Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (420 page)

FAMILIAL MEDITERRANEAN FEVER (FMF)

   Definition

Familial Mediterranean fever (FMF) is an inherited inflammatory disease caused by mutations in the MEFV gene, encoding a protein that has been named pyrin or marenostrin.

   Who Should Be Suspected?

Classic familial Mediterranean fever (FMF) is an autosomal recessive disorder, MIM #249100, associated with homozygous or compound heterozygous mutations in the MEFV gene and characterized by recurrent attacks of fever and inflammation in the peritoneum, synovium, or pleura and accompanied by pain. As a complication, patients may develop amyloidosis. Familial Mediterranean fever (FMF), autosomal dominant form of FMF, MIM #134610, is associated with heterozygous mutation in the MEFV gene and characterized by recurrent bouts of fever and abdominal pain, and amyloidosis in some patients. MEFV mutations lead to reduced amounts of pyrin or a malformed form of pyrin protein, and as a result, there is not enough normal protein to control inflammation, leading to an inappropriate or prolonged inflammatory response.

   Relevant Tests and Diagnostic Value

Mutation analysis of the MEFV gene; however, there are some patients with FMF for whom mutations have not been identified.

   Other Considerations

Some evidence suggests that another gene, called SAA1, can modify the risk of developing amyloidosis among people with the M694V mutation.

   
METABOLIC DISORDERS

FAMILIAL HYPERINSULINISM (FHI)

   Definition

Familial hyperinsulinism (FHI) is a disorder that causes abnormally high levels of insulin. Familial hyperinsulinemic hypoglycemia-1 (HHF1;
MIM #256450
) or persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is caused by mutations in the ABCC8 gene, encoding the SUR1 subunit of the pancreatic beta cell inwardly rectifying potassium channel.

HHF2 (
MIM #601820
) is caused by mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the pancreatic beta cell potassium channel.

HHF3 (
MIM #602485
) is caused by mutations in the glucokinase gene (GCK).

HHF4 (
MIM #609975
) is caused by mutations in the HADH gene.

HHF5 (
MIM #609968
) is caused by mutations in the insulin receptor gene (INSR).

HHF6 (
MIM #606762
) is caused by mutations in the GLUD1 gene.

HHF7 (
MIM #610021
) is caused by mutations in the SLC16A1.

Other genes that may be involved in hyperinsulinism: HNF4A and UCP2.

   Who Should Be Suspected?

People with this condition have frequent episodes of low blood sugar (hypoglycemia). Although it affects mainly infants and children, numerous cases have been reported in adults but at a much lower incidence.

   Relevant Tests and Diagnostic Value

   Blood and urine testing obtained during an episode of spontaneous hypoglycemia

   Histologic: abnormal pancreatic beta cell types: “diffuse,” “focal,” and “atypical” or “mosaic”

   Fluorodopa positron emission tomography (F-DOPA-PET) scanning