Genotype-phenotype associations in children with congenital hyperinsulinism

Maria Melikyan, Klaus Brusgaard, Elena Petraykina, Igor Volkov, Yulia Averyanova, Maria Kareva, Valentina Peterkova, larisa Gurevich, Henrik Thybo Christesen

Publikation: Konferencebidrag uden forlag/tidsskriftKonferenceabstrakt til konferenceForskningpeer review

Resumé

Congenital hyperinsulinism (CHI) is a heterogeneous disease in terms of clinical presentation, genetics and histology. Mutations in eight genes
are known to be a cause of CHI, of which ABCC8, KCNJ11 and GCK are among the most common.
We investigated genotype-phenotype associations in a cohort of Russian patients with CHI by clinical characterization and bidirectional direct
sequencing of the ABCC8, KCNJ11 and GCK genes.
33 children were identified, of which 18 (54,5%) responded to the medical therapy (diazoxide and/or somatostatine) and 15 (45,5%) were resistant and
underwent subtotal or partial pancreatectomy. Histological examination of the removed pancreatic tissue revealed 7 (47%) diffuse, 7(47%) focal, and 1
(6%) atypical form of CHI. Among medically responsive, 4 children (22%) spontaneously recovered during one year after the diagnosis. Mutations were
found in 12 patients (36%); 4 (22%) of the medical responsive and 8 (53%) of the medical resistant patients, Table 1. Ten (83%) of the mutations were
found in the KATP-channel genes ABCC8 and KCNJ11. The same heterozygous, novel ABCC8 mutation Q444H was seen in 4 unrelated families,
causing medically resistant focal form in 3 patients and diazoxide responsive form in 1. GCK mutations were medical responsive, and resistant,
respectively. There were no mutation carriers among children with spontaneously recovery.
Table 1. Gentotype-phenotype correlation in patients with mutations detected
ABCC8 KCNJ11 GCK
Number of patients 8 2 2
Mutations found in medically responsive cases R74L hetz
Q444H hetz A96T homoz V91L hetz, de novo
Mutations found in medically resistant cases of focal forms
Q444H hetz, paternal
Q444H hetz
Q444H hetz
R841P hetz, paternal
R136AfsX5 hetz, de novo -
Mutations found in medically resistant cases of diffuse forms R998X hetz
delF1387 hetz, de novo - Y241C hetz
Hetz – heterozygous; homoz – homozygous
Conclusion: A genetic cause was detected in 23%, and 53%, of children with mild, and severe CHI, respectively, in Russia. The ABCC8 mutation
Q444H was prevalent and found in both medical responsive and resistant patient. Further genetic investigations are pending.
OriginalsprogEngelsk
Publikationsdatosep. 2011
Antal sider1
StatusUdgivet - sep. 2011
Begivenhed50th ESPE Meeting - Glasgow, Storbritannien
Varighed: 25. sep. 2011 → …

Konference

Konference50th ESPE Meeting
LandStorbritannien
ByGlasgow
Periode25/09/2011 → …

Citer dette

Melikyan, M., Brusgaard, K., Petraykina, E., Volkov, I., Averyanova, Y., Kareva, M., ... Christesen, H. T. (2011). Genotype-phenotype associations in children with congenital hyperinsulinism. Abstract fra 50th ESPE Meeting , Glasgow, Storbritannien.
Melikyan, Maria ; Brusgaard, Klaus ; Petraykina, Elena ; Volkov, Igor ; Averyanova, Yulia ; Kareva, Maria ; Peterkova, Valentina ; Gurevich, larisa ; Christesen, Henrik Thybo. / Genotype-phenotype associations in children with congenital hyperinsulinism. Abstract fra 50th ESPE Meeting , Glasgow, Storbritannien.1 s.
@conference{20e34f4449974319a6555078ce81c6df,
title = "Genotype-phenotype associations in children with congenital hyperinsulinism",
abstract = "Congenital hyperinsulinism (CHI) is a heterogeneous disease in terms of clinical presentation, genetics and histology. Mutations in eight genesare known to be a cause of CHI, of which ABCC8, KCNJ11 and GCK are among the most common.We investigated genotype-phenotype associations in a cohort of Russian patients with CHI by clinical characterization and bidirectional directsequencing of the ABCC8, KCNJ11 and GCK genes.33 children were identified, of which 18 (54,5{\%}) responded to the medical therapy (diazoxide and/or somatostatine) and 15 (45,5{\%}) were resistant andunderwent subtotal or partial pancreatectomy. Histological examination of the removed pancreatic tissue revealed 7 (47{\%}) diffuse, 7(47{\%}) focal, and 1(6{\%}) atypical form of CHI. Among medically responsive, 4 children (22{\%}) spontaneously recovered during one year after the diagnosis. Mutations werefound in 12 patients (36{\%}); 4 (22{\%}) of the medical responsive and 8 (53{\%}) of the medical resistant patients, Table 1. Ten (83{\%}) of the mutations werefound in the KATP-channel genes ABCC8 and KCNJ11. The same heterozygous, novel ABCC8 mutation Q444H was seen in 4 unrelated families,causing medically resistant focal form in 3 patients and diazoxide responsive form in 1. GCK mutations were medical responsive, and resistant,respectively. There were no mutation carriers among children with spontaneously recovery.Table 1. Gentotype-phenotype correlation in patients with mutations detectedABCC8 KCNJ11 GCKNumber of patients 8 2 2Mutations found in medically responsive cases R74L hetzQ444H hetz A96T homoz V91L hetz, de novoMutations found in medically resistant cases of focal formsQ444H hetz, paternalQ444H hetzQ444H hetzR841P hetz, paternalR136AfsX5 hetz, de novo -Mutations found in medically resistant cases of diffuse forms R998X hetzdelF1387 hetz, de novo - Y241C hetzHetz – heterozygous; homoz – homozygousConclusion: A genetic cause was detected in 23{\%}, and 53{\%}, of children with mild, and severe CHI, respectively, in Russia. The ABCC8 mutationQ444H was prevalent and found in both medical responsive and resistant patient. Further genetic investigations are pending.",
author = "Maria Melikyan and Klaus Brusgaard and Elena Petraykina and Igor Volkov and Yulia Averyanova and Maria Kareva and Valentina Peterkova and larisa Gurevich and Christesen, {Henrik Thybo}",
year = "2011",
month = "9",
language = "English",
note = "null ; Conference date: 25-09-2011",

}

Melikyan, M, Brusgaard, K, Petraykina, E, Volkov, I, Averyanova, Y, Kareva, M, Peterkova, V, Gurevich, L & Christesen, HT 2011, 'Genotype-phenotype associations in children with congenital hyperinsulinism', 50th ESPE Meeting , Glasgow, Storbritannien, 25/09/2011.

Genotype-phenotype associations in children with congenital hyperinsulinism. / Melikyan, Maria; Brusgaard, Klaus; Petraykina, Elena; Volkov, Igor ; Averyanova, Yulia ; Kareva, Maria; Peterkova, Valentina; Gurevich, larisa; Christesen, Henrik Thybo.

2011. Abstract fra 50th ESPE Meeting , Glasgow, Storbritannien.

Publikation: Konferencebidrag uden forlag/tidsskriftKonferenceabstrakt til konferenceForskningpeer review

TY - ABST

T1 - Genotype-phenotype associations in children with congenital hyperinsulinism

AU - Melikyan, Maria

AU - Brusgaard, Klaus

AU - Petraykina, Elena

AU - Volkov, Igor

AU - Averyanova, Yulia

AU - Kareva, Maria

AU - Peterkova, Valentina

AU - Gurevich, larisa

AU - Christesen, Henrik Thybo

PY - 2011/9

Y1 - 2011/9

N2 - Congenital hyperinsulinism (CHI) is a heterogeneous disease in terms of clinical presentation, genetics and histology. Mutations in eight genesare known to be a cause of CHI, of which ABCC8, KCNJ11 and GCK are among the most common.We investigated genotype-phenotype associations in a cohort of Russian patients with CHI by clinical characterization and bidirectional directsequencing of the ABCC8, KCNJ11 and GCK genes.33 children were identified, of which 18 (54,5%) responded to the medical therapy (diazoxide and/or somatostatine) and 15 (45,5%) were resistant andunderwent subtotal or partial pancreatectomy. Histological examination of the removed pancreatic tissue revealed 7 (47%) diffuse, 7(47%) focal, and 1(6%) atypical form of CHI. Among medically responsive, 4 children (22%) spontaneously recovered during one year after the diagnosis. Mutations werefound in 12 patients (36%); 4 (22%) of the medical responsive and 8 (53%) of the medical resistant patients, Table 1. Ten (83%) of the mutations werefound in the KATP-channel genes ABCC8 and KCNJ11. The same heterozygous, novel ABCC8 mutation Q444H was seen in 4 unrelated families,causing medically resistant focal form in 3 patients and diazoxide responsive form in 1. GCK mutations were medical responsive, and resistant,respectively. There were no mutation carriers among children with spontaneously recovery.Table 1. Gentotype-phenotype correlation in patients with mutations detectedABCC8 KCNJ11 GCKNumber of patients 8 2 2Mutations found in medically responsive cases R74L hetzQ444H hetz A96T homoz V91L hetz, de novoMutations found in medically resistant cases of focal formsQ444H hetz, paternalQ444H hetzQ444H hetzR841P hetz, paternalR136AfsX5 hetz, de novo -Mutations found in medically resistant cases of diffuse forms R998X hetzdelF1387 hetz, de novo - Y241C hetzHetz – heterozygous; homoz – homozygousConclusion: A genetic cause was detected in 23%, and 53%, of children with mild, and severe CHI, respectively, in Russia. The ABCC8 mutationQ444H was prevalent and found in both medical responsive and resistant patient. Further genetic investigations are pending.

AB - Congenital hyperinsulinism (CHI) is a heterogeneous disease in terms of clinical presentation, genetics and histology. Mutations in eight genesare known to be a cause of CHI, of which ABCC8, KCNJ11 and GCK are among the most common.We investigated genotype-phenotype associations in a cohort of Russian patients with CHI by clinical characterization and bidirectional directsequencing of the ABCC8, KCNJ11 and GCK genes.33 children were identified, of which 18 (54,5%) responded to the medical therapy (diazoxide and/or somatostatine) and 15 (45,5%) were resistant andunderwent subtotal or partial pancreatectomy. Histological examination of the removed pancreatic tissue revealed 7 (47%) diffuse, 7(47%) focal, and 1(6%) atypical form of CHI. Among medically responsive, 4 children (22%) spontaneously recovered during one year after the diagnosis. Mutations werefound in 12 patients (36%); 4 (22%) of the medical responsive and 8 (53%) of the medical resistant patients, Table 1. Ten (83%) of the mutations werefound in the KATP-channel genes ABCC8 and KCNJ11. The same heterozygous, novel ABCC8 mutation Q444H was seen in 4 unrelated families,causing medically resistant focal form in 3 patients and diazoxide responsive form in 1. GCK mutations were medical responsive, and resistant,respectively. There were no mutation carriers among children with spontaneously recovery.Table 1. Gentotype-phenotype correlation in patients with mutations detectedABCC8 KCNJ11 GCKNumber of patients 8 2 2Mutations found in medically responsive cases R74L hetzQ444H hetz A96T homoz V91L hetz, de novoMutations found in medically resistant cases of focal formsQ444H hetz, paternalQ444H hetzQ444H hetzR841P hetz, paternalR136AfsX5 hetz, de novo -Mutations found in medically resistant cases of diffuse forms R998X hetzdelF1387 hetz, de novo - Y241C hetzHetz – heterozygous; homoz – homozygousConclusion: A genetic cause was detected in 23%, and 53%, of children with mild, and severe CHI, respectively, in Russia. The ABCC8 mutationQ444H was prevalent and found in both medical responsive and resistant patient. Further genetic investigations are pending.

M3 - Conference abstract for conference

ER -

Melikyan M, Brusgaard K, Petraykina E, Volkov I, Averyanova Y, Kareva M et al. Genotype-phenotype associations in children with congenital hyperinsulinism. 2011. Abstract fra 50th ESPE Meeting , Glasgow, Storbritannien.