Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

Published onlineJournal ArticleCONTEXT: Congenital hyperinsulinism (CHI), the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency. SETTING: International referral centre for the management of CHI. PATIENTS: Medically unresponsive diffuse CHI patients managed with near-total pancreatectomy between 1994 and 2012. INTERVENTION: Near-total pancreatectomy. MAIN OUTCOME MEASURES: Persistent hypoglycaemia post near-total pancreatectomy, insulin-dependent diabetes mellitus, clinical and biochemical (faecal elastase 1) pancreatic exocrine insufficiency. RESULTS: Of more than 300 patients with CHI managed during this time period, 45 children had medically unresponsive diffuse disease and were managed with near-total pancreatectomy. After near-total pancreatectomy, 60% of children had persistent hypoglycaemia requiring medical interventions. The incidence of insulin dependent diabetes mellitus was 96% at 11 years after surgery. Thirty-two patients (72%) had biochemical evidence of severe pancreatic exocrine insufficiency (Faecal elastase 1<100 µg/g). Clinical exocrine insufficiency was observed in 22 (49%) patients. No statistically significant difference in weight and height standard deviation score (SDS) was found between untreated subclinical pancreatic exocrine insufficiency patients and treated clinical pancreatic exocrine insufficiency patients. CONCLUSIONS: The outcome of diffuse CHI patients after near-total pancreatectomy is very unsatisfactory. The incidence of persistent hypoglycaemia and insulin-dependent diabetes mellitus is very high. The presence of clinical rather than biochemical pancreatic exocrine insufficiency should inform decisions about pancreatic enzyme supplementation

Sensitivity to point-like sources of the ALTO atmospheric particle detector array, designed for 200 GeV\rm 200\,GeV--50 TeV\rm 50\,TeV γ\gamma-ray astronomy

In the context of atmospheric shower arrays designed for $\gamma$-ray astronomy and in the context of the ALTO project, we present: a study of the impact of heavier nuclei in the cosmic-ray background on the estimated $\gamma$-ray detection performance on the basis of dedicated Monte Carlo simulations, a method to calculate the sensitivity to a point-like source, and finally the required observation times to reach a firm detection on a list of known point-like sources.Comment: 16 pages, 7 figures, accepted for publication in JHEAP (Journal of High-Energy Astrophysics

Intrafamilial Phenotypic Variability and Consequences of Non-Compliance with Treatment in Congenital Adrenal Hyperplasia and Congenital Hypothyroidism within a Single Family

BACKGROUND: Coexistence of congenital adrenal hyperplasia (CAH) and congenital hypothyroidism (CH) due to TG mutation in the same non-consanguineous family is rare. Case Series: We report 4 siblings born to unrelated parents, the father being an asymptomatic carrier of homozygous p.V281L and heterozygous p.I172N CYP21A2 mutations. Sibling 1 had salt-wasting CAH (CYP21A2 genotype Intron 2 splice/p.I172N and p.V281L). She also had CH (TG genotype p.R296/ p.T1416Rfs*30) and learning difficulties. Poor compliance and morbid obesity resulted in short stature, precocious puberty, hirsutism, amenorrhoea, insulin insensitivity and a possible adrenal adenoma. Sibling 3 (CYP21A2 and TG genotype similar to sibling 1) is a boy presenting with salt-wasting CAH, CH, and developmental delay. He was overweight and underwent precocious puberty. Although siblings 2 and 4 (both females) share the same CYP21A2 genotype (Intron 2 splice/p.V281L), the former only had biochemical evidence of CAH, while the latter presented at 9.8 years of age with a history of pubarche at 7 years and advanced bone age. CONCLUSIONS: We report the unusual occurrence of 2 rare autosomal recessive diseases, CAH and CH. Our cases highlight the phenotypic variability of CAH and CH due to TG mutations, even within a single family, and illustrate the importance of optimal disease control

Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome

Version 2; peer review: 3 approved. Available from F1000 Research via the DOI in this recordBackground: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.Wellcome TrustRoyal Societ

Variation in Glycemic Outcomes in Focal Forms of Congenital Hyperinsulinism - The UK Perspective

Context: In focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic β-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery. Objective: We describe surgical and nonsurgical outcomes of focal CHI in a national cohort. Methods: Patients with focal CHI were retrospectively reviewed at 2 specialist centers, 2003-2018. Results: Of 59 patients with focal CHI, 57 had heterozygous mutations in ABCC8/KCNJ11 (51 paternally inherited, 6 de novo). Fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography computed tomography scan identified focal lesions in 51 patients. In 5 patients, imaging was inconclusive; the diagnosis was established by frozen section histopathology in 3 patients, a lesion was not identified in 1 patient, and 1 declined surgery. Most patients (n = 56) were unresponsive to diazoxide, of whom 33 were unresponsive or partially responsive to somatostatin receptor analog (SSRA) therapy. Fifty-five patients underwent surgery: 40 had immediate resolution of CHI, 10 had persistent hypoglycemia and a focus was not identified on biopsy in 5. In the 10 patients with persistent hypoglycemia, 7 underwent further surgery with resolution in 4 and ongoing hypoglycemia requiring SSRA in 3. Nine (15% of cohort) patients (1 complex surgical access; 4 biopsy negative; 4 declined surgery) were managed conservatively; medication was discontinued in 8 children at a median (range) age 2.4 (1.5-7.7) years and 1 remains on SSRA at 16 years with improved fasting tolerance and reduction in SSRA dose. Conclusion: Despite a unifying genetic basis of disease, we report inherent heterogeneity in focal CHI patients impacting outcomes of both surgical and medical management

Evidence of 100 TeV γ-ray emission from HESS J1702-420 : a new PeVatron candidate

The identification of active PeVatrons, hadronic particle accelerators reaching the knee of the cosmic-ray spectrum (at the energy of few PeV), is crucial to understand the origin of cosmic rays in the Galaxy. In this context, we report on new H.E.S.S. observations of the PeVatron candidate HESS J1702-420, which bring evidence for the presence of γ-rays up to 100 TeV. This is the first time in the history of H.E.S.S. that photons with such high energy are observed. Remarkably, the new deep observations allowed the discovery of a new γ-ray source component, called HESS J1702-420A, that was previously hidden under the bulk emission traditionally associated with HESS J1702-420. This new object has a power-law spectral slope < 2 and a γ-ray spectrum that, extending with no sign of curvature up to 100 TeV, makes it an excellent candidate site for the presence of PeV-energy cosmic rays. This discovery brings new information to the ongoing debate on the nature of the unidentified source HESSJ1702-420, and on the origin of Galactic cosmic rays

Search for dark matter annihilation signals from unidentified Fermi-LAT objects with H.E.S.S.

Cosmological N-body simulations show that Milky-Way-sized galaxies harbor a population of unmerged dark matter subhalos. These subhalos could shine in gamma rays and be eventually detected in gamma-ray surveys as unidentified sources. We search for very-high-energy (VHE, E $\geq$ 100~GeV) gamma-ray emission using H.E.S.S. observations carried out from a thorough selection of unidentified Fermi-LAT Objects (UFOs) as dark matter subhalo candidates. Provided that the dark matter mass is higher than a few hundred GeV, the emission of the UFOs can be well described by dark matter annihilation models. No significant VHE gamma-ray emission is detected in any UFO dataset nor in their combination. We, therefore, derive constraints on the product of the velocity-weighted annihilation cross-section \left by the J-factor on dark matter models describing the UFO emissions. Upper limits at 95% confidence level are derived on \left J in W$^{+}$W$^{-}$ and τ$^{+}$τ$^{-}$ annihilation channels for the TeV dark matter particles. Focusing on thermal WIMPs, strong constraints on the J-factors are obtained from H.E.S.S. observations. Adopting model-dependent predictions from cosmological N-body simulations on the J-factor distribution function for Milky Way (MW)-sized galaxies, only $\lesssim$ 0.3 ~TeV mass dark matter models marginally allow to explain observed UFO emission

H.E.S.S. ToO program on nearby core-collapse Supernovae : search for very-high energy γ-ray emission towards the SN candidate AT2019krl in M74

While the youngest known supernova remnants (SNRs), such as Cassiopeia A (Cas A), have been proven to be able to accelerate cosmic rays (CRs) only up to ∼ 10$^{14}$ eV at their present evolutionary stages, recent studies have shown that particle energies larger than a few PeV (10$^{15}$ eV) could be reached during the early stages of a core-collapse Supernova (cc-SN), when the high-velocity forward shock expands into the dense circumstellar medium (CSM) shaped by the stellar progenitor wind. Such environments, in particular the type IIn SNe whose progenitors may exhibit mass loss rates as high as 10$^{-2}$ M$_{\bigodot}$ yr$^{-1}$, could thus lead to γ-ray emission from $\pi ^{0}$ decay in hadronic interactions, potentially detectable with current Cherenkov telescopes at very-high energies. Such a detection would provide direct evidence for efficient acceleration of CR protons/nuclei in supernovae, and hence new insights on the long-standing issue of the origin of Galactic Cosmic Rays. In that context, the High Energy Stereoscopic System (H.E.S.S.) has been carrying out a Target of Opportunity program since 2016 to search for such an early very-high-energy γ-ray emission towards nearby core-collapse supernovae and supernova candidates (up to ∼ 10 Mpc), within a few weeks after discovery. After giving an overview of this H.E.S.S. Target of Opportunity program, we present the results obtained from the July 2019 observations towards the transient AT2019krl, originally classified as a type IIn supernova, which occurred in the galaxy M74 at ∼ 9.8 Mpc. Although its nature still remains unclear, the derived H.E.S.S. constraints on this transient are placed in the general context of the expected VHE γ-ray emission from core-collapse supernovae