Focal and diffuse beta cell changes in persistent hyperinsulinemic hypoglycemia of infancy

Klöppel, Günter; Reinecke-Lüthge, Axel; Koschoreck, F.

doi:10.1007/bf02739772

Cited by 15 publications

(12 citation statements)

References 25 publications

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“…In patients with focal CHI, the pancreas lesion is generally unique and small sized (1,16,28,(32)(33)(34)(35). To our knowledge, few patients with more than one focal lesion have been reported, but no molecular data were available (32,36).…”

Section: Discussionmentioning

confidence: 99%

The Knudson’s Two-Hit Model and Timing of Somatic Mutation May Account for the Phenotypic Diversity of Focal Congenital Hyperinsulinism

Giurgea¹,

Sempoux²,

Bellanné‐Chantelot³

et al. 2006

The Journal of Clinical Endocrinology & Metabolism

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Background: Congenital hyperinsulinism (CHI) is associated with focal hyperplasia of endocrine tissue in 40 -65% of patients. Focal CHI is sporadic and is caused by a germline, paternally inherited, mutation of the SUR1 (ABCC8) or KIR6.2 (KCNJ11) genes (encoding subunits of the pancreatic ATP-dependent potassium channel) together with somatic maternal haploinsufficiency for 11p15.5. Plurifocal or large forms of focal CHI are a cause of apparent failure of surgery, and their underlying mechanism has not been thoroughly investigated.

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Section: Discussionmentioning

confidence: 99%

The Knudson’s Two-Hit Model and Timing of Somatic Mutation May Account for the Phenotypic Diversity of Focal Congenital Hyperinsulinism

Giurgea¹,

Sempoux²,

Bellanné‐Chantelot³

et al. 2006

The Journal of Clinical Endocrinology & Metabolism

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“…A high proliferation rate of β cells was shown inside the lesion, whereas in the normal adjacent pancreas, small resting islets, made of packed endocrine cells with scanty cytoplasm, exhibit no sign of proliferation [2]. Furthermore, loss of the maternally expressed CDKN1C gene within the lesion is evidenced by the absence of immunohistochemical staining of the corresponding protein, in contrast to normal surrounding islets [16, 17]. These features differ from true adult-type pancreatic adenoma or insulinoma which are microscopically less well distinguished from adjacent pancreatic tissue, sometimes extending between exocrine acini or including normal islets.…”

Section: Introductionmentioning

confidence: 99%

“…These features differ from true adult-type pancreatic adenoma or insulinoma which are microscopically less well distinguished from adjacent pancreatic tissue, sometimes extending between exocrine acini or including normal islets. Outside insulinomas, islets show regular nuclei and normally abundant cytoplasm and are thus very different from those located in non-lesional pancreas of focal forms [16, 17]. Diffuse hyperinsulinism is characterized histologically by the presence of β cells with a particularly abundant cytoplasm and a large nucleus in the islets throughout the whole pancreas [18,19,20,21].…”

Section: Introductionmentioning

confidence: 99%

“…Both forms share a similar clinical presentation. Histologically, focal adenomatous hyperplasia is a small poorly delineated lesion composed of normally structured hyperplastic islets (β cells surrounded by non-β cells), separated by few exocrine acini, thus maintaining a normal lobular pancreatic architecture [16]. A high proliferation rate of β cells was shown inside the lesion, whereas in the normal adjacent pancreas, small resting islets, made of packed endocrine cells with scanty cytoplasm, exhibit no sign of proliferation [2].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Mechanisms of Neonatal Hyperinsulinism

et al. 2006

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Congenital hyperinsulinism (CHI), characterized by profound hypoglycaemia related to inappropriate insulin secretion, may be associated histologically with either diffuse insulin hypersecretion or focal adenomatous hyperplasia, which share a similar clinical presentation, but result from different molecular mechanisms. Whereas diffuse CHI is of autosomal recessive, or less frequently of autosomal dominant, inheritance, focal CHI is sporadic. The most common mechanism underlying CHI is dysfunction of the pancreatic ATP-sensitive potassium channel (K⁺_ATP). The two subunits of the K⁺_ATP channel are encoded by the sulfonylurea receptor gene (SUR1 or ABCC8) and the inward-rectifying potassium channel gene (KIR6.2 or KCNJ11), both located in the 11p15.1 region. Germ-line, paternally inherited, mutations of the SUR1 or KIR6.2 genes, together with somatic maternal haplo-insufficiency for 11p15.5, were shown to result in focal CHI. Diffuse CHI results from germ-line mutations in the SUR1 or KIR6.2 genes, but also from mutations in several other genes, namely glutamate dehydrogenase (with associated hyperammonaemia), glucokinase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and insulin receptor gene. Hyperinsulinaemic hypoglycaemia may be observed in several overlapping syndromes, such as Beckwith-Wiedemann syndrome (BWS), Perlman syndrome, and, more rarely, Sotos syndrome. Mosaic genome-wide paternal isodisomy has recently been reported in patients with clinical signs of BWS and CHI. The primary causes of CHI are genetically heterogeneous and have not yet been completely unveiled. However, secondary causes of hyperinsulinism have to be considered such as fatty acid oxidation deficiency, congenital disorders of glycosylation and factitious hypoglycaemia secondary to Munchausen by proxy syndrome.

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“…The focal form is characterised by an isolated cluster of abnormal insulin producing cells with 'normal 'surrounding tissue within the pancreas (Figure 2). Histologically it involves focal adenomatous hyperplasia of the islet cells with ductuloinsular complexes and scattered giant β-cell nuclei surrounded by normal pancreatic parenchyma [2,10,11] . Focal CHI is always sporadic in inheritance and caused by the paternal heterozygous mutation in ABCC8/KCNJ11 genes along with somatic loss of maternal allele in the focal hyperplastic tissue requiring a focal lesionectomy [12] .…”

Section: Introductionmentioning

confidence: 99%

Congenital hyperinsulinism: Role of fluorine-18L-3, 4 hydroxyphenylalanine positron emission tomography scanning

Gopal‐Kothandapani

Hussain

2014

WJR

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Congenital hyperinsulinism (CHI) is a rare but complex heterogeneous disorder caused by unregulated secretion of insulin from the β-cells of the pancreas leading to severe hypoglycaemia and neuroglycopaenia. Swift diagnosis and institution of appropriate management is crucial to prevent or minimise adverse neurodevelopmental outcome in children with CHI. Histologically there are two major subtypes of CHI, diffuse and focal disease and the management approach will significantly differ depending on the type of the lesion. Patients with medically unresponsive diffuse disease require a near total pancreatectomy, which then leads on to the development of iatrogenic diabetes mellitus and pancreatic exocrine insufficiency. However patients with focal disease only require a limited pancreatectomy to remove only the focal lesion thus providing complete cure to the patient. Hence the preoperative differentiation of the histological subtypes of CHI becomes paramount in the management of CHI. Fluorine-18L-3, 4-hydroxyphenylalanine positron emission tomography ( 18 F-DOPA-PET) is now the gold standard for pre-operative differentiation of focal from diffuse disease and localisation of the focal lesion. The aim of this review article is to give a clinical overview of CHI, then review the role of dopamine in β-cell physiology and finally discuss the role of

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Focal and diffuse beta cell changes in persistent hyperinsulinemic hypoglycemia of infancy

Cited by 15 publications

References 25 publications

The Knudson’s Two-Hit Model and Timing of Somatic Mutation May Account for the Phenotypic Diversity of Focal Congenital Hyperinsulinism

The Knudson’s Two-Hit Model and Timing of Somatic Mutation May Account for the Phenotypic Diversity of Focal Congenital Hyperinsulinism

Molecular Mechanisms of Neonatal Hyperinsulinism

Congenital hyperinsulinism: Role of fluorine-18L-3, 4 hydroxyphenylalanine positron emission tomography scanning

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