Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith-Wiedemann syndrome

J Med Genet. 2016 Jan;53(1):53-61. doi: 10.1136/jmedgenet-2015-103394. Epub 2015 Nov 6.

Abstract

Background: Congenital hyperinsulinism (HI) can have monogenic or syndromic causes. Although HI has long been recognised to be common in children with Beckwith-Wiedemann syndrome (BWS), the underlying mechanism is not known.

Methods: We characterised the clinical features of children with both HI and BWS/11p overgrowth spectrum, evaluated the contribution of KATP channel mutations to the molecular pathogenesis of their HI and assessed molecular pathogenesis associated with features of BWS.

Results: We identified 28 children with HI and BWS/11p overgrowth from 1997 to 2014. Mosaic paternal uniparental isodisomy for chromosome 11p (pUPD11p) was noted in 26/28 cases. Most were refractory to diazoxide treatment and half required subtotal pancreatectomies. Patients displayed a wide range of clinical features from classical BWS to only mild hemihypertrophy (11p overgrowth spectrum). Four of the cases had a paternally transmitted KATP mutation and had a much more severe HI course than patients with pUPD11p alone.

Conclusions: We found that patients with pUPD11p-associated HI have a persistent and severe HI phenotype compared with transient hypoglycaemia of BWS/11p overgrowth patients caused by other aetiologies. Testing for pUPD11p should be considered in all patients with persistent congenital HI, especially for those without an identified HI gene mutation.

Keywords: Endocrinology; Epigenetics; Genetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Beckwith-Wiedemann Syndrome / diagnosis
  • Beckwith-Wiedemann Syndrome / genetics*
  • Beckwith-Wiedemann Syndrome / therapy
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 11*
  • Congenital Hyperinsulinism / diagnosis
  • Congenital Hyperinsulinism / drug therapy
  • Congenital Hyperinsulinism / genetics*
  • DNA Methylation
  • DNA Mutational Analysis
  • Epigenesis, Genetic
  • Female
  • Humans
  • Infant
  • KATP Channels / genetics
  • Male
  • Mutation
  • Pancreas / metabolism
  • Pancreas / pathology
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Uniparental Disomy*

Substances

  • KATP Channels