title: Juvenile hemochromatosis associated with heterozygosity for novel hemojuvelin mutations and with unknown cofactors.
abstract: OBJECTIVE
  Juvenile hemochromatosis (JH) is a rare autosomal recessive disorder characterized by severe early-onset iron overload, caused by mutations in hemojuvelin (HJV), hepcidin (HAMP), or a combination of genes regulating iron metabolism. Here we describe two JH cases associated with simple heterozygosity for novel HJV mutations and unknown genetic factors. Case 1: A 12 year-old male from Central Italy with beta-thalassemia trait, increased aminotransferases, ferritin 9035 ng/ml and transferrin saturation 84%, massive hepatocellular siderosis and hepatic bridging fibrosis. Case 2: A 12 year-old female from Northern Italy with ferritin 467 ng/ml, transferrin saturation 87-95%, and moderate hepatic iron overload.
  
  
  METHODS
  Direct sequencing of hemochromatosis genes (HFE-TfR2-HJV-HAMP-FPN-1) was performed in the children and siblings.
  
  
  RESULTS
  In case 1, we detected heterozygosity for a novel HJV mutation (g.3659_3660insG), which was inherited together with the beta thalassemia trait from the father, who (as well as the mother) had normal iron parameters. In case 2, we detected another novel HJV mutation (g.2297delC) in heterozygosity, which was inherited from the mother, affected by mild iron deficiency. The father had normal iron stores. Both mutations are frameshifts determining premature stop codons. No other disease causing variant was detected.
  
  
  CONCLUSIONS
  Although beta-thalassemia trait was a possible cofactor of iron overload in case 1, iron overload cannot be explained by simple heterozygosity for HJV mutations in both cases. Other genetic factors should be investigated, and further studies are needed to understand genotype-phenotype correlations in JH.
authors.affiliation: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pelusi
authors.affiliation: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.affiliation: Hepato-Metabolic Unit, Ospedale Bambin Gesù, Roma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Della Corte
authors.affiliation: Hepato-Metabolic Unit, Ospedale Bambin Gesù, Roma, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Congia
authors.affiliation: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.affiliation: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Edoardo A
authors.initials: EA
authors.lastname: Pulixi
authors.affiliation: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.affiliation: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Fracanzani
authors.affiliation: Hepato-Metabolic Unit, Ospedale Bambin Gesù, Roma, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Nobili
authors.affiliation: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
mesh_terms: D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006432:Hemochromatosis / Q000097:blood / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D000071020:Hemochromatosis Protein; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D007501:Iron / Q000097:blood*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors; D017086:beta-Thalassemia / Q000235:genetics
chemical_list: D015415:Biomarkers; D058851:GPI-Linked Proteins; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D007501:Iron