13 - Hemochromatosis associated with hemojuvelin gene (HJV) mutations

Summary

The term “juvenile hemochromatosis” (JH) (OMIM #602390) is used to describe rare forms of hereditary hemochromatosis characterized by severe iron overload, heart failure, and hypogonadotrophic hypogonadism in children, adolescents, or adults less than 30 years of age. The average daily rate of iron absorption in young persons with JH is much greater than that of adults with HFE hemochromatosis. Although the pattern of parenchymal iron deposition in these two disorders is similar, cardiac damage and hypogonadotrophic hypogonadism occur much earlier in life and are more prevalent in JH than in adult-onset HFE hemochromatosis. Testicular atrophy or amenorrhea are the most common presenting symptoms of JH. Heart failure and arrhythmia due to cardiomyopathy are the predominant causes of death. JH is associated with an autosomal recessive pattern of inheritance in most kinships. Most persons with JH have two mutations of the hemojuvelin gene (HJV) on chromosome 1q (OMIM *608374). A major pathophysiologic attribute of JH hemochromatosis is dysregulation of hepcidin. Animal studies confirm that hemojuvelin is critical for the regulation of iron homeostasis and the induction of hepcidin synthesis. JH is sometimes designated as “type 2” hemochromatosis to distinguish it from HFE hemochromatosis.

Other persons with JH phenotypes have autosomal recessive iron overload associated with mutations in the hepcidin gene (HAMP) (Chapter 14) or in the transferrin receptor-2 gene (TFR2) (Chapter 15). In rare cases, JH phenotypes may appear in young persons who have autosomal dominant hemochromatosis due to “gain-of-function” ferroportin gene (SLC40A1) mutations. (Chapter 12).