title: Listeria monocytogenes and recurrent mycobacterial infections in a child with complete interferon-gamma-receptor (IFNgammaR1) deficiency: mutational analysis and evaluation of therapeutic options.
abstract: We describe the history of a girl with interferon-gamma-receptor (IFNgammaR1) deficiency and studies performed to identify the molecular and clinical characteristics of this recently discovered disorder. This is the first report of a child from Northern Europe with IFNgammaR1 deficiency. The patient, now 7 years old, first presented with swelling and reddening at the Bacille Calmette-Guerin (BCG) vaccination site, swelling of lymph nodes, hepatomegaly, and an unusually severe varicella rash at the age of 4 months. At that time, she was diagnosed with BCG histiocytosis without typical granuloma formation and was treated with antituberculous agents. During the clinical course of her illness, several different types of atypical mycobacteria and (for the first time in an IFNgammaR1-deficient patient) Listeria monocytogenes were detected. Flow cytometric analysis showed that the patient's monocytes could not bind a monoclonal antibody specific for the IFNgamma-receptor. Our analysis of mRNA derived from the alpha-chain (IFNgammaR1) gene of this receptor revealed deletions of 173 bp and 4 bp in cDNA sequences originating from individual alleles. The 173 bp deletion was located between nucleotide positions 200 and 372, exactly matching those of exon 3, and the 4 bp deletion was located between nucleotide positions 561 and 564 of the coding region of the cDNA. Analysis of genomic DNA revealed the presence of a G to T transition at the 5'end of the splice consensus sequence of intron 3, which explains the absence of exon 3. The other allele carried the 4-base-pair deletion (ACTC) at nucleotide positions 15-18 of exon 5. Twelve months after an allo\geneic bone marrow transplantation, the patient had clinically improved.
authors.affiliation: Klinik und Poliklinik für Kinderheilkunde der Technischen Universität Dresden, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Roesler
authors.forename: B
authors.initials: B
authors.lastname: Kofink
authors.forename: J
authors.initials: J
authors.lastname: Wendisch
authors.forename: S
authors.initials: S
authors.lastname: Heyden
authors.forename: D
authors.initials: D
authors.lastname: Paul
authors.forename: W
authors.initials: W
authors.lastname: Friedrich
authors.forename: J L
authors.initials: JL
authors.lastname: Casanova
authors.forename: W
authors.initials: W
authors.lastname: Leupold
authors.forename: M
authors.initials: M
authors.lastname: Gahr
authors.forename: A
authors.initials: A
authors.lastname: Rösen-Wolff
mesh_terms: D000483:Alleles; D001500:BCG Vaccine / Q000009:adverse effects; D016026:Bone Marrow Transplantation; D002648:Child; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D015614:Histiocytosis / Q000209:etiology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008088:Listeriosis / Q000209:etiology*; D008103:Liver Cirrhosis / Q000209:etiology; D008199:Lymphadenitis / Q000209:etiology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009165:Mycobacterium Infections, Nontuberculous / Q000209:etiology*; D015270:Mycobacterium avium-intracellulare Infection / Q000209:etiology*; D010375:Pedigree; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics; D012008:Recurrence; D017384:Sequence Deletion; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D001500:BCG Vaccine; D018076:DNA, Complementary; D007371:Interferon-gamma; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor