Integrating genetic and imaging investigations into the clinical management of congenital hyperinsulinism

Banerjee, Indraneel; Avatapalle, Bindu; Padidela, Raja; Stevens, Adam; Cosgrove, Karen E.; Clayton, Peter E.; Dunne, Mark J.

doi:10.1111/cen.12153

Cited by 39 publications

(40 citation statements)

References 79 publications

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“…During this period, frequent undiagnosed hypoglycemic episodes occur. The current strategy of rapid diagnosis by genetic analysis [14], localization diagnosis [15], and restrictive pancreatectomy [16-18] has reduced the frequency of hypoglycemic events before definitive cure in the subgroup of focal CHI patients. Remarkably, our findings show no significant differences between the focal and diffuse CHI patients for all outcome variables.…”

Section: Discussionmentioning

confidence: 99%

Formal Neurocognitive Testing in 60 Patients with Congenital Hyperinsulinism

et al. 2017

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Background: Congenital hyperinsulinism (CHI) is hallmarked by persistent hypoketotic hypoglycemia in infancy. In the majority of all patients, CHI is caused by mutations in the KATP channel genes ABCC8 and KCNJ11, but other genes in the insulin-regulatory pathway have also been described. Repeated episodes of hypoglycemia include an increased risk of seizures and intellectual disability. So far, controlled psychometric studies on cognitive, motor, speech, and social-emotional outcome of CHI patients are missing. Until now, neurodevelopmental long-term outcome in CHI patients has only been measured by questionnaires, self-, parental-, or caregiver-administered instruments. Methods: This is a prospective study of 60 patients (median age 3.3 years, range 3 months to 57 years): 48 with a diffuse, 9 with a focal, and 3 with an atypical histology. Neurodevelopmental outcome was assessed using standardized psychological tests and questionnaires. Results: 28 of 60 patients showed developmental delay (46.7%). 9 of 57 patients had cognitive deficits (15.8%), 7 of 26 patients had speech problems (26.9%), and 17 of 44 patients had motor problems (38.6%). In 5 of 53 patients, social-emotional problems were reported. Outcome and the underlying genetic defect were not correlated. Conclusions: Motor problems seem to be prominent in CHI patients. Despite a high incidence of developmental delay, a permanent cognitive defect was only detectable in 9 of 58 patients.

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Section: Discussionmentioning

confidence: 99%

Formal Neurocognitive Testing in 60 Patients with Congenital Hyperinsulinism

et al. 2017

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“…They are usually associated with unresponsiveness of pancreatic β-cells to medical treatment. Recently, it has been suggested to implement rapid genetic analysis of ABCC8 and KCNJ11 in newborns with DZX-unresponsive CHI to improve patient management [7,8]. Gene defects in medically responsive or partially responsive CHI include mutations in GLUD1 , GCK , HADH , SLC16A1 , UCP2 , HNF4A and HNF1A [9] .…”

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Evaluation of Patients with K<sub>ATP</sub> Channel Mutations from the German Registry for Congenital Hyperinsulinism

Mohnike¹,

Wieland

Barthlen

et al. 2014

Horm Res Paediatr

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Congenital hyperinsulinism (CHI) causes hypoglycemia due to irregular insulin secretion. In infants, a rapid diagnosis and appropriate management to avoid severe hypoglycemia is mandatory. CHI is a heterogeneous condition at the clinical and genetic level, and disease-causing genes have been identified in about half of the patients. The majority of mutations have been identified in the ABCC8 and KCNJ11 genes encoding subunits of the K_ATP channel responsible for two distinct histological forms. The diffuse form is caused by autosomal recessive or dominant inherited mutations, whereas the focal form is caused by a paternally transmitted recessive mutation and a second somatic event. We report on an unselected cohort of 136 unrelated patients from the German CHI registry. Mutations in either the ABCC8 or KCNJ11 gene were identified in 61 of these patients (45%). In total, 64 different mutations including 38 novel ones were detected in this cohort. We observed biparental (recessive) inheritance in 34% of mutation-positive patients, dominant inheritance in 11% and paternal transmission of a mutation associated with a focal CHI type in 38%. In addition, we observed inheritance patterns that do not exactly follow the classical recessive or dominant mode, further adding to the genetic complexity of this disease.

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“…The Table summarizes the patients' clinical profiles, with the classification of CHI based on established diagnostic criteria. 1,2,4,9 Sequence analysis of the exons and intron/exon boundaries of the ABCC8 and KCNJ11 genes was performed on all patients using genomic DNA extracted from peripheral blood leukocytes. ABCC8 analysis included screening for the recently reported deep intronic cryptic splicing mutation.…”

Section: Methodsmentioning

confidence: 99%