Juvenile hemochromatosis

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Juvenile hemochromatosis is similar to HFE-associated he-

Table 13.1 Iron overload disorders.

Disorder

Chromosomal locations of defective genes

Gene (types of mutations)

Phenotype

Hemochromatosis disorders

HFE-associated hemochromatosis (also called Type 1 hemochromatosis)

6p, near the HLA complex

HFE (missense and splicing mutations; C282Y is the most important)

Iron accumulation in the parenchymal cells of the liver, heart, pancreas; elevated transferrin saturation; relative paucity of iron in macrophages. Clinical manifestations include liver fibrosis, cirrhosis, markedly increased incidence of hepatocellular carcinoma, cardiomyopathy, diabetes

Juvenile hemochromatosis (also called Type 2 hemochromatosis)

Hepcidin (all known mutations prevent production of any hepcidin protein)

Similar to HFE-associated hemochromatosis, but greatly accelerated, leading to severe cardiac and endocrine complications in the second decade of life

TFR2-associated hemochromatosis (also called Type 3 hemochromatosis)

7q

Transferrin receptor-2 (TFR2; missense and nonsense mutations)

Similar to HFE-associated hemochromatosis

Type 5 hemochromatosis

? (Postulated to explain hemochromatosis in patients without mutations in known genes)

?

Similar to HFE-associated hemochromatosis but apparently not due to mutations in HFE, TFR2 or hepcidin

Siderosis disorders

Autosomal dominant siderosis (also called Type 4 hemochromatosis)

2q

Ferroportin (missense mutations)

Macrophage-predominant iron loading; parenchymal iron loading can occur later. Some patients have anemia early in their course (particularly women). Ferritin levels are markedly elevated, but serum transferrin saturation generally is not

African siderosis

?

Unknown

Similar to autosomal dominant siderosis but ferroportin mutations have not been reported. Thought to be a combination of genetic and environmental factors

Disorders of iron balance

Atransferrinemia

3q

Transferrin (missense mutations)

Deficiency in serum transferrin leading to tissue iron overload and severe iron deficiency anemia

Aceruloplasminemia

3q

Ceruloplasmin (missense and null mutations)

Deposition of iron in the brain, liver and pancreas. Late-onset neurodegenerative disease, dementia and diabetes

mochromatosis, but very rare, and characterized by earlier onset of iron loading and its complications. The target organs are the same as those affected in HFE hemochromatosis, but cardiac and endocrine dysfunction are more problematic, and untreated patients typically die from cardiomyopathy by age 30 years. Liver cirrhosis and failure are uncommon. There are several possible explanations for this pattern. Firstly, experience with patients who develop siderosis from chronic transfusion therapy suggests that rapid iron loading is especially toxic for the heart and endocrine tissues. Secondly, pathological iron deposition in the adolescent years may be particularly bad for young hearts which are growing to meet the demands of a larger body mass; this is analogous to the problems noted with doxorubicin cardiotoxicity in this age group. Furthermore, endocrine problems are probably more apparent in adolescents because they fail to go through normal pubertal development. Juvenile hemochromatosis is a particularly lethal disorder, but it can be effectively treated by phlebotomy.

Studies of families with juvenile hemochromatosis have shown that there are at least two genetic loci responsible. Some individuals are homozygous for mutations in the hepcidin gene on human chromosome 19q. To date, only two hepcidin mutations have been reported, both of which completely prevent production of the hepcidin protein. Other juvenile hemochromatosis families show linkage to a small region of chromosome 1q. The gene responsible for this form of juvenile hemochromatosis has not yet been identified, but it has been speculated that it may encode the as yet unknown hepcidin receptor.

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