Treatment Burden of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Randomized Study.

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.

Safety and effectiveness of taliglucerase alfa in patients with Gaucher disease: an interim analysis of real-world data from a multinational drug registry (TALIAS).

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.

More than a decade of real-world experience of pegvisomant for acromegaly: ACROSTUDY.

OBJECTIVE: To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY. DESIGN: Global (15 countries), multicentre, non-interventional study (2004-2017). METHODS: The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. The main endpoints were long-term safety (comorbidities, adverse events (AEs), pituitary tumour volumes, liver tests) and efficacy (IGF1 changes). RESULTS: Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0-20.8 years) and followed up for a median of 7.4 years (range, 0-13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with the use of ≥30 mg PEGV/day in an increasing proportion of patients. CONCLUSION: This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.

Factors Driving Patient Preferences for Growth Hormone Deficiency (GHD) Injection Regimen and Injection Device Features: A Discrete Choice Experiment.

INTRODUCTION: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Patients prefer a less frequent injection regimen for treating GHD. Addressing patient preferences may improve compliance, adherence, and ultimately, clinical outcomes.

Development and Psychometric Evaluation of the Life Interference Questionnaire for Growth Hormone Deficiency (LIQ-GHD) to Assess Growth Hormone Injection Burden in Children and Adults.

BACKGROUND: Current recombinant human growth hormone (r-hGH) replacement therapy involves long-term daily subcutaneous injections to treat growth hormone deficiency (GHD) in children and adults. Daily r-hGH injections can be burdensome, often resulting in poor treatment compliance. Clinical outcome assessments (COAs) can capture the burden of these injections from the patient (and caregiver) perspective and may demonstrate the benefit of a less-frequent r-hGH injection regimen, which may ultimately improve treatment compliance and long-term outcomes. OBJECTIVE: To address this knowledge gap, qualitative research was conducted to inform the development of a new Life Interference Questionnaire for Growth Hormone Deficiency (LIQ-GHD), designed to measure the experiences of patients taking r-hGH GHD injections. A second objective was to evaluate the hypothesized factor structure and preliminary performance of the LIQ-GHD in a cross-sectional observational study. METHODS: An empirical literature review and expert advice meetings were conducted to inform development of the draft LIQ-GHD (pediatric and adult versions). In-person concept elicitation and cognitive debriefing interviews were conducted with GHD patients (and patient dyads including caregivers) to explore and confirm concept coverage and evaluate respondents' ability to understand the questionnaire. The draft LIQ-GHD was then tested in a cross-sectional field study involving pediatric and adult patients receiving daily r-hGH injections for GHD. The factor structure, reliability, and validity were analyzed for the overall sample and for pediatric, adolescent, and adult subgroups. RESULTS: Results from the literature review and input from six experts were used to develop and refine the LIQ-GHD, with content covering pen ease of use; regimen convenience; life interference due to regimen; benefit/satisfaction/willingness to continue treatment; regimen choice/preference; intent to comply with regimen; injection-related signs/symptoms; and reasons for missed injections. Twenty-one patient interviews confirmed comprehensive concept coverage and patient/caregiver comprehension of the LIQ-GHD. A total of 224 patients (n = 70 children/caregiver dyads, n = 79 adolescents/caregiver dyads, n = 75 adults) participated in the field study. While most items showed floor effects, confirmatory factor analysis fit statistics were good for the overall sample (root mean square error of approximation = 0.07, comparative fit index = 0.98) and for the full pediatric sample after dropping co-dependent questions from the model. Cronbach's alpha (α) ranged from 0.746 to 0.905 and intra-class correlation coefficients ranged from 0.761 to 0.918 for the overall sample on LIQ-GHD domains. Scores correlated as predicted with an existing criterion measure in the overall sample and LIQ-GHD domain scores distinguished known groups as expected. CONCLUSIONS: The LIQ-GHD is a new COA for the measurement of r-hGH injection treatment burden. This research provides evidence supporting its content validity, hypothesized factor structure, score reliability, and construct validity in pediatric and adult populations.

Glargine co-administration with intravenous insulin in pediatric diabetic ketoacidosis is safe and facilitates transition to a subcutaneous regimen.

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.

Late Presentation of Fulminant Necrotizing Enterocolitis in a Child with Hyperinsulinism on Octreotide Therapy.

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children. In cases of diazoxide-unresponsive HI, alternative medical and surgical approaches may be required to reduce the risk of hypoglycemia. Octreotide, a somatostatin analog, often has a role in the management of these children, but a dose-dependent reduction in splanchnic blood flow is a recognized complication. Necrotizing enterocolitis (NEC) has been reported within the first few weeks of initiating predominantly high doses of octreotide. We describe the case of an infant with Beckwith-Wiedemann syndrome and diazoxide-unresponsive HI, who had persistent hypoglycemia after two pancreatectomy surgeries. She developed NEC 2 months after beginning octreotide therapy at a relatively low dose of 8 µg/kg/day. This complication has occurred later, and at a lower dose, than has previously been described. We review the case and identify the known and suspected multifactorial risk factors for NEC that may contribute to the development of this complication in patients with HI.

Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith-Wiedemann syndrome.

BACKGROUND: Congenital 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: We 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.

Peak cortisol response to corticotropin-releasing hormone is associated with age and body size in children referred for clinical testing: a retrospective review.

BACKGROUND: Corticotropin-Releasing Hormone (CRH) testing is used to evaluate suspected adrenocorticotropic hormone (ACTH) deficiency, but the clinical characteristics that affect response in young children are incompletely understood. Our objective was to determine the effect of age and body size on cortisol response to CRH in children at risk for ACTH deficiency referred for clinical testing. METHODS: Retrospective, observational study of 297 children, ages 30 days - 18 years, undergoing initial, clinically indicated outpatient CRH stimulation testing at a tertiary referral center. All subjects received 1mcg/kg corticorelin per institutional protocol. Serial, timed ACTH and cortisol measurements were obtained. Patient demographic and clinical factors were abstracted from the medical record. Patients without full recorded anthropometric data, pubertal assessment, ACTH measurements, or clear indication for testing were excluded (number remaining = 222). Outcomes of interest were maximum cortisol after stimulation (peak) and cortisol rise from baseline (delta). Bivariable and multivariable linear regression analyses were used to assess the effects of age and size (weight, height, body mass index (BMI), body surface area (BSA), BMI z-score, and height z-score) on cortisol response while accounting for clinical covariates including sex, race/ethnicity, pubertal status, indication for testing, and time of testing. RESULTS: Subjects were 27 % female, with mean age of 8.9 years (SD 4.5); 75 % were pre-pubertal. Mean peak cortisol was 609.2 nmol/L (SD 213.0); mean delta cortisol was 404.2 nmol/L (SD 200.2). In separate multivariable models, weight, height, BSA and height z-score each remained independently negatively associated (p < 0.05) with peak and delta cortisol, controlling for indication of testing, baseline cortisol, and peak or delta ACTH, respectively. Age was negatively associated with peak but not delta cortisol in multivariable analysis. CONCLUSIONS: Despite the use of a weight-based dosing protocol, both peak and delta cortisol response to CRH are negatively associated with several measures of body size in children referred for clinical testing, raising the question of whether alternate CRH dosing strategies or age- or size-based thresholds for adequate cortisol response should be considered in pediatric patients, or, alternatively, whether this finding reflects practice patterns followed when referring children for clinical testing.

A novel case of compound heterozygous congenital hyperinsulinism without high insulin levels.

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.

The surgical management of insulinomas in children.

PURPOSE: Insulinomas are rare pediatric tumors for which optimal localization studies and management remain undetermined. We present our experience with surgical management of insulinomas during childhood. METHODS: A retrospective review was performed of patients who underwent surgical management for an insulinoma from 1999 to 2012. RESULTS: The study included eight patients. Preoperative localization was successful with abdominal ultrasound, abdominal CT, endoscopic ultrasound, or MRI in only 20%, 28.6%, 40%, and 50% of patients, respectively. Octreotide scan was non-diagnostic in 4 patients. For diagnostic failure, selective utilization of 18-Fluoro-DOPA PET/CT scanning, arterial stimulation/venous sampling, or transhepatic portal venous sampling were successful in insulinoma localization. Intraoperatively, all lesions were identified by palpation or with the assistance of intraoperative ultrasound. Surgical resection using pancreas sparing techniques (enucleation or distal pancreatectomy) resulted in a cure in all patients. Postoperative complications included a pancreatic fistula in two patients and an additional missed insulinoma in a patient with MEN-1 requiring successful reoperation. CONCLUSIONS: Preoperative tumor localization may require many imaging modalities to avoid unsuccessful blind pancreatectomy. Intraoperative palpation with the assistance of ultrasound offers a reliable method to precisely locate the insulinoma. Complete surgical resection results in a cure. Recurrent symptoms warrant evaluation for additional lesions.

Pancreatic surgery in infants with Beckwith-Wiedemann syndrome and hyperinsulinism.

PURPOSE: To present our experience in the care of infants with Beckwith-Wiedemann syndrome (BWS) who required pancreatectomy for the management of severe Congenital Hyperinsulinism (HI). METHODS: We did a retrospective chart review of patients with BWS who underwent pancreatectomy between 2009 and 2012. RESULTS: Four patients with BWS and severe HI underwent pancreatectomy, 3 females and one male. Eight other BWS patients with HI could be managed medically. The diagnosis of BWS was established by the presence of mosaic 11p15 loss of heterozygosity and uniparental disomy in peripheral blood and/or pancreatic tissue. All patients had hypoglycemia since birth that did not respond to medical management with diazoxide or octreotide, and required glucose infusion rates of up to 30 mg/kg/min. Preoperative 18-F-DOPA PET/CT scans showed diffuse uptake of the radiotracer throughout an enlarged pancreas in three patients and a normal sized pancreas with a large area of focal uptake in the pancreatic body in one patient. None of the patients had mutations in the ABCC8 or KCNJ1 genes that are typically associated with diazoxide-resistant HI. Age at surgery was 1, 2, 4, and 12 months and the procedures were 85%, 95%, 90%, and 75% pancreatectomy, respectively, with the pancreatectomy extent tailored to HI severity. Pathologic analysis revealed marked diffuse endocrine proliferation throughout the pancreas that occupied up to 80% of the parenchyma with scattered islet cell nucleomegaly. One patient had a small pancreatoblastoma in the pancreatectomy specimen. The HI improved in all cases after the pancreatectomy, with patients being able to fast safely for more than 8 h. All patients are under close surveillance for embryonal tumors. One patient developed a hepatoblastoma at age 2. CONCLUSION: The pathophysiology of HI in BWS patients is likely multifactorial and is associated with a dramatic increase in pancreatic endocrine tissue. Severe cases of HI that do not respond to medical therapy improve when the mass of endocrine tissue is reduced by subtotal or near-total pancreatectomy.

Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy.

Here we describe three subjects with mosaic genome-wide paternal uniparental isodisomy (GWpUPD) each of whom presented initially with overgrowth, hemihyperplasia (HH), and hyperinsulinism (HI). Due to the severity of findings and the presence of additional features, SNP array testing was performed, which demonstrated mosaic GWpUPD. Comparing these individuals to 10 other live-born subjects reported in the literature, the predominant phenotype is that of pUPD11 and notable for a very high incidence of tumor development. Our subjects developed non-metastatic tumors of the adrenal gland, kidney, and/or liver. All three subjects had pancreatic hyperplasia resulting in HI. Notably, our subjects to date display minimal features of other diseases associated with paternal UPD loci. Both children who survived the neonatal period have displayed near-normal cognitive development, likely due to a favorable tissue distribution of the mosaicism. To understand the range of UPD mosaicism levels, we studied multiple tissues using SNP array analysis and detected levels of 5-95%, roughly correlating with the extent of tissue involvement. Given the rapidity of tumor growth and the difficulty distinguishing malignant and benign tumors in these GWpUPD subjects, we have utilized increased frequency of ultrasound (US) and alpha-fetoprotein (AFP) screening in the first years of life. Because of a later age of onset of additional tumors, continued tumor surveillance into adolescence may need to be considered in these rare patients.

Accuracy of PET/CT Scan in the diagnosis of the focal form of congenital hyperinsulinism.

PURPOSE: The purpose of the study was to determine the sensitivity of the (18)fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography scan (18F-PET/CT) in the diagnosis of focal congenital hyperinsulinism (HI). METHODS: A retrospective review of children with HI who underwent a preoperative 18F-PET/CT scan was performed. RESULTS: Between 1/2008 and 2/2012 we performed 105 consecutive 18F-PET/CT scans on infants with HI. Fifty-three patients had focal HI. Of those fifty-three patients, eight had a preoperative 18F-PET/CT scan read as "diffuse disease". The sensitivity of the study in the diagnosis of focal HI was 85%. The location of the eight missed focal lesions was: head (3), body (2), and tail (3). The 18F-PET/CT of the missed head lesions showed homogeneous tracer uptake (n =2) or heterogeneous uptake throughout the pancreas (n=1). The 18F-PET/CT of the 2 missed body lesions and 1 missed tail lesion showed heterogeneous uptake throughout the pancreas. The 18F-PET/CT of the other 2 missed tail lesions showed lesions adjacent to and obscured by the signal of the upper renal pole, identified retrospectively by closer observation. Fifty-two of the 105 patients had diffuse HI. Two of them had 18F-PET/CT studies read as "focal disease". Therefore, the specificity of the study was 96%. Of the forty-seven 18F-PET/CT studies read as "focal disease", forty-five had true focal HI. Therefore, the positive predictive value of the study in the diagnosis of focal HI was 96%. CONCLUSION: The sensitivity and specificity of 18 F-PET/CT can be affected by certain anatomic features of the pancreas, by the location of the lesion, and by the reader's experience.

Measurement of tissue acyl-CoAs using flow-injection tandem mass spectrometry: acyl-CoA profiles in short-chain fatty acid oxidation defects.

The primary accumulating metabolites in fatty acid oxidation defects are intramitochondrial acyl-CoAs. Typically, secondary metabolites such as acylcarnitines, acylglycines and dicarboxylic acids are measured to study these disorders. Methods have not been adapted for tissue acyl-CoA measurement in defects with primarily acyl-CoA accumulation. Our objective was to develop a method to measure fatty acyl-CoA species that are present in tissues of mice with fatty acid oxidation defects using flow-injection tandem mass spectrometry. Following the addition of internal standards of [(13)C(2)] acetyl-CoA, [(13)C(8)] octanoyl-CoA, and [C(17)] heptadecanoic CoA, acyl-CoA's are extracted from tissue samples and are injected directly into the mass spectrometer. Data is acquired using a 506.9 neutral loss scan and multiple reaction-monitoring (MRM). This method can identify all long, medium and short-chain acyl-CoA species in wild type mouse liver including predicted 3-hydroxyacyl-CoA species. We validated the method using liver of the short-chain-acyl-CoA dehydrogenase (SCAD) knock-out mice. As expected, there is a significant increase in [C(4)] butyryl-CoA species in the SCAD -/- mouse liver compared to wild type. We then tested the assay in liver from the short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficient mice to determine the profile of acyl-CoA accumulation in this less predictable model. There was more modest accumulation of medium chain species including 3-hydroxyacyl-CoA's consistent with the known chain-length specificity of the SCHAD enzyme.

Pancreatic head resection and Roux-en-Y pancreaticojejunostomy for the treatment of the focal form of congenital hyperinsulinism.

PURPOSE: To determine the outcome of patients who underwent pancreatic head resection and Roux-en-Y pancreaticojejunostomy to the remaining normal pancreatic body and tail for the treatment of a focal lesion in the pancreatic head causing congenital hyperinsulinism (HI). METHODS: One hundred thirty-eight patients underwent pancreatic resection for focal HI between 1998 and 2010. Twenty-three patients in the group underwent pancreatic head resection and Roux-en-Y pancreaticojejunostomy. RESULTS: There were 13 females and 10 males. Median age and weight at surgery were 8 weeks and 5.8 kg, respectively. Twenty-one patients had a near-total pancreatic head resection, and 2 patients had a pylorus-preserving Whipple procedure. The pancreaticojejunostomy anastomosis was performed with interrupted fine monofilament sutures such that the transected end of the pancreatic body was tucked within the end of the Roux-en-Y jejunal limb. Median hospital stay was 22 days. All patients were cured of HI. CONCLUSION: We conclude that pancreatic head resection with Roux-en-Y pancreaticojejunostomy is a safe and effective procedure for the treatment of the HI patient with a large focal lesion in the pancreatic head that is not amenable to local resection alone.

A specialized team approach to diagnosis and medical versus surgical treatment of infants with congenital hyperinsulinism.

Hyperinsulinism (HI) is the most common cause of transient and permanent forms of hypoglycemia in infancy. Establishing the correct diagnosis and initiating appropriate therapy without delay is of utmost importance. Once the diagnosis is made and if medical therapy with diazoxide fails, one should assume that the infant has a K(ATP) channel defect and may require surgery. In this case, the infant should be referred to a center that specializes in HI with 18-fluoro L-3,4-dihydroxyphenylalanine positron emission tomography scan. This report describes a center specializing in HI with a team of experts consisting of endocrinologists, nurse practitioners, geneticists, radiologists, pathologists, and a surgeon. It describes the center's paradigm for managing severe HI on the basis of more than 250 cases of HI in the past 10 years, including the diagnosis of HI, medical options, genetics of HI, imaging in HI, the surgical approach to HI, and outcomes.

Rare forms of congenital hyperinsulinism.

Rare forms of congenital hyperinsulinism (CHI) are caused by mutations in GLUD1 (encoding glutamate dehydrogenase), GCK (encoding glucokinase), HADH (encoding for L-3-hydroxyacyl-CoA dehydrogenase), SLC16A1 (encoding the monocarboxylat transporter 1), HNF4A (encoding hepatocyte nuclear factor 4α) or UCP2 (encoding mitochondrial uncoupling protein 2). The clinical presentation is very heterogeneous in regards to age of onset, severity, and manner of symptoms, as well as the response to medical treatment. Special individual characteristics have to be accounted in diagnosis and treatment. Diazoxide is the first-line drug for the rare forms of CHI for long-term treatment but is not entirely effective in some of these rarer defects (GCK, MCT1). The use of diazoxide is often limited by side effects and the use of octreotide as second-line drug has to be considered. A near-total pancreatectomy is only reserved for patients with diffuse disease and resistance to medical treatment as a last resort. Patients with CHI should be managed by centers with a highly experienced team in diagnostic work-up and treatment of this disease.