Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the loss of FOXA2 or its regulatory elements.

Persistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1 Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene, FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent to FOXA2 that encompasses multiple non-coding regulatory elements that are in conformational contact with FOXA2. Our data suggests that the deletions in these three children may cause disease through the dysregulation of FOXA2 expression. These findings provide new insights into the regulation of FOXA2 in the beta-cell and confirm an aetiological role for chromosome 20p11.2 deletions in syndromic HI.

Diabetes control is worse in children and young people with type 1 diabetes requiring interpreter support.

Introduction: Language barriers can pose a significant hurdle to successfully educating children and young people with type 1 diabetes (CYPD) and their families, potentially influencing their glycaemic control. Methods: Retrospective case-control study assessing HbA1c values at 0, 3, 6, 9, 12 and 18 months post-diagnosis in 41 CYPD requiring interpreter support (INT) and 100 age-, sex- and mode-of-therapy-matched CYPD not requiring interpreter support (CTR) in our multi-diverse tertiary diabetes centre. Data were captured between 2009-2016. English indices of deprivation for each cohort are reported based on the UK 2015 census data. Results: The main languages spoken were Somali (27%), Urdu (19.5%), Romanian (17%) and Arabic (12%), but also Polish, Hindi, Tigrinya, Portuguese, Bengali and sign language. Overall deprivation was worse in the INT group according to the Index of Multiple Deprivation (IMD [median]: INT 1.642; CTR 3.741; p=0.001). The median HbA1c was higher at diagnosis in the CTR group (9.95% [85.2 mmol/mol] versus 9.0% [74.9 mmol/mol], p=0.046) but was higher in the INT group subsequently: the median HbA1c at 18 months post diagnosis was 8.3% (67.2 mmol/mol; INT) versus 7.9% (62.8 mmol/mol; CTR) (p=0.014). There was no hospitalisation secondary to diabetes-related complications in either cohorts. Summary and conclusions: Glycaemic control is worse in CYPD with language barriers. These subset of patients also come from the most deprived areas which adds to the disadvantage. Health care providers should offer tailored support for CYP/families with language barriers, including provision of diabetes-specific training for interpreters, and explore additional factors contributing to poor glycaemic control. The findings of this study suggest that poor health outcomes in CYPD with language barriers is multifactorial and warrants a multi-dimensional management approach.

The Incidence and Outcomes for Children with Cleft Palate and/or Lip and CHARGE Syndrome.

OBJECTIVES: Published literature on children with cleft palate and/or lip (CP + /-L) and CHARGE syndrome (CS) is limited. This study investigated cleft characteristics including surgery, and feeding and communication outcomes in children identified with CP + /-L and CS. DESIGN: Retrospective cross-sectional review. SETTING: Regional Referral Centre for Paediatric Cleft Surgery. PATIENTS: All children diagnosed with CP + /-L and CS (based on clinical features and/or CHD7 mutation testing) between 1989-2019. MAIN OUTCOME MEASURES: Cleft type, timing of CP + /-L repair, reasons for 'delayed' repair, feeding methods and communication modality. RESULTS: Twenty-two children with CP + /-L and CS were identified. Cleft sub-types (%) were: Eleven (50%) had bilateral cleft lip and palate (BCLP), six (27%) had unilateral cleft lip and palate (UCLP) and five (23%) had cleft palate (CP). Cleft repair was delayed compared to protocol care for non-syndromic children with CP + /-L. Median age for lip repair + /- vomerine flap was 9 months (range 4-22 months), and palate repair was 21 months (range 11-40 months). Median age for isolated CP repair was 13 months (range 7-23). Surgery for cardiac anomalies (36%) before cleft repair, and (59%) were classed as having severe systemic disease at the time of cleft surgery. Only 27% of the children in this study had both full oral feeding and verbal communication. CONCLUSIONS: Children with CP + /-L and CS had severe cleft types and complex medical problems leading to delayed cleft surgery. Feeding and speech outcomes were better in the children aged over ten years.

An effective and cost-saving structured education program teaching dynamic glucose management strategies to a socio-economically deprived cohort with type 1 diabetes in a VIRTUAL setting.

OBJECTIVES: Compare the clinical and cost-effectiveness of an established face to face (F2F) structured education program to a new remote (VIRTUAL) program teaching dynamic glucose management (DynamicGM) to children and young people with type 1 diabetes (CYPD) using continuous glucose monitoring (CGM). To ascertain the most effective DynamicGM strategies predicting time in range (TIR) (3.9-10.0 mmol/L) and incorporating these into a user-friendly teaching aid. DESIGN AND METHODS: Effectiveness of the F2F and VIRTUAL programs were ascertained by comparing the mean change (Δ) from baseline to 6 months in HbA1c, TIR and severe hypoglycemia. Delivery cost for the two programs were evaluated. Factors predicting TIR in the combined cohort were determined and incorporated into a user-friendly infographic. RESULTS: First 50 graduates per group were evaluated. The mean difference in Δ HbA1c, Δ TIR and Δ episodes of severe hypoglycemia between VIRTUAL and F2F groups were 1.16 (p = 0.47), 0.76 (p = 0.78) and -0.06 (p = 0.61) respectively. Delivery cost per 50 CYPD for VIRTUAL and F2F were $5752 and $7020, respectively. The strongest predictors of TIR (n = 100) were short bursts of exercise (10-40 min) to lower hyperglycemia (p < 0.001), using trend arrow adjustment tools (p < 0.001) and adjusting pre-meal bolus timing based on trend arrows (p < 0.01). These strategies were translated into a GAME (Stop highs), SET (Stay in target), MATCH (Prevent lows) mnemonic. CONCLUSION: Teaching DynamicGM VIRTUALLY is just as effective as F2F delivery and cost saving. Short bursts of exercise and using CGM trend arrows to adjust insulin dose and timing improves TIR.

Fifteen-minute consultation: Practical use of continuous glucose monitoring.

Type 1 diabetes is a self-managed condition. Regular monitoring of blood glucose (BG) levels has been the cornerstone of diabetes management. Finger prick BG testing traditionally has been the standard method employed. More recently, rapid advancements in the development of continuous glucose monitoring devices have led to increased use of technology to help children and young people with diabetes manage their condition. These devices have the potential to improve diabetes control and reduce hypoglycaemia especially if used in conjunction with a pump to automate insulin delivery. This paper aims to provide an update on main CGM devices available and practical considerations for doctors if they come across a child with diabetes who is using one of these devices.

Hemoglobin A1c trajectories in the first 18 months after diabetes diagnosis in the SWEET diabetes registry.

AIM: A majority of youth with type 1 diabetes do not meet recommended hemoglobin A1c (HbA1c) targets. The SWEET diabetes registry is a multi-national registry of youth with diabetes. We used data from this registry to identify characteristics associated with glycemic control. METHODS: Patients in the SWEET diabetes registry with at least one HbA1c value within 10 days of diagnosis and three follow up measurements in the first 18 months of diagnosis were included (~10% of the SWEET diabetes registry). Locally weighted scatterplot smoothing was used to generate curves of HbA1c. Wilcoxon, Kruskal-Wallis, or χ2-tests were used to calculate differences between groups. RESULTS: The mean HbA1c of youth in the SWEET diabetes registry is highest at diagnosis and lowest between months 4 and 5 post-diabetes diagnosis. HbA1c continues to increase steadily through the first 18 months of diagnosis. There are no differences in HbA1c trajectories based on sex or use of diabetes technology. Youth in North America/Australia/New Zealand had the highest HbA1c throughout the first 18 months of diagnosis. The trajectory of youth from countries with nationalized health insurance was lower than those countries without nationalized health insurance. Youth from countries with the highest gross domestic product (GDP) had the highest HbA1c throughout the first 18 months of diagnosis. CONCLUSIONS: In this subset of patients, the trajectory of youth from countries with nationalized health insurance was lower than those countries without nationalized health insurance. High GDP and high use of technology did not seem to protect from a higher trajectory.

Obesity-Associated GNAS Mutations and the Melanocortin Pathway.

BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).

A Worldwide Perspective on COVID-19 and Diabetes Management in 22,820 Children from the SWEET Project: Diabetic Ketoacidosis Rates Increase and Glycemic Control Is Maintained.

Aims: To investigate the short-term effects of the first wave of COVID-19 on clinical parameters in children with type 1 diabetes (T1D) from 82 worldwide centers participating in the Better Control in Pediatric and Adolescent DiabeteS: Working to CrEate CEnTers of Reference (SWEET) registry. Materials and Methods: Aggregated data per person with T1D ≤21 years of age were compared between May/June 2020 (first wave), August/September 2020 (after wave), and the same periods in 2019. Hierarchic linear and logistic regression models were applied. Models were adjusted for gender, age-, and diabetes duration-groups. To distinguish the added burden of the COVID-19 pandemic, the centers were divided into quartiles of first wave COVID-19-associated mortality in their country. Results: In May/June 2019 and 2020, respectively, there were 16,735 versus 12,157 persons, 52% versus 52% male, median age 13.4 (Q1; Q3: 10.1; 16.2) versus13.5 (10.2; 16.2) years, T1D duration 4.5 (2.1; 7.8) versus 4.5 (2.0; 7.8) years, and hemoglobin A1c (HbA1c) 60.7 (53.0; 73.8) versus 59.6 (50.8; 70.5) mmol/mol [7.8 (7.0; 8.9) versus 7.6 (6.8; 8.6) %]. Across all country quartiles of COVID-19 mortality, HbA1c and rate of severe hypoglycemia remained comparable to the year before the first wave, while diabetic ketoacidosis rates increased significantly in the centers from countries with the highest mortality rate, but returned to baseline after the wave. Continuous glucose monitoring use decreased slightly during the first wave (53% vs. 51%) and increased significantly thereafter (55% vs. 63%, P < 0.001). Conclusions: Although glycemic control was maintained, a significant rise in DKA at follow-up was seen during first wave in the quartile of countries with the highest COVID mortality. Trial Registration: NCT04427189.

Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism.

INTRODUCTION: Autosomal recessive forms of pseudohypoaldosteronism are caused by genetic defects in the epithelial sodium channel. Little is known about the long-term outcome and medication needs during childhood and adolescence. OBJECTIVE: This study reports a single-centre experience of children affected with this ultra-rare condition over a 37-year period. METHODS: We report the clinical presentation, growth, neuro-development, associated conditions, mortality and medication dosing and administration for 12 affected children from eight families. RESULTS: All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia. All parents were consanguineous and of South Asian, Middle Eastern or African ethnic origin. Eight children had homozygous mutations in the SCNN1A and SCNN1G genes, encoding the epithelial sodium channel subunits alpha and gamma, respectively, including one novel mutation. Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia. One affected female had a successful pregnancy at the age of 28 years. CONCLUSION: Despite high mortality and morbidity in this condition, survival with normal physical and neurological outcome is possible, justifying intensive management to prevent electrolyte imbalance.

DYNAMIC: Dynamic glucose management strategies delivered through a structured education program improves time in range in a socioeconomically deprived cohort of children and young people with type 1 diabetes with a history of hypoglycemia.

OBJECTIVES: Create and evaluate the effectiveness of a structured education program in children and young people (CYP) with type 1 diabetes using continuous glucose monitoring (CGM). DESIGN AND METHODS: Step 1: CGM devices were evaluated for predetermined criteria using a composite score. Step 2: The education program was developed following review of international structured education guidance, dynamic glucose management (DynamicGM) literature, award-winning diabetes educators' websites, and CGM user feedback. Step 3: Program effectiveness was assessed at six months by change in time below range (TBR) (<3.9mmol/L), time in range (TIR) (3.9-10.0mmol/L), time above range level 2 (TAR2) (>13.9mmol/L), severe hypoglycemia and HbA1c using a paired T-test. A DynamicGM score was developed to assess proactive glucose management. Factors predicting TBR and TIR were assessed using regression analysis. RESULTS: Dexcom G6 was chosen for integrated CGM (iCGM) status and highest composite score (29/30). Progressive DynamicGM strategies were taught through five sessions delivered over two months. Fifty CYP (23 male) with a mean (±SD) age and diabetes duration of 10.2 (±4.8) and 5.2 (±3.7) years respectively, who completed the education program were prospectively evaluated. Evaluation at six months showed a significant reduction in TBR (10.4% to 2.1%, p<.001), TAR2 (14.1% to 7.3%, p<.001), HbA1c [7.4 to 7.1% (57.7 to 53.8 mmol/mol), p<.001] and severe hypoglycemic episodes (10 to 1, p<.05); TIR increased (47.4% to 57.0%, p<.001). Number of Dexcom followers (p<.05) predicted reduction in TBR and DynamicGM score (p<.001) predicted increased TIR. CONCLUSION: Teaching DynamicGM strategies successfully improves TIR and reduces hypoglycemia.

Presentation of newly diagnosed type 1 diabetes in children and young people during COVID-19: a national UK survey.

In the UK, there have been reports of significant reductions in paediatric emergency attendances and visits to the general practitioners due to COVID-19. A national survey undertaken by the UK Association of Children's Diabetes Clinicians found that the proportion of new-onset type 1 diabetes (T1D) presenting with diabetes ketoacidosis (DKA) during this COVID-19 pandemic was higher than previously reported, and there has been an increase in presentation of severe DKA at diagnosis in children and young people under the age of 18 years. Delayed presentations of T1D have been documented in up 20% of units with reasons for delayed presentation ranging from fear of contracting COVID-19 to an inability to contact or access a medical provider for timely evaluation. Public health awareness and diabetes education should be disseminated to healthcare providers on the timeliness of referrals of children with T1D.

Causes, patterns and severity of androgen excess in 487 consecutively recruited pre- and post-pubertal children.

Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess. Design Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years. Methods Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review. Results In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (>20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione. Conclusions Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.

Management of children with type 1 diabetes during illness: a national survey.

AIM: Adequate sick-day management at home can reduce the risk of progression to diabetic ketoacidosis and admission to hospital. The aim of this project was to review the management of diabetes during illness. METHOD: The Association of Children's Diabetes Clinicians (ACDC) carried out a questionnaire survey of all paediatric diabetes units. In addition, parents of children with type 1 diabetes completed an online questionnaire. RESULTS: The survey of 127 units had a 73% response rate. Sick-day management guidelines were in place in 93%. All guidelines advised giving extra insulin during illness. In 67%, the extra dose was based on a fraction of total daily dose. 22% used units per kg body weight (U/kg). 21% used locally derived formulae to calculate extra dose of insulin. 3% of units advised only blood ketone monitoring. Although all units had an out-of-hours access policy for the families, 45% received advice from the general paediatric registrar. Only in 15%, the advice was directly from a member of the paediatric diabetes team. 680 parents completed the questionnaire. 86% reported receiving training on managing sick days. The majority (52.2%) receiving an informal session at diagnosis. 40% did not know what to do in the presence of raised blood glucose and high blood ketones. CONCLUSIONS: There was a wide variation in the practice of monitoring and advice given during illness. Both surveys highlight need for national guidance as well and to improve quality of sick-day rule education programmes for parents of children with type 1 diabetes.