A5008575862- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Pancreatic function and diabetes
- Diabetes Management and Research
- Neonatal Respiratory Health Research
- Metabolism, Diabetes, and Cancer
- Neuroblastoma Research and Treatments
- Diabetes and associated disorders
- Blood disorders and treatments
- Genomics and Rare Diseases
- Pituitary Gland Disorders and Treatments
- Neuroendocrine Tumor Research Advances
- Respiratory Support and Mechanisms
- Diabetes Treatment and Management
- Neuroscience of respiration and sleep
- Myasthenia Gravis and Thymoma
- Congenital Diaphragmatic Hernia Studies
- Cardiovascular Function and Risk Factors
- Adrenal Hormones and Disorders
- Gastroesophageal reflux and treatments
- Hormonal and reproductive studies
- Adrenal and Paraganglionic Tumors
- Pulmonary Hypertension Research and Treatments
- Diet and metabolism studies
- Sexual Differentiation and Disorders
- Cancer, Hypoxia, and Metabolism
Great Ormond Street Hospital
2017-2025
University College London
2017-2025
Great Ormond Street Hospital for Children NHS Foundation Trust
2018-2023
University College Hospital
2018
National and Kapodistrian University of Athens
2013-2014
Nonclassical congenital adrenal hyperplasia (NC-CAH) is caused by mutations of the CYP21A2 gene. The clinical manifestations and hormonal derangements NC-CAH are quite variable.(i) To define phenotype its relation to genotype according gender age (ii) evaluate validity currently applied criteria for establishing diagnosis NC-CAH.The clinical, molecular data 280 subjects (235 female) with a median 17·6 years were analysed. genotyping was performed in all subjects.The majority females aged...
Congenital hyperinsulinism (CHI) is a significant cause of hypoglycaemia in neonates and infants with the potential for permanent neurologic injury.Accurate calculations incidence rare diseases such as CHI are important they inform health care planning can aid interpretation genetic testing results when assessing frequency variants large-scale, unselected sequencing databases.Whilst minimal rates have been calculated four European countries, UK not known.In this study we used referral to...
Diazoxide is first-line treatment for hyperinsulinaemic hypoglycaemia (HH) but diazoxide-induced pulmonary hypertension (PH) can occur. We aim to characterize the incidence and risk factors of PH in a large HH cohort provide recommendations anticipating preventing diazoxide-treated patients with HH.Retrospective study involving four UK regional centres; review case notes on diazoxide.The diagnosis was based clinical echocardiography evidence. Patient treatment-related were analysed...
Objective Continuous Glucose Monitoring (CGM) is gaining in popularity for patients with paediatric hypoglycaemia disorders such as Congenital Hyperinsulinism (CHI), but no standard measures of accuracy or associated clinical risk are available. The small number prior assessments CGM CHI have thus been incomplete. We aimed to develop a novel Hypoglycaemia Error Grid (HEG) assessment those based on expert consensus opinion applied large paired (CGM/blood glucose) dataset. Design and methods...
We recently reported non-coding variants in a cis-regulatory element of the beta-cell disallowed gene hexokinase 1 (HK1) as novel cause congenital hyperinsulinism. These lead to loss repression HK1 pancreatic beta-cells, causing insulin secretion during hypoglycaemia. In this study, we aimed determine prevalence, genetics, and phenotype HK1-hyperinsulinism by screening large international cohort patients living with condition. screened region 1761 probands hyperinsulinism unknown aetiology...
Introduction Congenital Hyperinsulinism (HI) is a rare disease that causes severe and recurrent hypoglycemia due to dysregulated insulin secretion. HI the most frequent cause of severe, persistent in newborns children. Disease management focused on preventing neurological consequences associated with hypoglycemic brain injury; however, treatment complex, often suboptimal, places large burden families individuals living HI. International (CHI) an international patient organization received...
Sirolimus, a mammalian target of rapamycin inhibitor, has been used in congenital hyperinsulinism (CHI) unresponsive to diazoxide and octreotide. Reported response sirolimus is variable, with high incidence adverse effects. To the best our knowledge, we report largest group CHI patients treated followed for longest period date.Retrospective study tertiary service review 15 publications reporting inhibitors. Comparison was made between findings this those previously published.Twenty-two were...
The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) maturity-onset diabetes of the young (MODY).We characterised an international multicentre paediatric cohort patients with HNF4Aor HNF1Amutations presenting HH over a 25-year period (1995-2020).Clinical genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as ability to maintain normoglycaemia without intravenous glucose....
Hypoglycemia is often recurrent and severe in patients with congenital hyperinsulinism (CHI). However, there little information regarding frequency or patterns of episodes to inform clinical management future trial design.We aimed describe hypoglycemia by varying thresholds through a large continuous glucose monitoring (CGM) dataset. Through the UK CHI centers excellence, data were analyzed from over 5-year period. 3.0 (H3.0), 3.5 (H3.5) 3.9 (H3.9) mmol/L used test threshold change on...
A long-acting somatostatin analogue (lanreotide) is used in the management of a diazoxide-unresponsive diffuse form congenital hyperinsulinism (CHI). However, no reports its use patients with focal CHI exist. Case 1: 1-month-old boy diagnosed due to paternal heterozygous ABCC8 gene mutation showed partial response octreotide. 18F-DOPA-PET/CT scan revealed lesion pancreatic head. Surgical removal was unsuccessful. He switched monthly lanreotide treatment at age 11 months, which stabilised his...
Genetic aetiology remains unknown in up to 50% of patients with persistent hyperinsulinaemic hypoglycaemia (HH). Several syndromes are associated HH. We report Rubinstein-Taybi syndrome (RSTS) as one the possible causes Early diagnosis and treatment HH is crucial prevent hypoglycaemic brain injury.Four RSTS were retrospectively analysed.Genetic investigations included next-generation sequencing-based gene panels exome sequencing. Clinical characteristics, metabolic profile during...
The question of the contribution <i>CYP21A2</i> heterozygosity to development polycystic ovary syndrome (PCOS) has repeatedly been raised in literature. available data, however, do not offer a satisfactory answer. discrepancy must be attributed, primarily, small number subjects various studies, type selected phenotype, and searched mutations. aim study was define heterozygous mutations pathogenesis PCOS. We for 14 molecular defects gene 197 PCOS women, employing allele specific PCR. Androgen...
Phosphomannomutase 2 (PMM2) deficiency causes Congenital Disorder of Glycosylation (PMM2-CDG), but does not have a recognised association with Inflammatory Bowel Disease (IBD). A distinct clinical syndrome hyperinsulinism and autosomal recessive polycystic kidney disease (HIPKD) arises in the context specific variant PMM2 promotor, either homozygosity, or compound heterozygous deleterious variant. Here, we describe development IBD three patients PMM2-HIPKD, onset at 0, 6, 10 years age. In...
Abstract Context Hyperinsulinemic hypoglycemia (HI) can be the presenting feature of Kabuki syndrome (KS), which is caused by loss-of-function variants in KMT2D or KDM6A. As these genes play a critical role maintaining methylation status chromatin, individuals with pathogenic have disease-specific epigenomic profile—an episignature. Objective We evaluated pathogenicity 3 novel partial KDM6A duplications identified neonatal-onset HI without typical features KS at time genetic testing. Methods...
Sirolimus (mTOR inhibitor) is proven to be effective in children with congenital hyperinsulinism (CHI). Studies animals suggest that sirolimus may have diabetogenic actions. However, its role precipitating diabetes mellitus (DM) CHI has not been reported.A 16-year-old female due a dominant ABCC8 gene mutation was switched from diazoxide therapy sirolimus, the hypertrichosis side effect of diazoxide. She developed facial cellulitis treated clarithromycin and month later, once infection...
Background Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital hyperinsulinism caused by an activating GLUD1 mutation. Objective The aim this study was to determine clinical profile and long-term neurological outcomes in children with HI/HA syndrome. Method This a retrospective review patients mutation, treated at two centers UK Russia, over 15-year period. Different risk factors for neuro-developmental disorders were analysed Mann–Whitney U test...
Abstract Context In focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic β-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery. Objective We describe surgical nonsurgical outcomes CHI in a national cohort. Methods Patients with were retrospectively reviewed at 2 specialist centers, 2003-2018. Results Of 59 patients CHI, 57 had heterozygous mutations ABCC8/KCNJ11 (51 paternally inherited, 6...
Hyperinsulinism results from inappropriate insulin secretion during hypoglycaemia. Down syndrome is causally linked to a number of endocrine disorders including Type 1 diabetes and neonatal diabetes. We noted high individuals with referred for hyperinsulinism genetic testing, therefore aimed investigate whether the prevalence was increased in our cohort compared population. Methods identified testing Exeter Genomics Laboratory between 2008 2020. sequenced known genes all investigated their...
Summary We report a case of partial diazoxide responsiveness in child with severe congenital hyperinsulinaemic hypoglycaemia (CHI) due to homozygous ABCC8 mutation. A term baby, birth weight 3.8 kg, born consanguineous parents presented on day 1 life hypoglycaemia. Hypoglycaemia screen confirmed CHI. Diazoxide was commenced 7 ongoing elevated glucose requirements (15 mg/kg/min), but despite escalation maximum dose mg/kg/day), intravenous (i.v.) requirement remained high (13 mg/kg/min)....
<b><i>Background:</i></b> Mutations of the insulin receptor (INSR) gene lead to a wide spectrum inherited resistance (IR) syndromes. Among these, type A-IR, usually caused by dominant negative <i>INSR</i> mutations, generally presents peri-pubertally in girls. <b><i>Case:</i></b> A 2.8-year-old girl was referred due recurrent postprandial and fasting hypoglycemia. She had been born at full-term with birth weight 1.89 kg, developed...