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

Arya, Vivek; Güemes, María; Nessa, Azizun; Alam, Shamsul; Shah, Pratik; Gilbert, Clare; Senniappan, Senthil; Flanagan, Sarah E.; Ellard, Sian; Hussain, Khalid

doi:10.1530/eje-14-0353

Cited by 47 publications

(40 citation statements)

References 45 publications

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“…The A1153T mutation is probably pathogenic. This result is consistent with a diagnosis of autosomal dominant congenital hyperinsulinism (16). …”

Section: Discussionsupporting

confidence: 89%

A Case Series: Congenital Hyperinsulinism

Alaei¹,

Akbaroghli²,

Keramatipour³

et al. 2016

Int J Endocrinol Metab

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IntroductionCongenital hyperinsulinism is a rare inherited disease caused by mutations in genes responsible for β-cell’s function in glucose hemostasis leading to profound and recurrent hypoglycemia. The incidence of the disease is about 1 in 50000 newborns. Mutations in at least 8 genes have been reported to cause congenital hyperinsulinism. Mutations in ABCC8 gene are the most common cause of the disease that account for approximately 40% of cases. Less frequently KCNJ11 gene mutations are responsible for the disease. Mutations in other genes such as HADH account for smaller fractions of cases. In nearly half of the cases the cause remains unknown.Case PresentationDuring the period between 2005 and 2010, a total of six patients with persistent hyperinsulinism were investigated at Mofid Children’s Hospital. In this study all of the patients had early onset hyperinsulinemia. Five patients had consanguineous parents. After failure of medical treatment in three patients, They were undergone pancreatectomy. Two diffuse types and one focal type had been recognized in pathological analysis of intra-operative frozen specimens of pancreas in these patients. Genetic analysis was performed using polymerase chain reaction followed by Sanger sequencing for ABCC8, KCNJ11and HADH genes. In five patients homozygous mutations in these genes were identified that indicated an autosomal recessive pattern of inheritance. In one patient a heterozygous mutation in ABCC8 was identified, indicating possible autosomal dominant inheritance of the disease.ConclusionsCongenital hyperinsulinism can have different inheritance pattern. Autosomal recessive inheritance is more common but less frequently autosomal dominant inheritance can be seen. It appears that mutations in ABCC8 gene can show both autosomal recessive and autosomal dominant inheritance of the disease. PCR followed by Sanger sequencing proved to be an efficient method for mutation detection in three investigated genes. Despite early diagnosis, psychomotor retardation was seen in two patients.

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“…The A1153T mutation is probably pathogenic. This result is consistent with a diagnosis of autosomal dominant congenital hyperinsulinism (16). …”

Section: Discussionsupporting

confidence: 89%

A Case Series: Congenital Hyperinsulinism

Alaei¹,

Akbaroghli²,

Keramatipour³

et al. 2016

Int J Endocrinol Metab

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“…K-ATP channel genotyping has stratified treatment protocols of focal and diffuse CHI with paternal heterozygosity most commonly associating with focal CHI and maternal heterozygous, homozygous or compound heterozygous mutations in ABCC8 / KCNJ11 associating with diffuse disease [2]. Although paternal heterozygosity has a higher predilection for focal CHI, additional investigation such as 18-fluoro-dopa PET-CT scanning is necessary to localise the lesion in focal CHI; a significant proportion, as many as half with paternal heterozygous mutations in some reports may have diffuse CHI [9] which could be explained by dominant inheritance or inability to identify a maternal mutation in recessively-inherited disease.…”

Section: Introductionmentioning

confidence: 99%

Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time

Salomon‐Estebanez

Flanagan

Ellard

et al. 2016

Orphanet J Rare Dis

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BackgroundPatients with Congenital Hyperinsulinism (CHI) due to mutations in K-ATP channel genes (K-ATP CHI) are increasingly treated by conservative medical therapy without pancreatic surgery. However, the natural history of medically treated K-ATP CHI has not been described; it is unclear if the severity of recessively and dominantly inherited K-ATP CHI reduces over time. We aimed to review variation in severity and outcomes in patients with K-ATP CHI treated by medical therapy.MethodsTwenty-one consecutively presenting patients with K-ATP CHI with dominantly and recessively inherited mutations in ABCC8/KCNJ11 were selected in a specialised CHI treatment centre to review treatment outcomes. Medical treatment included diazoxide and somatostatin receptor agonists (SSRA), octreotide and somatuline autogel. CHI severity was assessed by glucose infusion rate (GIR), medication dosage and tendency to resolution. CHI outcome was assessed by glycaemic profile, fasting tolerance and neurodevelopment.ResultsCHI presenting at median (range) age 1 (1, 240) days resolved in 15 (71%) patients at age 3.1(0.2, 13.0) years. Resolution was achieved both in patients responsive to diazoxide (n = 8, 57%) and patients responsive to SSRA (n = 7, 100%) with earlier resolution in the former [1.6 (0.2, 13.0) v 5.9 (1.6, 9.0) years, p = 0.08]. In 6 patients remaining on treatment, diazoxide dose was reduced in follow up [10.0 (8.5, 15.0) to 5.4 (0.5, 10.8) mg/kg/day, p = 0.003]. GIR at presentation did not correlate with resolved or persistent CHI [14.9 (10.0, 18.5) v 16.5 (13.0, 20.0) mg/kg/min, p = 0.6]. The type of gene mutation did not predict persistence; resolution could be achieved in recessively-inherited CHI with homozygous (n = 3), compound heterozygous (n = 2) and paternal mutations causing focal CHI (n = 2). Mild developmental delay was present in 8 (38%) patients; adaptive functioning assessed by Vineland Adaptive Behavior Scales questionnaire showed a trend towards higher standard deviation scores (SDS) in resolved than persistent CHI [−0.1 (−1.2, 1.6) v −1.2 (−1.7, 0.03), p = 0.1].ConclusionsIn K-ATP CHI patients managed by medical treatment only, severity is reduced over time in the majority, including those with compound heterozygous and homozygous mutations in ABCC8/KCNJ11. Severity and treatment requirement should be assessed periodically in all children with K-ATP CHI on medical therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0547-3) contains supplementary material, which is available to authorized users.

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“…The search for a focal lesion causing CHI should start from an early stage in clinical management. The identification of a paternally inherited recessive pathogenic gene variant in ABCC8/KCNJ11 indicates a high probability of focal CHI . However, it is well recognized that a second ‘hit’ is required within the pancreas which cannot be determined by investigations other than by a biopsy of the focal lesion.…”

Section: The Impact Of Subtypes Of Chi On Treatmentmentioning

confidence: 99%

Complexities in the medical management of hypoglycaemia due to congenital hyperinsulinism

Worth

Yau²,

Estebanez

et al. 2020

Clinical Endocrinology

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Congenital Hyperinsulinism (CHI) is a rare disease of hypoglycaemia but is the most common form of recurrent and severe hypoglycaemia causing brain injury and neurodisability in children. The management of CHI is complex due to the limited choice of medications, all with a limited therapeutic window, often lacking efficacy and associated with serious side effects. The therapeutic strategy in CHI is to recognize and treat hypoglycaemia promptly, thereby optimizing long-term neurological outcomes; this should be achieved through individualized treatment plans that deliver glycaemic stability while minimizing side effects. Further, such a strategy should consider the likelihood of reduction in disease severity over time, with dose adjustments and medication withdrawal as indicated to optimize both safety and tolerability. The option for pancreatic surgery should also be considered in specific circumstances as appropriate for the patient's best long-term interests. K E Y W O R D Scongenital hyperinsulinism, glucose, hypoglycaemia, insulin, management, medication

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

Cited by 47 publications

References 45 publications

A Case Series: Congenital Hyperinsulinism

A Case Series: Congenital Hyperinsulinism

Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time

Complexities in the medical management of hypoglycaemia due to congenital hyperinsulinism

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