Jennifer M Kalish1, Kara E Boodhansingh2, Tricia R Bhatti3, Arupa Ganguly4, Laura K Conlin3, Susan A Becker2, Stephanie Givler2, Lindsey Mighion4, Andrew A Palladino5, N Scott Adzick6, Diva D De León5, Charles A Stanley5, Matthew A Deardorff1. 1. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. 2. Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 3. Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Department of Pathology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. 4. Department of Genetics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. 5. Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 6. Department of Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Department of Surgery, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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