Journal
CLINICAL ENDOCRINOLOGY
Volume 93, Issue 3, Pages 346-354Publisher
WILEY
DOI: 10.1111/cen.14267
Keywords
diazoxide; hyperinsulinism; hypoglycaemia; Kabuki syndrome; KDM6A; KMT2D; medical genetics
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Background and Objective Kabuki syndrome (KS), caused by pathogenic variants inKMT2DorKDM6A, is associated with hyperinsulinaemic hypoglycaemia (HH) in 0.3%-4% of patients. We characterized the clinical, biochemical and molecular data of children with KS and HH compared to children with KS without HH in a multicentre meta-analysis. Methods Data of seven new and 17 already published children with KS and HH were compared to 373 recently published KS patients without HH regarding molecular and clinical characteristics. Results Seven new patients were identified with seven different pathogenic variants inKDM6A(n = 4) orKMT2D(n = 3). All presented with HH on the first day of life and were responsive to diazoxide. KS was diagnosed between 9 months and 14 years of age. In the meta-analysis, 24 KS patients with HH had a significantly higher frequency of variants inKDM6Acompared to 373 KS patients without HH (50% vs 11.5%,P < .001), andKDM6A-KS was more likely to be associated with HH thanKMT2D-KS (21.8% vs. 3.5%,P < .001). Sex distribution and other phenotypic features did not differ between KS with and without HH. Conclusion The higher incidence of HH inKDM6A-KS compared toKMT2D-KS indicates thatKDM6Aloss of function variants predispose more specifically to beta cell dysfunction compared toKMT2Dvariants. As difficulties to assign syndromic characteristics to KS in early infancy often lead to delayed diagnosis, genetic testing for KS should be considered in children with HH, especially in the presence of other extrapancreatic/syndromic features.
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