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Background Diabetes ketoacidosis (DKA) is a common presentation and complication of type 1 diabetes (T1D). While intravenous insulin is typically used to treat acute metabolic abnormalities, the transition from intravenous to subcutaneous treatment can present a challenge. We hypothesize that co‐administration of glargine, a subcutaneous long‐acting insulin analog, during insulin infusion may facilitate a flexible and safe transition from intravenous to subcutaneous therapy. Objective To determine if the practice of administering subcutaneous glargine during intravenous insulin is associated with an increased risk of hypoglycemia, hypokalemia, or other complications in children with DKA. Methods Retrospective chart review of patients aged 2 to 21 years, presenting to our center with DKA between April 2012 and June 2014. Patients were divided into two groups: those co‐administered subcutaneous glargine with intravenous insulin for over 4 hours (G+); and patients with less than 2 hours of overlap (G−). Results We reviewed 149 DKA admissions (55 G+, 94 G−) from 129 unique patients. There was a similar incidence of hypoglycemia between groups (25% G+ vs 20% G−, P = 0.46). Hypokalemia (<3.5 mmol/L) occurred more frequently in the G+ group (OR = 3.4, 95% CI 1.7‐7.0, P = 0.001). Cerebral edema occurred in 2/55 (3.6%) of the G− group and none of the G+ subjects. Conclusion Co‐administration of glargine early in the course of DKA treatment is well tolerated and convenient for discharge planning; however, this approach is associated with an increased risk of hypokalemia.

BackgroundCongenital hyperinsulinism (HI) can have monogenic or syndromic causes. Although HI has long been recognised to be common in children with Beckwith–Wiedemann syndrome (BWS), the underlying mechanism is not known.MethodsWe characterised the clinical features of children with both HI and BWS/11p overgrowth spectrum, evaluated the contribution of KATP channel mutations to the molecular pathogenesis of their HI and assessed molecular pathogenesis associated with features of BWS.ResultsWe identified 28 children with HI and BWS/11p overgrowth from 1997 to 2014. Mosaic paternal uniparental isodisomy for chromosome 11p (pUPD11p) was noted in 26/28 cases. Most were refractory to diazoxide treatment and half required subtotal pancreatectomies. Patients displayed a wide range of clinical features from classical BWS to only mild hemihypertrophy (11p overgrowth spectrum). Four of the cases had a paternally transmitted KATP mutation and had a much more severe HI course than patients with pUPD11p alone.ConclusionsWe found that patients with pUPD11p-associated HI have a persistent and severe HI phenotype compared with transient hypoglycaemia of BWS/11p overgrowth patients caused by other aetiologies. Testing for pUPD11p should be considered in all patients with persistent congenital HI, especially for those without an identified HI gene mutation.

The daily injection burden of recombinant human growth hormone (r-hGH) replacement therapy to treat growth hormone deficiency (GHD) may reduce compliance and limit treatment benefit. Research is needed to evaluate patient preferences for GHD injection regimen and device features. Quantitatively evaluate factors driving preferences for r-hGH injection regimen and device features among pediatric (3-17 years, and caregivers) and adult (≥25 years) patients with GHD using a discrete choice experiment (DCE) approach. The DCE was part of a broader, cross-sectional observational field study to develop clinical outcome assessments (COAs) that assess the experience of patients taking r-hGH injections. Following ethics approval, discrete choice data were collected through an online questionnaire from consented participants recruited from eight sites in the United States. Participants were presented with 20 choice tasks, each comprising different combinations of two profiles. Participants were then shown the same set of three hypothetical device and injection profiles (ie, storage, preparation, injection type device, maintenance, dose setting, injection schedule) and asked whether they would choose each profile over their current device and schedule. Choice-based conjoint analyses were used to estimate the marginal utilities and values for treatment attributes. Subject preferences were estimated at individual and aggregate levels. Two hundred and twenty-four participants completed the DCE (n=75 adults, n=79 adolescent/caregiver dyads, n=70 child/caregiver dyads). Injection schedule was the strongest predictor of choice for the total sample and each patient group. Less frequent injection schedules were more likely to be chosen by participants. A \"ready to use\" injection was preferred, with no preference for auto-injector versus needle-free device. Most participants would choose the hypothetical injection devices and less frequent dosing over their current daily administered device schedule. Patients prefer a less frequent injection regimen for treating GHD. Addressing patient preferences may improve compliance, adherence, and ultimately, clinical outcomes.

Background: Hypoglycemia in infants and children can lead to seizures, developmental delay, and permanent brain damage. Hyperinsulinism (HI) is the most common cause of both transient and permanent disorders of hypoglycemia. HI is characterized by dysregulated insulin secretion, which results in persistent mild to severe hypoglycemia. The various forms of HI represent a group of clinically, genetically, and morphologically heterogeneous disorders. Content: Congenital hyperinsulinism is associated with mutations of SUR-1 and Kir6.2, glucokinase, glutamate dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase, and ectopic expression on β-cell plasma membrane of SLC16A1. Hyperinsulinism can be associated with perinatal stress such as birth asphyxia, maternal toxemia, prematurity, or intrauterine growth retardation, resulting in prolonged neonatal hypoglycemia. Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann Syndrome, and congenital disorders of glycosylation. Laboratory testing for hyperinsulinism may include quantification of blood glucose, plasma insulin, plasma β-hydroxybutyrate, plasma fatty acids, plasma ammonia, plasma acylcarnitine profile, and urine organic acids. Genetic testing is available through commercial laboratories for genes known to be associated with hyperinsulinism. Acute insulin response (AIR) tests are useful in phenotypic characterization. Imaging and histologic tools are also available for diagnosing and classifying hyperinsulinism. The goal of treatment in infants with hyperinsulinism is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels above 700 mg/L (70 mg/dL) through pharmacologic or surgical therapy. Summary: The management of hyperinsulinism requires a multidisciplinary approach that includes pediatric endocrinologists, radiologists, surgeons, and pathologists who are trained in diagnosing, identifying, and treating hyperinsulinism.

The hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common form of congenital hyperinsulinism (HI). Children affected by this syndrome have both fasting and protein sensitive hypoglycemia combined with persistently elevated ammonia levels. Gain of function mutations in the mitochondrial enzyme glutamate dehydrogenase (GDH) are responsible for the HI/HA syndrome. GDH is expressed in liver, kidney, brain, and pancreatic beta-cells. Patients with the HI/HA syndrome have an increased frequency of generalized seizures, especially absence-type seizures, in the absence of hypoglycemia. The hypoglycemia of the HI/HA syndrome is well controlled with diazoxide, a KATP channel agonist. GDH has also been implicated in another form of HI, short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency associated HI. The HI/HA syndrome provides a rare example of an inborn error of intermediary metabolism in which the effect of the mutation on enzyme activity is a gain of function.

Background Limited real-world data from routine clinical care are available on the safety and effectiveness of treatment with taliglucerase alfa in patients with Gaucher disease (GD). Methods Taliglucerase Alfa Surveillance (TALIAS), a multinational prospective Drug Registry of patients with GD, was established to evaluate the long-term safety (primary objective) and effectiveness (secondary objective) of taliglucerase alfa. We present an interim analysis of the data from the Drug Registry collected over the 5-year period from September 2013 to January 2019. Results A total of 106 patients with GD (15.1% children aged < 18 years; 53.8% females) treated with taliglucerase alfa have been enrolled in the Drug Registry, as of January 7, 2019. The median duration of follow-up was 795 days with quartiles (Q1, Q3) of 567 and 994 days. Fifty-three patients (50.0%) were from Israel, 28 (26.4%) were from the United States, and 25 (23.6%) were from Albania. At the time of enrollment, most patients (87.7%) had received prior enzyme replacement therapy (ERT). Thirty-nine of the 106 patients had treatment-emergent adverse events (AEs). Twelve of the 106 patients experienced serious AEs; two patients experienced four treatment-related serious AEs. Four patients died, although none of the deaths was considered to be related to taliglucerase alfa treatment by the treating physicians. Nine patients discontinued from the study, including the four who died. At baseline, patients with prior ERT had a higher mean hemoglobin concentration and platelet counts than treatment-naïve patients, likely reflecting the therapeutic effects of prior treatments. During follow-up, the hemoglobin concentration and platelet counts increased in the treatment-naïve patients and remained relatively constant or increased slightly in patients with prior ERT. Spleen and liver volumes decreased in treatment-naïve patients. Conclusions The interim data showed no new or emergent safety signals. The overall interim data are consistent with the clinical program experience and known safety and effectiveness profile of taliglucerase alfa.

Abstract Context Somatrogon is a long-acting recombinant human growth hormone treatment developed as a once-weekly treatment for pediatric patients with growth hormone deficiency (GHD). Objective Evaluate patient and caregiver perceptions of the treatment burden associated with the once-weekly somatrogon injection regimen vs a once-daily Somatropin injection regimen. Methods Pediatric patients (≥3 to <18 years) with GHD receiving once-daily somatropin at enrollment were randomized 1:1 to Sequence 1 (12 weeks of once-daily Somatropin, then 12 weeks of once-weekly somatrogon) or Sequence 2 (12 weeks of once-weekly somatrogon, then 12 weeks of once-daily Somatropin). Treatment burden was assessed using validated questionnaires completed by patients and caregivers. The primary endpoint was the difference in mean overall life interference (LI) total scores after each 12-week treatment period (somatrogon vs Somatropin), as assessed by questionnaires. Results Of 87 patients randomized to Sequence 1 (n = 43) or 2 (n = 44), 85 completed the study. Once-weekly somatrogon had a significantly lower treatment burden than once-daily Somatropin, based on mean overall LI total scores after somatrogon (8.63) vs Somatropin (24.13) treatment (mean difference –15.49; 2-sided 95% CI –19.71, –11.27; P < .0001). Once-weekly somatrogon was associated with greater convenience, higher satisfaction with treatment experience, and less LI. The incidence of treatment-emergent adverse events (TEAEs) for Somatropin and somatrogon was 44.2% and 54.0%, respectively. No severe or serious AEs were reported. Conclusion In pediatric patients with GHD, once-weekly somatrogon had a lower treatment burden and was associated with a more favorable treatment experience than once-daily Somatropin.

• For children with growth hormone deficiency, once-weekly somatrogon injections were less of a burden than once-daily somatropin injections. • The safety of weekly somatrogon was similar to that of daily somatropin. • Compared with daily somatropin injections, children with growth hormone deficiency may be less likely to miss weekly somatrogon injections.  ○ This is because weekly somatrogon injections were less of a burden and were less likely to interfere with daily activities compared with daily somatropin injections. The purpose of this plain language summary is to help you to understand the findings from recent research. • Somatrogon is used to treat the condition under study that is discussed in this summary. Approval varies by country; please check with your local provider for more details. • The results of this study may differ from those of other studies. Health professionals should make treatment decisions based on all available evidence and not on the results of a single study. This original scientific article on which this summary is based was published in the Journal of the Endocrine Society and can be accessed for free at: https://academic.oup.com/jes/article/6/10/bvac117/6695276. The details of the original article are as follows: Aristides K. Maniatis, Mauri Carakushansky, Sonya Galcheva, Gnanagurudasan Prakasam, Larry A. Fox, Adriana Dankovcikova, Jane Loftus, Andrew A. Palladino, Maria de los Angeles Resa, Carrie Turich Taylor, Mehul T. Dattani, Jan Lebl. Treatment burden of weekly somatrogon versus daily somatropin in children with growth hormone deficiency: a randomized study. J Endocr Soc 2022; 6(10): bvac117. DOI: 10.1210/jendso/bvac117.

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in pediatric patients and is associated with significant risk of hypoglycemic seizures and developmental delays. CHI results from mutations in at least nine genes that play a role in regulating beta-cell insulin secretion. Thus, patients with CHI have dysregulated insulin secretion that is unresponsive to blood glucose level. Each different genetic etiology of CHI is associated with particular clinical characteristics that affect management decisions. Given the broad phenotypic spectrum and relatively rare prevalence of CHI, it is important that patients with CHI be evaluated by clinicians experienced with CHI and the multiple subspecialty services that are necessary for the management of the disorder. In this review, we summarize the pathophysiology and genetic causes of CHI and then focus primarily on the most common genetic cause (mutations in the ATP-gated potassium [KATP] channel) for further discussion of diagnosis, medical and surgical management, and potential acute and chronic complications. We provide insight from relevant published studies and reports, in addition to anecdotal information from our center's clinical experience in caring for over 400 patients with CHI. Careful assessment of each patient's individual pathophysiology is necessary to determine the appropriate treatment regimen, and continued close follow-up and monitoring of disease- and treatment-related complications are essential. Although significant improvements have been made in the past several years with regard to diagnosis and management, given the continued high morbidity rate in patients with CHI, improved diagnostic techniques and new therapeutic options would be welcomed. Keywords: hypoglycemia, hyperinsulinism, beta-cell, congenital, monogenic

Background Congenital hyperinsulinism leads to unregulated insulin secretion and hypoglycemia. Diagnosis can be difficult and genetic testing may be warranted. Case This patient initially presented at 11 months with seizure activity secondary to severe hypoglycemia. Her diagnostic evaluation included genetic studies, which confirmed congenital hyperinsulinism. A novel combination of mutations in the ABCC8 gene leading to diffuse, diazoxide-unresponsive congenital hyperinsulinism was identified. Mutation analysis of ABCC8 showed three variants (R1215W – paternal, pathogenic; W739C – maternal, variant of unknown significance; R1393L – maternal, variant of unknown significance). Her clinical course continues to be complicated by severe, refractory hypoglycemia at age 3 years. Conclusion We describe a novel compound heterozygous mutation leading to diffuse, diazoxide-unresponsive congenital hyperinsulinism. This case illustrates challenges associated with diagnosing and managing congenital hyperinsulinism and the importance of genetic testing.