Neutrophil dysfunction triggers inflammatory bowel disease in G6PC3 deficiency

From Wiley via Jisc Publications RouterHistory: received 2019-12-09, rev-recd 2020-08-28, accepted 2020-08-29, pub-electronic 2020-09-15, pub-print 2021-06Article version: VoRPublication status: PublishedFunder: Medical Research Council Clinical Research Training Fellowship; Grant(s): MR/N001427/1Funder: European Society of Paediatric Infectious Diseases FellowshipFunder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269; Grant(s): 202865/Z/16/ZAbstract: The glucose‐6‐phosphatase catalytic subunit 3 (G6PC3) encodes a ubiquitously expressed enzyme that regulates cytoplasmic glucose availability. Loss‐of‐function biallelic G6PC3 mutations cause severe congenital neutropenia and a diverse spectrum of extra‐hematological manifestations, among which inflammatory bowel disease (IBD) has been anecdotally reported. Neutrophil function and clinical response to granulocyte colony‐stimulating factor (G‐CSF) and hematopoietic stem cell transplantation (HSCT) were investigated in 4 children with G6PC3 deficiency‐associated IBD. G6PC3 deficiency was associated with early‐onset IBD refractory to treatment with steroids and infliximab. The symptoms of IBD progressed despite G‐CSF treatment. In vitro studies on the patients’ blood showed that neutrophils displayed higher levels of activation markers (CD11b, CD66b, and CD14), excessive IL‐8 and reactive oxygen species, and increased apoptosis and secondary necrosis. Secondary necrosis was exaggerated after stimulation with Escherichia coli and could be partially rescued with supplemental exogenous glucose. HSCT led to normalization of neutrophil function and remission of gastrointestinal symptoms. We conclude that neutrophils in G6PC3 deficiency release pro‐inflammatory mediators when exposed to gut bacteria, associated with intestinal inflammation, despite treatment with G‐CSF. HSCT is an effective therapeutic option in patients with G6PC3 deficiency‐associated IBD refractory to immune suppressants

Unravelling the genetic causes of mosaic islet morphology in congenital hyperinsulinism

Congenital hyperinsulinism (CHI) causes dysregulated insulin secretion which can lead to life-threatening hypoglycaemia if not effectively managed. CHI can be sub-classified into three distinct groups: diffuse, focal and mosaic pancreatic disease. Whilst the underlying causes of diffuse and focal disease have been widely characterised, the genetic basis of mosaic pancreatic disease is not known. To gain new insights into the underlying disease processes of mosaic-CHI we studied the islet tissue histopathology derived from limited surgical resection from the tail of the pancreas in a patient with CHI. The underlying genetic aetiology was investigated using a combination of high depth next-generation sequencing, microsatellite analysis and p57kip2 immunostaining. Histopathology of the pancreatic tissue confirmed the presence of a defined area associated with marked islet hypertrophy and a cytoarchitecture distinct from focal CHI but compatible with mosaic CHI localised to a discrete region within the pancreas. Analysis of DNA extracted from the lesion identified a de novo mosaic ABCC8 mutation and mosaic paternal uniparental disomy which were not present in leukocyte DNA or the surrounding unaffected pancreatic tissue. This study provides the first description of two independent disease-causing somatic genetic events occurring within the pancreas of an individual with localised mosaic CHI. Our findings increase knowledge of the genetic causes of islet disease and provide further insights into the underlying developmental changes associated with β-cell expansion in CHI

Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown.Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled.Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated.Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers

Management and outcome of paediatric testicular tumours - A 20 year experience.

ObjectiveTo report a 20-year experience highlighting management and outcome(s) of paediatric testicular tumours.Patients and methodsAll males (ResultsA total of 34 male patients were identified. Median age at primary diagnosis was 94 months (range: 0-229 months). Eighteen tumours were benign and 16 malignant. Twenty cases (59%) were recorded in pre pubertal children and 14 (41%) in post pubertal males . In the pre pubertal group (0-11 years) - 15 cases of germ cell tumours (unrelated to germ cell neoplasia in situ - non-GCNIS derived) were recorded, including six yolk sac lesions, eight teratomas and one mixed teratoma/yolk sac tumour (pre-pubertal type). Four males with sex cord-stromal tumours included one juvenile granulosa cell tumour, two Sertoli cell tumours and one Leydig cell tumour. One miscellaneous type tumour notably a papillary cyst adenoma was also identified. In the post pubertal male cohort (>12 years) (n = 14) - four non-GCNIS derived tumours were identified (3 epidermoid cysts and one teratoma), eight cases of germ cell tumour derived from germ cell neoplasia in situ (GCNIS derived) included one teratoma, six with mixed germ cell tumours and one embryonal carcinoma. Two males had sex cord stromal tumours: (Leydig cell and granulosa cell biology). Twenty-eight patients underwent high radical inguinal orchidectomy(s) with one male also requiring retroperitoneal surgery to clear distant locoregional disease and a further single case thoracotomy and metastasectomy. Six patients had lesions suitable for 'testicular sparing' surgery. Six patients had metastatic disease at presentation (18%). Overall study survival was 97%. A single fatality occurred in an adolescent male with a mixed GCT harbouring liver, lung and para-aortic disease who died 48 months after initiating treatment.ConclusionWe highlight one of the largest study series of paediatric testicular tumours in the UK and Europe. Non-GCNIS derived tumours accounted for the most common tumour biology (56%). Survival for paediatric testicular tumours is reassuringly generally excellent. Delayed presentation however with a malignant testicular tumour may be associated with poor outcome(s)

Life-threatening pulmonary interstitial lung disease complicating pediatric non-humoral immunodeficiencies

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