Novel Homozygous Mutation (R329X) in the Hemojuvelin Gene Is Associated with Hypogonadotrophic Hypogonadism, Diabetes Mellitus and Heart Failure Duo to Juvenile Hemochromatosis.

Juvenile hemochromatosis (JH) is a rare autosomal recessive disorder characterized by the early onset of severe iron overload. A large variety of mutations within the genes encoding hepcidin (HAMP) and hemojuvelin (HJV) have been identified in patients with JH. But in the Chinese population, the prevalence of JH is quite low. No HJV mutation has been reported so far.

The proband was a 25-year-old young man of Asia decent presented with hypogonadotrophic hypogonadism, diabetes mellitus and heart failure but no family history of iron disorders. His serum iron level was 34μmol/L, with a transferrin concentration of 8.5g/L, serum ferritin concentration was 8140 μg/L. Echocardiography revealed that he had generalized cardiac enlargement, cardiac dysfunction, and severe mitral and tricuspidal insufficiency, pulmonary hypertension. Ultra-sonography showed diffuse hepatomegaly and splenomegaly, seroperitoneum and right hydrothorax. Liver biopsy showed severe diffuse hepatocellular siderosis and cirrhosis,hemosiderin pigmentation. To search for possible variants in the HJV gene, we performed PCR and direct sequencing in proband and his family. A homozygous nonsense mutation in exon 4 of HJV (R329X) was identified in the JH patient and heterozygous mutation of R329X in his father and mother. No mutations were found in other genes associated with adult or juvenile hemochromatosis including HFE, transferrin receptor-2 (TFR2), ferroportin (SLC40A1), hepcidin (HAMP).

A novel nonsense mutation (R329X) has been identified in the HJV gene for the first time in China. This mutation elevates ferritin levels and leads to JH associated with hypogonadotrophic hypogonadism, diabetes mellitus and severe cardiomyopathy.

No relevant conflicts of interest to declare.