Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease

Kam Sandhu, Kaledas Flintoff, Mark D. Chatfield, Jeannette L. Dixon, Louise E. Ramm, Grant A. Ramm, Lawrie W. Powell, V. Nathan Subramaniam and Daniel F. Wallace

Key Points

  • This comprehensive comparison of the genetic subtypes of hemochromatosis reveals more severe iron overload and disease in non-HFE forms.

  • Arthropathy is more common in HFE-related hemochromatosis, suggesting that joint disease may not be associated with iron.

Publisher's Note: There is a Blood Commentary on this article in this issue.


The clinical progression of HFE-related hereditary hemochromatosis (HH) and its phenotypic variability has been well studied. Less is known about the natural history of non-HFE HH caused by mutations in the HJV, HAMP, or TFR2 genes. The purpose of this study was to compare the phenotypic and clinical presentations of hepcidin-deficient forms of HH. A literature review of all published cases of genetically confirmed HJV, HAMP, and TFR2 HH was performed. Phenotypic and clinical data from a total of 156 patients with non-HFE HH was extracted from 53 publications and compared with data from 984 patients with HFE-p.C282Y homozygous HH from the QIMR Berghofer Hemochromatosis Database. Analyses confirmed that non-HFE forms of HH have an earlier age of onset and a more severe clinical course than HFE HH. HJV and HAMP HH are phenotypically and clinically very similar and have the most severe presentation, with cardiomyopathy and hypogonadism being particularly prevalent findings. TFR2 HH is more intermediate in its age of onset and severity. All clinical outcomes analyzed were more prevalent in the juvenile forms of HH, with the exception of arthritis and arthropathy, which were more commonly seen in HFE HH. This is the first comprehensive analysis comparing the different phenotypic and clinical aspects of the genetic forms of HH, and the results will be valuable for the differential diagnosis and management of these conditions. Importantly, our analyses indicate that factors other than iron overload may be contributing to joint pathology in patients with HFE HH.

  • Submitted February 1, 2018.
  • Accepted May 3, 2018.
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