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juvenile hemochromatosis

Tuesday 5 August 2008

The juvenile-onset phenotype of hemochromatosis is much more severe. Plasma iron loading and tissue iron excesses (reflected by increased transferrin-saturation values and serum ferritin levels, respectively) are evident early in life in both sexes.

Functional iron-metabolism data from patients with juvenile-onset disease are limited, but estimated rates of iron accumulation markedly exceed those observed in the adult-onset forms.

Liver biopsies and autopsies reveal a parenchymal iron distribution resembling that seen in both HFE- and TFR2-related disease.

Symptomatic organ involvement occurs as early as the second decade of life. Although liver involvement is a constant feature, diabetes, hypogonadotropic hypogonadism, cardiomyopathy, arrhythmias, and heart failure are far more evident than in the adult-onset form.

This difference may reflect different susceptibilities to massive iron overload among the developing organs. Death, usually from intractable heart failure, before the age of 30 years is not uncommon.

Rare cases of juvenile hereditary hemochromatosis have recently been linked to a homozygous mutation in the HAMP gene which encodes hepcidin, a peptide that plays a key role in human iron metabolism.

However, most juvenile-onset cases have been mapped to chromosome 1q,25 where the gene that produces hemojuvelin, HJV (originally called HFE2), has recently been identified.

Deleterious HJV mutations have been documented in families with 1q-linked juvenile hemochromatosis.

The phenotypic similarities between HJV-associated hemochromatosis and HAMP-associated hemochromatosis are reflected in their OMIM classification as hereditary hemochromatosis subtypes 2A and 2B, respectively (whereas the adult forms caused by HFE and TFR2 mutations are listed separately as hemochromatosis type 1 (classic hemochromatosis) and 3 (hemochromatosis type 3).

The severity of the phenotype in juvenile hereditary hemochromatosis suggests that there are underlying genetic alterations involving proteins that play more critical roles in iron homeostasis than either HFE or TFR2, and hepcidin (HAMP) certainly fits this description.


Hepcidin (HAMP) is synthesized by hepatocytes in response to both inflammatory stimuli and iron overload.

Studies in transgenic mice indicate that it has a key role in down-regulating the intestinal absorption and placental transport of iron and the release of iron by macrophages. It has been hailed as "the iron-regulatory hormone," although the mechanisms underlying its effects are unclear.


Very little is known about the newly identified HJV gene, but current observations suggest that its product, hemojuvelin, modulates hepcidin (HAMP) expression


Juvenile hemochromatosis (JH) is caused by mutation in the gene encoding hemojuvelin (MIM.608374) (HFE2A), which maps to chromosome 1q21, or by mutation in the gene encoding hepcidin antimicrobial peptide (HAMP) (MIM.606464), which maps to chromosome 19q13 (HFE2B).

The 2 forms of juvenile hemochromatosis (HFE2) are here designated HFE2A and HFE2B, respectively.

See also

- primary hemochromatoses

  • classic hemochromatosis (HFE) (MIM.235200) is an autosomal recessive disorder, caused by mutation in a gene designated HFE on chromosome 6p21.3.
  • hemochromatosis type 3 (HFE3) (MIM.604250) is an autosomal recessive disorder, caused by mutation in the gene encoding transferrin receptor-2 (TFR2) (MIM.604720), which maps to 7q22.
  • hemochromatosis type 4 (HFE4) (MIM.606069) is an autosomal dominant disorder, caused by mutation in the SLC40A1 gene (MIM.604653), which encodes ferroportin and maps to 2q32.