ESPE Abstracts (2019) 92 P1-65

Congenital Hyperinsulinism Due to Pancreatic Mosaicism for Paternal Uniparental Disomy of all Chromosome 11, with the Additional Finding of Pancreatic Mosaicism for Trisomy 12

Louise Conwell1,2, James Harraway3, Mark Williams4, Christopher Joy3, Bonnie Scurry5, Kevin Lee2,6, Craig McBride2,7, Kelvin Choo8, Tony Huynh9,2,10, Carolyn Ng11, Sarah Flanagan12

1Department of Endocrinology and Diabetes, Queensland Children's Hospital, Brisbane, Australia. 2School of Clinical Medicine, Faculty of Medicine, Brisbane, Australia. 3Molecular Pathology Department, Mater Health, Brisbane, Australia. 4Molecular Pathology Department, Mater Health, Brisbane, Austria. 5Anatomical Pathology, Pathology Queensland, Brisbane, Aruba. 6Department of Nuclear Medicine and Queensland PET Service, Royal Brisbane and Women's Hospital, Brisbane, Australia. 7Department of Paediatric Surgery, Queensland Children's Hospital, Brisbane, Australia. 8Department of Paediatric Surgery, Queensland Children's Hospital, Brisbane, Bahrain. 9Department of Endocrinology and Diabetes, Queensland Children's Hospital, Brisbane, Austria. 10Chemical Pathology Department, Mater Health, Brisbane, Australia. 11Department of Paediatrics, Bundaberg, Australia. 12Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom

We report a term male with diazoxide-unresponsive congenital hyperinsulinism (CHI) (spontaneous conception, non-consanguineous, no family history). The patient did not have macroglossia, exomphalos or lateralised overgrowth (cardinal Beckwith-Wiedemann spectrum (BWSp) features) (1). There was no polyhydramnios, macrosomia, facial naevus simplex, ear creases/pits, diastasis recti or nephromegaly/hepatomegaly (suggestive BWSp features) (1).

A targeted massively parallel sequencing (MPS) panel identified a heterozygous maternally-inherited ABCC8 variant (c.1332+4del) (minimal splicing effect predicted, classified as likely benign).

[18F]-DOPA PET/CT imaging had unexpected focal increased uptake in the pancreatic distal body and tail. Histopathology of subtotal pancreatectomy (day 22) showed focal adenomatous hyperplasia (trabeculae and islet nests composed of regular, oval or columnar cells; lacking atypia or conspicuous nuclear enlargement). Adjacent lobules had a relatively normal distribution of islets and exocrine acini. There was aberrant p57 expression in islet cytoplasm (nuclear in normal islets; negative in focal-CHI due to a paternal KATP mutation).

Within 2 weeks, medical support was again required with residual, increased [18F]-DOPA pancreatic uptake. A second resection (5% left in-situ) (day 36) achieved normoglycaemia.

At 21 months, he remains normoglycaemic with age-appropriate feeding (exocrine pancreatic supplements) and normal neurodevelopmental progress.

Aim: Extended genetic analyses in context of CHI, focal increased [18F]-DOPA PET/CT pancreatic uptake and atypical histology.

Methods: Pancreas (region of islet hyperplasia): (i) Targeted MPS hyperinsulinism panel with mosaic variant calling programme on the sequence data (ii) Single-nucleotide polymorphism (SNP) array analysis. Peripheral blood and buccal cells: SNP array analysis.

Results: Pancreas: maternal likely benign ABCC8 variant was identified with a skewed allelic frequency; high level of paternal uniparental disomy (pUPD) (whole of chromosome 11); mosaicism for trisomy 12 (up to 50% of sample). Peripheral blood and buccal cells: no mosaic paternal uniparental disomy (pUPD) or trisomy 12 identified.

Conclusions: With 2 cardinal BWSp features (hyperinsulinism >1week, escalating treatment; and pancreatic adenomatosis), the requirement of the international consensus statement for BWS clinical diagnosis is met (1). Placenta was not retained to assess size / mesenchymal dysplasia (1).

Chr11pUPD is the likely cause of hyperinsulinism. Pancreatic mosaic trisomy 12 is likely a coincidental finding and unrelated to the hyperinsulinism.

Even in the absence of overt overgrowth features, BWSp due to pUPD11 should be considered if (i) persistent, severe CHI without identified pathogenic KATP channel mutation(s) (ii) large focal pancreatic lesions (with/without a KATP mutation) or (iii) atypical histology.

(1) Brioude F et al. Nat Rev Endocrinol, 2018