Hyperinsulinemic Hypoglycemia, Familial, 4

A number sign (#) is used with this entry because of evidence that familial hyperinsulinemic hypoglycemia-4 is (HHF4) is caused by homozygous mutation in the gene encoding 3-hydroxyacyl-CoA dehydrogenase (HADH; 601609) on chromosome 4q25.

For a phenotypic description and discussion of genetic heterogeneity of familial hyperinsulinemic hypoglycemia, see HHF1 (256450).

Clinical Features

Gotlin and Silver (1970) reported a male infant who had profound hypoglycemia at birth, with abnormally high insulin/glucose ratios. Attempts to control his hypoglycemia with conventional dietary and drug management were only partially successful. At 10 months of age he had a prolonged hypoglycemic convulsion resulting in coma, at which time severe hyperinsulinism was confirmed. He underwent partial pancreatectomy; microscopically there was a marked decrease in the secretory granules of the beta cells and an absence of alpha cells.

Vidnes (1976) was the first to document glucagon deficiency in a case of persistent hereditary neonatal hypoglycemia. Vidnes and Oyasaeter (1977) described an inbred Pakistani family in which 2 brothers and a sister appear to have had hypoglycemia due to isolated glucagon deficiency. Two of the 3 had died before the nature of the problem was identified. Treatment with glucagon replacement was successful.

Molven et al. (2002) restudied the family described by Vidnes and Oyasaeter (1977). Another affected sib, a sister 19 years old at the time of the report, had hypoglycemia, but had been diagnosed with hyperinsulinism. Indeed, Molven et al. (2002) questioned the existence of congenital glucagon deficiency in this family. They concluded that the family had hereditary hyperinsulinism.

Clayton et al. (2001) reported an Indian child who presented at age 4 months with a hypoglycemic convulsion. She continued to have frequent episodes of hypoketotic hypoglycemia associated with increased plasma insulin levels. Biochemical studies indicated increased blood acylcarnitine levels, suggesting a disorder of fatty acid oxidation.

Molecular Genetics

In a 4-month-old Indian girl with hyperinsulinemic hypoglycemia, Clayton et al. (2001) identified homozygosity for a mutation in the HADH gene (601609.0003); her apparently nonconsanguineous parents were heterozygous for the mutation.

In 4 sibs with hyperinsulinemic hypoglycemia from a consanguineous Pakistani family originally reported by Vidnes and Oyasaeter (1977), Molven et al. (2004) identified homozygosity for a deletion in the HADH gene (601609.0004). The parents were heterozygous for the mutation.

In 11 (10%) of 115 unrelated patients with diazoxide-responsive hyperinsulinemic hypoglycemia who were negative for mutation in the hyperinsulinemia-associated genes ABCC8 (600509), KCNJ11 (600937), GCK (138079), and HNF4A (600281), Flanagan et al. (2011) identified homozygous mutations in the HADH gene (see, e.g., 601609.0005 and 601609.0006). When DNA was available, carrier status was confirmed in the unaffected parents; none of the probands had an affected sib. Although screening tests were not complete in all patients, Flanagan et al. (2011) noted that none of them were reported to have abnormalities in plasma acylcarnitines or urine organic acids.

In a Turkish proband with diazoxide-responsive hyperinsulinemic hypoglycemia mapping to chromosome 4q25, previously studied by Flanagan et al. (2011) and in whom no coding mutation in the HADH gene had been found but who showed a reduction in HADH activity in cultured skin fibroblasts, Flanagan et al. (2013) performed next-generation sequencing of the entire genomic region of HADH and identified homozygosity for a deep intronic splicing variant (636+471G-T; 601609.0007). Screening for the variant in an additional 56 consanguineous and/or Turkish diazoxide-responsive HHF probands revealed homozygosity for 636+471G-T in 8 more Turkish probands, including 2 patients previously studied by Flanagan et al. (2011). All 9 mutation-positive Turkish patients were also homozygous for an HADH SNP, 636+385A-G (rs732941), and 5 of the patients were known to share a 1.6-Mb haplotype at chromosome 4q25. Flanagan et al. (2013) stated that the 636+471G-T Turkish founder mutation was the most common HADH mutation in their cohort and accounted for 9 (32%) of 28 individuals with HADH mutations.