Aortic dilatation and gastrointestinal disease: expansion of the hyperinsulinism-polycystic kidney disease phenotype

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Abstract
Context: Congenital hyperinsulinism (HI) with polycystic kidney disease (PKD), or HIPKD, is a recently described syndrome caused by a specific promotor variant in PMM2, a gene otherwise associated with PMM2 congenital disorder of glycosylation. Objective: To describe the HIPKD clinical phenotype, expanding our understanding and its distinction from the congenital disorder of glycosylation phenotype. Design: Retrospective multicenter cohort study of individuals with HIPKD identified through an international HI genetic referral center. Patients: Ten individuals from 9 families compound heterozygous for the promoter variant c.-167G > T and a pathogenic intragenic variant in PMM2. Intervention: None. Main Outcome Measures: Observed clinical features and outcomes. Results: Median age of presentation was 5 months (range 0-42). Median age at follow up was 12.7 years (range 5.4-20.1). HI was managed with diazoxide monotherapy (7/10 patients), diazoxide and nifedipine (2/10 patients), and carbohydrate supplementation alone (1/10 patient). PKD age at diagnosis and severity was variable, ranging from antenatal presentation requiring renal transplantation, to incidental detection in mid-childhood. Liver cysts were noted in 6/10 patients (5/6 with normal liver function). Five of 7 patients had systemic hypertension and 3/5 were normotensive on losartan at last follow up. Inflammatory bowel disease (IBD) with gastric antral foveolar hyperplasia occurred in 4/10 patients, and aortic root and/or ascending aortic dilation in 4/7 patients who underwent echocardiography, 3 of whom also had IBD. Conclusion: HIPKD due to a PMM2 promoter variant is associated with broad, multisystem phenotype, including IBD and aortic dilation. These findings support targeted screening for IBD and cardiovascular surveillance in addition to standard endocrine and renal follow up.

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