TFR2-related haemochromatosis in the Netherlands: a cause of arthralgia in young adulthood

Neth J Med. 2017 Mar;75(2):56-64.


Background: Type 3 hereditary haemochromatosis (HH) is a rare iron overload disorder caused by variants in the transferrin 2 receptor (TFR2) gene. We aim to present characteristics of patients diagnosed with TFR2-HH in the Netherlands, in order to increase knowledge and awareness of this disease.

Methods: We collected clinical, biochemical and genetic data from four patients from three families diagnosed with HH type 3 in the Netherlands between 2009 and 2016.

Results: Three women and one man diagnosed with HH type 3 presented with arthralgia and elevated ferritin levels and transferrin saturation (TSAT) at ages 25-41 years. The hepcidin/ferritin ratio as measured in three patients was low. Liver iron content in two patients as assessed by MRI or liver biopsy was highly increased (250 and 362.7 μmol iron/g dry weight, respectively, reference < 35 μmol/g). DNA analysis revealed four different TFR2 pathogenic variants: one nonsense, one splicing and two missense variants, of which three are novel. Phlebotomy decreased the serum iron parameters but did not relieve the arthralgia.

Conclusion: In patients with a combination of elevated TSAT and ferritin in the absence of anaemia, and after exclusion of HFE-related HH, rare forms of HH should be considered. In these cases, presentation with arthralgia in young adulthood, low hepcidin/ferritin ratio and/or liver iron content > 100 μmol/g form an indication for analysis of the TFR2 gene. Although type 3 HH is extremely rare, awareness of the disease among physicians is important in order to achieve an early diagnosis and prevent complications, such as liver damage.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Arthralgia / blood
  • Arthralgia / genetics*
  • Female
  • Ferritins / blood
  • Genotype
  • Hemochromatosis / blood
  • Hemochromatosis / genetics*
  • Hepcidins / blood
  • Humans
  • Male
  • Netherlands
  • Receptors, Transferrin / blood
  • Receptors, Transferrin / deficiency*
  • Receptors, Transferrin / genetics
  • Transferrin / analysis


  • Hepcidins
  • Receptors, Transferrin
  • TFR2 protein, human
  • Transferrin
  • Ferritins

Supplementary concepts

  • Hemochromatosis, type 3