hrp0082p1-d1-175 | Perinatal and Neonatal Endocrinology | ESPE2014

The Role of mTORC1/RagGTPase and IGF1R/mTORC2/Akt Pathways and the Response of Diffuse Congenital Hyperinsulinism to Sirolimus

Senniappan Senthil , Tatevian Nina , Shah Pratik , Arya Ved Bhushan , Flanagan Sarah , Ellard Sian , Brown Robert , Hussain Khalid

Background: The gene expression microarray and morphoproteomics in diffuse congenital hyperinsulinism (CHI) revealed activation of the mammalian target of rapamycin (mTOR) pathway and the subsequent treatment of four diffuse CHI patients with sirolimus (mTOR inhibitor) avoided pancreatectomy.Objective and hypotheses: To further evaluate the mechanism of action of sirolimus by studying the expression of mTORC1/RagGTPase and IGF1R/mTORC2/Akt pathways in pa...

hrp0084fc9.4 | Beta cell disorders | ESPE2015

Novel Molecular Mechanisms of Congenital Hyperinsulinism due to Autosomal Dominant Mutations in ABCC8

Nessa Azizun , Aziz Qadeer , Thomas Alison , Harmer Stephen , Flanagan Sarah , Ellard Sian , Kapoor Ritika , Tinker Andrew , Hussain Khalid

Background: Dominant mutations in ABCC8 can cause congenital hyperinsulinism (CHI), which is characterised by unregulated insulin secretion.Objective and hypotheses: To understand the molecular basis of medically unresponsive CHI due to dominant ABCC8 mutations.Method: We investigated ten patients with diazoxide unresponsive CHI who required a near total pancreatectomy. DNA sequencing revealed seven dominant heter...

hrp0084p3-1067 | Hypo | ESPE2015

Discontinuation of Diazoxide Therapy in Children with Hyperinsulinaemic Hypoglycaemia with no Identified Genetic Aetiology: a Long-term Follow-up Study

Al Yahyaei Mouza , Shah Pratik , Guemes Maria , Gilbert Clare , Morgan Kate , Flanagan Sarah , Ellard Sian , Hussain Khalid

Background: Congenital hyperinsulinism (CHI) is a cause of severe persistent hypoglycaemia in children. Diazoxide is the first line medical therapy for CHI; however diazoxide is usually ineffective in CHI with KATP channel gene mutations. Patients with no mutations in the KATP channel genes do respond to therapy with diazoxide. There are no previous studies assessing how long diazoxide therapy is needed in those patients with no genetic aetiology identifi...

hrp0084p1-30 | Diabetes | ESPE2015

A Novel Mutation in the abcc8 Gene Causing a Variable Phenotype of Impaired Glucose Metabolism in the Same Family

Maines Evelina , Hussain Khalid , Flanagan Sarah E , Ellard Sian , Piona Claudia , Morandi Grazia Grazia , Ben Sarah Dal , Cavarzere Paolo , Antoniazzi Franco Franco , Gaudino Rossella

Background: Dominantly acting loss-of-function mutations in the ABCC8 gene, encoding the sulfonylurea receptor 1 (SUR1) subunit of the β-cell potassium channel (KATP), are usually responsible for mild diazoxide-responsive congenital hyperinsulinism (CHI). In rare cases dominant ABCC8 mutations can cause diffuse diazoxide-unresponsive CHI. Recent reports suggest that medically responsive CHI due to a dominant ABCC8 mutation may confer an increase...

hrp0092p1-65 | Fetal, Neonatal Endocrinology and Metabolism (to include Hypoglycaemia) | ESPE2019

Congenital Hyperinsulinism Due to Pancreatic Mosaicism for Paternal Uniparental Disomy of all Chromosome 11, with the Additional Finding of Pancreatic Mosaicism for Trisomy 12

Conwell Louise , Harraway James , Williams Mark , Joy Christopher , Scurry Bonnie , Lee Kevin , McBride Craig , Choo Kelvin , Huynh Tony , Ng Carolyn , Flanagan Sarah

We report a term male with diazoxide-unresponsive congenital hyperinsulinism (CHI) (spontaneous conception, non-consanguineous, no family history). The patient did not have macroglossia, exomphalos or lateralised overgrowth (cardinal Beckwith-Wiedemann spectrum (BWSp) features) (1). There was no polyhydramnios, macrosomia, facial naevus simplex, ear creases/pits, diastasis recti or nephromegaly/hepatomegaly (suggestive BWSp features) (1).A targeted massi...

hrp0089fc3.5 | Diabetes and Insulin 1 | ESPE2018

Genotype and Phenotype Correlation in Syndromic Forms of Hyperinsulinaemic Hypoglycaemia – a 10-year follow-up Study in a Tertiary Centre

Dastamani Antonia , Kostopoulou Eirini , Clements Emma , Caiulo Silvana , Shanmugananda Prateek , Morgan Kate , Gilbert Clare , Dattani Mehul , Flanagan Sarah , Ellard Sian , Hurst Jane , Shah Pratik

Introduction: Hyperinsulinaemic Hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in infancy. It is characterised by hypoketotic, hypofattyacidaemic and hyperinsulinaemic hypoglycaemia. The molecular basis of HH includes defects in pathways that regulate insulin release; to date, 12 genes have been associated with monogenic forms of HH (ABCC8, KCNJ11, GLUD1, GCK, HADH1, UCP2, MCT1, HNF4A, HNF1A, HK1, PGM1, PMM2). However, no genetic aetiology has been...

hrp0089p2-p110 | Diabetes & Insulin P2 | ESPE2018

Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins

London Shira , Elias-Assad Ghadir , Barhoum Marie Noufi , Felszer Clari , Paniakov Marina , Vainer Scott , Flanagan Sarah , Houghton Jayne , Rakover Yardena Tenenbaum

Background: GLIS3 is a transcription factor involved in the development of pancreatic β-cells, the thyroid, eyes, liver and kidneys. In the pancreas, GLIS3 is expressed at various stages of ductal and endocrine cell development, and is a critical regulator of β-cell development and insulin expression. Mutations in GLIS3 have been recently described as a rare cause of neonatal diabetes and congenital hypothyroidism (CH), reported in only 20 ...

hrp0089p2-p182 | Fetal, Neonatal Endocrinology and Metabolism P2 | ESPE2018

Clinical Characterstics, Genotype-Phenotype Correlations and Follow Up of Patients with Congenital Hyperinsulinaemic Hypoglycaemia; Single Center Experience from a Southeastern City of Turkey

Ozbek Mehmet Nuri , Demirbilek Huseyin , Haliloglu Belma , Demiral Meliha , Baran Riza Taner , Ellard Sian , Houghton Jayne , Flanagan Sarah E , Hussain Khalid

Objective: Congenital Hyperinsulinism (CHI) is a clinically, genetically and histologically heterogenous diesease. In recent years substantial developements have been observed in the genetics, imaging techniques and treatment options. We herein present the clinical characteristics, genetics and follow-up of 31 CHI patients from a single paediatric endocrine center with a particular emphasis on the new treatment options.Patients and method: Clinical chara...

hrp0089p3-p175 | Fetal, Neonatal Endocrinology and Metabolism P3 | ESPE2018

Neonatal Diabetes Mellitus in Vietnam National Children Hospital

Ngoc Can Thi Bich , Dung Vu Chi , Thao Bui Phuong , Khanh Nguyen Ngoc , Mai Do Thi Thanh , Ellard Sian , Jayne Houghton , Flanagan Sarah , Mackay Deborah , Hoan Nguyen Thi

Introduction: Neonatal diabetes mellitus (NDM) is a rare (1:300,000–400,000 newborns) but potentially devastating metabolic disorder characterized by hyperglycemia combined with low levels of insulin. Two main groups have been recognized, transient NDM (TNDM) and permanent NDM (PNDM).Objective: To describle clinical features and laboratory manifestations of patient with NDM and evaluate outcome of management.Subject and method...

hrp0086rfc9.5 | Pathophysiology of Disorders of Insulin Secretion | ESPE2016

Non-Mody Monogenic Diabetes: A Very Heterogenous and Problematic Group of Diabetes

Siklar Zeynep , De Franco Elisa , FlanagaN Sarah , Ellard Sian , Ceylaner Serdar , Boztug Kaan , Dogu Figen , Ikinciogullari Aydan , Kuloglu Zarife , Kansu Aydan , Berberoglu Merih

Background: Monogenic diabetes represents a group of disorders resulting from a single gene defect leading to disruption of insulin secretion or a reduction in the number of beta cells. Despite the classification of monogenic diabetes according to age of onset, with neonatal DM (<6 months of age) and maturity onset diabetes of young (MODY) (>6 months and <25 years of age); not every case can be classified into those groups.Objective and hypot...