An <i>ABCC8</i> Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

Hussain, Khalid; Flanagan, Sarah E.; Smith, Virpi V.; Ashworth, Michael; Day, Michael; Pierro, Agostino; Ellard, Sian

doi:10.2337/db07-0998

Cited by 55 publications

(44 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A novel genetic mechanism of diffuse disease due to mosaic paternal uniparental isodisomy in a patient with heterozygous ABCC8/KCNJ11 mutations was recently described (36). Lastly, it could also very rarely be due to failure of Sanger sequencing to detect the second ABCC8/KCNJ11 mutation or a missed histological diagnosis of focal CHI in these patients.…”

Section: Discussionmentioning

confidence: 93%

“…The patients with diffuse tracer pancreatic uptake were either managed with near-total pancreatectomy (nZ3) or octreotide injections (nZ3). One patient from this subgroup had atypical histology with pancreatic b-cell enlargement in parts of body and head of the pancreas due to mosaic interstitial paternal uniparental isodisomy for chromosome 11p15.1 (36).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

See 1 more Smart Citation

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Arya

Güemes

Nessa

et al. 2014

European Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

Context: Congenital hyperinsulinism (CHI) has two main histological types: diffuse and focal. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to either phenotype. However, the relative proportion of these two phenotypes in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations has not been reported. Objective: The purpose of this study is to highlight the variable clinical phenotype and to characterise the distribution of diffuse and focal disease in a large cohort of CHI patients due to paternally inherited heterozygous ABCC8/KCNJ11 mutations. Design: A retrospective chart review of the CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted. Results: Paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 CHI patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. Fluorine-18 L-3, 4-dihydroxyphenylalanine positron emission tomography computerised tomography ( 18 F DOPA-PET CT) scanning in 3/18 children showed diffuse disease. The remaining 35 (66%) diazoxide-unresponsive children either had pancreatic venous sampling (nZ8) or 18

show abstract

Section: Discussionmentioning

confidence: 93%

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Arya

Güemes

Nessa

et al. 2014

European Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Histologic presentation may be focal or diffuse 5 (and very rarely atypical 6 ) based on the spread of affected regions in the pancreas. Differentiation between these subgroups can be made by using 18 F 3,4-dihydroxyphenylalanine positron emission tomography scans.…”

Section: Discussionmentioning

confidence: 99%

Severe Hyperinsulinemic Hypoglycemia in a Neonate: Response to Sirolimus Therapy

et al. 2015

View full text Add to dashboard Cite

Hyperinsulinemic hypoglycemia (HH) is one of the most common causes of persistent hypoglycemic episodes in neonates. Current pharmacologic treatment of neonatal HH includes diazoxide and octreotide, whereas for diffuse, unresponsive cases a subtotal pancreatectomy may be the last resort, with questionable efficacy. Here we report a case of congenital diffuse neonatal HH, first suspected when severe hypoglycemia presented with extremely high serum insulin levels immediately after birth. Functional imaging and genetic tests later confirmed the diagnosis. Failure to respond to a sequence of different treatments and to avoid extensive surgery with predictable morbidity prompted us to introduce a recently suggested alternative therapy with sirolimus, a mammalian target of rapamycin inhibitor. Glucose intake could be reduced gradually while euglycemia was maintained, and we were able to achieve exclusively enteral feeding within 6 weeks. Sirolimus was found to be effective and well tolerated, with no major adverse side effects attributable to its administration. PATIENT PRESENTATIONOur patient, a male infant, was born by normal vaginal delivery during the 37th week of gestation after an uneventful pregnancy. Birth weight was 4400 g, and 1-and 5-minute Apgar scores were 10 and 10. Both parents and the baby's 2 older siblings had unremarkable medical histories. A right-sided clavicular fracture was noted on first examination, which did not warrant additional intervention. Two hours after delivery, tremor and irritability were observed, with severe hypoglycemia (0.5 mmol/L, 9 mg/dL). High doses of intravenous glucose (up to 20 mg/kg per minute) and occasional glucagon boluses were needed to normalize the persistently low blood glucose levels. The diagnosis of hyperinsulinemic hypoglycemia (HH) was based on the clinical picture and on the laboratory values (glucose, 0.5 mmol/L; concomitant serum insulin, 130.7 mU/mL; growth hormone, 18.3 ng/mL; thyroidstimulating hormone, 8.2 mU/L; free thyroxine, 20.5 pmol/L; cortisol, 835 nmol/L), and samples were sent for genetic testing.Diazoxide therapy (with hydrochlorothiazide 1 mg/kg per day) was commenced on day 4 and was gradually increased to a maximum dose of 20 mg/kg per day without any effect. Somatostatin treatment (introduced as intravenous, subsequently modified to subcutaneous) was initiated on week 2 and increased to a maximum dose (35 mg/kg per day), but only a 20% reduction in total glucose requirements was achieved. On week 4 nifedipine was added to the therapeutic regimen, but it was discontinued after a week because of lack of response (Fig 1).

show abstract

“…Histologically, atypical forms of CHI are categorised when the pancreatic morphology does not fit into the FCHI or DCHI types and are a mosaic pattern of the two (Hussain et al 2008. The islets can be either enlarged or shrunken.…”

Section: Molecular Basis Of Atypical Chimentioning

confidence: 99%

Molecular mechanisms of congenital hyperinsulinism

Rahman¹,

Nessa²,

Hussain³

2015

Journal of Molecular Endocrinology

Self Cite

View full text Add to dashboard Cite

Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic b-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin-sensitive tissues, such as the muscle, liver and adipose tissue, leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2 and HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically unresponsive CHI. Mutations in GLUD1 and HADH lead to leucine-induced HH, and these two genes encode the key enzymes glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase which play a key role in amino acid and fatty acid regulation of insulin secretion respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in the newborn period and maturity onset-diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.

show abstract

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

Cited by 55 publications

References 20 publications

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Clinical and histological heterogeneity of congenital hyperinsulinism due to paternally inherited heterozygous ABCC8/KCNJ11 mutations

Severe Hyperinsulinemic Hypoglycemia in a Neonate: Response to Sirolimus Therapy

Molecular mechanisms of congenital hyperinsulinism

Contact Info

Product

Resources

About