Refractory hyperinsulinaemic hypoglycaemia in beckwith-wiedemann syndrome due to imprinting centre 1 gain of methylation: Severity discordant to genotype

Abstract

Introduction: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome caused by multiple epigenetic/genetic changes affecting imprinted genes in 11p15.5 region. Phenotypic expression is variable. Hyperinsulinaemic hypoglycaemia is common (30-60%). Persistent, severe, refractory cases are usually associated with 11p15 paternal uniparental disomy, particularly the rare context of a coexisting paternal inactivating KATP channel variant. Those cases may have large, focal pancreatic lesions. In BWS due to other molecular defects, hypoglycaemia usually resolves within days. Persistent cases are usually diazoxide-responsive. Case: BWS, suspected antenatally, was confirmed postnatally in a female (35 weeks gestation, unaffected parents, spontaneous nonconsanguineous conception, no family history of hypoglycaemia). She had macroglossia, but no exomphalos, lateralised overgrowth or placental mesenchymal hyperplasia (cardinal Beckwith- Wiedemann spectrum, BWSp features). Of suggestive features, she was macrosomic with diastasis recti, umbilical hernia; without polyhydramnios, nephromegaly, ear creases/pits or facial naevus simplex. The molecular defect was gain of methylation at H19/IGF2 intergenic differentially methylated region (IGDMR), known as Imprinting Centre 1 (IC1). This genotype accounts for 5% of BWS. Wilms' tumour risk is high (24%). Unexpected for genotype, she had severe, congenital hyperinsulinism (CHI) refractory to medical therapy (diazoxide, octreotide). There were no detected ABCC8 or KCNJ11 variants. This genotype would not predict focal disease. At 11 weeks, a subtotal pancreatectomy (80-85%) was performed. In this context, reducing endocrine tissue mass may suffice. Histology was atypical for focal or diffuse CHI, with large, numerous islets as previously observed in BWS. Complications included catheter-related bloodstream infections and thromboses. Macroglossia exacerbated feeding difficulties. CHI was again refractory to octreotide. Sirolimus exacerbated transaminitis and anaemia. The brief trial was ceased at the onset of a sepsis episode. [18F]-DOPA PET/CT scan did not indicate the unlikely scenario of ectopic disease. Further resection to equivalent of at least 95% pancreatectomy was performed two weeks after the initial resection. Exocrine pancreatic insufficiency resulted, however CHI persisted. After further medical support including Lanreotide from 8 months, she was discharged at 9 months. At 14 months, she continues monthly Lanreotide. She is orally fed with pancreatic enzyme and fat-soluble vitamin supplements. Tumour surveillance is negative. There is no evident neurocognitive impairment. Macroglossia has impeded expressive language development. She has mixed sleep-disordered breathing. Tonguereduction surgery is planned. Conclusion: The CHI severity was discordant to that previously reported for this BWS genotype. Although clinical heterogeneity has been described in the different genotype of IC2 hypomethylation (accounts for 50% of BWS), those cases were diazoxideresponsive.L6306022012020-01-20 <br />