Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations

Abstract

ObjectiveThe phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH).Subjects and methodsWe sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype.ResultsA genetic diagnosis was possible for 59/220 (27%) patients. KATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years.ConclusionsIn this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded.

Hipoglicemia hiperinsulinêmica da infância

“…O quadro clínico envolve o desenvolvimento de hipoglicemia induzida pelo exercício físico anaeróbico (9,(43)(44)(45).…”

“…Concomitantemente, também infusão endovenosa ou subcutânea contínua de Glucagon, com doses variando entre 1 e 20 ug/kg/hora, pode ser utilizada na tentativa de se utilizar menores concentrações de glicose, principalmente por veia periférica (9,(43)(44)(45).…”

“…Essa medicação se liga aos canais K ATP e os mantêm abertos evitando a despolarização da membrana e consequente secreção de insulina pelas células B pancreáti-cas (9,(43)(44)(45).…”

“…O tiazídico, além de proteger contra a sobrecarga de volume, também possui efeito hiperglicemiante e, dessa forma, age em sinergismo ao diazóxido. Pode provocar hiponatremia e hipocalemia e, desse modo, os níveis séricos desses eletrólitos devem ser periodicamente monitorizados (9,(43)(44)(45).…”

Macrosomia, transient neonatal hypoglycemia, and monogenic diabetes in a family with heterozygous mutation R154X of HNF4A gene

“…Mutations of HNF4A have been associated to both transient (1, 3, 4) or persistent, diazoxide-responsive form of CHI (1,5,6), with no apparent correlation between mutation type and clinical outcome of hypoglycemia (i.e. transient vs persistent) (1).…”