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.

Keywords: Endocrinology; Epigenetics; Genetics.

Figure 1

Mechanisms of Beckwith–Wiedemann syndrome (BWS). Chromosome 11 includes the BWS region and the KATP genes. Expressed genes are noted with a bold box surrounding. The hyperinsulinism (HI) genes KCNJ11 and ABCC8 are biallelically expressed. (A) 11p15 contains two adjacent imprinting control regions that are altered in BWS. Normally, imprinting control region 1 (IC1) is methylated on the paternal allele resulting in paternal expression of IGF2 and unmethylated on the maternal allele resulting in maternal expression of H19. Imprinting control region 2 (IC2) is methylated on the maternal allele resulting in KCNQ1 and CDKN1C (p57) expression and unmethylated on the paternal allele. Closed circles indicate methylation. (B) In paternal uniparental isodisomy (pUPD11p), IC1 is methylated on both alleles resulting in biallelic IGF2 expression and loss of H19 expression. IC2 is unmethylated on both alleles, resulting in loss of KCNQ1 and CDKN1C expression. (C) Hypomethylation at IC2 leads to loss of KCNQ1 and CDKN1C expression. (D) Hypermethylation at IC1, a rarer cause of BWS, leads to biallelic IGF2 expression and loss of H19 expression. Maternally transmitted CDKN1C mutations, and rare deletions or duplications of the imprinted region(s) can also lead to BWS.

Figure 2

Pancreatic histology in Beckwith–Wiedemann syndrome (BWS) hyperinsulinism (HI). The histology of the BWS pancreas is similar to focal pancreatic lesions but demonstrates a larger area of affected pancreas compared with focal lesions. (A) Normal pancreas by H&E staining, (B) p57 and (C) chromogranin. (D–F) Images from a UPD-BWS patient’s pancreas that demonstrate an increase in the size of islets associated with a more prominent trabecular arrangement of islet cell nuclei (D). The expanded islets and overgrown endocrine tissue correlate with a decrease in p57 (CDKN1C) expression (E). The chromogranin staining demonstrates that the region of expanded endocrine cells also includes exocrine acinar tissue (F). The variable degree of overgrown endocrine tissue with expanded islets and preservation of lobular architecture is distinct from both focal and diffuse HI histology.

Figure 3

Region of mosaic paternal uniparental isodisomy for chromosome 11p in cases of Beckwith–Wiedemann syndrome (BWS) and hyperinsulinism (HI). The location of the BWS region genes and the HI genes on chromosome 11 are indicated on the chromosome at the top of the figure. The grey bars indicate the extent of paternal uniparental isodisomy along chromosome 11 as determined by single-nucleotide polymorphism array analysis. * indicates the presence of a KATP gene mutation (see table 3). ND, not determined because a sample was not available.