TFR2-Related Hereditary Hemochromatosis

Excerpt

Clinical characteristics: TFR2-related hereditary hemochromatosis (TFR2-HHC) is characterized by increased intestinal iron absorption resulting in iron accumulation in the liver, heart, pancreas, and endocrine organs. Age of onset is earlier than in HFE-HHC. The majority of individuals present with signs and symptoms of iron overload in the third decade (e.g., weakness, fatigue, abdominal pain, hepatomegaly, arthritis, arthralgia, progressive increase in skin pigmentation). Others present as young adults with nonspecific symptoms and abnormal serum iron studies or as adults with abnormal serum iron studies and signs of organ involvement including cirrhosis, diabetes mellitus, and arthropathy.

Diagnosis/testing: The diagnosis of TFR2-HHC is established in a proband by identification of biallelic pathogenic variants in TFR2 on molecular genetic testing.

Management: Treatment of manifestations: Removal of excess iron by routine phlebotomy to maintain serum ferritin concentration at 50 ng/mL or lower and transferrin-iron saturation below 50%; lifelong hormone replacement therapy for hypogonadism; gonadotropins for fertility/pregnancy; nonsteroidal anti-inflammatory drugs and joint replacement for arthropathy; routine treatment for cardiac failure, diabetes mellitus, and hepatic complications.

Prevention of primary manifestations: Routine phlebotomy; see Treatment of manifestations.

Surveillance: Monitoring serum ferritin concentration every three to four months once serum ferritin concentration is lower than 50 ng/mL.

Agents/circumstances to avoid: Medicinal iron and nutritional supplements containing iron, excessive alcohol intake, vitamin C supplements, uncooked seafood.

Evaluation of relatives at risk: If the pathogenic variants in the family are known, molecular genetic testing of at-risk relatives to allow early diagnosis and treatment.

Genetic counseling: TFR2-HHC is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and do not have abnormalities of iron parameters. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible once both pathogenic variants in the family have been identified.