Lindsey Rigby

Abnormal Neurodevelopmental Outcomes are Common in Children with Transient Congenital Hyperinsulinism

Introduction: Neuroglycopenia is recognized to be associated with abnormal neurodevelopmental outcomes in 26–44% of children with persistent congenital hyperinsulinism (P-CHI). The prevalence of abnormal neurodevelopment in transient CHI (T-CHI) is not known. We have aimed to investigate abnormal neurodevelopment and associated factors in T-CHI and P-CHI. Materials and Methods: A cohort of children with CHI (n = 67, age 2.5–5 years) was assessed at follow-up review and noted to have normal or abnormal (mild or severe) neurodevelopmental outcomes for the domains of speech and language, motor, and vision. Children were classified as P-CHI (n = 33), if they had undergone surgery or remained on medical therapy, or T-CHI (n = 34), if medical treatment for hypoglycemia was stopped. Results: Overall, abnormal neurodevelopment was present in 26 (39%) children with CHI, of whom 18 (69%) were severe. Importantly, the incidence of abnormal neurodevelopment in T-CHI was similar to that in P-CHI (30 vs. 47% respectively, p = 0.16). The prevalence of severe abnormal neurodevelopment in speech, motor, and vision domains was similar in both T-CHI and P-CHI children. For this cohort, we found that the severity of disease [based upon maximal diazoxide dose (odds ratio 95% confidence intervals) 1.3 (1.1; 1.5), p = 0.03], and early presentation of CHI <7 days following birth [5.9 (1.3; 27.8), p = 0.02] were significantly associated with abnormal neurodevelopment. There was no significant association with gender, genotype, or the histopathological basis of CHI. Conclusion: Abnormal neurodevelopment was evident in one third of children with both T-CHI and P-CHI, early presentation and severe CHI being risk factors. Early recognition and rapid correction of hypoglycemia are advocated to avoid abnormal neurodevelopment in children with CHI.

Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease.

Objectives: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation. Methods: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly. Results: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation. Conclusions: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.

Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time

BackgroundPatients with Congenital Hyperinsulinism (CHI) due to mutations in K-ATP channel genes (K-ATP CHI) are increasingly treated by conservative medical therapy without pancreatic surgery. However, the natural history of medically treated K-ATP CHI has not been described; it is unclear if the severity of recessively and dominantly inherited K-ATP CHI reduces over time. We aimed to review variation in severity and outcomes in patients with K-ATP CHI treated by medical therapy.MethodsTwenty-one consecutively presenting patients with K-ATP CHI with dominantly and recessively inherited mutations in ABCC8/KCNJ11 were selected in a specialised CHI treatment centre to review treatment outcomes. Medical treatment included diazoxide and somatostatin receptor agonists (SSRA), octreotide and somatuline autogel. CHI severity was assessed by glucose infusion rate (GIR), medication dosage and tendency to resolution. CHI outcome was assessed by glycaemic profile, fasting tolerance and neurodevelopment.ResultsCHI presenting at median (range) age 1 (1, 240) days resolved in 15 (71%) patients at age 3.1(0.2, 13.0) years. Resolution was achieved both in patients responsive to diazoxide (n = 8, 57%) and patients responsive to SSRA (n = 7, 100%) with earlier resolution in the former [1.6 (0.2, 13.0) v 5.9 (1.6, 9.0) years, p = 0.08]. In 6 patients remaining on treatment, diazoxide dose was reduced in follow up [10.0 (8.5, 15.0) to 5.4 (0.5, 10.8) mg/kg/day, p = 0.003]. GIR at presentation did not correlate with resolved or persistent CHI [14.9 (10.0, 18.5) v 16.5 (13.0, 20.0) mg/kg/min, p = 0.6]. The type of gene mutation did not predict persistence; resolution could be achieved in recessively-inherited CHI with homozygous (n = 3), compound heterozygous (n = 2) and paternal mutations causing focal CHI (n = 2). Mild developmental delay was present in 8 (38%) patients; adaptive functioning assessed by Vineland Adaptive Behavior Scales questionnaire showed a trend towards higher standard deviation scores (SDS) in resolved than persistent CHI [−0.1 (−1.2, 1.6) v −1.2 (−1.7, 0.03), p = 0.1].ConclusionsIn K-ATP CHI patients managed by medical treatment only, severity is reduced over time in the majority, including those with compound heterozygous and homozygous mutations in ABCC8/KCNJ11. Severity and treatment requirement should be assessed periodically in all children with K-ATP CHI on medical therapy.

Increased Plasma Incretin Concentrations Identifies a Subset of Patients with Persistent Congenital Hyperinsulinism without KATP Channel Gene Defects

Congenital hyperinsulinism causes profound hypoglycemia, which may persist or resolve spontaneously. Among 13 children with congenital hyperinsulinism, elevated incretin hormone concentrations were detected in 2 with atypical, persistent disease. We suggest that incretin biomarkers may identify these patients, and that elevated hormone levels may contribute to their pathophysiology.

The association of cardiac ventricular hypertrophy with congenital hyperinsulinism.

OBJECTIVE Ventricular hypertrophy (VH) has been observed in children with congenital hyperinsulinism (CHI), a condition of hypoglycaemia characterised by dysregulated insulin secretion, but the prevalence is not known. PATIENTS AND METHODS Cardiac assessment was performed in children (n=49) with CHI at diagnosis and follow-up. Two dimensional and Doppler echocardiography studies were used to assess cardiac structures, while M-mode study was used to measure left ventricular (LV) dimensions, subsequently converted to Z scores. Where possible, LV hypertrophy was confirmed by LV mass index (g/m(2.7)) >95th centile. RESULTS Cardiac structural lesions were found in 14 (28%) children. At initial echocardiography, VH was present in 31 (65%) children with median (range) LV posterior wall dimension in diastole Z scores of +1.6 (-2.4 to +5.8) and interventricular septal wall dimension in end diastole Z scores of +1.9 (-1.7 to +17.2). At follow-up echocardiography, performed after an interval of 178 (45-390) days, VH persisted in 16 (33%) children. In regression analysis, the presence of VH (odds ratio (95% confidence intervals) 1.1 (1.0-1.2), P=0.04) at initial echocardiography was correlated with maximum glucose requirement at diagnosis, indicating that severity of CHI at presentation may play a role in the pathogenesis of VH. CONCLUSIONS A significant proportion of children with CHI have cardiac structural lesions. A majority also have VH, which may be associated with the severity of CHI at diagnosis. VH may persist in some children, which requires careful long-term cardiac review.

Feeding Problems Are Persistent in Children with Severe Congenital Hyperinsulinism

Background Congenital hyperinsulinism (CHI) is a rare but severe disorder of hypoglycemia in children, often complicated by brain injury. In CHI, the long-term prevention of hypoglycemia is dependent on reliable enteral intake of glucose. However, feeding problems (FPs) often impede oral glucose delivery, thereby complicating the management of hypoglycemia. FPs have not been systematically characterized in follow-up in a cohort with CHI. Aims We aimed to determine the prevalence, types, and persistence of FPs in a cohort of children with CHI and investigate potential causal factors. Methods FPs were defined as difficulty with sucking, swallowing, vomiting, and food refusal (or a combination) in an observational study in 83 children in a specialized CHI treatment center. The prevalence of FPs at diagnosis, 6, and 12 months after diagnosis were noted. Genetic mutation status and markers of severity of CHI were tested for association with FPs. Results A third of children with CHI had FPs (n = 28), of whom 93% required antireflux medication and 75% required nasogastric and gastrostomy tube feeding. Sucking and swallowing problems were present at diagnosis but absent later. Vomiting was present in 54% at 6 months, while food refusal was present in 68% at 6 months and 52% at 12 months. The age at commencing and stopping nasogastric tube feeding did not correlate with FPs frequency at 6 and 12 months. Children with FPs had severe hypoglycemia at diagnosis and required glucagon infusion more often [odds ratio (OR) (95% confidence intervals) (95% CI) 28.13 (2.6–300.1), p = 0.006] to normalize glucose levels. FPs were more frequent in those with diffuse CHI undergoing subtotal pancreatectomy [n (%) = 10 (35%) vs. 0 (0%), p < 0.001], in contrast to those with spontaneous resolution [6 (22%) vs. 32 (58%), p = 0.002]. Those undergoing focal lesionectomy also had reduced FPs at 6 months after diagnosis [OR (95% CI) 0.01 (0.0–0.2), R2 = 0.42, p = 0.004]. These observations suggest that persistence of hyperinsulinism was associated with FPs. Conclusion FPs occur in a significant proportion of children with CHI. Severe hyperinsulinism, rather than nasogastric tube feeding or medications, is the main factor associated with FPs.

Reduced Glycemic Variability in Diazoxide-Responsive Children with Congenital Hyperinsulinism Using Supplemental Omega-3-Polyunsaturated Fatty Acids; A Pilot Trial with MaxEPAR

Objective: Congenital hyperinsulinism (CHI) is a rare condition of hypoglycemia where therapeutic options are limited and often complicated by side-effects. Omega-3-polyunsaturated fatty acids (PUFA), which can suppress cardiac myocyte electrical activity, may also reduce ion channel activity in insulin-secreting cells. PUFA supplements in combination with standard medical treatment may improve glucose profile and may reduce glycemic variability in diazoxide-responsive CHI. Design: Open label pilot trial with MaxEPAR liquid (eicosapentaenoic and docosahexaenoic acid) PUFA (3 ml/day for 21 days) in diazoxide-responsive CHI patients (https://eudract.ema.europa.eu/, EudraCT number 201100363333). Methods: Glucose levels were monitored pre-treatment, end of treatment, and at follow-up by subcutaneous continuous glucose monitoring systems (CGMS) in 13 patients (7 girls) who received PUFA. Outcome measures were an improved glucose profile, reduced glycemic variability quantified by a reduction in the frequency of glucose levels <4 and >10 mmol/l, and safety of PUFA. All children were analyzed either as intention to treat (n = 13) or as per protocol (n = 7). Results: Mean (%) CGMS glucose levels increased by 0.1 mmol/l (2%) in intention to treat and by 0.4 mmol/l (8%) in per protocol analysis (n = 7). The frequency of CGMS <4 mmol/l was significantly less at the end of treatment than in the pre-treatment period [556 (7%) vs. 749 (10%)]. Similarly, the frequency of CGMS >10 mmol/l, was also less at the end of treatment [27 (0.3%) vs. 49 (0.7%)]. Except for one child with increased LDL cholesterol, all safety parameters were normal. Conclusion: MaxEPAR was safe and reduced glycemic variability, but did not increase glucose profiles significantly in diazoxide-responsive CHI. The supplemental value of PUFA should be evaluated in a comprehensive clinical trial.

Vineland adaptive behavior scales to identify neurodevelopmental problems in children with Congenital Hyperinsulinism (CHI)

BackgroundCongenital Hyperinsulinism (CHI) is a disease of severe hypoglycaemia caused by excess insulin secretion and associated with adverse neurodevelopment in a third of children. The Vineland Adaptive Behavior Scales Second Edition (VABS-II) is a parent report measure of adaptive functioning that could be used as a developmental screening tool in patients with CHI. We have investigated the performance of VABS-II as a screening tool to identify developmental delay in a relatively large cohort of children with CHI. VABS-II questionnaires testing communication, daily living skills, social skills, motor skills and behaviour domains were completed by parents of 64 children with CHI, presenting both in the early neonatal period (Early-CHI, n = 48) and later in infancy (Late-CHI, n = 16). Individual and adaptive composite (Total) domain scores were converted to standard deviation scores (SDS). VABS-II scores were tested for correlation with objective developmental assessment reported separately by developmental paediatricians, clinical and educational psychologists. VABS-II scores were also investigated for correlation with the timing of hypoglycaemia, gender and phenotype of CHI.ResultsMedian (range) total VABS-II SDS was low in CHI [-0.48 (-3.60, 4.00)] with scores < -2.0 SDS in 9 (12%) children. VABS-II Total scores correctly identified developmental delay diagnosed by objective assessment in the majority [odds ratio (OR) (95% confidence intervals, CI) 0.52 (0.38, 0.73), p < 0.001] with 95% specificity [area under curve (CI) 0.80 (0.68, 0.90), p < 0.001] for cut-off < -2.0 SDS, although with low sensitivity (26%). VABS-II Total scores were inversely correlated (adjusted R2 = 0.19, p = 0.001) with age at presentation (p = 0.024) and male gender (p = 0.036), males having lower scores than females in those with Late-CHI [-1.40 (-3.60, 0.87) v 0.20 (-1.07, 1.27), p = 0.014]. The presence of a genetic mutation representing severe CHI also predicted lower scores (R2 = 0.19, p = 0.039).ConclusionsThe parent report VABS-II is a reliable and specific tool to identify developmental delay in CHI patients. Male gender, later age at presentation and severity of disease are independent risk factors for lower VABS-II scores.

G613 Children’s nurses: Influencing policy and practice

Theme ‘Working together across boundaries’ (generating best practice for C&YP). The Royal College of Nursing (RCN) provides a focus for the ‘field of practice’ which brings together the work of five professional Forums which encompass the breadth of child health care. These UK nurse practitioners, managers, educationalists and researchers work collaboratively with the college’s Professional Lead and in partnership with each other to influence nursing policy and practice throughout the four countries and beyond. The Forums promote children’s nursing as a unique part of the nursing paradigm, whilst generating best practice for C&YP, which is fundamental within our profession standards.1 Methods Collaborative work of these CYP Forums (Specialist Care; Acute Care; Continuing and Community Care; Professional Issues; Staying Healthy): is to promote and deliver high quality evidence- based nursing care of CYP and their families. are a focus for RCN members committed to nursing CYP, providing them with networks and opportunities for support, advice and professional development. are a voice for children and young people’s nursing influence and lobby external organisations to ensure the voice of CYP and those nurses working with them, is heard. Results Effective communication is extremely important and key to strategy process when raising the profile of children’s nursing. Each CYP Forum has a website www.rcn.org.uk identifying committee members, new links to Facebook and Blogs, a wide range of resources and policy/guidance documents2,3 which are regularly updated. Conference events such as the RCPCH/RCN Conference and RCN Congress which has the biggest gathering of the ‘nursing family’ are highlighted and scheduled throughout the year. Members highly value the work of the CYP Forums and exposure to the various levels of professional activity.4 Conclusions These Forums support professional activity focussed on the care of children and young people and provide members with access to on-line resources and opportunities for networking; sharing information and best practice. They help children’s nurses and nursing students keep up-to-date with their personal and professional development, as well as influencing healthcare improvements for CYP. References Nursing & Midwifery Council (NMC, 2015) The Code: Professional standards of practice and behaviour for nurses and midwives. London: NMC Royal College of Nursing (RCN, 2013) Supporting parents and health care professionals when breaking bad news: RCN best practice guidance. London: RCN Royal College of Nursing (RCN, 2014) Specialist and advanced children’s and young people’s nursing practice in contemporary health care: guidance for nurses and commissioners. London: RCN Royal College of Paediatrics and Child Health (RCPCH, 2015) Facing the Future: together for child health. London: RCPCH

Islet cell proliferation is inappropriately maintained in the pancreas of children with congenital hyperinsulinism in infancy

o s te r T e m p la te ro m w w w .m a n c h e s te .a c .u k /p h o to g ra p h ic s Age (months) Congenital Hyperinsulinism of Infancy (CHI) is a potentially lethal condition of profound hypoglycaemia caused by unregulated insulin release in the neonatal period and early infancy. CHI mainly arises due to mutations in ATPsensitive K-channel genes (ABCC8 and KCNJ11) which can manifest in all islets cells – diffuse CHI (CHI-D), or can be localised to a focal lesion, focal CHI (CHI-F). Increased rates of cell proliferation have been reported in the CHI-D and this may be liked to ABCC8 and KCNJ11 defects. Here, we examined the proliferative index (PI) of islet cells in CHI-D patients and compared this with focal CHI (CHI-F), which is caused by loss of cell cycle repression in β-cells specifically within the focal domain. We also examined islet PI in patient tissues with severe CHI unrelated to defects in ABCC8 and KCNJ11, atypical CHI (CHI-A). Background