Hyperinsulinaemic hypoglycaemia, renal Fanconi syndrome and liver disease due to a mutation in the HNF4A gene

Abstract

SummaryHNF4A gene mutations have been reported in cases of transient and persistent hyperinsulinaemic hypoglycaemia of infancy (HHI), particularly in families with adulthood diabetes. The case of a patient with HHI, liver impairment and renal tubulopathy due to a mutation in HNF4A is reported.Learning points:Urine specimen study in cases of HHI with diazoxide response is necessary to rule out specific metabolic conditions (l-3-hydroxyacyl-coenzyme A dehydrogenase deficiency) or tubular renal involvement.Hyperinsulinaemic hypoglycaemia due to the heterozygous mutation (p.Arg63Trp, c. 187C > T) in the HNF4A gene is associated with renal tubulopathy and liver involvement.Follow-up of patients diagnosed of HHI is mandatory to detect associated conditions.

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

“…Mutations in HNF4A were shown to cause increased insulin production in the human foetus, causing faster growth, higher body weight and even macrosomia. The hyperinsulinaemic hypoglycaemia can be detected in the early life of HNF4A-MODY carriers, leading to MODY manifestation later on [ 73 , 74 , 75 ]. This is thought to reflect a switch later in life to defective insulin secretion, although a prolonged hyperinsulinaemic phase in adulthood was described as well [ 74 ].…”

Hyperechoic Content of the Fetal Colon Is Not Always Cystinuria—Case Report

“…In order to determine whether other R76W patients had high cystinuria, we retrospectively studied the aminograms (unpublished) of five R76W cases ( 9 , 11 , 13 , 14 ). All had late onset Fanconi syndrome.…”

“…Other HNF4A variants are known causes of neonatal hyperinsulinemic hypoglycemia (HH) and in the diabetes in the young (MODY 1) (9). Liu et al reviewed the phenotype of all described 15 cases harboring the recurrent p.Arg76Trp variant (10)(11)(12)(13)(14)(15). All patients presented with Fanconi syndrome including nephrocalcinosis, chronic kidney failure, and short stature; all patients showed transient neonatal HH, two of them secondarily developed MODY 1, and half of them developed recurrent benign hepatic disorders.…”

Genomic medicine for kidney disease

“…Attempts have been made to catalogue the genes that are associated with hereditary forms of nephropathy and classify them by their associated broad phenotype 1,4,185 , but no systematic procedures or consensus guidelines exist regarding which genes should be evaluated for a given category of kidney disease. The choice is becoming increasingly complex owing to phenotypic expansions and is complicated because genes that are traditionally associated with nonrenal disorders can also present with nephropathy 186–188 . For example, mutations in HNF4A are classically implicated in maturity-onset diabetes of the young type 1 (MODY1; OMIM 125850) without renal involvement; however, the p.R76W has been noted in patients presenting with both Fanconi proximal tubular syndrome and MODY1 (REFS 186,187).…”

“…The choice is becoming increasingly complex owing to phenotypic expansions and is complicated because genes that are traditionally associated with nonrenal disorders can also present with nephropathy 186–188 . For example, mutations in HNF4A are classically implicated in maturity-onset diabetes of the young type 1 (MODY1; OMIM 125850) without renal involvement; however, the p.R76W has been noted in patients presenting with both Fanconi proximal tubular syndrome and MODY1 (REFS 186,187). Similarly, the identification of mutations in FOXP1 in patients with CAKUT suggest that the phenotypic spectrum of these mutations encompasses CAKUT as well as intellectual disability (OMIM 613670) 188 .…”