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Ismail D.,Hospital for Children National Health Service Trust | Kapoor R.R.,Hospital for Children National Health Service Trust | Smith V.V.,Hospital for Children National Health Service Trust | Ashworth M.,Hospital for Children National Health Service Trust | And 6 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Background: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia due to unregulated insulin secretion from pancreatic β-cells. Histologically, there are two major subgroups, focal and diffuse. Focal CHI is typically unresponsive to diazoxide and can be cured with surgical removal of the focal lesion. Aims: We report on three patients with focal CHI to illustrate the marked clinical, genetic, radiological, and histological heterogeneity. Methods and Results: The first two patients had focal CHI due to a paternal (c.3992-9G→A) ABCC8 mutation. One of these patients was fully responsive to a small dose (5 mg/kg·d) of diazoxide, whereas the other patient was medically unresponsive. In both patients, the focal lesions were accurately localized preoperatively by [ 18F]dihydroxyphenylalanine (DOPA) positron emission tomography (PET) and surgically resected. The third patient had a paternally inherited ABCC8 (A1493T) mutation, and the initial [ 18F]DOPA PET scan indicated extensive uptake of DOPA in the body and tail of the pancreas. However, despite surgical resection of the body and tail, this patient continued to have severe CHI. A subsequent [ 18F]DOPA PET scan now showed markedly increased DOPA uptake in the remaining body and head of the pancreas. This focal lesion occupied virtually the whole of the pancreas. Conclusions: These three cases illustrate that focal lesions even with the same genotype (c.3992-9G→A) may have a different clinical presentation and that [ 18F]DOPA PET scans in very large focal lesions may be difficult to interpret. Copyright © 2012 by The Endocrine Society.


Quarta G.,University College London | Quarta G.,University of Rome La Sapienza | Syrris P.,University College London | Ashworth M.,Hospital for Children National Health Service Trust | And 8 more authors.
European Heart Journal | Year: 2012

Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease predominantly caused by mutations in desmosomal protein genes. Lamin A/C gene (LMNA) mutations are associated with dilated cardiomyopathy, conduction abnormalities and high incidence of sudden cardiac death. In this study, we screened a large cohort of ARVC patients for LMNA mutations. Methods and resultsOne hundred and eight patients from unrelated families with borderline (n 27) or definite (n 81) diagnosis of ARVC were genetically tested for five desmosomal genes and LMNA. Sixty-one (56.5) were positive for desmosomal gene mutations. Standard polymerase chain reaction (PCR) amplification of the 12 protein-coding LMNA exons was performed and mutational screening performed by direct sequencing. Four patients (4) without desmosomal gene mutations carried LMNA variants. Three had severe right ventricular involvement, and during follow-up three died (two suddenly and one from congestive heart failure); all three had conduction abnormalities on resting 12-lead electrocardiogram (ECG). Myocardial tissue from two patients showed myocyte loss and fibro-fatty replacement. In one of these, immunohistochemical staining with antibody to plakoglobin showed reduced/absent staining of the intercalated discs in the myocardium. ConclusionLamin A/C gene mutations can be found in severe forms of ARVC. Lamin A/C gene should be added to desmosomal genes when genetically testing patients with suspected ARVC, particularly when they also have ECG evidence for conduction disease. Published on behalf of the European Society of Cardiology. © The Author 2012.

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