Aortic dilatation and gastrointestinal disease: expansion of the hyperinsulinism-polycystic kidney disease phenotype
Daphne Yau, Unai Diaz-Moreno, Elena Cervi, Meera Shaunak, Ereny Bassilious, Jonathan Kraus Friedmann, Craig Jefferies, Clare Gilbert, Kate Morgan, Nicola Townsend, Stephen Marks, Jelena Stojanovic, Iona Madden, Detlef Bockenhauer, Fevronia Kiparissi, Kelsey Jones, Stephanie Grunewald, Sarah E Flanagan, Antonia DastamaniAbstract
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 (PMM2-CDG).
Objective
To describe the HIPKD clinical phenotype, expanding our understanding and its distinction from the CDG phenotype.
Design
Retrospective multicentre cohort study of individuals with HIPKD identified through an international HI genetic referral centre.
Patients
10 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). 5/7 patients had systemic hypertension and 3/5 were normotensive on losartan at last follow up. IBD with gastric antral foveolar hyperplasia occurred in 4/10 patients, and aortic root and/or ascending aortic dilatation in 4/7 patients who underwent echocardiography, 3 of whom also had IBD.
Conclusions
HIPKD due to a PMM2 promoter variant is associated with broad, multisystem phenotype, including IBD and aortic dilatation. These findings support targeted screening for IBD and cardiovascular surveillance in addition to standard endocrine and renal follow-up.