secretion was elevated in both FoCHI and DiCHI tissue. Affected tissues were heterogeneous in their secretory responses, with increased glucose levels often producing a rapid increase in insulin secretion that could be followed by a paradoxical decrease below prestimulatory levels. The KATP channel blocker tolbutamide was consistently ineffective in stimulating insulin secretion; conversely, the KATP channel activator diazoxide often caused an unanticipated increase in insulin secretion. These observed alterations in secretory behavior were similar in focal lesion and DiCHI tissue, and independent of the specific mutation in ABCC8 or KCNJ11. They cannot be explained by classic models of β cell function. Our results provide insight into the excessive and sometimes paradoxical changes in insulin secretion observed in CHI patients with inactivating mutations of KATP channels.
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Affiliation(s)
- Jean-Claude Henquin
- Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, Brussels, Belgium.
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Palladino AA, Stanley CA. A specialized team approach to diagnosis and medical versus surgical treatment of infants with congenital hyperinsulinism. Semin Pediatr Surg 2011; 20:32-7. [PMID: 21186002 DOI: 10.1053/j.sempedsurg.2010.10.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Hyperinsulinism (HI) is the most common cause of transient and permanent forms of hypoglycemia in infancy. Establishing the correct diagnosis and initiating appropriate therapy without delay is of utmost importance. Once the diagnosis is made and if medical therapy with diazoxide fails, one should assume that the infant has a K(ATP) channel defect and may require surgery. In this case, the infant should be referred to a center that specializes in HI with 18-fluoro L-3,4-dihydroxyphenylalanine positron emission tomography scan. This report describes a center specializing in HI with a team of experts consisting of endocrinologists, nurse practitioners, geneticists, radiologists, pathologists, and a surgeon. It describes the center's paradigm for managing severe HI on the basis of more than 250 cases of HI in the past 10 years, including the diagnosis of HI, medical options, genetics of HI, imaging in HI, the surgical approach to HI, and outcomes.
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Affiliation(s)
- Andrew A Palladino
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA.
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30
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First successful application of preimplantation genetic diagnosis and haplotyping for congenital hyperinsulinism. Reprod Biomed Online 2011; 22:72-9. [DOI: 10.1016/j.rbmo.2010.09.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2010] [Revised: 09/20/2010] [Accepted: 09/22/2010] [Indexed: 11/18/2022]
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Abstract
Congenital hyperinsulinism is a leading cause of severe hypoglycaemia in the newborn period. There are two (diffuse and focal) histological subtypes of congenital hyperinsulinism. The diffuse form affects the entire pancreas and if medically unresponsive will require a near total (95%-98%) pancreatectomy. The focal form affects only a small region of the pancreas (with the rest of the pancreas being normal in endocrine and exocrine function) and only requires a limited pancreatectomy. This limited section of the focal lesion has the potential for curing the patient. Thus the pre-operative differentiation of these two subgroups is extremely important. Recent advances in Fluorine-18-L-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET/CT) have radically changed the clinical approach to patient with congenital hyperinsulinism. In most patients this novel imaging technique is able to offer precise pre-operative localisation of the focal lesion, thus guiding the extent of surgical resection.
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Affiliation(s)
- Dunia Ismail
- Clinical and Molecular Genetics Unit, The Developmental Endocrinology Research Group, Institute of Child Health, University College London, Great Ormond Street Hospital for Children NHS Trust, 30 Guilford Street, London, WC1N 1EH, UK
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32
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Dutta S, Venkataseshan S, Bal C, Rao KLN, Gupta K, Bhattacharya A, Narang A. Novel use of somatostatin receptor scintigraphy in localization of focal congenital hyperinsulinism: promising but fallible. J Pediatr Endocrinol Metab 2009; 22:965-9. [PMID: 20020586 DOI: 10.1515/jpem.2009.22.10.965] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children. The pre-operative differentiation of focal from diffuse forms is extremely important from the management point of view. The current methods for pre-operative differentiation are invasive. We report a patient with CHI where somatostatin receptor scintigraphy was used to diagnose CHI but with limited success. A preoperative 68gallium DOTATOC-PET scan was performed which revealed highly localized radiotracer uptake in the body of the pancreas. 80% of the pancreas including the body was resected. The clinical problems did not completely resolve after surgery. Histopathology revealed hyperplastic islet cells at the resected margin and randomly throughout the pancreas. This case highlights the use of 68gallium DOTATOC-PET scan in a patient with severe CHI. The satellite foci that were missed may be either an inherent limitation of 68Ga DOTATOC scan or an underinterpretation due to lack of expertise. This report opens up a new option of using somatostatin analogue scintigraphy for pre-operative localization of hyperplastic islet cells in patients with CHI.
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Affiliation(s)
- Sourabh Dutta
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
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Abstract
Congenital hyperinsulinism is the principle cause of hypoglycemia during infancy but successful treatment is difficult and persistent hypoglycemia carries the risk of neurologic damage. Focal and diffuse abnormalities are the common forms of hyperinsulinism. Identification and localization of focal hyperinsulinism can be cured by partial pancreatectomy. It has been shown that affected pancreatic areas utilize LDOPA in a higher rate than normal pancreatic tissue and, thus, labeling L-DOPA with fluorine-18 (FDOPA) allows functional mapping of hyperinsulinism using PET. This article presents a fundamental overview of the genetics background, pathology, management, and the role of FDOPA-PET imaging in hyperinsulinism.
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Flanagan SE, Clauin S, Bellanné-Chantelot C, de Lonlay P, Harries LW, Gloyn AL, Ellard S. Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat 2009; 30:170-80. [PMID: 18767144 DOI: 10.1002/humu.20838] [Citation(s) in RCA: 181] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The beta-cell ATP-sensitive potassium (K(ATP)) channel is a key component of stimulus-secretion coupling in the pancreatic beta-cell. The channel couples metabolism to membrane electrical events bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis it is therefore not surprising that mutations in the genes encoding for the two essential subunits of the channel can result in both hypo- and hyperglycemia. The channel consists of four subunits of the inwardly rectifying potassium channel Kir6.2 and four subunits of the sulfonylurea receptor 1 (SUR1). It has been known for some time that loss of function mutations in KCNJ11, which encodes for Kir6.2, and ABCC8, which encodes for SUR1, can cause oversecretion of insulin and result in hyperinsulinism of infancy, while activating mutations in KCNJ11 and ABCC8 have recently been described that result in the opposite phenotype of diabetes. This review focuses on reported mutations in both genes, the spectrum of phenotypes, and the implications for treatment on diagnosing patients with mutations in these genes.
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Affiliation(s)
- Sarah E Flanagan
- Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, United Kingdom
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Pinney SE, MacMullen C, Becker S, Lin YW, Hanna C, Thornton P, Ganguly A, Shyng SL, Stanley CA. Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations. J Clin Invest 2008; 118:2877-86. [PMID: 18596924 DOI: 10.1172/jci35414] [Citation(s) in RCA: 134] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2008] [Accepted: 05/19/2008] [Indexed: 11/17/2022] Open
Abstract
Congenital hyperinsulinism is a condition of dysregulated insulin secretion often caused by inactivating mutations of the ATP-sensitive K+ (KATP) channel in the pancreatic beta cell. Though most disease-causing mutations of the 2 genes encoding KATP subunits, ABCC8 (SUR1) and KCNJ11 (Kir6.2), are recessively inherited, some cases of dominantly inherited inactivating mutations have been reported. To better understand the differences between dominantly and recessively inherited inactivating KATP mutations, we have identified and characterized 16 families with 14 different dominantly inherited KATP mutations, including a total of 33 affected individuals. The 16 probands presented with hypoglycemia at ages from birth to 3.3 years, and 15 of 16 were well controlled on diazoxide, a KATP channel agonist. Of 29 adults with mutations, 14 were asymptomatic. In contrast to a previous report of increased diabetes risk in dominant KATP hyperinsulinism, only 4 of 29 adults had diabetes. Unlike recessive mutations, dominantly inherited KATP mutant subunits trafficked normally to the plasma membrane when expressed in COSm6 cells. Dominant mutations also resulted in different channel-gating defects, as dominant ABCC8 mutations diminished channel responses to magnesium adenosine diphosphate or diazoxide, while dominant KCNJ11 mutations impaired channel opening, even in the absence of nucleotides. These data highlight distinctive features of dominant KATP hyperinsulinism relative to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy, without the need for surgical pancreatectomy.
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Affiliation(s)
- Sara E Pinney
- Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
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Arbizu Lostao J, Fernández-Marmiesse A, Garrastachu Zumarrán P, Martino Casado E, Azcona San Julián C, Carracedo A, Richter Echevarría JA. [18F-fluoro-L-DOPA PET-CT imaging combined with genetic analysis for optimal classification and treatment in a child with severe congenital hyperinsulinism]. An Pediatr (Barc) 2008; 68:481-5. [PMID: 18447993 DOI: 10.1157/13120046] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy. The differential diagnosis between focal and diffuse forms of CHI is of great importance when planning surgery. The aim of this article is to show the first case of focal CHI diagnosed in Spain using PET-CT imaging combined with genetic analysis. METHODS A 13 month child with CHI and normal conventional radiological investigations treated with diazoxide, diet control and feeding by gastrostomy is presented. Genetic analysis of ABCC8 and KCNJ11 genes and PET-TAC using 18F-fluoro-L-DOPA were performed. RESULTS A pathological mutation (G111R) in the paternal allele of ABCC8 was detected. PET-CT scanning using 18F-fluoro-L-DOPA showed a focus of high uptake in the body of the pancreas compatible with adenoma that was hystopathologically confirmed. After surgical resection the patient is asymptomatic without needing either pharmacological treatment or dietetic control. CONCLUSIONS The combination of genetic analysis and 18F-fluoro-L-DOPA PET-TAC shows a great potential for the identification, location and guideline for surgery in CHI.
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Affiliation(s)
- J Arbizu Lostao
- Servicio de Medicina Nuclear, Clínica Universitaria de Navarra, Facultad de Medicina, Universidad de Navarra, Pamplona, España.
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Chamroonrat W, Houseni M, Li G, Alavi A, Zhuang H. PET and PET/CT in Pediatric Gastrointestinal Tract Oncology. PET Clin 2008; 3:227-38. [DOI: 10.1016/j.cpet.2008.10.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Barthlen W, Blankenstein O, Mau H, Koch M, Höhne C, Mohnike W, Eberhard T, Fuechtner F, Lorenz-Depiereux B, Mohnike K. Evaluation of [18F]fluoro-L-DOPA positron emission tomography-computed tomography for surgery in focal congenital hyperinsulinism. J Clin Endocrinol Metab 2008; 93:869-75. [PMID: 18073294 DOI: 10.1210/jc.2007-2036] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT In congenital hyperinsulinism (CHI), the identification and precise localization of a focal lesion is essential for successful surgery. OBJECTIVE Our objective was to evaluate the predictive value and accuracy of integrated [18F]fluoro-L-DOPA ([18F]FDOPA) positron emission tomography (PET)-computed tomography (CT) for the surgical therapy of CHI. DESIGN This was an observational study. SETTING The study was performed in the Department of Pediatric Surgery at a university hospital. PATIENTS From February 2005 to September 2007, 10 children with the clinical signs of CHI and an increased radiotracer uptake in a circumscribed area of the pancreas in the [18F]FDOPA PET-CT were evaluated. INTERVENTIONS Guided by the [18F]FDOPA PET-CT report, all children underwent partial pancreatic resection, in two cases twice. MAIN OUTCOME MEASURES Correlation of the anatomical findings at surgery with the report of the [18F]FDOPA PET-CT, and the results of surgery and clinical outcome were determined. RESULTS In nine children the intraoperative situation corresponded exactly to the description of the [18F]FDOPA PET-CT. A limited resection of the pancreas was curative in eight cases at the first surgery, in one case at the second intervention. We observed no diabetes mellitus or exocrine insufficiency in the follow up so far. In one child, hypoglycemia persisted even after two partial resections of the pancreatic head. Histological analysis finally revealed an atypical intermediate form of CHI. CONCLUSIONS The integrated [18F]FDOPA PET-CT is accurate to localize the lesion in focal CHI and is a valuable tool to guide the surgeon in limited pancreatic resection.
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Affiliation(s)
- Winfried Barthlen
- Clinic for Pediatric Surgery, Institute for Pathology, Charité University Medicine Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, Mittelallee 8, D-13353 Berlin, Germany.
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Palladino AA, Bennett MJ, Stanley CA. Hyperinsulinism in Infancy and Childhood: When an Insulin Level Is Not Always Enough. Clin Chem 2008; 54:256-63. [DOI: 10.1373/clinchem.2007.098988] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Abstract
Background: Hypoglycemia in infants and children can lead to seizures, developmental delay, and permanent brain damage. Hyperinsulinism (HI) is the most common cause of both transient and permanent disorders of hypoglycemia. HI is characterized by dysregulated insulin secretion, which results in persistent mild to severe hypoglycemia. The various forms of HI represent a group of clinically, genetically, and morphologically heterogeneous disorders.
Content: Congenital hyperinsulinism is associated with mutations of SUR-1 and Kir6.2, glucokinase, glutamate dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase, and ectopic expression on β-cell plasma membrane of SLC16A1. Hyperinsulinism can be associated with perinatal stress such as birth asphyxia, maternal toxemia, prematurity, or intrauterine growth retardation, resulting in prolonged neonatal hypoglycemia. Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann Syndrome, and congenital disorders of glycosylation. Laboratory testing for hyperinsulinism may include quantification of blood glucose, plasma insulin, plasma β-hydroxybutyrate, plasma fatty acids, plasma ammonia, plasma acylcarnitine profile, and urine organic acids. Genetic testing is available through commercial laboratories for genes known to be associated with hyperinsulinism. Acute insulin response (AIR) tests are useful in phenotypic characterization. Imaging and histologic tools are also available for diagnosing and classifying hyperinsulinism. The goal of treatment in infants with hyperinsulinism is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels above 700 mg/L (70 mg/dL) through pharmacologic or surgical therapy.
Summary: The management of hyperinsulinism requires a multidisciplinary approach that includes pediatric endocrinologists, radiologists, surgeons, and pathologists who are trained in diagnosing, identifying, and treating hyperinsulinism.
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Affiliation(s)
| | - Michael J Bennett
- The Children’s Hospital of Philadelphia, Division of Endocrinology, Philadelphia, PA
| | - Charles A Stanley
- The Children’s Hospital of Philadelphia, Division of Endocrinology, Philadelphia, PA
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Hardy OT, Hernandez-Pampaloni M, Saffer JR, Scheuermann JS, Ernst LM, Freifelder R, Zhuang H, MacMullen C, Becker S, Adzick NS, Divgi C, Alavi A, Stanley CA. Accuracy of [18F]fluorodopa positron emission tomography for diagnosing and localizing focal congenital hyperinsulinism. J Clin Endocrinol Metab 2007; 92:4706-11. [PMID: 17895314 DOI: 10.1210/jc.2007-1637] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Focal lesions in infants with congenital hyperinsulinism (HI) represent areas of adenomatosis that express a paternally derived ATP-sensitive potassium channel mutation due to embryonic loss of heterozygosity for the maternal 11p region. This study evaluated the accuracy of 18F-fluoro-l-dihydroxyphenylalanine ([18F]DOPA) positron emission tomography (PET) scans in diagnosing focal vs. diffuse disease and identifying the location of focal lesions. DESIGN A total of 50 infants with HI unresponsive to medical therapy were studied. Patients were injected iv with [18F]DOPA, and PET scans were obtained for 50-60 min. Images were coregistered with abdominal computed tomography scans. PET scan interpretations were compared with histological diagnoses. RESULTS The diagnosis of focal or diffuse HI was correct in 44 of the 50 cases (88%). [18F]DOPA PET identified focal areas of high uptake of radiopharmaceutical in 18 of 24 patients with focal disease. The locations of these lesions matched the areas of increased [18F]DOPA uptake on the PET scans in all of the cases. PET scan correctly located five lesions that could not be visualized at surgery. The positive predictive value of [18F]DOPA in diagnosing focal adenomatosis was 100%, and the negative predictive value was 81%. CONCLUSIONS [18F]DOPA PET scans correctly diagnosed 75% of focal cases and were 100% accurate in identifying the location of the lesion. These results suggest that [18F]DOPA PET imaging provides a useful guide to surgical resection of focal adenomatosis and should be considered as a guide to surgery in all infants with congenital HI who have medically uncontrollable disease.
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Affiliation(s)
- Olga T Hardy
- Division of Endocrinology, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA
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Shi Y, Wu Z, Cui N, Shi W, Yang Y, Zhang X, Rojas A, Ha BT, Jiang C. PKA phosphorylation of SUR2B subunit underscores vascular KATP channel activation by beta-adrenergic receptors. Am J Physiol Regul Integr Comp Physiol 2007; 293:R1205-14. [PMID: 17596331 PMCID: PMC2258221 DOI: 10.1152/ajpregu.00337.2007] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
ATP-sensitive K(+) (K(ATP)) channels are activated by several vasodilating hormones and neurotransmitters through the PKA pathway. Here, we show that phosphorylation at Ser1387 of the SUR2B subunit is critical for the channel activation. Experiments were performed in human embryonic kidney (HEK) 293 cells expressing the cloned Kir6.1/SUR2B channel. In whole cell patch, the Kir6.1/SUR2B channel activity was stimulated by isoproterenol via activation of beta(2) receptors. This effect was blocked in the presence of inhibitors for adenylyl cyclase or PKA. Similar channel activation was seen by exposing inside-out patches to the catalytic subunit of PKA. Because none of the previously suggested PKA phosphorylation sites accounted for the channel activation, we performed systematic mutational analysis on Kir6.1 and SUR2B. Two serine residues (Ser1351, Ser1387) located in the NBD2 of SUR2B were critical for the channel activation. In vitro phosphorylation experiments showed that Ser1387 but not Ser1351 was phosphorylated by PKA. The PKA-dependent activation of cell-endogenous K(ATP) channels was observed in acutely dissociated mesenteric smooth myocytes and isolated mesenteric artery rings, where activation of these channels contributed significantly to the isoproterenol-induced vasodilation. Taken together, these results indicate that the Kir6.1/SUR2B channel is a target of beta(2) receptors and that the channel activation relies on PKA phosphorylation of SUR2B at Ser1387.
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MESH Headings
- ATP-Binding Cassette Transporters/metabolism
- Adrenergic beta-Agonists/pharmacology
- Amino Acid Sequence
- Animals
- Blood Vessels/drug effects
- Blood Vessels/metabolism
- Cell Line
- Colforsin/pharmacology
- Cyclic AMP-Dependent Protein Kinases/metabolism
- Humans
- In Vitro Techniques
- Isoproterenol/pharmacology
- Molecular Sequence Data
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/physiology
- Patch-Clamp Techniques
- Phosphorylation
- Potassium Channels/metabolism
- Potassium Channels, Inwardly Rectifying/metabolism
- Rats
- Rats, Sprague-Dawley
- Receptors, Adrenergic, beta/drug effects
- Receptors, Adrenergic, beta/physiology
- Receptors, Drug/metabolism
- Sulfonylurea Receptors
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Affiliation(s)
- Yun Shi
- Department of Biology, Georgia State University, 24 Peachtree Center Ave., Atlanta, GA 30302, USA
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Biagiotti L, Proverbio MC, Bosio L, Gervasi F, Rovida E, Cerioni V, Bove M, Valin PS, Albarello L, Zamproni I, Grassi S, Doglioni C, Mora S, Chiumello G, Biunno I. Identification of two Novel Frameshift Mutations in the KCNJ11 gene in two Italian patients affected by Congenital Hyperinsulinism of Infancy. Exp Mol Pathol 2007; 83:59-64. [PMID: 17316607 DOI: 10.1016/j.yexmp.2006.11.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2006] [Revised: 11/02/2006] [Accepted: 11/02/2006] [Indexed: 11/21/2022]
Abstract
Congenital Hyperinsulinism of Infancy (CHI) is a genetically heterogeneous disorder characterized by profound hypoglycemia related to inappropriate insulin secretion. Two histopathologically and genetically distinct groups are recognized among patients with CHI due to ATP-sensitive potassium channel (KATP) defects: a diffuse type (Di-CHI), which involves the whole pancreas, and a focal form (Fo-CHI), which shows adenomatous islet-cell hyperplasia of a particular area within the normal pancreas. The beta-cell KATP channel consists of two essential subunits: Kir6.2 encoded by the KCNJ11 gene which is the pore-forming unit and belongs to the inwardly rectifying potassium channel family, and SUR1 (sulfonylurea receptor 1) encoded by the ABCC8 gene, which belongs to the ATP-binding cassette (ABC) transporter family. The KATP channel is an octameric complex of four Kir6.2 and four SUR1 subunits. More than one hundred mutations have been found in KATP channel genes ABCC8 and KCNJ11, but to date only twenty mutations have been identified in KCNJ11, most of them are missense mutations and only one is a single base deletion. The Fo-CHI has been demonstrated to arise in individuals who have a germline mutation in the paternal allele of ABCC8 or KCNJ11 in addition to a somatic loss of the maternally derived chromosome region 11p15 in adenomatous pancreatic beta-cells, while Di-CHI predominantly arises from the autosomal recessive inheritance of KATP channel gene mutations. Here we describe the molecular findings in nine children who presented, in the neonatal period, with signs and symptoms of hypoglycemia and diagnosed affected by CHI according to international diagnostic criteria. Direct sequencing of the complete coding exon and promoter region of KCNJ11 gene showed, in two Italian patients, two new heterozygous mutations which result in the appearance of premature translation termination codons resulting in the premature end of Kir6.2. Interestingly most of the CHI mutations detected in other population studies are situated in the ABCC8 gene.
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Affiliation(s)
- Laura Biagiotti
- Department of Sciences and Biomedical Technologies, University of Milan, Italy
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Ribeiro MJ, Boddaert N, Bellanné-Chantelot C, Bourgeois S, Valayannopoulos V, Delzescaux T, Jaubert F, Nihoul-Fékété C, Brunelle F, De Lonlay P. The added value of [18F]fluoro-L-DOPA PET in the diagnosis of hyperinsulinism of infancy: a retrospective study involving 49 children. Eur J Nucl Med Mol Imaging 2007; 34:2120-8. [PMID: 17661030 DOI: 10.1007/s00259-007-0498-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2007] [Accepted: 05/17/2007] [Indexed: 11/28/2022]
Abstract
PURPOSE Neuroendocrine diseases are a heterogeneous group of entities with the ability to take up amine precursors, such as L-DOPA, and convert them into biogenic amines, such as dopamine. Congenital hyperinsulinism of infancy (HI) is a neuroendocrine disease secondary to either focal adenomatous hyperplasia or a diffuse abnormal pancreatic insulin secretion. While focal hyperinsulinism may be reversed by selective surgical resection, diffuse forms require near-total pancreatectomy when resistant to medical treatment. Here, we report the diagnostic value of PET with [(18)F]fluoro-L-DOPA in distinguishing focal from diffuse HI. METHODS Forty-nine children were studied with [(18)F]fluoro-L-DOPA. A thoraco-abdominal scan was acquired 45-65 min after the injection of 4.2 +/- 1.0 MBq/kg of [(18)F]fluoro-L-DOPA. Additionally, 12 of the 49 children were submitted to pancreatic venous catheterisation for blood samples (PVS) and 31 were also investigated using MRI. RESULTS We identified abnormal focal pancreatic uptake of [(18)F]fluoro-L-DOPA in 15 children, whereas diffuse radiotracer uptake was observed in the pancreatic area in the other 34 patients. In children studied with both PET and PVS, the results were concordant in 11/12 cases. All patients with focal radiotracer uptake and nine of the patients with diffuse pancreatic radiotracer accumulation, unresponsive to medical treatment, were submitted to surgery. In 21 of these 24 patients, the histopathological results confirmed the PET findings. In focal forms, selective surgery was followed by clinical remission without carbohydrate intolerance. CONCLUSION These data demonstrate that PET with [(18)F]fluoro-L-DOPA is an accurate non-invasive technique allowing differential diagnosis between focal and diffuse forms of HI.
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Affiliation(s)
- Maria-João Ribeiro
- Biomedical Imaging Institute, Life Sciences Division, Commissariat à l'Energie Atomique, Frédéric Joliot Hospital, 4 place du Général Leclerc, Orsay, France.
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Hardy OT, Litman RS. Congenital hyperinsulinism - a review of the disorder and a discussion of the anesthesia management. Paediatr Anaesth 2007; 17:616-21. [PMID: 17564642 DOI: 10.1111/j.1460-9592.2007.02192.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children. In most affected infants, CHI is caused by a specific genetic defect that results in the altered expression of pancreatic beta cells causing unregulated oversecretion of insulin. Infants with CHI may have either focal or diffuse abnormalities of the pancreatic beta-cells. Both forms of CHI manifest as hypoglycemia, usually in the early newborn period. Focal disease can be treated effectively with surgical resection of the affected area, resulting in a total cure or rendering the patient amenable to medical management. Most children with diffuse disease are unresponsive to medical therapy, and require near-total pancreatectomy. At The Children's Hospital of Philadelphia, we have developed a multidisciplinary program for diagnosis and treatment of CHI. Anesthesiologists have played an integral role in the perioperative care of these infants, which includes diagnostic procedures, partial or near-total pancreatectomy, and postoperative pain management. In this review, we describe the clinical features, diagnostic methods and anesthetic concerns in children with CHI.
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Affiliation(s)
- Olga T Hardy
- Division of Endocrinology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Bremer AA, Nobuhara KK, Gitelman SE. Congenital hyperinsulinism in an infant caused by a macroscopic insulin-producing lesion. J Pediatr Endocrinol Metab 2007; 20:437-40. [PMID: 17451083 DOI: 10.1515/jpem.2007.20.3.437] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Congenital hyperinsulinism is the most common cause of persistent neonatal hypoglycemia. Severe congenital hyperinsulinism is most often due to inactivating mutations in either the ABCC8 or KCNJ11 genes, which encode the SUR1 and Kir6.2 proteins, respectively--the two components of the ATP-sensitive K+ (KATP) channel; neonatal hypoglycemia due to macroscopic insulin-producing pancreatic lesions or adenomas are extremely rare. KATP channel hyperinsulinism is classified as diffuse or focal, the latter being associated with paternally-derived mutations of ABCC8 or KCNJ11 and somatic loss of heterozygosity of the maternal alleles. KATP channelopathies usually produce microscopic intra-pancreatic lesions and are typically unresponsive to drug therapy, requiring > 95% pancreatectomy for diffuse disease and occasionally more limited pancreatic resection for focal disease; macroscopic pancreatic lesions and adenomas are focally excised. We describe a 1 month-old infant with severe congenital hyperinsulinism who had a macroscopic insulin-producing pancreatic lesion successfully treated with focal lesion enucleation.
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Affiliation(s)
- Andrew A Bremer
- Department of Pediatrics, Division of Endocrinology, University of California, San Francisco 94143-0434, USA.
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De León DD, Stanley CA. Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates. ACTA ACUST UNITED AC 2007; 3:57-68. [PMID: 17179930 DOI: 10.1038/ncpendmet0368] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2006] [Accepted: 08/25/2006] [Indexed: 11/09/2022]
Abstract
Hyperinsulinism is the single most common mechanism of hypoglycemia in neonates. Dysregulated insulin secretion is responsible for the transient and prolonged forms of neonatal hypoglycemia, and congenital genetic disorders of insulin regulation represent the most common of the permanent disorders of hypoglycemia. Mutations in at least five genes have been associated with congenital hyperinsulinism: they encode glucokinase, glutamate dehydrogenase, the mitochondrial enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase, and the two components (sulfonylurea receptor 1 and potassium inward rectifying channel, subfamily J, member 11) of the ATP-sensitive potassium channels (K(ATP) channels). K(ATP) hyperinsulinism is the most common and severe form of congenital hyperinsulinism. Infants suffering from K(ATP) hyperinsulinism present shortly after birth with severe and persistent hypoglycemia, and the majority are unresponsive to medical therapy, thus requiring pancreatectomy. In up to 40-60% of the children with K(ATP) hyperinsulinism, the defect is limited to a focal lesion in the pancreas. In these children, local resection results in cure with avoidance of the complications inherent to a near-total pancreatectomy. Hyperinsulinism can also be part of other disorders such as Beckwith-Wiedemann syndrome and congenital disorders of glycosylation. The diagnosis and management of children with congenital hyperinsulinism requires a multidisciplinary approach to achieve the goal of therapy: prevention of permanent brain damage due to recurrent hypoglycemia.
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Sperling MA. PET scanning for infants with HHI: a small step for affected infants, a giant leap for the field. J Pediatr 2007; 150:122-4. [PMID: 17236885 DOI: 10.1016/j.jpeds.2006.11.058] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2006] [Accepted: 11/21/2006] [Indexed: 10/23/2022]
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Hardy OT, Hernandez-Pampaloni M, Saffer JR, Suchi M, Ruchelli E, Zhuang H, Ganguly A, Freifelder R, Adzick NS, Alavi A, Stanley CA. Diagnosis and localization of focal congenital hyperinsulinism by 18F-fluorodopa PET scan. J Pediatr 2007; 150:140-5. [PMID: 17236890 DOI: 10.1016/j.jpeds.2006.08.028] [Citation(s) in RCA: 191] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2006] [Revised: 07/05/2006] [Accepted: 08/12/2006] [Indexed: 11/24/2022]
Abstract
OBJECTIVES To assess the accuracy of 18F-fluoro-L-dihydroxyphenylalanine ([18F]-DOPA) PET scans to diagnose focal versus diffuse disease and to localize focal lesions in infants with congenital hyperinsulinism. STUDY DESIGN Twenty-four infants with hyperinsulinism unresponsive to medical therapy were studied. Patients were injected intravenously with [18F]-DOPA, and PET scans were obtained for 1 hour. Images were coregistered with abdominal CT scans. RESULTS The diagnosis of focal or diffuse hyperinsulinism was correct in 23 of the 24 cases (96%) and equivocal in 1 case. [18F]-DOPA PET identified focal areas of high uptake of radiopharmaceutical in 11 patients. Pathology results confirmed that all 11 had focal adenomatosis, and the locations of these lesions matched the areas of increased [18F]-DOPA uptake on the PET scans in all of the cases. CONCLUSIONS [18F]-DOPA PET scans were 96% accurate in diagnosing focal or diffuse disease and 100% accurate in localizing the focal lesion. These results suggest that [18F]-DOPA PET imaging should be considered in all infants with congenital hyperinsulinism who need to have pancreatectomy.
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Affiliation(s)
- Olga T Hardy
- Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
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Greer RM, Shah J, Jeske YW, Brown D, Walker RM, Cowley D, Bowling FG, Liaskou D, Harris M, Thomsett MJ, Choong C, Bell JR, Jack MM, Cotterill AM. Genotype-phenotype associations in patients with severe hyperinsulinism of infancy. Pediatr Dev Pathol 2007; 10:25-34. [PMID: 17378627 DOI: 10.2350/06-04-0083.1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2006] [Accepted: 07/01/2006] [Indexed: 11/20/2022]
Abstract
In hyperinsulinism of infancy (HI), unregulated insulin secretion causes hypoglycemia. Pancreatectomy may be required in severe cases, most of which result from a defect in the beta-cell KATP channel, encoded by ABCC8 and KCNJ11. Pancreatic histology may be classified as diffuse or focal disease (the latter associated with single paternal ABCC8 mutations), indicated by the presence of islet cell nuclear enlargement in areas of diffuse abnormality. We investigated genotype-phenotype associations in a heterogeneous Australian cohort. ABCC8 and KCNJ11 genes were sequenced and case histology was reviewed in 21 infants who had pancreatectomy. Ninety-eight control DNA samples were tested by single nucleotide polymorphism analysis. Eighteen ABCC8 mutations were identified, 10 novel. Eleven patients (4 compound heterozygote, 4 single mutation, 3 no mutation detected) had diffuse hyperinsulinism. Nine patients had focal hyperinsulinism (6 single paternal mutation, 2 single mutation of undetermined parental origin, 1 none found) with absence of islet cell nuclear enlargement outside the focal area, although centroacinar cell proliferation and/or nesidiodysplasia was present in 7 cases. Regeneration after near-total pancreatectomy was documented in 4 patients, with aggregates of endocrine tissue observed at subsequent operations in 3. Although the absence of enlarged islet cell nuclei is a useful discriminant of focal hyperinsulinism associated with a paternal ABCC8 mutation, further research is needed to understand the pathophysiology of other histological abnormalities in patients with HI, which may have implications for mechanisms of ductal and islet cell proliferation. Previous surgery should be taken into account when interpreting pancreatic histology.
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Affiliation(s)
- Ristan M Greer
- Department of Paediatrics and Child Health, University of Queensland, Brisbane, and Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Western Australia, Australia.
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