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Pajno R, Visconti C, Bucolo C, Guarneri MP, Del Barba P, Silvani P, Gregnanin M, Barera G. Diazoxide toxicity in congenital hyperinsulinism: A case report. World J Clin Pediatr 2024; 13:94156. [PMID: 39654669 PMCID: PMC11572624 DOI: 10.5409/wjcp.v13.i4.94156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/06/2024] [Accepted: 07/02/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Diazoxide is the sole approved drug for congenital hyperinsulinism; however, diuretic administration and vigilant monitoring are crucial to prevent and promptly identify potentially life-threatening adverse effects. This report aims to highlight a seldom-considered rare side effect of diazoxide. We believe that this brief report is of general interest to World Journal of Clinical Pediatric readership and increase the physicians' awareness of the guideline importance. Moreover, it underlines the importance of stopping immediately the drug if suspected side effects. CASE SUMMARY The manuscript describes a patient diagnosed with congenital hyperinsulinism (CHI) treated with diazoxide not overlapping with diuretic. He resulted in sudden respiratory distress and therefore was transferred to the Neonatal Intensive Care Unit. The cardiological evaluation showed pericardial effusion and left ventricular myocardial hypertrophy, absent before. In suspicion of an iatrogenic effect of diazoxide it was progressively reduced until stop while introducing diuretic treatment, with resolution of symptoms. Once clinically stabilized, an 18 fluoro-diydroxy-phenylalanine positron emission tomography/computed tomography (PET/CT) was performed to differentiate between a focal or diffuse form of CHI. The PET/CT highlighted the presence of a single focal accumulation of the tracer located in the pancreatic tail, consistent with a focal form of hyperinsulinism. At the age of four months, the patient underwent a distal pancreatectomy with histological confirmation of a focal form of nesidioblastosis, resulting in a curative operation. CONCLUSION Diuretic administration and vigilant monitoring of diazoxide therapy are crucial to prevent and promptly identify potentially life-threatening adverse effects.
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Affiliation(s)
- Roberta Pajno
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
| | - Camilla Visconti
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
- Università Vita-Salute San Raffaele, Facoltà di Medicina e Chirurgia, Milan 20132, Lombardy, Italy
| | - Carmen Bucolo
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
| | - Maria Pia Guarneri
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
| | - Paolo Del Barba
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
| | - Paolo Silvani
- Department of Anesthesia and Intensive Care, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan 20132, Lombardy, Italy
| | - Marco Gregnanin
- Department of Neonatology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
| | - Graziano Barera
- Department of Pediatrics, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
- Department of Neonatology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Institute, Milan 20132, Lombardy, Italy
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Lord K, De León DD. Approach to the Neonate With Hypoglycemia. J Clin Endocrinol Metab 2024; 109:e1787-e1795. [PMID: 38629854 PMCID: PMC11319000 DOI: 10.1210/clinem/dgae267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Indexed: 08/15/2024]
Abstract
After birth, healthy neonates undergo a period of altered glucose metabolism, known as "transitional hypoglycemia." During the first 0 to 4 hours of life, the mean plasma glucose concentration decreases to 57 mg/dL, then by 72 to 96 hours of life increases to 82 mg/dL, well within the normal adult range. Recent data suggest that transitional hypoglycemia is due to persistence of the fetal beta cell's lower threshold for insulin release, resulting in a transient hyperinsulinemic state. While hypoglycemia is an expected part of the transition to postnatal life, it makes the identification of infants with persistent hypoglycemia disorders challenging. Given the risk of neurologic injury from hypoglycemia, identifying these infants is critical. Hyperinsulinism is the most common cause of persistent hypoglycemia in neonates and infants and carries a high risk of neurocognitive dysfunction given the severity of the hypoglycemia and the inability to generate ketones, a critical alternative cerebral fuel. Screening neonates at risk for persistent hypoglycemia disorders and completing evaluations prior to hospital discharge is essential to prevent delayed diagnoses and neurologic damage.
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Affiliation(s)
- Katherine Lord
- The Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Diva D De León
- The Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
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Stanley CA, De Leon DD. Etiology of the Neonatal Hypoglycemias. Adv Pediatr 2024; 71:119-134. [PMID: 38944478 DOI: 10.1016/j.yapd.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/01/2024]
Abstract
To provide a more appropriate foundation for dealing with the problem of hypoglycemia in newborn infants, this article focuses on the mechanisms which underlie the various forms of neonatal hypoglycemia and discusses their implications for newborn care. Evidence indicates that all of the major forms of neonatal hypoglycemia are the result of hyperinsulinism due to dysregulation of pancreatic islet insulin secretion. Based on these observations, the authors propose that routine measurement of B-hydroxybutyrate should be considered an essential part of glucose monitoring in newborn infants.
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Affiliation(s)
- Charles A Stanley
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Diva D De Leon
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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Laing D, Walsh EPG, Alsweiler JM, Hanning SM, Meyer MP, Ardern J, Cutfield WS, Rogers J, Gamble GD, Chase JG, Harding JE, McKinlay CJD. Diazoxide for Severe or Recurrent Neonatal Hypoglycemia: A Randomized Clinical Trial. JAMA Netw Open 2024; 7:e2415764. [PMID: 38869900 PMCID: PMC11177163 DOI: 10.1001/jamanetworkopen.2024.15764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/09/2024] [Indexed: 06/14/2024] Open
Abstract
Importance Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment. Objective To evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia. Design, Setting, and Participants This 2-arm, placebo-controlled randomized clinical trial was conducted from May 2020 to February 2023 in tertiary neonatal units at 2 New Zealand hospitals. Participants were neonates born at 35 or more weeks' gestation and less than 1 week of age with severe hypoglycemia (blood glucose concentration <22 mg/dL or <36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration <47 mg/dL within 48 hours). Interventions Newborns were randomized 1:1 to receive diazoxide suspension (loading dose, 5 mg/kg; maintenance, 1.5 mg/kg every 12 hours) or placebo, titrated per protocol. Main Outcome and Measures The primary outcome was time to resolution of hypoglycemia, defined as enteral bolus feeding without intravenous fluids and normoglycemia (blood glucose concentration of 47-98 mg/dL) for at least 24 hours, compared between groups using adjusted Cox proportional hazards regression. Hazard ratios adjusted for stratification variables and gestation length are reported. Prespecified secondary outcomes, including number of blood glucose tests and episodes of hypoglycemia, duration of hypoglycemia, and time to enteral bolus feeding and weaning from intravenous fluids, were compared by generalized linear models. Newborns were followed up for at least 2 weeks. Results Of 154 newborns screened, 75 were randomized and 74 with evaluable data were included in the analysis (mean [SD] gestational age for the full cohort, 37.6 [1.6] weeks), 36 in the diazoxide group and 38 in the placebo group. Baseline characteristics were similar: in the diazoxide group, mean (SD) gestational age was 37.9 (1.6) weeks and 26 (72%) were male; in the placebo group, mean (SD) gestational age was 37.4 (1.5) weeks and 27 (71%) were male. There was no significant difference in time to resolution of hypoglycemia (adjusted hazard ratio [AHR], 1.39; 95% CI, 0.84-2.23), possibly due to increased episodes of elevated blood glucose concentration and longer time to normoglycemia in the diazoxide group. Resolution of hypoglycemia, when redefined post hoc as enteral bolus feeding without intravenous fluids for at least 24 hours with no further hypoglycemia, was reached by more newborns in the diazoxide group (AHR, 2.60; 95% CI, 1.53-4.46). Newborns in the diazoxide group had fewer blood glucose tests (adjusted count ratio [ACR], 0.63; 95% CI, 0.56-0.71) and episodes of hypoglycemia (ACR, 0.32; 95% CI, 0.17-0.63), reduced duration of hypoglycemia (adjusted ratio of geometric means [ARGM], 0.18; 95% CI, 0.06-0.53), and reduced time to enteral bolus feeding (ARGM, 0.74; 95% CI, 0.58-0.95) and weaning from intravenous fluids (ARGM, 0.72; 95% CI, 0.60-0.87). Only 2 newborns (6%) treated with diazoxide had hypoglycemia after the loading dose compared with 20 (53%) with placebo. Conclusions and Relevance In this randomized clinical trial, early treatment of severe or recurrent neonatal hypoglycemia with low-dose oral diazoxide did not reduce time to resolution of hypoglycemia but reduced time to enteral bolus feeding and weaning from intravenous fluids, duration of hypoglycemia, and frequency of blood glucose testing compared with placebo. Trial Registration ANZCTR.org.au Identifier: ACTRN12620000129987.
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Affiliation(s)
- Don Laing
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | | | - Jane M. Alsweiler
- Department of Paediatrics: Child and Youth Health, University of Auckland, Auckland, New Zealand
- Te Whatu Ora Te Toka Tumai Auckland, Auckland, New Zealand
| | - Sara M. Hanning
- School of Pharmacy, University of Auckland, Auckland, New Zealand
| | - Michael P. Meyer
- Kidz First Neonatal Care, Te Whatu Ora Counties Manukau, Auckland, New Zealand
| | - Julena Ardern
- Kidz First Neonatal Care, Te Whatu Ora Counties Manukau, Auckland, New Zealand
| | | | - Jenny Rogers
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | | | - J. Geoffrey Chase
- Department of Mechanical Engineering, University of Canterbury, Christchurch, New Zealand
| | - Jane E. Harding
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Christopher J. D. McKinlay
- Department of Paediatrics: Child and Youth Health, University of Auckland, Auckland, New Zealand
- Kidz First Neonatal Care, Te Whatu Ora Counties Manukau, Auckland, New Zealand
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Meleis MM, Vithayaveroj PP, Ebeling-Koning NE, DelBianco JD, Surmaitis RM. Mind the Decimal Point: A Case of Diazoxide Overdose-Induced Ileus. Cureus 2024; 16:e62088. [PMID: 38989349 PMCID: PMC11235150 DOI: 10.7759/cureus.62088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 06/08/2024] [Indexed: 07/12/2024] Open
Abstract
Diazoxide is the only medication approved by the United States Food and Drug Administration for the treatment of hyperinsulinism-induced hypoglycemia. Overdose is infrequently reported. This case describes a preterm four-week-old male who was prescribed diazoxide and chlorothiazide for perinatal stress-induced hyperinsulinism. The patient presented to the emergency department with feeding intolerance and abdominal distension following an accidental 10-fold diazoxide overdose. On presentation, vital signs were remarkable for tachycardia and intermittent tachypnea. Physical exam revealed a grossly distended abdomen. Laboratory abnormalities included a glucose of 216 mg/dL, sodium of 132 mmol/L, and chloride of 98 mmol/L. Abdominal X-ray interpretation found moderate gaseous distension suggestive of generalized ileus. The patient was admitted to the neonatal intensive care unit (NICU), and a nasogastric tube was placed. He received intravenous dextrose fluids, and enteral feeds were resumed as serial X-rays showed interval improvement. The patient remained in the NICU for several days to monitor bowel movements and resolution of ileus and he was discharged after improvement. While diazoxide overdose is rarely reported, and ileus due to such is documented even less frequently, 10-fold medication dose errors are common among infants. The source of the 10-fold mistake is often decimal points, leading zeros, or trailing zeros. Utilizing the smallest possible syringe for the prescribed dose may reduce the incidence of medication errors.
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Affiliation(s)
- Mostafa M Meleis
- Department of Emergency and Hospital Medicine, Lehigh Valley Health Network/University of South Florida (USF) Morsani College of Medicine, Allentown, USA
| | - Putt P Vithayaveroj
- Department of Emergency and Hospital Medicine, Lehigh Valley Health Network/University of South Florida (USF) Morsani College of Medicine, Allentown, USA
| | - Natalie E Ebeling-Koning
- Department of Emergency and Hospital Medicine, Lehigh Valley Health Network/University of South Florida (USF) Morsani College of Medicine, Allentown, USA
| | - John D DelBianco
- Department of Emergency and Hospital Medicine, Lehigh Valley Health Network/University of South Florida (USF) Morsani College of Medicine, Allentown, USA
| | - Ryan M Surmaitis
- Department of Emergency and Hospital Medicine, Lehigh Valley Health Network/University of South Florida (USF) Morsani College of Medicine, Allentown, USA
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Rattanasakol T, Kitsommart R. Factors associated with neonatal hyperinsulinemic hypoglycemia, a case-control study. J Pediatr Endocrinol Metab 2024; 37:243-249. [PMID: 38235510 DOI: 10.1515/jpem-2023-0526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 01/04/2024] [Indexed: 01/19/2024]
Abstract
OBJECTIVES We aimed to identify perinatal risk factors associated with hyperinsulinemic hypoglycemia in neonates. Secondary objectives included an examination of clinical and biochemical characteristics at the time of diagnosis and an exploration of the duration of diazoxide therapy. METHODS A case-control study was conducted, involving individual chart reviews of inborn infants diagnosed with hyperinsulinemic hypoglycemia (the HH group) between 2014 and 2021. These cases were paired with controls (the non-HH group) belonging to the same gestational age (GA) strata who did not exhibit HH or only had transient postnatal hypoglycemia. RESULTS A total of 52 infants with HH were matched with corresponding controls. The mean GA in the HH group was 34.4 ± 3.1 weeks. Notably, the HH group exhibited lower mean minimum plasma glucose (PG) levels and required higher glucose infusion rates in comparison to the non-HH group (26.5 ± 15.6 vs. 49.1 ± 37.7 mg/dL and 12.9 ± 3.8 vs. 5.7 ± 2.1 mg/kg/min, respectively; p<0.001 for both). After adjusting for potential confounding factors, only two variables, fetal growth restriction (FGR) and neonatal sepsis, demonstrated significant associations with HH (adjusted odds ratio [95 % confidence interval]: 8.1 [2.1-31.0], p=0.002 and 6.3 [1.9-21.4], p=0.003, respectively). The median duration of diazoxide therapy for the HH group was 4 months. CONCLUSIONS FGR and neonatal sepsis emerged as notable risk factors for HH. These infants exhibited lower PG levels and necessitated higher glucose infusion rates compared to their non-HH counterparts. Importantly, a substantial proportion of the HH group received diazoxide therapy, with a median treatment duration of 4 months.
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Affiliation(s)
- Thanaporn Rattanasakol
- Division of Neonatology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ratchada Kitsommart
- Division of Neonatology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Malhotra N, Yau D, Cunjamalay A, Gunasekara B, S A, Gilbert C, Morgan K, Dattani M, Dastamani A. Low-dose diazoxide is safe and effective in infants with transient hyperinsulinism. Clin Endocrinol (Oxf) 2024; 100:132-137. [PMID: 38059644 DOI: 10.1111/cen.14987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/19/2023] [Accepted: 10/25/2023] [Indexed: 12/08/2023]
Abstract
OBJECTIVE Transient hyperinsulinism (THI) is the most common form of recurrent hypoglycaemia in neonates beyond the first week of life. Although self-resolving, treatment can be required. Consensus guidelines recommend the lower end of the diazoxide 5-15 mg/kg/day range in THI to reduce the risk of adverse events. We sought to determine if doses <5 mg/kg/day of diazoxide can be effective in THI. DESIGN, PATIENTS, MEASURMENTS Infants with THI (duration <6 months) were treated with low-dose diazoxide from October 2015 to February 2021. Dosing was based on weight at diazoxide start: 2 mg/kg/day in infants 1000-2000 g (cohort 1), 3 mg/kg/day in those 2000-3500 g (cohort 2) and 5 mg/kg/day in those >3500 g. RESULTS A total of 73 infants with THI (77% male, 33% preterm, 52% small-for-gestational age) were commenced on diazoxide at a median age of 11 days (range 3-43) for a median duration of 4 months (0.3-6.8), with no difference between cohorts. The mean effective diazoxide dose was 3 mg/kg/day (range 1.5-10); 35% (26/73) required an increase from their starting dose, including 60% (9/15) of cohort 1. There was no association between perinatal stress risk factors or treatment-related characteristics and dose increase. Adverse events occurred in 13 patients (18%); oedema (12%) and hyponatraemia (5%) were the most common. Two infants developed suspected necrotising enterocolitis (NEC); none had pulmonary hypertension. CONCLUSION Diazoxide doses <5 mg/kg/day are effective in THI. While the nature of the association between diazoxide and NEC was unclear, other adverse events were mild. We suggest considering starting doses as low as 2-3 mg/kg/day in THI to balance the side effect risk while maintaining euglycaemia.
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Affiliation(s)
- Neha Malhotra
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Daphne Yau
- Department of Pediatrics, Division of Endocrinology, University of Saskatchewan, Saskatoon, Canada
| | - Annaruby Cunjamalay
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Buddhi Gunasekara
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Athanasakopoulou S
- Faculty of Medicine and Dentistry, Medical School of Queen Mary University, London, UK
| | - Clare Gilbert
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Kate Morgan
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Mehul Dattani
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
| | - Antonia Dastamani
- Endocrinology Department, Great Ormond Street Hospital for Children, London, UK
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Sasidharan Pillai S, Fredette ME, Tanzer JR, Hoffman L, Topor LS. The Rising Incidence of Hyperinsulinemic Hypoglycemia: Connection With Maternal Health. Endocr Pract 2023; 29:980-985. [PMID: 37683825 DOI: 10.1016/j.eprac.2023.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/24/2023] [Accepted: 09/01/2023] [Indexed: 09/10/2023]
Abstract
OBJECTIVE Due to a perceived rise in hyperinsulinemic hypoglycemia (HH) cases over time, notably during the COVID-19 pandemic, institutional experiences between 2013 and 2021 were reviewed to evaluate trends, characteristics, and outcomes in children with HH. METHODS Charts of all children diagnosed with HH during the study period and evaluated by Pediatric Endocrinology were reviewed. HH was defined per Pediatric Endocrine Society guidelines. Regression analysis compared rates of change in HH cases and maternal risk factors over time. RESULTS The incidence of HH began to rise in April 2016 and became significant in March 2017 (P < .001), with a more rapid rate of rise during the first year of the COVID-19 pandemic (P < .001). Seventy-four children with HH were identified over 9 years; 43% (n = 32) were diagnosed in 2020-2021. Maternal hypertensive disorders demonstrated longitudinal association with hyperinsulinism cases (P < .001). CONCLUSION While HH diagnoses were on the rise for much of the 9-year study period, nearly half of all infants were diagnosed during the COVID-19 pandemic in 2020 to 21. The trends in HH diagnoses correlated with maternal hypertensive disorders. More studies exploring the roles of maternal health, hypertension, and stress and development of HH in offspring are needed.
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Affiliation(s)
- Sabitha Sasidharan Pillai
- Division of Pediatric Endocrinology, Hasbro Children's Hospital, Providence, Rhode Island, USA; The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Meghan E Fredette
- Division of Pediatric Endocrinology, Hasbro Children's Hospital, Providence, Rhode Island, USA; The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Joshua Ray Tanzer
- Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA
| | - Laurie Hoffman
- Women and Infants Hospital, Providence, Rhode Island, USA
| | - Lisa Swartz Topor
- Division of Pediatric Endocrinology, Hasbro Children's Hospital, Providence, Rhode Island, USA; The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
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Solís-García G, Yeung T, Jasani B. Does the use of diazoxide for hyperinsulinaemic hypoglycaemia increase the risk of necrotising enterocolitis in neonates? Arch Dis Child 2023; 108:775-778. [PMID: 37369382 DOI: 10.1136/archdischild-2023-325726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023]
Affiliation(s)
- Gonzalo Solís-García
- Neonatology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Telford Yeung
- Neonatology, Windsor Regional Hospital, Windsor, Ontario, Canada
| | - Bonny Jasani
- Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
- The Hospital for Sick Children, Toronto, Ontario, Canada
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Quarta A, Iannucci D, Guarino M, Blasetti A, Chiarelli F. Hypoglycemia in Children: Major Endocrine-Metabolic Causes and Novel Therapeutic Perspectives. Nutrients 2023; 15:3544. [PMID: 37630734 PMCID: PMC10459037 DOI: 10.3390/nu15163544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Hypoglycemia is due to defects in the metabolic systems involved in the transition from the fed to the fasting state or in the hormone control of these systems. In children, hypoglycemia is considered a metabolic-endocrine emergency, because it may lead to brain injury, permanent neurological sequelae and, in rare cases, death. Symptoms are nonspecific, particularly in infants and young children. Diagnosis is based on laboratory investigations during a hypoglycemic event, but it may also require biochemical tests between episodes, dynamic endocrine tests and molecular genetics. This narrative review presents the age-related definitions of hypoglycemia, its pathophysiology and main causes, and discusses the current diagnostic and modern therapeutic approaches.
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Affiliation(s)
| | | | | | | | - Francesco Chiarelli
- Department of Pediatrics, University of Chieti—Pescara, Gabriele D’Annunzio, 66100 Chieti, Italy; (A.Q.); (D.I.); (M.G.); (A.B.)
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11
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Reynolds D, Mitteer LM, Sigal W, Boyajian L, McKnight H, Bhatti T, States L, Becker S, Adzick NS, Lord K, De Leon DD. Novel Use of Dasiglucagon, a Soluble Glucagon Analog, for the Treatment of Hyperinsulinemic Hypoglycemia Secondary to Suspected Insulinoma: A Case Report. Horm Res Paediatr 2023; 97:187-194. [PMID: 37454652 DOI: 10.1159/000531251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 05/15/2023] [Indexed: 07/18/2023] Open
Abstract
INTRODUCTION Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. In adolescents and adults, hyperinsulinemic hypoglycemia is most frequently caused by an insulin-producing tumor. CASE PRESENTATION A 17-year-old, previously healthy male presented with recurrent and severe episodes of hypoglycemia. Diagnostic evaluation was consistent with hyperinsulinemic hypoglycemia, and an insulinoma was suspected. Multiple imaging studies and surgical exploration failed to identify a lesion. Over the course of months, the patient was found to be refractory to conventional medical interventions. CONCLUSION Upon approval from the US Food and Drug Administration and the Institutional Review Board, the patient was treated with dasiglucagon, a novel soluble glucagon analog, under a single-patient Investigational New Drug. The patient has tolerated the medication and has been able to achieve appropriate glycemic control.
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Affiliation(s)
- Dana Reynolds
- Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Lauren M Mitteer
- Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA,
- Congenital Hyperinsulinism Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA,
| | - Winifred Sigal
- Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Congenital Hyperinsulinism Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Linda Boyajian
- Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Congenital Hyperinsulinism Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Heather McKnight
- Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Congenital Hyperinsulinism Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Tricia Bhatti
- Congenital Hyperinsulinism Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Lisa States
- Congenital Hyperinsulinism Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Radiology, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Susan Becker
- Congenital Hyperinsulinism Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - N Scott Adzick
- Congenital Hyperinsulinism Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Surgery, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Katherine Lord
- Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Congenital Hyperinsulinism Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Diva D De Leon
- Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Congenital Hyperinsulinism Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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12
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De Leon DD, Arnoux JB, Banerjee I, Bergada I, Bhatti T, Conwell LS, Fu J, Flanagan SE, Gillis D, Meissner T, Mohnike K, Pasquini TL, Shah P, Stanley CA, Vella A, Yorifuji T, Thornton PS. International Guidelines for the Diagnosis and Management of Hyperinsulinism. Horm Res Paediatr 2023; 97:279-298. [PMID: 37454648 PMCID: PMC11124746 DOI: 10.1159/000531766] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 05/16/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI; however, there have been almost no new therapeutic modalities since the development of diazoxide. SUMMARY Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in "developed" countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. KEY MESSAGES This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.
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Affiliation(s)
- Diva D. De Leon
- Congenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Jean Baptiste Arnoux
- Reference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital, AP-HP, University of Paris-Cité, Paris, France
| | - Indraneel Banerjee
- Paediatric Endocrinology, Royal Manchester Children’s Hospital, University of Manchester, Manchester, UK
| | - Ignacio Bergada
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CONICET – FEI), Division de Endrocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Tricia Bhatti
- Department of Clinical Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Louise S. Conwell
- Australia and Children’s Health Queensland Clinical Unit, Department of Endocrinology and Diabetes, Queensland Children’s Hospital, Children’s Health Queensland, Greater Brisbane Clinical School, Medical School, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Junfen Fu
- National Clinical Research Center for Child Health, Department of Endocrinology, The Children’s Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Sarah E. Flanagan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - David Gillis
- Hadassah Medical Center, Department of Pediatrics, Ein-Kerem, Jerusalem and Faculty of Medicine, Hebrew-University, Jerusalem, Israel
| | - Thomas Meissner
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany
| | - Klaus Mohnike
- Department of General Pediatrics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Tai L.S. Pasquini
- Research and Policy Director, Congenital Hyperinsulinism International, Glen Ridge, NJ, USA
| | - Pratik Shah
- Pediatric Endocrinology, The Royal London Children’s Hospital, Queen Mary University of London, London, UK
| | - Charles A. Stanley
- Congenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Adrian Vella
- Division of Diabetes, Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA
| | - Tohru Yorifuji
- Pediatric Endocrinology and Metabolism, Children’s Medical Center, Osaka City General Hospital, Osaka, Japan
| | - Paul S. Thornton
- Congenital Hyperinsulinism Center, Cook Children’s Medical Center and Texas Christian University Burnett School of Medicine, Fort Worth, TX, USA
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13
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Komal FNU, Olajide O. A Very Rare Case of Diabetes Mellitus Occurring in a Patient With Hyperinsulinism Hyperammonemia Syndrome. AACE Clin Case Rep 2023; 9:122-124. [PMID: 37520762 PMCID: PMC10382607 DOI: 10.1016/j.aace.2023.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 08/01/2023] Open
Abstract
Background/Objective To illustrate an unusual case of type 2 diabetes mellitus (T2DM) developing many years after the diagnosis of hyperinsulinism hyperammonemia (HI/HA) syndrome. Case Report This article reports about a 36-year-old female with a history of congenital hyperinsulinism due to HI/HA syndrome, which was diagnosed in infancy. The patient presented with hypoglycemia and seizures as an infant and was treated with diazoxide and a low-protein diet for many years with reduction in her hypoglycemic events. She subsequently developed T2DM >30 years later. Genetic analysis was positive for a glutamate dehydrogenase 1 gene (GLUD1) alteration. She was treated with metformin and a glucagon-like peptide 1 agonist, with significant improvement in her blood glucose control and weight loss. Discussion HI/HA syndrome is a rare genetic syndrome that manifests in childhood with signs and symptoms of hypoglycemia and neurologic symptoms. This is the first case reported in the literature of a patient with HI/HA syndrome due to a GLUD1 alteration who developed T2DM much later in life. Patients with this disorder usually have recurrent hypoglycemia and require long-term medical therapy or very occasionally may have a resolution. She had class 3 obesity and evidence of insulin resistance, which likely contributed to her risk of diabetes. Conclusion This is a rare case of T2DM presenting in a patient with HI/HA syndrome. This should be considered a possible outcome in patients with this disorder, especially in the presence of obesity.
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Affiliation(s)
| | - Omolola Olajide
- Address correspondence to Dr Omolola Olajide, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232.
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14
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Wee E, Herriges J, Dileepan K, Tsai SL, Alaimo JT, Paprocki E. Hyperinsulinemic Hypoglycemia and Growth Hormone Deficiency Secondary to 20p11 Deletion. Case Rep Endocrinol 2023; 2023:8658540. [PMID: 37404330 PMCID: PMC10317580 DOI: 10.1155/2023/8658540] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 03/30/2023] [Accepted: 06/14/2023] [Indexed: 07/06/2023] Open
Abstract
Hypoglycemia is concerning for neurological complications in infants and children. Determining the cause of hypoglycemia is essential in providing appropriate treatment. Hyperinsulinism and growth hormone deficiency are known causes of hypoglycemia but are not commonly found together. We report a 4-month-old boy who presented with severe hypoglycemia and was found to have both hyperinsulinism and growth hormone deficiency. Treatment with both recombinant human growth hormone and diazoxide led to blood glucose normalization. Subsequently, he was found to have a genetic diagnosis of 20p11.22p11.21 deletion. 20p11 deletions have been associated with hypopituitarism, most commonly seen in growth hormone deficiency causing hypoglycemia. This case is one of a few to report hyperinsulinism as a manifestation of this deletion.
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Affiliation(s)
- Erica Wee
- Division of Pediatric Endocrinology and Diabetes, Children's Mercy Kansas City, Kansas City, MO, USA
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - John Herriges
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
- Department of Pathology and Laboratory Medicine, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Kavitha Dileepan
- Division of Pediatric Endocrinology and Diabetes, Children's Mercy Kansas City, Kansas City, MO, USA
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Sarah L. Tsai
- Division of Pediatric Endocrinology and Diabetes, Children's Mercy Kansas City, Kansas City, MO, USA
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Joseph T. Alaimo
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
- Department of Pathology and Laboratory Medicine, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Emily Paprocki
- Division of Pediatric Endocrinology and Diabetes, Children's Mercy Kansas City, Kansas City, MO, USA
- University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
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15
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Chandran S, Jaya-Bodestyne SL, Rajadurai VS, Saffari SE, Chua MC, Yap F. Watchful waiting versus pharmacological management of small-for-gestational-age infants with hyperinsulinemic hypoglycemia. Front Endocrinol (Lausanne) 2023; 14:1163591. [PMID: 37435482 PMCID: PMC10332304 DOI: 10.3389/fendo.2023.1163591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 05/23/2023] [Indexed: 07/13/2023] Open
Abstract
Introduction Given that reports on severe diazoxide (DZX) toxicity are increasing, we aimed to understand if the short-term clinical outcomes of small-for-gestational-age (SGA) infants with hyperinsulinemic hypoglycemia (HH) managed primarily by supportive care, termed watchful waiting (WW), are different from those treated with DZX. Method A real-life observational cohort study was conducted from 1 September 2014 to 30 September 2020. The WW or DZX management decision was based on clinical and biochemical criteria. We compared central line duration (CLD), postnatal length of stay (LOS), and total intervention days (TIDs) among SGA-HH infants treated with DZX versus those on a WW approach. Fasting studies determined the resolution of HH. Result Among 71,836 live births, 11,493 were SGA, and 51 SGA infants had HH. There were 26 and 25 SGA-HH infants in the DZX and WW groups, respectively. Clinical and biochemical parameters were similar between groups. The median day of DZX initiation was day 10 of life (range 4-32), at a median dose of 4 mg/kg/day (range 3-10). All infants underwent fasting studies. Median CLD [DZX, 15 days (6-27) vs. WW, 14 days (5-31), P = 0.582] and postnatal LOS [DZX, 23 days (11-49) vs. WW, 22 days (8-61), P = 0.915] were comparable. Median TID was >3-fold longer in the DZX than the WW group [62.5 days (9-198) vs. 16 days (6-27), P < 0.001]. Conclusion CLD and LOS are comparable between WW and DZX groups. Since fasting studies determine the resolution of HH, physicians should be aware that clinical intervention of DZX-treated SGA-HH patients extends beyond the initial LOS.
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Affiliation(s)
- Suresh Chandran
- Department of Neonatology, Kandang Kerbau (KK) Women’s and Children’s Hospital, Singapore, Singapore
- Pediatric Academic Clinical Programme, Lee Kong Chian School of Medicine, Singapore, Singapore
- Pediatric Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore
- Pediatric Academic Clinical Programme, Yong Loo Lin School of Medicine, Singapore, Singapore
| | | | - Victor Samuel Rajadurai
- Department of Neonatology, Kandang Kerbau (KK) Women’s and Children’s Hospital, Singapore, Singapore
- Pediatric Academic Clinical Programme, Lee Kong Chian School of Medicine, Singapore, Singapore
- Pediatric Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore
- Pediatric Academic Clinical Programme, Yong Loo Lin School of Medicine, Singapore, Singapore
| | - Seyed Ehsan Saffari
- Center for Quantitative Medicine, Office of Clinical Science, Duke-NUS Medical School, Singapore, Singapore
| | - Mei Chien Chua
- Department of Neonatology, Kandang Kerbau (KK) Women’s and Children’s Hospital, Singapore, Singapore
- Pediatric Academic Clinical Programme, Lee Kong Chian School of Medicine, Singapore, Singapore
- Pediatric Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore
- Pediatric Academic Clinical Programme, Yong Loo Lin School of Medicine, Singapore, Singapore
| | - Fabian Yap
- Pediatric Academic Clinical Programme, Lee Kong Chian School of Medicine, Singapore, Singapore
- Pediatric Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore
- Pediatric Academic Clinical Programme, Yong Loo Lin School of Medicine, Singapore, Singapore
- Department of Pediatric Endocrinology, Kandang Kerbau (KK) Women’s and Children’s Hospital, Singapore, Singapore
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16
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Zeng Q, Sang YM. Glutamate dehydrogenase hyperinsulinism: mechanisms, diagnosis, and treatment. Orphanet J Rare Dis 2023; 18:21. [PMID: 36721237 PMCID: PMC9887739 DOI: 10.1186/s13023-023-02624-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 01/23/2023] [Indexed: 02/01/2023] Open
Abstract
Congenital hyperinsulinism (CHI) is a genetically heterogeneous disease, in which intractable, persistent hypoglycemia is induced by excessive insulin secretion and increased serum insulin concentration. To date,15 genes have been found to be associated with the pathogenesis of CHI. Glutamate dehydrogenase hyperinsulinism (GDH-HI) is the second most common type of CHI and is caused by mutations in the glutamate dehydrogenase 1 gene. The objective of this review is to summarize the genetic mechanisms, diagnosis and treatment progress of GDH-HI. Early diagnosis and treatment are extremely important to prevent long-term neurological complications in children with GDH-HI.
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Affiliation(s)
- Qiao Zeng
- grid.411360.1Department of Anesthesiology, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310052 China
| | - Yan-Mei Sang
- Department of Endocrinology, Genetics and Metabolism Centre, Beijing Children's Hospital, Capital Medical University, National Centre for Children's Health, Beijing, 100045, China.
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17
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Boskabadi SJ, Ramezaninejad S, Sohrab M, Farhadi R. Diazoxide-Induced Hypertrichosis in a Neonate With Transient Hyperinsulinism. CLINICAL MEDICINE INSIGHTS-CASE REPORTS 2023; 16:11795476231151330. [PMID: 36726424 PMCID: PMC9885027 DOI: 10.1177/11795476231151330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 12/28/2022] [Indexed: 01/28/2023]
Abstract
Diazoxide is one of the FDA-approved pharmacologic treatments for hyperinsulinemic hypoglycemia, however, its adverse effects in infants are not well described. We reported a 37-week-old boy with the diagnosis of hypoglycemia. We started a dextrose infusion, but we used oral diazoxide, due to hypoglycemia episodes despite the increase in dextrose intake. The newborn had a normoglycemic condition after gradually increasing the diazoxide dose to 15 mg/kg/day. He was fully breastfed and discharged at 14 days of age with ongoing diazoxide. In weekly serial clinical follow-ups, the parents noticed an increase in the growth of forehead and facial hair that was diagnosed as diazoxide-induced hypertrichosis. Diazoxide was gradually tapered, and hypertrichosis continued until 1 month after dioxide discontinuation. Diazoxide use in NICU settings has increased over time. Diazoxide has many side effects, one of which is hypertrichosis. Many diazoxide side effects have been reported in adults or children and few studies have reported the prevalence of these adverse effects of diazoxide in neonates and infants.
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Affiliation(s)
- Seyyed Javad Boskabadi
- Department of Clinical Pharmacy,
Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sima Ramezaninejad
- Department of Clinical Pharmacy,
Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Masoumeh Sohrab
- Department of Clinical Pharmacy,
Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Roya Farhadi
- Department of Neonatology, Pediatrics
Infectious Diseases Research Center, Mazandaran University of Medical Sciences,
Sari, Iran
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18
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Stanley CA, Thornton PS, De Leon DD. New approaches to screening and management of neonatal hypoglycemia based on improved understanding of the molecular mechanism of hypoglycemia. Front Pediatr 2023; 11:1071206. [PMID: 36969273 PMCID: PMC10036912 DOI: 10.3389/fped.2023.1071206] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 02/23/2023] [Indexed: 03/29/2023] Open
Abstract
For the past 70 years, controversy about hypoglycemia in newborn infants has focused on a numerical "definition of neonatal hypoglycemia", without regard to its mechanism. This ignores the purpose of screening newborns for hypoglycemia, which is to identify those with pathological forms of hypoglycemia and to prevent hypoglycemic brain injury. Recent clinical and basic research indicates that the three major forms of neonatal hypoglycemia are caused by hyperinsulinism (recognizing also that other rare hormonal or metabolic conditions may also present during this time frame). These include transitional hypoglycemia, which affects all normal newborns in the first few days after birth; perinatal stress-induced hypoglycemia in high-risk newborns, which afflicts ∼1 in 1,200 newborns; and genetic forms of congenital hyperinsulinism which afflict ∼1 in 10,000-40,000 newborns. (1) Transitional hyperinsulinism in normal newborns reflects persistence of the low glucose threshold for insulin secretion during fetal life into the first few postnatal days. Recent data indicate that the underlying mechanism is decreased trafficking of ATP-sensitive potassium channels to the beta-cell plasma membrane, likely a result of the hypoxemic state of fetal life. (2) Perinatal stress-induced hyperinsulinism in high-risk infants appears to reflect an exaggeration of this normal low fetal glucose threshold for insulin release due to more severe and prolonged exposure to perinatal hypoxemia. (3) Genetic hyperinsulinism, in contrast, reflects permanent genetic defects in various steps controlling beta-cell insulin release, such as inactivating mutations of the K ATP-channel genes. The purpose of this report is to review our current knowledge of these three major forms of neonatal hyperinsulinism as a foundation for the diagnosis and management of hypoglycemia in newborn infants. This includes selection of appropriate interventions based on underlying disease mechanism; combined monitoring of both plasma glucose and ketone levels to improve screening for infants with persistent forms of hypoglycemia; and ultimately to ensure that infants at risk of persistent hyperinsulinemic hypoglycemia are recognized prior to discharge from the nursery.
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Affiliation(s)
- Charles A. Stanley
- Congenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
| | - Paul S. Thornton
- Congenital Hyperinsulinism Center, Division of Endocrinology, Cook Children’s Medical Center, Fort Worth, TX, United States
- Department of Pediatrics, Texas Christian University Burnett School of Medicine, Fort Worth, TX, United States
- Correspondence: Paul S. Thornton Diva D. De Leon
| | - Diva D. De Leon
- Congenital Hyperinsulinism Center and Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
- Correspondence: Paul S. Thornton Diva D. De Leon
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19
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Diazoxide for Neonatal Hyperinsulinemic Hypoglycemia and Pulmonary Hypertension. CHILDREN (BASEL, SWITZERLAND) 2022; 10:children10010005. [PMID: 36670556 PMCID: PMC9856357 DOI: 10.3390/children10010005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/17/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Hypoglycemia in neonates is associated with long-term neurodevelopmental effects. Hyperinsulinemic hypoglycemia (HH) is the most common cause of persistent hypoglycemia in neonatal intensive care units. Diazoxide is the only medication that is currently recommended for treatment of HH in neonates. However, the use of diazoxide in neonates is associated with pulmonary hypertension as an adverse effect. In this article, we review the literature on the mechanism of action and adverse effects with the use of diazoxide in neonatal hyperinsulinism. We then present a case series of neonates treated with diazoxide in our neonatal intensive care unit over a 5-year period. Among 23 neonates who received diazoxide, 4 developed pulmonary hypertension and 1 died. All infants who developed pulmonary hypertension were born preterm at less than 36 weeks gestation and had pre-existing risk factors for pulmonary hypertension. HH in preterm neonates, with pre-existing pulmonary hypertension or with risk factors for pulmonary hypertension requires thoughtful management.
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20
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Muacevic A, Adler JR, P. Murthi S, Alsaffar H, Al Mandhari H. Predictors of the Need to Use Medications in the Management of Neonatal Hypoglycemia. Cureus 2022; 14:e32197. [PMID: 36620829 PMCID: PMC9811335 DOI: 10.7759/cureus.32197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/03/2022] [Indexed: 12/12/2022] Open
Abstract
Background and objective Neonatal hypoglycemia (NH) is one of the most common causes of admission to the neonatal intensive care unit (NICU). Persistent NH despite adequate feeding and intravenous dextrose may often require medications to maintain normal blood glucose levels (BGL). Several medications are used in the management of persistent NH, such as glucagon, diazoxide, and octreotide. In this study, we aimed to determine the factors that predict the need for medications to treat persistent NH. Methods This was a retrospective cohort study conducted at the Sultan Qaboos University Hospital (SQUH), Muscat, Oman. Infants admitted to the NICU between 2015 and 2019 with hypoglycemia (capillary blood glucose <2.6 mmol/l) were eligible to be included in the study. A prespecified dataset was collected from electronic patient records, including birth weight (BW), APGAR scores, gestational age, BGL, maternal risk factors such as diabetes mellitus (DM), hypertension, or antenatal use of medications, and the NICU management during admission. Data analysis was performed using SPSS Statistics for Windows, version 27.0 (IBM Corp., Armonk, NY). Results A total of 89 neonates were admitted due to NH during the study period. Of them, 10 (11.2%) patients had received medication (diazoxide). Use of medication for persistent NH was significantly associated with maternal gestational diabetes/diabetes mellitus (GDM/DM) status (p=0.041), higher BW (p=0.001), and large for gestational age [LGA (defined as BW >90th percentile)] (p=0.014), severe hypoglycemia (mean glucose level of 1-1.5 mmol/l) at two hours of life and at admission, and elevated maximum glucose infusion rate (GIR). GIR for the medication-requiring cohort was 12.95 mg/kg/min and that for the non-medication-requiring cohort was 6.77 mg/kg/min (p<0.001). Conclusion Based on our findings, the need for using certain medications to treat persistent NH, such as diazoxide in neonates admitted with NH, can be predicted by factors such as maternal GDM/DM status, BW >90th percentile, very low BGL at two hours of age and on admission, and elevated GIR. Elevated maximum GIR was a leading indicator for using medications in the treatment of NH.
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21
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Krawczyk S, Urbanska K, Biel N, Bielak MJ, Tarkowska A, Piekarski R, Prokurat AI, Pacholska M, Ben-Skowronek I. Congenital Hyperinsulinaemic Hypoglycaemia-A Review and Case Presentation. J Clin Med 2022; 11:jcm11206020. [PMID: 36294341 PMCID: PMC9604599 DOI: 10.3390/jcm11206020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/24/2022] [Accepted: 10/06/2022] [Indexed: 11/22/2022] Open
Abstract
Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of persistent hypoglycaemia in infants and children with incidence estimated at 1 per 50,000 live births. Congenital hyperinsulinism (CHI) is symptomatic mostly in early infancy and the neonatal period. Symptoms range from ones that are unspecific, such as poor feeding, lethargy, irritability, apnoea and hypothermia, to more serious symptoms, such as seizures and coma. During clinical examination, newborns present cardiomyopathy and hepatomegaly. The diagnosis of CHI is based on plasma glucose levels <54 mg/dL with detectable serum insulin and C-peptide, accompanied by suppressed or low serum ketone bodies and free fatty acids. The gold standard in determining the form of HH is fluorine-18-dihydroxyphenyloalanine PET ((18)F-DOPA PET). The first-line treatment of CHI is diazoxide, although patients with homozygous or compound heterozygous recessive mutations responsible for diffuse forms of CHI remain resistant to this therapy. The second-line drug is the somatostatin analogue octreotide. Other therapeutic options include lanreotide, glucagon, acarbose, sirolimus and everolimus. Surgery is required in cases unresponsive to pharmacological treatment. Focal lesionectomy or near-total pancreatectomy is performed in focal and diffuse forms of CHI, respectively. To prove how difficult the diagnosis and management of CHI is, we present a case of a patient admitted to our hospital.
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Affiliation(s)
- Sylwia Krawczyk
- Department of Paediatric Endocrinology and Diabetology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Karolina Urbanska
- Department of Paediatric Endocrinology and Diabetology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Natalia Biel
- Department of Paediatric Endocrinology and Diabetology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Michal Jakub Bielak
- Department of Paediatric Endocrinology and Diabetology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Agata Tarkowska
- Department of Neonate and Infant Pathology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Robert Piekarski
- Department of Paediatric Endocrinology and Diabetology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Andrzej Igor Prokurat
- Department of Paediatric Surgery, Regional Children’s Hospital in Bydgoszcz, 85-667 Bydgoszcz, Poland
| | - Malgorzata Pacholska
- Department of Paediatric Surgery, Regional Children’s Hospital in Bydgoszcz, 85-667 Bydgoszcz, Poland
| | - Iwona Ben-Skowronek
- Department of Paediatric Endocrinology and Diabetology, Medical University of Lublin, 20-093 Lublin, Poland
- Correspondence:
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22
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Cuff H, Lord K, Ballester L, Scully T, Stewart N, De Leon DD. The Use of Lanreotide in the Treatment of Congenital Hyperinsulinism. J Clin Endocrinol Metab 2022; 107:e3115-e3120. [PMID: 35587448 DOI: 10.1210/clinem/dgac322] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Congenital hyperinsulinism (HI) results in severe, persistent hypoglycemia and is associated with high risk of neurodevelopmental deficits. Sixty percent of HI cases are unresponsive to diazoxide, the only Food and Drug Administration-approved drug. Somatostatin analogs are used off-label as second-line treatment; the long-acting somatostatin analogue, lanreotide, has been used to treat HI over the past decade. Existing reports are limited to small case series. OBJECTIVE To assess the effectiveness and safety of lanreotide in individuals with HI. DESIGN Retrospective cohort study of individuals with HI treated with lanreotide between 2015 and 2020. SETTING The Congenital Hyperinsulinism Center at The Children's Hospital of Philadelphia. PATIENTS Fifty-four individuals with hyperinsulinism treated with lanreotide. MAIN OUTCOME MEASURES Fasting duration with plasma glucose > 70 mg/dL; frequency of lanreotide-associated side effects. RESULTS The median duration of lanreotide therapy was 28.7 (2.8-64.5) months. Thirty-four patients (63%) had HI due to inactivating mutations of the adenosine 5'-triphosphate (ATP) sensitive potassium channel (KATP-HI), and 39% had undergone a pancreatectomy. Of 52 patients receiving other HI therapies, 22 (42%) were able to discontinue other treatments and were managed on lanreotide alone. Fasting duration with plasma glucose > 70 mg/dL was significantly longer during therapy with lanreotide compared to prior to lanreotide initiation (8.6 ± 6.5 vs 5.1 ± 4.7 hours, P = 0.001). The most common side effects were subcutaneous nodules (26%) and gallstones (11%). CONCLUSIONS Lanreotide is a well-tolerated treatment for patients with HI. It results in a longer duration of fasting and a simplification of treatment regimens.
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Affiliation(s)
- Heather Cuff
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Congenital Hyperinsulinism Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Katherine Lord
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Congenital Hyperinsulinism Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Lance Ballester
- Biostatistics and Data Management Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Tryce Scully
- Biostatistics and Data Management Core, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Nicole Stewart
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Congenital Hyperinsulinism Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Diva D De Leon
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Congenital Hyperinsulinism Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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23
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Chandran S, R PR, Mei Chien C, Saffari SE, Rajadurai VS, Yap F. Safety and efficacy of low-dose diazoxide in small-for-gestational-age infants with hyperinsulinaemic hypoglycaemia. Arch Dis Child Fetal Neonatal Ed 2022; 107:359-363. [PMID: 34544689 DOI: 10.1136/archdischild-2021-322845] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 09/06/2021] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Diazoxide (DZX) is the drug of choice for treating hyperinsulinaemic hypoglycaemia (HH), and it has potentially serious adverse effects. We studied the safety and efficacy of low-dose DZX in small-for-gestational-age (SGA) infants with HH. DESIGN An observational cohort study from 1 September 2014 to 31 September 2020. SETTING A tertiary Women's and Children's Hospital in Singapore. PATIENTS All SGA infants with HH. INTERVENTION Diazoxide, at 3-5 mg/kg/day. MAIN OUTCOME MEASURES Short-term outcomes; adverse drug events and fasting studies to determine 'safe to go home' and 'resolution' of HH. RESULTS Among 71 836 live births, 11 493 (16%) were SGA. Fifty-six (0.5%) SGA infants with HH were identified, of which 27 (47%) with a mean gestational age of 36.4±2 weeks and birth weight of 1942±356 g required DZX treatment. Diazoxide was initiated at 3 mg/kg/day at a median age of 10 days. The mean effective dose was 4.6±2.2 mg/kg/day, with 24/27 (89%) receiving 3-5 mg/kg/day. Generalised hypertrichosis occurred in 2 (7.4%) and fluid retention in 1 (3.7%) infant. A fasting study was performed before home while on DZX in 26/27 (96%) cases. Diazoxide was discontinued at a median age of 63 days (9-198 days), and resolution of HH was confirmed in 26/27 (96%) infants on passing a fasting study. CONCLUSION Our study demonstrates that low-dose DZX effectively treats SGA infants with HH as measured by fasting studies. Although the safety profile was excellent, minimal adverse events were still observed with DZX, even at low doses.
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Affiliation(s)
- Suresh Chandran
- Department of Neonatology, KK Women's and Children's Hospital, Singapore .,Paediatrics Academic Clinical Programme, Duke-NUS Medical School, Singapore.,Paediatrics Academic Clinical Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Pravin R R
- Department of Pediatrics, KK Women's and Children's Hospital, Singapore
| | - Chua Mei Chien
- Department of Neonatology, KK Women's and Children's Hospital, Singapore.,Paediatrics Academic Clinical Programme, Duke-NUS Medical School, Singapore.,Paediatrics Academic Clinical Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Seyed Ehsan Saffari
- Center for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore
| | - Victor Samuel Rajadurai
- Department of Neonatology, KK Women's and Children's Hospital, Singapore.,Paediatrics Academic Clinical Programme, Duke-NUS Medical School, Singapore.,Paediatrics Academic Clinical Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Fabian Yap
- Paediatrics Academic Clinical Programme, Duke-NUS Medical School, Singapore .,Paediatrics Academic Clinical Programme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.,Department of Pediatrics, KK Women's and Children's Hospital, Singapore
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24
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Salguero MV, Chan K, Greeley SAW, Dyamenahalli U, Waggoner D, del Gaudio D, Rajiyah T, Lemelman M. Novel KDM6A Kabuki Syndrome Mutation with Hyperinsulinemic Hypoglycemia and Pulmonary Hypertension requiring ECMO. J Endocr Soc 2022; 6:bvac015. [PMID: 35237736 PMCID: PMC8884118 DOI: 10.1210/jendso/bvac015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Indexed: 11/30/2022] Open
Abstract
Kabuki syndrome (KS) is a multisystem disorder estimated to occur in 1:32 000 newborns. Pathogenic mutations cause the majority but not all cases of KS in either KMT2D or KDM6A. KS can be suspected by phenotypic features, including infantile hypotonia, developmental delay, dysmorphic features, congenital heart defects, and others. Still, many of these features are not readily apparent in a newborn. Although neonatal hypoglycemia has been reported in 8% to 10% of patients with KS, the incidence and severity of hyperinsulinemic hypoglycemia (HH) is not well-studied. We present a full-term female infant with HH who was responsive to low-dose diazoxide. At 3 months of age, she was admitted for septic shock, worsening respiratory status, and severe pulmonary hypertension, requiring extracorporeal membrane oxygenation support. Her neonatal history was notable for hypotonia, dysphagia with aspiration requiring gastrostomy tube placement, and a cardiac defect—hypoplastic aortic arch requiring aortic arch repair. She has characteristic facial features, including prominent eyelashes, long palpebral fissures, and a short nasal columella. Next-generation sequencing for HH revealed a de novo likely pathogenic missense variant in KDM6A gene: c.3479G > T, p.Gly1160Val that was absent from population databases. Genetic testing for causes of HH should include testing of the KS genes KMT2D and KDM6A. Early detection of the underlying genetic defect will help guide management as all reported HH cases associated with KS have been responsive to diazoxide. Affected infants with underlying cardiac conditions may be at higher risk of serious respiratory complications such as pulmonary hypertension.
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Affiliation(s)
- Maria V Salguero
- Department of Pediatrics, Section of Adult and Pediatric Endocrinology, University of Chicago
| | - Karen Chan
- Department of Pediatrics, University of Chicago
| | - Siri Atma W Greeley
- Department of Pediatrics, Section of Adult and Pediatric Endocrinology, University of Chicago
| | - Umesh Dyamenahalli
- Department of Pediatrics, Section of Pediatric Cardiology, University of Chicago
| | | | | | - Tara Rajiyah
- Department of Pediatrics, Section of Adult and Pediatric Endocrinology, University of Chicago
| | - Michelle Lemelman
- Department of Pediatrics, Section of Adult and Pediatric Endocrinology, University of Chicago
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25
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Chen C, Sang Y. Phosphomannomutase 2 hyperinsulinemia: Recent advances of genetic pathogenesis, diagnosis, and management. Front Endocrinol (Lausanne) 2022; 13:1102307. [PMID: 36726472 PMCID: PMC9884677 DOI: 10.3389/fendo.2022.1102307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 12/27/2022] [Indexed: 01/17/2023] Open
Abstract
Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and childhood. There are 16 subtypes of CHI-related genes. Phosphomannomutase 2 hyperinsulinemia (PMM2-HI) is an extremely rare subtype which is first reported in 2017, with only 18 families reported so far. This review provides a structured description of the genetic pathogenesis, and current diagnostic and therapeutic advances of PMM2-HI to increase clinicians' awareness of PMM2-HI.
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26
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Martino M, Sartorelli J, Gragnaniello V, Burlina A. Congenital hyperinsulinism in clinical practice: From biochemical pathophysiology to new monitoring techniques. Front Pediatr 2022; 10:901338. [PMID: 36210928 PMCID: PMC9538154 DOI: 10.3389/fped.2022.901338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 09/01/2022] [Indexed: 11/13/2022] Open
Abstract
Congenital hyperinsulinism comprises a group of diseases characterized by a persistent hyperinsulinemic hypoglycemia, due to mutation in the genes involved in the regulation of insulin secretion. The severity and the duration of hypoglycemic episodes, primarily in the neonatal period, can lead to neurological impairment. Detecting blood sugar is relatively simple but, unfortunately, symptoms associated with hypoglycemia may be non-specific. Research in this field has led to novel insight in diagnosis, monitoring and treatment, leading to a better neurological outcome. Given the increased availability of continuous glucose monitoring systems that allow glucose level recognition in a minimally invasive way, monitoring the glycemic trend becomes easier and there are more possibilities of a better follow-up of patients. We aim to provide an overview of new available technologies and new discoveries and their potential impact on clinical practice, convinced that only with a better awareness of the disease and available tools we can have a better impact on CHI diagnosis, prevention and clinical sequelae.
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Affiliation(s)
| | | | - Vincenza Gragnaniello
- Division of Inborn Metabolic Disease, Department of Pediatrics, University Hospital Padua, Padua, Italy
| | - Alberto Burlina
- Division of Inborn Metabolic Disease, Department of Pediatrics, University Hospital Padua, Padua, Italy
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27
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Pasquini TLS, Mesfin M, Schmitt J, Raskin J. Global Registries in Congenital Hyperinsulinism. Front Endocrinol (Lausanne) 2022; 13:876903. [PMID: 35721728 PMCID: PMC9201947 DOI: 10.3389/fendo.2022.876903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Congenital hyperinsulinism (HI) is the most frequent cause of severe, persistent hypoglycemia in newborn babies and children. There are many areas of need for HI research. Some of the most critical needs include describing the natural history of the disease, research leading to new and better treatments, and identifying and managing hypoglycemia before it is prolonged and causes brain damage or death. Patient-reported data provides a basis for understanding the day-to-day experience of living with HI. Commonly identified goals of registries include performing natural history studies, establishing a network for future product and treatment studies, and supporting patients and families to offer more successful and coordinated care. Congenital Hyperinsulinism International (CHI) created the HI Global Registry (HIGR) in October 2018 as the first global patient-powered hyperinsulinism registry. The registry consists of thirteen surveys made up of questions about the patient's experience with HI over their lifetime. An international team of HI experts, including family members of children with HI, advocates, clinicians, and researchers, developed the survey questions. HIGR is managed by CHI and advised by internationally recognized HI patient advocates and experts. This paper aims to characterize HI through the experience of individuals who live with it. This paper includes descriptive statistics on the birthing experience, hospitalizations, medication management, feeding challenges, experiences with glucose monitoring devices, and the overall disease burden to provide insights into the current data in HIGR and demonstrate the potential areas of future research. As of January 2022, 344 respondents from 37 countries consented to participate in HIGR. Parents or guardians of individuals living with HI represented 83.9% of the respondents, 15.3% were individuals living with HI. Data from HIGR has already provided insight into access challenges, patients' and caregivers' quality of life, and to inform clinical trial research programs. Data is also available to researchers seeking to study the pathophysiology of HI retrospectively or to design prospective trials related to improving HI patient outcomes. Understanding the natural history of the disease can also guide standards of care. The data generated through HIGR provides an opportunity to improve the lives of all those affected by HI.
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28
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Karlekar MP, Sarathi V, Arya S, Flanagan SE, Patil V, Lila A, Shah N, Bandgar T. Octreotide-LAR is a Useful Alternative for the Management of Diazoxide-Responsive Congenital Hyperinsulinism. Horm Metab Res 2021; 53:723-729. [PMID: 34740273 DOI: 10.1055/a-1654-8542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The data on the congenital hyperinsulinism (CHI) in Asian Indian patients is limited. Diazoxide is often unavailable in India, which poses challenge in managing CHI. The study was aimed to present our experience with CHI with a special focus on the effectiveness and cost-effectiveness of octreotide long-acting release (OCT-LAR) among diazoxide-responsive CHI. The data of 14 index cases with CHI registered at our center were retrospectively analyzed. The diagnosis of CHI was based on elevated serum insulin (3.4-32.5 μIU/ml) and C-peptide (0.58-1.98 ng/ml) at the time of symptomatic hypoglycemia (BG≤41 mg/dl). Fourteen patients (13 males) presented at a median (range) age of 3 (1-270) days, seizures being the most common mode of presentation (78.6%). Ten patients were diazoxide-responsive, two were partially responsive, while two were unresponsive. Genetics was available for eight patients; ABCC8 (n=3, 1 novel) and HADH (n=2, both novel) were the most commonly mutated genes. OCT-LAR was offered to eight patients including four with diazoxide-responsive disease and was universally effective. We propose a cost-effective approach to use OCT-LAR in the management of CHI, which may also make it more cost-effective than diazoxide for diazoxide-responsive disease. Five of the 11 (45.5%) patients had evidence of neurological impairment; notably, two patients with HADH mutations had intellectual disability despite diazoxide-responsiveness. We report three novel mutations in CHI-associated genes. We demonstrate the effectiveness of and propose a cost-effective approach to use OCT-LAR in diazoxide-responsive CHI. Mutations in HADH may be associated with abnormal neurodevelopmental outcomes despite diazoxide-responsiveness.
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Affiliation(s)
- Manjiri Pramod Karlekar
- Department of Endocrinology and Metabolism, Seth G. S. Medical College and KEM Hospital, Mumbai, India
| | - Vijaya Sarathi
- Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Center, Bangalore, India
| | - Sneha Arya
- Department of Endocrinology and Metabolism, Seth G. S. Medical College and KEM Hospital, Mumbai, India
| | - Sarah E Flanagan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Virendra Patil
- Department of Endocrinology and Metabolism, Seth G. S. Medical College and KEM Hospital, Mumbai, India
| | - Anurag Lila
- Department of Endocrinology and Metabolism, Seth G. S. Medical College and KEM Hospital, Mumbai, India
| | - Nalini Shah
- Department of Endocrinology and Metabolism, Seth G. S. Medical College and KEM Hospital, Mumbai, India
| | - Tushar Bandgar
- Department of Endocrinology and Metabolism, Seth G. S. Medical College and KEM Hospital, Mumbai, India
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29
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Hoermann H, Roeper M, Salimi Dafsari R, Koestner F, Reinauer C, Mayatepek E, Meissner T, Kummer S. Challenges in management of transient hyperinsulinism - a retrospective analysis of 36 severely affected children. J Pediatr Endocrinol Metab 2021; 34:867-875. [PMID: 33860651 DOI: 10.1515/jpem-2020-0639] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 02/12/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Transient hyperinsulinism (THI) is a hypoglycemia disorder which resolves spontaneously within the first weeks or months of life. The pathomechanism of THI is not elucidated yet; however, it is known that perinatal stress predisposes for THI. We aimed to characterize the clinical phenotype and treatment of children with THI, and to identify options for improved management. METHODS A retrospective analysis of 36 children with THI treated at the University Children's Hospital Düsseldorf between 2007 and 2019 was performed. RESULTS All children had risk factors for neonatal hypoglycemia or indicators of perinatal stress. Eighty three percent were diagnosed with hypoglycemia on day of life (DOL)1. None of the six diagnosed later had routine blood glucose screening and showed significantly lower blood glucose levels at the time of first blood glucose measurement compared to the children diagnosed on DOL1. Ninety seven percent of all children received intravenous glucose, 42% received continuous glucagon and 81% were started on diazoxide. Diazoxide withdrawal and subsequent fasting tests lacked standardization and were based on clinical experience. Three patients had a subsequent episode of hypoglycemia, after fasting studies only demonstrated "clinical" remission without proving the ability to ketogenesis. CONCLUSIONS Any kind of perinatal stress might pose a risk to develop THI, and postnatal monitoring for hypoglycemia still needs to be improved. Diazoxide is effective in children with THI; however, further studies are needed to guide the development of criteria and procedures for the initiation and discontinuation of treatment. Furthermore, establishing consensus diagnostic criteria/definitions for THI would improve comparability between studies.
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Affiliation(s)
- Henrike Hoermann
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Marcia Roeper
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Roschan Salimi Dafsari
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Felix Koestner
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Christina Reinauer
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Thomas Meissner
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Sebastian Kummer
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
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30
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Kim JM, Kim SK, Kim SH, Cho WK, Cho KS, Jung MH, Suh BK, Ahn MB. Transient Hyperinsulinemic Hypoglycemia Linked to PAX6 Mutation. Medicina (B Aires) 2021; 57:medicina57060582. [PMID: 34200146 PMCID: PMC8227506 DOI: 10.3390/medicina57060582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 05/31/2021] [Accepted: 06/03/2021] [Indexed: 12/15/2022] Open
Abstract
Prolonged hyperinsulinemic hypoglycemia in infancy can result in developmental sequelae. A mutation in the paired box-6 gene (PAX6) has been reported to cause disorders in oculogenesis and neurogenesis. A limited number of cases of diabetes mellitus in adults with a PAX6 mutation suggest that the gene also plays a role in glucose homeostasis. The present case report describes a boy with a PAX6 mutation, born with anophthalmia, who underwent hypoglycemic seizures starting at 5 months old, and showed a prediabetic condition at 60 months. This patient provides novel evidence that connects PAX6 to glucose homeostasis and highlights that life-threatening hypoglycemia or early onset glucose intolerance may be encountered. The role of PAX6 in glucose metabolism and insulin regulation should be further investigated.
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Affiliation(s)
| | | | | | | | | | | | | | - Moon-Bae Ahn
- Correspondence: ; Tel.: +82-2-2258-6756 or +82-2-537-4544
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31
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Exosomal miR-486-5p derived from human placental microvascular endothelial cells regulates proliferation and invasion of trophoblasts via targeting IGF1. Hum Cell 2021; 34:1310-1323. [PMID: 33977502 PMCID: PMC8338855 DOI: 10.1007/s13577-021-00543-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 04/27/2021] [Indexed: 01/12/2023]
Abstract
Preeclampsia (PE) is a serious complication of pregnancy. Exosomes are known to be upregulated in PE. In this study, we sought to investigate the effect of miR-486-5p from human placental microvascular endothelial cells, on the function of trophoblast cells. To investigate the function of human placental microvascular endothelial cell (HPVEC)-derived exosomes on trophoblast cells, HPVECs were treated with hypoxia/reoxygenation (H/R). The separation efficiency of exosomes was determined by transmission electron microscopy, nanosight and Western blot. Cell Counting Kit-8, EdU staining, wound-healing, and transwell assay were performed to detect the effect of exosomally transferred miR-486-5p inhibitor on proliferation, migration and invasion of trophoblast cells. MiRDB and dual-luciferase report assay were used to find the target of miR-486-5p. Our data revealed that miR-486-5p was significantly upregulated in H/R-treated HPVEC-Exo, and miR-486-5p was enriched in HPVEC-Exo. miR-486-5p inhibitor carried by HPVEC-Exo significantly inhibited the proliferation, migration and invasion of trophoblast cells. Insulin-like growth factor 1 (IGF1) was found to be the target of miR-486-5p, and IGF1 overexpression notably reversed the effect of miR-486-5p inhibitor from HPVEC-Exo on trophoblast cell function. In summary, H/R-treated HPVEC-derived exosomally expressing miR-486-5p inhibitor significantly inhibited the proliferation, migration and invasion of trophoblast cells via downregulation of IGF1. The findings from the present study may be useful in the development of treatments for PE.
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32
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Banas JL, Viswalingam B, Rajadurai VS, Yap F, Chandran S. Asymptomatic Hyperinsulinemic Hypoglycemia and Grade 4 Intraventricular Hemorrhage in a Late Preterm Infant. J Investig Med High Impact Case Rep 2021; 9:23247096211051918. [PMID: 34654342 PMCID: PMC8524697 DOI: 10.1177/23247096211051918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/07/2021] [Accepted: 09/21/2021] [Indexed: 11/15/2022] Open
Abstract
Hyperinsulinemic hypoglycemia (HH) has the potential to cause acute neurologic dysfunction and neurodevelopmental impairment. Parieto-occipital neuronal injuries have been reported in hypoglycemic infants, but intraparenchymal hemorrhage is rare. On day 5 of life, a late preterm infant was transferred to our care with recurrent asymptomatic hypoglycemia. Prior to arrival, plasma glucose levels were at a median of 1.25 mmol/L (22.5 mg/dL) in the first 6 hours of life, and he required a glucose infusion rate (GIR) of 22.6 mg/kg/min. Hyperinsulinism was confirmed in the presence of detectable insulin, low ketones, and fatty acid when hypoglycemic. A left grade 4 intraventricular hemorrhage (IVH) was noted in the cranial ultrasound scan during the workup for sepsis on the day of admission. However, magnetic resonance imaging of the brain on day 7 of life revealed extensive bilateral IVH. On day 9, he was initiated on diazoxide, and HH resolved within 48 to 72 hours, allowing increment of feeds while weaning GIR. Ventricular drain for post-hemorrhagic ventriculomegaly was advised but not performed. At 3 months, post-hemorrhagic ventriculomegaly was stable, and there were early signs of neurodevelopmental delay. After discontinuing diazoxide at 4 months of age, he passed an 8-hour fasting study confirming the resolution of HH. Severe hypoglycemia has been associated with cerebral hyperperfusion in preterm infants and potentially could cause IVH. Close monitoring and prompt intervention in preterm infants to prevent severe hypoglycemia are paramount. In addition to long-term neurodevelopmental follow-up, infants with recurrent hypoglycemia may benefit from neuroimaging and thereby early intervention if required.
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Affiliation(s)
| | | | - Victor Samuel Rajadurai
- KK Women’s and Children’s
Hospital, Singapore
- National University of Singapore,
Singapore
- Nanyang Technological University,
Singapore
- Duke-NUS Medical School, National
University of Singapore, Singapore
| | - Fabian Yap
- KK Women’s and Children’s
Hospital, Singapore
- Nanyang Technological University,
Singapore
- Duke-NUS Medical School, National
University of Singapore, Singapore
| | - Suresh Chandran
- KK Women’s and Children’s
Hospital, Singapore
- National University of Singapore,
Singapore
- Nanyang Technological University,
Singapore
- Duke-NUS Medical School, National
University of Singapore, Singapore
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