Laparoscopic Surgery for Focal-Form Congenital Hyperinsulinism Located in Pancreatic Head

Background and AimsCongenital hyperinsulinism of infancy (CHI) is a rare condition that may cause irreversible severe neurological damage in infants. For children in whom medical management fails, partial or near-total pancreatectomy is then required according to the type of lesion. Currently, open surgery of near-total pancreatic head resection is a mature technique for the treatment of focal-form CHI located in the head of the pancreas, but a minimally invasive laparoscopic procedure has not been reported yet. The aim of this study was to verify the feasibility, safety, and efficacy of laparoscopic pancreatic head resection and Roux-en-Y pancreaticojejunostomy for focal-form CHI.MethodsTwo infants with persistent hypoglycemia and increased insulin levels were diagnosed with CHI and underwent laparoscopic near-total pancreatic head resection due to a suboptimal response to medical therapy and the likelihood of focal disease amenable to surgery. Clinical records, operative findings, and postoperative follow-up were collected and analyzed.ResultsThe operative duration was 300–330 min, and the intraoperative blood loss was minimal. The duration of postoperative abdominal drainage was 4–5 days. Neither intra- nor postoperative abdominal complications occurred. Oral feeding was resumed 3–4 days after the operation, and the blood glucose level was gradually stabilized to within the normal range. Normal blood glucose was observed in both patients over a follow-up period of 3–6 months.ConclusionsLaparoscopic pancreatic head resection and Roux-en-Y pancreaticojejunostomy can be considered a safe and effective procedure with minimal morbidity and excellent outcomes for the treatment of focal CHI in the head of the pancreas

Is re-Rex shunt a better choice for patients with failed Rex shunt?

PurposeTo review our single-center surgical outcomes of redo operations after failed Rex shunt procedures.MethodsFrom September 2017 to October 2021, a total of 20 patients (11 males, 9 females; median age: 8.6 years) with Rex shunt occlusions were admitted to our hospital. Two of these patients were previously operated on in our hospital, and the remaining 18 were from other centers. All patients underwent repeat operations after detailed preoperative evaluations.ResultsPreoperative wedged hepatic vein portography (WHVP) was conducted for 18 patients. Thirteen patients exhibited well-developed Rex recessus and intrahepatic portal vein during WHPV examination, consistent with the intraoperative exploration results. Fifteen patients (75%, 15/20) underwent redo-Rex shunt, four underwent Warren shunt and one underwent devascularization surgery. During the redo-Rex shunt operations, the left internal jugular veins (IJV) were used as bypass grafts in 11 patients; the intra-abdominal veins were used in 4 patients. The patients were followed up for 12–59 months (mean, 24.8 months). After redo Rex shunts, the grafts were patent in 14 patients (93.3%, 14/15), but 1 graft had thrombosis (6.7%, 1/15). Three patients suffered from postoperative anastomotic stenosis, and all of the stenosis was relieved with balloon dilatations. After re-Rex shunts, esophageal varices and spleen size were substantially reduced, and the platelet count significantly increased. Postoperative graft thrombosis was found in 1 patient after Warren shunt (1/4, 25%), and there was no graft stenosis. Compared with Warren surgery, patients who underwent re-Rex shunt had a significantly higher rate of platelet increase.ConclusionsRedo-rex shunts can be finished in most patients with failed Rex shunts. Re-Rex shunt is a preferred surgical choice after a failed Rex shunt when a good bypass graft is available, and the surgical success rate can reach more than 90%. A suitable bypass graft is essential for a successful redo Rex shunt. Preoperative WHVP is recommended for the design of a redo surgical plan preoperatively

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Whole-genome sequence-based analysis of thyroid function

Tiina Paunio on työryhmän UK10K Consortium jäsen.Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N = 2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF >= 1%) associated with TSH and FT4 (N = 16,335). For TSH, we identify a novel variant in SYN2 (MAF = 23.5%, P = 6.15 x 10(-9)) and a new independent variant in PDE8B (MAF = 10.4%, P = 5.94 x 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/ SLC25A52 (MAF = 3.2%, P = 1.27 x 10(-9)) tagging a rare TTR variant (MAF = 0.4%, P = 2.14 x 10(-11)). All common variants explain >= 20% of the variance in TSH and FT4. Analysis of rare variants (MAFPeer reviewe

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)