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Congenital hyperinsulinism in children with paternal 11p uniparental isodisomy and Beckwith–Wiedemann syndrome
  1. Jennifer M Kalish1,2,
  2. Kara E Boodhansingh3,
  3. Tricia R Bhatti4,5,
  4. Arupa Ganguly6,
  5. Laura K Conlin4,5,
  6. Susan A Becker3,
  7. Stephanie Givler3,
  8. Lindsey Mighion6,
  9. Andrew A Palladino2,3,
  10. N Scott Adzick7,8,
  11. Diva D De León2,3,
  12. Charles A Stanley2,3,
  13. Matthew A Deardorff1,2
  1. 1Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  2. 2Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  3. 3Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  4. 4Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  5. 5Department of Pathology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  6. 6Department of Genetics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  7. 7Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  8. 8Department of Surgery, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Jennifer M Kalish, Division of Human Genetics, The Children's Hospital of Philadelphia, 1002 Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA; kalishj{at}email.chop.edu

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.

  • Endocrinology
  • Epigenetics
  • Genetics

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