title: TFR2-related haemochromatosis in the Netherlands: a cause of arthralgia in young adulthood.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Radboudumc Expertise Center for Iron Disorders, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: T M A
authors.initials: TM
authors.lastname: Peters
authors.forename: A F M
authors.initials: AF
authors.lastname: Meulders
authors.forename: K
authors.initials: K
authors.lastname: Redert
authors.forename: M L H
authors.initials: ML
authors.lastname: Cuijpers
authors.forename: A J M
authors.initials: AJ
authors.lastname: Rennings
authors.forename: M C H
authors.initials: MC
authors.lastname: Janssen
authors.forename: N M A
authors.initials: NM
authors.lastname: Blijlevens
authors.forename: D W
authors.initials: DW
authors.lastname: Swinkels
mesh_terms: D000328:Adult; D018771:Arthralgia / Q000097:blood / Q000235:genetics*; D005260:Female; D005293:Ferritins / Q000097:blood; D005838:Genotype; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics*; D064451:Hepcidins / Q000097:blood; D006801:Humans; D008297:Male; D009426:Netherlands; D011990:Receptors, Transferrin / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D014168:Transferrin / Q000032:analysis
chemical_list: D064451:Hepcidins; D011990:Receptors, Transferrin; C503640:TFR2 protein, human; D014168:Transferrin; D005293:Ferritins