title: Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy.
abstract: Iron-refractory iron-deficiency anemia (IRIDA) is an autosomal recessive disorder caused by mutations in TMPRSS6. Patients have hypochromic microcytic anemia refractory to oral iron and are only partially responsive to parenteral iron administration. We report a French-Canadian kindred in which 2 siblings presented in early childhood with severe microcytic anemia, hypoferremia, and hyperferritinemia. Both children have been successfully treated solely with low-dose oral iron since diagnosis. Clinical and biological presentation did not fit any previously described genetic iron-deficiency anemia. Whole exome sequencing identified in both patients compound heterozygous mutations of TMPRSS6 leading to p.G442R and p.E522K, 2 mutations previously reported to cause classic IRIDA, and no additional mutations in known iron-regulatory genes. Thus, the phenotype associated with the unique combination of mutations uncovered in both patients expands the spectrum of disease associated with TMPRSS6 mutations to include iron deficiency anemia that is accompanied by hyperferritinemia at initial presentation and is responsive to continued oral iron therapy. Our results have implications for genetic testing in early childhood iron deficiency anemia. Importantly, they emphasize that whole exome sequencing can be used as a diagnostic tool and greatly facilitate the elucidation of the genetic basis of unusual clinical presentations, including hypomorphic mutations or compound heterozygosity leading to different phenotypes in known Mendelian diseases.
authors: Department of Pediatrics, McGill University/McGill University Health Center, 4060 Ste Catherine West, PT-239, Montreal, QC H3Z 2Z3 Canada.
authors: Dong-Anh
authors: DA
authors: Khuong-Quang
authors: Jeremy
authors: J
authors: Schwartzentruber
authors: Mark
authors: M
authors: Westerman
authors: Pierre
authors: P
authors: Lepage
authors: Karin E
authors: KE
authors: Finberg
authors: Jacek
authors: J
authors: Majewski
authors: Nada
authors: N
authors: Jabado
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000747:Anemia, Hypochromic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D018798:Anemia, Iron-Deficiency / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D000753:Anemia, Refractory / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D005293:Ferritins / Q000097:blood*; D005500:Follow-Up Studies; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D007501:Iron / Q000008:administration & dosage*; D008134:Long-Term Care; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020125:Mutation, Missense; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D005293:Ferritins; D007501:Iron; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human