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

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.

Congenital Hyperinsulinism in Infants with Turner Syndrome: Possible Association with Monosomy X and <b><i>KDM6A</i></b> Haploinsufficiency

“…Similarly, most patients with Kabuki Syndrome have de novo mutations and potential mosacism for the genetic defect between tissues which could determine variations in phenotypic features. Differences in mosaicism between tissues also appear to explain the variability in severity of hyperinsulinism seen in Beckwith Wiedemann Syndrome due to paternal 11p isodisomy [40]. …”

Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes

“…However, 5% of BWS patients have persistent HI that does not respond to diazoxide and may require pancreatectomy. 73,74 Pancreas tissue sections from those severely hypoglycemic BWS patients demonstrated a range in the degree of islet expansion across the entire pancreas. The islet cell expansion was accompanied by a corresponding decrease in nuclear CDKN1C (P57) expression.…”

“…The KCNQ1 defects in BWS may be dramatically amplified by the overgrowth of islet tissue. 74 Voltage-dependent calcium channel mutation and CHI L-type voltage-dependent calcium channels (VDCC, gene: CACNA1D) play a key role in the process of insulin secretion. The activating mutation of VDCC (p.Gly403Asp) was recently identified in a diazoxide-sensitive HI patient.…”

Coexistence of Mosaic Uniparental Isodisomy and a KCNJ11 Mutation Presenting as Diffuse Congenital Hyperinsulinism and Hemihypertrophy

“…The report by Kocaay et al [2] and 2 previous reports [3,4] highlight several important aspects of patients with BWS and HH due to paternal UPD of chromosome 11. Patients with BWS and HH may not always have the classical features of macrosomia, macroglossia, hemihypertrophy, and abdominal wall defects at birth.…”

“…Further analysis confirmed paternal UPD of chromosome 11 that extended across the KCNJ11 gene at 11p15.1 and the BWS locus at 11p15.5 and was confirmed in the blood and pancreatic tissue. However, not all patients with HH and BWS due to UPD of chromosome 11 have mutations in the ABCC8/KCNJ11 genes [4],suggesting other possible molecular mechanisms of HH in these patients.…”