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.

A realist synthesis of multicentre comparative audit implementation: exploring what works and in which healthcare contexts.

BACKGROUND: Multicentre comparative clinical audits have the potential to improve patient care, allow benchmarking and inform resource allocation. However, implementing effective and sustainable large-scale audit can be difficult within busy and resource-constrained contemporary healthcare settings. There are little data on what facilitates the successful implementation of multicentre audits. As healthcare environments are complex sociocultural organisational environments, implementing multicentre audits within them is likely to be highly context dependent. OBJECTIVE: We aimed to examine factors that were influential in the implementation process of multicentre comparative audits within healthcare contexts-what worked, why, how and for whom? METHODS: A realist review was conducted in accordance with the Realist and Meta-narrative Evidence Syntheses: Evolving Standards reporting standards. A preliminary programme theory informed two systematic literature searches of peer-reviewed and grey literature. The main context-mechanism-outcome (CMO) configurations underlying the implementation processes of multicentre audits were identified and formed a final programme theory. RESULTS: 69 original articles were included in the realist synthesis. Four discrete CMO configurations were deduced from this synthesis, which together made up the final programme theory. These were: (1) generating trustworthy data; (2) encouraging audit participation; (3) ensuring audit sustainability; and (4) facilitating audit cycle completion. CONCLUSIONS: This study elucidated contexts, mechanisms and outcomes influential to the implementation processes of multicentre or national comparative audits in healthcare. The relevance of these contextual factors and generative mechanisms were supported by established theories of behaviour and findings from previous empirical research. These findings highlight the importance of balancing reliability with pragmatism within complex adaptive systems, generating and protecting human capital, ensuring fair and credible leadership and prioritising change facilitation.

International Newborn Screening Practices for the Early Detection of Congenital Adrenal Hyperplasia.

INTRODUCTION: Newborn screening (NBS) programmes vary internationally in their approach to screening. Guidelines for congenital adrenal hyperplasia (CAH) screening recommend the use of two-tier testing and gestational age cutoffs to minimise false-positive results. The aims of this study were to describe (1) the approaches; (2) protocols used; and (3) available outcomes for CAH screening internationally. METHODS: All members of the International Society for Neonatal Screening were asked to describe their CAH NBS protocols, with an emphasis on the use of second-tier testing, 17-hydroxyprogesterone (17OHP) cutoffs, and gestational age and birth weight adjustments. If available, screening outcomes were requested. RESULTS: Representatives from 23 screening programmes provided data. Most (n = 14; 61%) recommend sampling at 48-72 h of life. Fourteen (61%) use single-tier testing and 9 have a two-tier testing protocol. Gestational age cutoffs are used in 10 programmes, birth weight cutoffs in 3, and a combination of both in 9. One programme does not use either method of adjusting 17OHP cutoffs. Case definition of a positive test and the response to a positive test differed between programmes. CONCLUSIONS: We have demonstrated significant variation across all aspects of NBS for CAH, including timing, the use of single versus two-tier testing and cutoff interpretation. Collaboration between international screening programmes and implementation of new techniques to improve screen efficacy will facilitate ongoing expansion and quality improvement in CAH NBS.

Relationship between parent-adolescent communication and parent involvement in adolescent Type 1 diabetes management, parent/family wellbeing and glycaemic control.

OBJECTIVES: This study investigated the relationship between parent-reported degree of openness and extent of problems in parent-adolescent communication and parent involvement in adolescent Type 1 diabetes management, parent and family wellbeing and adolescent glycaemic control. METHODS: A cross-sectional quantitative survey was conducted. Parents completed measures of parent-adolescent communication, parent monitoring of diabetes care, diabetes family responsibility, parent knowledge of diabetes care, parent activation, parent diabetes distress, and diabetes family conflict. RESULTS: In total, 146 parents/guardians (121 mothers, mean age 46.56 years, SD 5.18) of adolescents aged 11-17 years (mean age 13.9 years, SD 1.81) with Type 1 diabetes completed the survey. Open parent-adolescent communication was significantly correlated to adolescents' voluntarily disclosing diabetes-specific information to their parents more frequently, increased parental knowledge of their adolescent's diabetes care completion, parents feeling more capable and willing to take action in relation to their adolescent's diabetes health, lower levels of diabetes-related parental distress, less diabetes-specific family conflict, and optimal glycaemic control. DISCUSSION: Parent-adolescent communication has an important role to play in Type 1 diabetes healthcare management and psychosocial wellbeing during adolescence. Optimising open parent-adolescent communication represents a potentially useful target for interventional research and should be considered by healthcare professionals during healthcare encounters.

Adolescent perspectives on negotiating self-management responsibilities for type 1 diabetes with their parents.

OBJECTIVE: The overall purpose of this study was to explore adolescent perspectives on communicating about self-management of type 1 diabetes (T1D) and negotiating responsibilities for self-management with parents. METHODS: Semi-structured interviews were conducted with 28 adolescents aged 11-17 years living with T1D. Interviews were audio-recorded, transcribed verbatim and thematically analysed. RESULTS: Two themes and five subthemes were identified. The first theme, 'changing levels of involvement in self-management' describes the division of responsibility for self-management within the family and adolescents collaborating and sharing responsibilities with parents for self-management. The second theme, 'talking about self-management with parents' describes changes in patterns of parent-adolescent communication about T1D over time, adolescents' seeking parental feedback and advice and the factors that contribute to the promotion of self-management communication between adolescents and parents. CONCLUSION: This study identified that how adolescents perceive communication with their parents contributes to negotiation of responsibilities for self-management during adolescence. The findings provide a nuanced understanding of adolescent perspectives on communication with parents about T1D self-management and how parent-adolescent communication can be framed in ways that promote positive adolescent engagement with T1D self-management. PRACTICE IMPLICATIONS: Targeting parent-adolescent communication strategies may result in more optimal sharing of responsibilities and improved self-management.

Parents' perspectives of factors affecting parent-adolescent communication about type 1 diabetes and negotiation of self-management responsibilities.

Adolescence is an important time in which young people take on type 1 diabetes (T1D) self-management responsibility. Parents are key facilitators of this process. Little is known about parents' experiences of communicating with their children about T1D during adolescence. Semi-structured interviews were conducted with 32 parents (24 mothers and 8 fathers) of adolescents (11-17 years) living with T1D to explore how parents communicate about T1D and self-management with their adolescent children. Parents were recruited through two national child and adolescent diabetes and endocrine clinics and online advertisement through a national diabetes advocacy organisation. Interviews were transcribed verbatim and thematically analysed. Six themes were identified: parent factors, quality of the parent-adolescent relationship, communication strategies, adolescent factors, communication triggers and family/system factors. Understanding factors that impact communication about self-management between parents and adolescents will enable healthcare professionals to provide support and targeted interventions as parent and adolescent roles change over time.

Secondary Hyperparathyroidism in Children with Mucolipidosis Type II (I-Cell Disease): Irish Experience.

Mucolipidosis type II (ML II) is an autosomal recessive lysosomal targeting disorder that may present with features of hyperparathyroidism. The aim of this study was to describe in detail the clinical cases of ML II presenting to a tertiary referral centre with biochemical and/or radiological features of hyperparathyroidism. There were twenty-three children diagnosed with ML II in the Republic of Ireland from July 1998 to July 2021 inclusive (a 23-year period). The approximate incidence of ML II in the Republic of Ireland is, therefore, 1 per 64,000 live births. Medical records were available and were reviewed for 21 of the 23 children. Five of these had been identified as having biochemical and/or radiological features of hyperparathyroidism. Of these five, three children were born to Irish Traveller parents and two to non-Traveller Irish parents. All five children had radiological features of hyperparathyroidism (on skeletal survey), with evidence of antenatal fractures in three cases and an acute fracture in one. Four children had biochemical features of secondary hyperparathyroidism. Three children received treatment with high dose Vitamin D supplements and two who had antenatal/acute fractures were managed with minimal handling. We observed resolution of secondary hyperparathyroidism in all cases irrespective of treatment. Four of five children with ML II and hyperparathyroidism died as a result of cardiorespiratory failure at ages ranging from 10 months to 7 years. Biochemical and/or radiological evidence of hyperparathyroidism is commonly identified at presentation of ML II. Further studies are needed to establish the pathophysiology and optimal management of hyperparathyroidism in this cohort. Recognition of this association may improve diagnostic accuracy and management, facilitate family counseling and is also important for natural history data.

Increased referrals for congenital hyperinsulinism genetic testing in children with trisomy 21 reflects the high burden of non-genetic risk factors in this group.

BACKGROUND: 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 a high number of individuals with Down syndrome referred for hyperinsulinism genetic testing, and therefore aimed to investigate whether the prevalence of Down syndrome was increased in our hyperinsulinism cohort compared to the population. METHODS: We identified individuals with Down syndrome referred for hyperinsulinism genetic testing to the Exeter Genomics Laboratory between 2008 and 2020. We sequenced the known hyperinsulinism genes in all individuals and investigated their clinical features. RESULTS: We identified 11 individuals with Down syndrome in a cohort of 2011 patients referred for genetic testing for hyperinsulinism. This represents an increased prevalence compared to the population (2.5/2011 expected vs. 11/2011 observed, p = 6.8 × 10-5 ). A pathogenic ABCC8 mutation was identified in one of the 11 individuals. Of the remaining 10 individuals, five had non-genetic risk factors for hyperinsulinism resulting from the Down syndrome phenotype: intrauterine growth restriction, prematurity, gastric/oesophageal surgery, and asparaginase treatment for leukaemia. For five individuals no risk factors for hypoglycaemia were reported although two of these individuals had transient hyperinsulinism and one was lost to follow-up. CONCLUSIONS: Down syndrome is more common in patients with hyperinsulinism than in the population. This is likely due to an increased burden of non-genetic risk factors resulting from the Down syndrome phenotype. Down syndrome should not preclude genetic testing as coincidental monogenic hyperinsulinism and Down syndrome is possible.

Clinical and genetic heterogeneity of HNF4A/HNF1A mutations in a multicentre paediatric cohort with hyperinsulinaemic hypoglycaemia.

OBJECTIVE: The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY). DESIGN: We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995-2020). METHODS: Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis. RESULTS: A total of 34 patients (70.6% female, n = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2-6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0-13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%). CONCLUSIONS: We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.

The presentation of congenital adrenal hyperplasia in an unscreened population.

BACKGROUND: The aim of this study was to describe the incidence and spectrum of early clinical presentations of congenital adrenal hyperplasia (CAH) in an unscreened population. METHODS: A national retrospective observational study was undertaken to identify all children diagnosed with CAH in the Republic of Ireland, between January 2005 and December 2019. Reporting clinicians completed anonymized clinical questionnaires. RESULTS: There were 103 cases of CAH reported and 69 cases met the study inclusion criteria. The estimated annualized incidence of CAH in the Republic of Ireland was 1:14,754 or 0.07 cases per 1,000 live births. Forty-seven children presented clinically in the first six months of life, but only 17 of these had a confirmed diagnosis by day 10. Of these early presentations, there were 28 infants with salt-wasting, 15 females presented with virilized genitalia and four infants were detected due to a family history of CAH. Female infants presented at a median age of 0 days [IQR 0-1] and males at 14 days [IQR 9-21]. Seventy-eight percent of salt-wasting presentations occurred after day 10. Delays in clinical presentation, biochemical diagnosis and treatment initiation were identified. CONCLUSIONS: The incidence of CAH is higher in Ireland than in other unscreened populations. In the absence of screening, clinicians should be aware of the possibility of CAH and appropriate investigations should be urgently requested. Life-threatening salt-wasting is the most frequent clinical presentation and many cases could be detected prior to decompensation if newborn screening were introduced.

Infants Diagnosed with Athyreosis on Scintigraphy May Have a Gland Present on Ultrasound and Have Transient Congenital Hypothyroidism.

Scintigraphy using technetium-99m (99mTc) is the gold standard for imaging the thyroid gland in infants with congenital hypothyroidism (CHT) and is the most reliable method of diagnosing an ectopic thyroid gland. One of the limitations of scintigraphy is the possibility that no uptake is detected despite the presence of thyroid tissue, leading to the spurious diagnosis of athyreosis. Thyroid ultrasound is a useful adjunct to detect thyroid tissue in the absence of 99mTc uptake. AIMS: We aimed to describe the incidence of sonographically detectable in situ thyroid glands in infants scintigraphically diagnosed with athyreosis using 99mTc and to describe the clinical characteristics and natural history in these infants. METHODS: The newborn screening records of all infants diagnosed with CHT between 2007 and 2016 were reviewed. Those diagnosed with CHT and athyreosis confirmed on scintigraphy were invited to attend a thyroid ultrasound. RESULTS: Of the 488 infants diagnosed with CHT during the study period, 18/73 (24.6%) infants with absent uptake on scintigraphy had thyroid tissue visualised on ultrasound (3 hypoplastic thyroid glands and 15 eutopic glands). The median serum thyroid-stimulating hormone (TSH) concentration at diagnosis was significantly lower than that in infants with confirmed athyreosis (no gland on ultrasound and no uptake on scintigraphy) (74 vs. 270 mU/L), and median free T4 concentration at diagnosis was higher (11.9 vs. 3.9 pmol/L). Six of 10 (60%) infants with no uptake on scintigraphy but a eutopic gland on ultrasound had transient CHT. CONCLUSION: Absent uptake on scintigraphy in infants with CHT does not rule out a eutopic gland, especially in infants with less elevated TSH concentrations. Clinically, adding thyroid ultrasound to the diagnostic evaluation of infants who have athyreosis on scintigraphy may avoid committing some infants with presumed athyreosis to lifelong levothyroxine treatment.

Children and young people's experiences and perceptions of self-management of type 1 diabetes: A qualitative meta-synthesis.

The aim of this review was to conduct a meta-synthesis of the experiences and perceptions of self-management of type 1 diabetes of children and young people living with type 1 diabetes (CYPDs). Six databases were systematically searched for studies with qualitative findings relevant to CYPDs' (aged 8-18 years) experiences of self-management. A thematic synthesis approach was used to combine articles and identify analytical themes. Forty articles met the inclusion criteria. Two analytical themes important to CYPDs' experiences and perceptions of self-management were identified: (1) negotiating independence and (2) feeling in control. The synthesis contributes to knowledge on contextual factors underpinning self-management and what facilitates or impedes transition towards autonomous self-management for CYPDs.

Coeliac screening in a high-risk population: paediatric type 1 diabetes-a review of current guidelines and practice.

BACKGROUND AND AIMS: Coeliac disease (CD) is more common in those with type 1 diabetes mellitus (T1DM) and may be asymptomatic despite the presence of intestinal histological changes. Optimal screening practice guidelines differ internationally. We undertook a retrospective audit to determine the efficacy of current screening practice for CD in T1DM in our centre. METHODS: All children and adolescents < 16 years, diagnosed with T1DM in our service and continuing to attend the service in January 2017 were included. Data on CD screening was collected and compared to current NICE, NASPGHAN and ESPGHAN guidelines. RESULTS: Of the 355 patients attending our service, 253 attended from T1DM diagnosis and all had CD screening performed in our centre. In 37 of 253 patients, IgA-TTG was positive, providing a cumulative prevalence of 14.6%. Of these, 31(83.78%) with an elevated TTG on screening had no recorded gastrointestinal symptoms or CD-related clinical signs. Of the 35 TTG plus EMA-positive patients, 22/35 (59.46%) had diagnostic endoscopic biopsy. Nineteen (83.4%) had CD confirmed, 1 (4.54%) had negative biopsy and 2 (9%) had equivocal, non-diagnostic changes. CONCLUSIONS: Timely diagnosis of CD can prevent chronic ill health in affected individuals, and in patients with T1DM, CD is an independent risk factor for increased morbidity and mortality. Given the high prevalence of atypical symptoms and silent CD in those with T1DM, in this and other studies, and the benefits of detection and treatment of CD, screening is essential. Large-scale data collection allowing for the development of evidence-based guidelines is required.

Optimal Timing of Repeat Newborn Screening for Congenital Hypothyroidism in Preterm Infants to Detect Delayed Thyroid-Stimulating Hormone Elevation.

OBJECTIVES: To evaluate the timing of a delayed rise in thyroid-stimulating hormone (TSH) levels in preterm infants with congenital hypothyroidism, and to determine whether cases of congenital hypothyroidism would be missed by using current consensus guidelines of repeat screening at approximately 2 weeks of age or 2 weeks after the first screening. STUDY DESIGN: The study was performed over a 13-year period (January 2004-December 2016). Whole-blood TSH samples were collected between 72 and 120 hours after birth. Repeat samples were collected weekly in preterm infants until the infant was term-corrected (37 weeks' gestation). Patients were followed up to determine whether congenital hypothyroidism was permanent or transient. RESULTS: Twenty-seven (50.9%) preterm infants born at <33 weeks of gestation who were diagnosed with congenital hypothyroidism had delayed TSH elevation and would not have been detected on first newborn screen. Twelve of these infants (40.7%) with delayed TSH elevation had decompensated hypothyroidism at diagnosis (free thyroxine [FT4] <10 pmol/L), and 4 had severe congenital hypothyroidism (FT4 <5.5 pmol/L) at diagnosis. If screening had been repeated only at 2 weeks of life, 13 infants (48%) with delayed TSH elevation would not have been identified. Of the 27 infants with delayed TSH elevation, 6 (22%) have permanent congenital hypothyroidism, and another 12 will be reevaluated at age 3 years. CONCLUSION: Repeat screening for congenital hypothyroidism in preterm infants is necessary to avoid missing cases of congenital hypothyroidism with delayed TSH elevation. Repeat screening once at 2 weeks of life will miss infants with delayed TSH elevation and decompensated permanent congenital hypothyroidism.

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

Incidence of Congenital Hypothyroidism Over 37 Years in Ireland.

BACKGROUND AND OBJECTIVES: Congenital hypothyroidism (CHT) is one of the most common preventable causes of learning disability. Newborn screening with whole-blood thyroid-stimulating hormone measurements was introduced in the Republic of Ireland in 1979 and is coordinated from a single center with an unchanged protocol since its inception. Our objective in this study was to describe the incidence of CHT in the Republic of Ireland over the past 37 years in the context of a complete national population and an unchanged screening protocol. METHODS: The newborn screening records of all individuals who were diagnosed with CHT between 1979 and 2016 were reviewed. Infants with positive screening results had a whole-blood thyroid-stimulating hormone value of ≥15 mU/L at 72 to 120 hours of life; values of 8 to 15 mU/L required a repeat whole-blood screening test. RESULTS: Of 2 361 174 infants who were screened between July 1979 and December 2016, 1063 (662 girls) were diagnosed with CHT (incidence: 0.45 cases per 1000 live births). The number of detected cases increased from 0.27 cases per 1000 live births treated between 1979 and 1991 to 0.41 cases per 1000 live births treated between 1992 and 2004 to 0.65 cases per 1000 live births treated between 2005 and 2016. The increase in detected cases of CHT was predominantly in the normal or hyperplastic gland category. CONCLUSIONS: The incidence of CHT has increased significantly in the Republic of Ireland over the past 37 years despite a consistent screening cutoff. The increased rate was not explained by an increased survival rate of preterm infants or a changing population heterogeneity.

Outcomes of using flash glucose monitoring technology by children and young people with type 1 diabetes in a single arm study.

BACKGROUND AND OBJECTIVE: Outcomes of using flash glucose monitoring have been reported in adults. This trial evaluated use in children and teenagers with type 1 diabetes. METHODS: Prospective, single arm, non-inferiority multicenter study to demonstrate equivalence of time in range (TIR [70-180 mg/dL]) by comparing 14-day masked sensor wear (baseline) with self-monitored blood glucose (SMBG) testing to the final 14-days of 8-week open-label system use for diabetes self-management including insulin dosing. RESULTS: A total of 76 children and teenagers (46.1% male; age 10.3 ± 4.0 years, type 1 diabetes duration 5.4 ± 3.7 years; mean ± SD) from 10 sites participated. TIR improved significantly by 0.9 ± 2.8 h/d (P = 0.005) vs SMBG baseline. Time in hyperglycemia (>180 mg/dL) reduced by -1.2 ± 3.3 h/d (P = 0.004). HbA1c reduced by -0.4% (-4.4 mmol/mol), from 7.9 ± 1.0% (62.9 ± 11.2 mmol/mol) baseline to 7.5 ± 0.9% (58.5 ± 9.8 mmol/mol) study end (P < 0.0001) with reductions across all age-subgroups (4-6, 7-12 and 13-17 years). Time in hypoglycemia (<70 mg/dL) was unaffected. Throughout the treatment phase system utilization was 91% ± 9; sensor scanning was 12.9 ± 5.7/d with SMBG dropping to 1.6 ± 1.9 from 7.7 ± 2.5/d. Diabetes Treatment Satisfaction Questionnaire "Total Treatment Satisfaction" score improved for parents (P < 0.0001) and teenagers (P < 0.0001). No adverse events (n = 121) were associated with sensor accuracy, 42 participants experienced sensor insertion signs and symptoms. Three participants experienced three mild device-related (sensor wear) symptoms, resolving quickly (without treatment [n = 2], non-prescription antihistamines [n = 1]). CONCLUSIONS: Children with diabetes improved glycemic control safely and effectively with short-term flash glucose monitoring compared to use of SMBG in a single arm study.

Permanent Decompensated Congenital Hypothyroidism in Newborns with Whole-Blood Thyroid-Stimulating Hormone Concentrations between 8 and 10 mU/L: The Case for Lowering the Threshold.

BACKGROUND: Congenital hypothyroidism (CHT) has a reported incidence of approximately 1 in 2,000-4,000 births. There is no consensus on the optimal cut-off whole-blood thyroid-stimulating hormone (TSH) concentration that should be used for newborn screening (NBS). The NBS programme in the Republic of Ireland has used a cut-off of 8 mU/L since 1979. The aim of this study was to determine if raising the cut-off to 10 mU/L would have resulted in undetected cases of permanent or decompensated CHT. METHODS: All cases of CHT with a screening whole-blood TSH concentration between 8.0 and 9.9 mU/L were identified from the Republic of Ireland's NBS programme. Baseline demographics and imaging results were recorded. All cases over 3 years of age were evaluated to determine if CHT was permanent or transient. RESULTS: Of 2,361,174 infants screened in the Republic of Ireland between July 1979 and December 2016, a total of 1,063 babies were diagnosed with CHT and treated with levothyroxine. This included 33 (3.5%) infants with a whole-blood TSH concentration between 8 and 9.9 mU/L. Thirteen of these 33 infants had decompensated hypothyroidism with low plasma free thyroxine level at diagnosis and 9 (41%) of the 21 evaluable cases have confirmed permanent CHT. CONCLUSION: Although lowering screening TSH cut-offs can increase the cost of NBS, as well as anxiety for families, many infants with borderline increases in whole-blood TSH concentrations on NBS have persistent CHT and low thyroxine concentrations in infancy. We recommend that this is considered when developing and reviewing NBS protocols for identifying infants with CHT.

Catalogue of inherited disorders found among the Irish Traveller population.

Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios. Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population. Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers. Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication. Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.