Familial hyperinsulinism (referred to as FHI in this GeneReview) is characterized by hypoglycemia that ranges from severe neonatal-onset, difficult-to-manage disease to childhood-onset disease with mild symptoms and difficult-to-diagnose hypoglycemia. Neonatal-onset disease manifests within hours to two days after birth. Childhood-onset disease manifests during the first months or years of life. In the newborn period, presenting symptoms may be nonspecific, including seizures, hypotonia, poor feeding, and apnea. In severe cases, serum glucose concentrations are typically extremely low and thus easily recognized, whereas in milder cases, variable and mild hypoglycemia may make the diagnosis more difficult. Even within the same family, disease manifestations can range from mild to severe. Individuals with autosomal recessive familial hyperinsulinism, caused by mutations in either ABCC8 or KCNJ11 (FHI-KATP), tend to be large for gestational age and usually present with severe refractory hypoglycemia in the first 48 hours of life; affected infants usually respond only partially to diet or medical management (i.e., diazoxide therapy) and thus may require pancreatic resection. Individuals with autosomal dominant FHI-KATP tend to be appropriate for gestational age at birth, to present at approximately age one year (range: 2 days - 30 years), and to respond to diet and diazoxide therapy. Exceptions to both of these generalities have been reported. FHI-GCK, caused by mutations in GCK, may be much milder than FHI-KATP; however, some persons have severe, diazoxide-unresponsive hypoglycemia. FHI-HADH, caused by mutations in HADH, tends to be relatively mild, although severe cases have been reported. Individuals with FHI-HNF4A, caused by mutations in HNF4A, are typically born large for gestational age and have mild features that respond to diazoxide treatment. FHI-UCP2, caused by mutations in UCP2, is a rare cause of diazoxide-responsive FH1. Hyperammonemia/hyperinsulinism (HA/HI) is associated with mild-to-moderate hyperammonemia and with relatively mild, late-onset hypoglycemia; most but not all affected individuals have mutations in GLUD1.
Approximately 45% of affected individuals have mutations in either ABCC8, which encodes the protein SUR1, or KCNJ11, which encodes the protein Kir6.2. In the Ashkenazi Jewish population, two ABCC8 founder mutations are responsible for approximately 97% of FHI. Other ABCC8 founder mutations are present in the Finnish population (p.Val187Asp and p.Asp1506Lys). Mutations in GLUD1 and HNF4A each account for approximately 5% of individuals with FHI. Activating mutations in GCK or inactivating mutations in HADH occur in fewer than 1% of individuals with FHI. Mutations in UCP2 have been reported in only two families to date. Approximately 40% of individuals with FHI do not have an identifiable mutation in any of the genes known to be associated with FHI. Molecular genetic testing of ABCC8, KCNJ11, GLUD1, GCK, HADH and HNF4A is available on a clinical basis.
FHI-KATP, caused by mutations in either ABCC8 or KCNJ11, is most commonly inherited in an autosomal recessive manner and less commonly in an autosomal dominant manner, although de novo mutations have been reported. FHI-GCK, caused by mutations in GCK, and HA/HI, caused by mutations in GLUD1, are inherited in an autosomal dominant manner; de novo mutations are not rare. FHI-HADH, caused by mutations in HADH, is inherited in an autosomal recessive manner. The focal form of FHI, caused by biallelic mutations of ABCC8 or KCNJ11, is inherited in an autosomal dominant manner, but only manifests when the mutation occurs on the paternally derived allele and a somatic event results in the loss of the maternal allele in a beta cell precursor. Risk to sibs of a proband depends on the underlying genetic mechanism. Carrier testing for relatives at risk for the autosomal recessive forms of FHI and prenatal diagnosis for pregnancies at increased risk for the diffuse form of FHI are possible if the family-specific mutation(s) are known. Prenatal or preimplantation genetic diagnosis for focal FHI is not possible, as a somatic mutation in the pancreas is required for clinical disease.