title: Azathioprine-induced severe pancytopenia due to a homozygous two-point mutation of the thiopurine methyltransferase gene in a patient with juvenile HLA-B27-associated spondylarthritis.
abstract: Severe pancytopenia due to azathioprine (AZA) toxicity in patients with autoimmune diseases is not uncommon. We describe a 14-year-old girl with HLA-B27+ spondylarthritis who was treated with AZA 3 mg/kg/day and who suddenly developed severe pancytopenia in the seventh week of treatment. Analysis of the catabolic pathway of AZA revealed a homozygous deficiency of thiopurine methyltransferase (TPMT) on the basis of a combined 2-point mutation at nucleotide positions 460 and 719 in the gene for TPMT, causing a toxic level of the metabolic active 6-thioguanine nucleotides (6-TGN) (2,394 pmoles/8 x 10(8) red blood cells). The patient was transfusion dependent and finally recovered 8 weeks after the development of the pancytopenia. At that time, 6-TGN had already returned to normal therapeutic levels. Family studies revealed another homozygous deficiency in the mother, while the other family members were heterozygous.
authors.affiliation: Children's Hospital of University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Leipold
authors.forename: E
authors.initials: E
authors.lastname: Schütz
authors.forename: J P
authors.initials: JP
authors.lastname: Haas
authors.forename: M
authors.initials: M
authors.lastname: Oellerich
mesh_terms: D000293:Adolescent; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D015796:HLA-B27 Antigen / Q000032:analysis; D006720:Homozygote; D006801:Humans; D008780:Methyltransferases / Q000235:genetics*; D010198:Pancytopenia / Q000139:chemically induced*; D017354:Point Mutation; D013122:Spinal Diseases / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology
chemical_list: D018501:Antirheumatic Agents; D015796:HLA-B27 Antigen; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine