Persistent Neonatal Hyperinsulinism

Mathew, P. M.; Young, Janet M.; Abu-Osba, Yousef K.; Mulhern, B.D.; Hammoudi, S.; Hamdan, Jahed A.; Sa'di, Abdul Rahman M.

doi:10.1177/000992288802700307

Cited by 116 publications

(56 citation statements)

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“…Mutations in ABCC8 (MIM# 600509) and KCNJ11 (MIM# 600937) genes have been shown to result in defects in the KATP channel function leading to Hyperinsulinism of Infancy HI, a disease characterized by deregulated insulin secretion that leads to severe and recurrent hypoglycaemias DOI: 10.1002/humu.9401 2 Fernández-Marmiesse et al ; references therein). Estimates for the incidence of this disorder vary from 1/40.000 live births in Northern Europe (Bruining et al 1990) to 1/2675 live births in Saudi Arabia (Mathew et al 1988). The severity of the disease varies from a mild form, which responds to medical treatment, to severe drug-resistant form, which may need resection of the pancreas.…”

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Mutation spectra ofABCC8 gene in Spanish patients with hyperinsulinism of infancy (HI)

et al. 2006

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Hyperinsulinism of Infancy (HI) is a clinical disorder characterized by deregulation of insulin secretion that leads to profound hypoglycemia. Mutations in genes encodingthe ATP-regulated potassium channels of the pancreatic β-cell, namely ABCC8 (SUR1) and KCNJ11 (Kir6.2), are the major genetic known cause of the disease. To elucidate the genetic etiology of HI in the uncharacterized Spanish population, we conducted extensive sequencing analysis of the ABCC8 (83.5Kb) and KCNJ11 (1.7Kb) genes in 34 Spanish HI patients. Mutations in ABCC8 were detected for both alleles in 13 patients, while ten patients carried only one mutation in one of the ABCC8 alleles. We have detected 22 novel and seven previously described mutations in ABCC8, ∼60% of them lead to a premature termination signal, which would result in truncated SUR1 proteins. No mutations were found in the KCNJ11 gene. In addition, we report for the first time a 3914bp macrodeletion associated with the HI disorder. The potential pathogenicity of several additional variants is discussed. The spatial pattern of three pathological mutations suggests possible geographical founder effects. This work reveals for first time the involvement of KATP channels in the pathogenesis of an important proportion (∼68%) of Spanish HI patients. The spectrum of mutations in Spanish HI patients provides an important tool for diagnosis and prognosis of HI patients in the Spanish population, as well as for genetic counseling of HI families. © 2006 Wiley-Liss, Inc.KEY WORDS: hyperinsulinism; ABCC8; KCNJ11; mutation spectra; Spanish INTRODUCTIONATP-sensitive potassium channels (KATP) are major regulators of glucose-induced insulin secretion in pancreatic ß cells . Mutations in ABCC8 (MIM# 600509) and KCNJ11 (MIM# 600937) genes have been shown to result in defects in the KATP channel function leading to Hyperinsulinism of Infancy HI, a disease characterized by deregulated insulin secretion that leads to severe and recurrent hypoglycaemias DOI: 10.1002/humu.9401 2 Fernández-Marmiesse et al. ; references therein). Estimates for the incidence of this disorder vary from 1/40.000 live births in Northern Europe (Bruining et al. 1990) to 1/2675 live births in Saudi Arabia (Mathew et al. 1988). The severity of the disease varies from a mild form, which responds to medical treatment, to severe drug-resistant form, which may need resection of the pancreas. Early diagnosis is important to avoid irreversible brain damage due to profound hypoglycaemia. Clinical manifestations of HI, which occurs predominantly in neonates and infants, include large birth weight for gestational age, seizures, cyanosis and coma (Hussain et al. 2000).Although both autosomal dominant and recessive inheritance of HI have been described, this disorder is inherited as an autosomal recessive trait in the majority of familial cases. Most of HI cases (>95%) are sporadic, and two histopathologic lesions can be distinguished, a diffuse and a focal form, each with a prevalence of ∼50% . It has been demonstrated that focal ca...

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Mutation spectra ofABCC8 gene in Spanish patients with hyperinsulinism of infancy (HI)

et al. 2006

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“…An incidence as high as 1/2,500 has been reported in inbred populations (2,3). The molecular basis of the disease was recently elucidated, and most cases are caused by mutations in either the sulfonylurea receptor-1 (SUR1) gene ABCC8 or the inward rectifying K ϩ channel Kir6.2 gene KCNJ11, the two subunits of the ␤-cell ATP-sensitive K ϩ channel (K ATP channel) (4 -7).…”

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p57KIP2 Expression in Normal Islet Cells and in Hyperinsulinism of Infancy

Kassem

Ariel²,

Thornton³

et al. 2001

Diabetes

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Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea receptor-1 (SUR1) or the inward rectifying K ؉ channel Kir6.2, two subunits of the ␤-cell ATP-sensitive K ؉ channel (K ATP channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all ␤-cells within the pancreas. Focal HI consists of adenomatous hyperplasia within a limited region of the pancreas, and it is caused by somatic loss of heterozygosity (LOH), including maternal Ch11p15-ter in a ␤-cell precursor carrying a germline mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, some of which, including p57 KIP2 and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57 KIP2 expression in different islet cell types, in control pancreases from different developmental stages (n ‫؍‬ 15), and in pancreases from patients with both diffuse (n ‫؍‬ 4) and focal HI (n ‫؍‬ 9). Using immunofluorescence and computerized image analysis, we quantified IGF-II expression in ␤-cells from patients with focal HI (n ‫؍‬ 8). Within the pancreas, p57 KIP2 was specifically localized to the endocrine portion. ␤-Cells demonstrated the highest frequency of expression (34.9 ؎ 2.7%) compared with ϳ1-3% in other cell types. The fraction of ␤-cells expressing p57 KIP2 did not vary significantly during development. ␤-Cells within the focal lesions did not express p57 KIP2 , whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57 KIP2 is expressed and is paternally imprinted in human pancreatic ␤-cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57 KIP2 expression in ␤-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the ␤-cell failure observed in diabetes.

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“…A forma familiar é comum em comunidades com alto grau de consangüinidade -1/2.500 nascidos vivos -não havendo entretanto, descrição em gemelares [2][3][4][5] . A ocorrên-cia familiar dessa condição, presente como severa hipoglicemia neonatal persistente, foi primeiramente descrita numa família greco-cipriota, por Woo et al, em 1976 30 , e posteriormente por vários outros autores 13,16,[31][32][33][34] .…”

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Persistent hyperinsulinemic hypoglycemia of infancy: case report

Lazarine¹,

Pahl²,

Damiani³

et al. 2000

J Pediatr (Rio J)

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ResumoObjetivo: Relatar a ocorrência de Hipoglicemia Hiperinsulinê-mica Persistente da Infância em gêmeos, forma de apresentação ainda não descrita na literatura Métodos: Relato de convulsões em gêmeos univitelinos, filhos de pais consangüíneos, com hipoglicemia persistente levando ao quadro convulsivo. Na investigação etiológica da hipoglicemia, foram realizadas dosagens de hormônios tireóideos (T4 e TSH), insulina, cortisol e hormônio de crescimento; teste de estímulo com glucagon (para avaliação da relação insulina/glicose) e estudo histopatológico do pâncreas.Resultados: A investigação laboratorial mostrou hiperinsulinemia e hipoglicemia persistentes, confirmadas pelo teste de estímulo com glucagon. O exame do tecido pancreático revelou persistência de ilhotas pancreáticas de primeira geração, com hiperplasia e hipertrofia das ilhotas de Langherhans, confirmando o diagnóstico de Hipoglicemia Hiperinsulinêmica Persistente da Infância (nova denominação para nesidioblastose).Conclusões: Embora rara, esta condição deve ser suspeitada precocemente entre as hipoglicemias do lactente, mesmo fora do período neonatal, especialmente se houver consangüinidade entre os pais. A terapêutica adequada deve ser instalada rapidamente a fim de evitar seqüelas neurológicas. J. pediatr. (Rio J.). 2000; 76(2): 162-168:hipoglicemia, hiperinsulinismo, convulsões, gêmeos. AbstractObjective: To report a case of Persistent Hyperinsulinemic Hypoglycemia in twins which is a situation not yet reported in the literature.Methods: Report of seizures in identical twins, from consanguineous parents, with persistent hypoglycemia as cause of the seizures. Laboratory tests, performed for etiological investigation of the hypoglycemia, included thyroid hormones (T4/TSH), insulin, cortisol, growth hormone, stimulation test with glucagon (to evaluate the insulin/glucose relation), and histopathological study of the pancreas.Results: Laboratorial investigation revealed a persistent hypoglycemia with hyperinsulinism which were confirmed with the stimulation test with glucagon. The histopathological exam showed a persistence of first generation pancreatic islet, confirming the diagnosis of Persistent Hyperinsulinemic Hypoglycemia in Infancy (the new denomination of Nesidioblastosis). Conclusion:Although rare, this condition must be early suspected early in the evaluation of hypoglycemia of the young infant, even out of the neonatal period, specially if the parents are consanguineous. The adequate therapy must be quickly initiated in order to prevent neurological damage. Introdução A Hipoglicemia Hiperinsulinêmica Persistente da Infância (HHPI), constitui importante etiologia a ser cogitada nos casos de hipoglicemia persistente de difícil controle. Trata-se de emergência médica que requer diagnóstico etiológico preciso e representa um sério problema terapêu-tico. O termo HHPI foi proposto por Glaser em 1989 e vem sendo utilizado nas publicações mais recentes, em substituição à nesidioblastose e à síndrome de dismaturidade das ilhotas pancreáticas, para ...

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Persistent Neonatal Hyperinsulinism

Cited by 116 publications

References 19 publications

Mutation spectra ofABCC8 gene in Spanish patients with hyperinsulinism of infancy (HI)

Mutation spectra ofABCC8 gene in Spanish patients with hyperinsulinism of infancy (HI)

p57KIP2 Expression in Normal Islet Cells and in Hyperinsulinism of Infancy

Persistent hyperinsulinemic hypoglycemia of infancy: case report

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