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PEDIATRICS Vol. 107 No. 4 April 2001, p. e47
,,,
,, and
From the * University Hospitals, Case Western Reserve
University, Cleveland, Ohio; Laboratory of Human Genetics of
Infectious Diseases, Necker-Enfants Malades Medical School, Paris,
France; § Private practice, Miami, Florida; Metro Health Center,
Cleveland, Ohio; and ¶ Private practice, South Euclid, Ohio.
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ABSTRACT |
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Abstract
Discussion
References
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Mycobacterium avium causes
infections in immunocompromised individuals. Recurrent infection with
this organism has been associated with a deletion at the 818 residue of
the interferon-
receptor (IFN-R). This mutation produces a
truncated receptor without an intracytoplasmic tail, resulting in
diminished signaling. We describe a substitution at the 832 residue of
the IFN-R causing a similar truncated receptor in a 7-year-old girl
with recurrent M avium osteomyelitis.
Mycobacterium avium complex (MAC) is the name
given to M avium and Mycobacterium
intracellulare Jouanguy et al8 described a series of patients with
recurrent or disseminated mycobacterial infections with a single small deletion at the 818 residue of the IFN- A 7-year-old white female presented with left wrist pain and
swelling. Radiographic studies showed a destructive lesion in the
midshaft of the left radius. Bone scan showed increased reactivity in
the left radius, with additional activity in the right femur. Open
biopsy revealed chronic osteomyelitis, but no organisms were isolated.
The patient did not receive antimicrobial therapy and the lesion
resolved spontaneously. Six months later, the patient was evaluated
again with complaints of right heel pain and swelling. Radiographic
studies showed both lytic and sclerotic lesions of the calcaneus. She
was treated with nonsteroidal antiinflammatory agents and slowly
improved.
Three years from her initial presentation, she sustained a minor trauma
to her left arm and complained of right calcaneus pain. Radiographic
images showed osteomyelitis with numerous sinus tracts in both areas.
Open biopsies of her left radius and right calcaneus were performed and
the specimen cultures grew M avium complex from both. She
was treated with rifampin, ethambutal, and clarithromycin. After
several months of this regimen, the lesions resolved.
She was subsequently evaluated for an immunodeficiency. Serum
immunoglobulins (Ig) showed a mildly elevated IgG total and IgG1
subclass with a mildly lowered IgG2. Total T-cell numbers as well as
T-cell subpopulations were normal. B cells and natural killer cells
were normal in number and percentage. Mitogen stimulation with
concanavalin A and phytohemagglutinin were normal. Antigen stimulation
with Candida was normal. Serology was negative for Cytomegalovirus, Epstein-Barr virus, and
Toxoplasmosis. After consent was obtained for genetic
testing, DNA sequencing of her IFN-
2 nearly indistinguishable organisms classified as
atypical mycobacteria or nontuberculous mycobacteria.1
These organisms, like Mycobacterium tuberculosis, are
aerobic, pleomorphic, weakly Gram-positive bacilli that are acid-fast
positive.2 MAC is a minimally virulent, intracellular
pathogen and is ubiquitous in soil, water, vegetables, and
animals.3 It is rarely associated with disease in normal
hosts other than localized lymphadenitis in childhood.4
Systemic infections and infections of the bone by this organism are
typically found in immunocompromised hosts, such as patients infected
with the human immunodeficiency virus.2-5 Recurrent
infections with this and other similar intracellular organisms have recently been described with rare genetic defects of the
interferon- receptor (IFN-R).6-13 Various mutations
have been described that result in either complete or partial
deficiency of either of the 2 chains of the receptor showing a
recessive or dominant inheritance.
R1, resulting in a reading frame shift and a subsequent downstream stop codon. Translation of the
gene product resulted in a truncated receptor. We describe a patient
with recurrent M avium osteomyelitis with a truncated IFN-R1 secondary to a unique and not previously described nucleotide substitution at position 832.
CASE REPORT
R1 gene showed a single base
substitution of thymidine for guanine at position 832, resulting in an
immediate stop codon in 1 of the patient's 2 IFN-R1 alleles. The
subsequent translated mutant protein would be predicted to lack most of
its' cytoplasmic tail (Fig 1).
Evaluation of the patient's parents and siblings showed no other
members with the substitution, suggesting that the mutational event
occurred de novo in a parental germline. Cell surface expression of the
IFNR1 on both T lymphocytes and monocytes was increased as compared
with normal control (Fig 2). This
increase in surface expression has been noted previously in patients
heterozygous for other similarly truncated IFN-R1 proteins and may
be attributable in part to impaired recycling of the mutated
receptor.8
View larger version (13K):
[in a new window]
Fig. 1.
Substitution/mutation of the IFN- R in the patient.
View larger version (37K):
[in a new window]
Fig. 2.
Direct immunofluorescent staining with monoclonal antibodies was
performed on aliquots of heparinized peripheral blood collected from
patient and control as described previously.14 Expression
of IFN- R1, as assessed by the mAb GIR-218, on CD3+ (T lymphocytes)
and CD14+ (monocytes) cells is shown in a normal control, A, and the
patient, B. The negative control (isotype matched) is shown as the
dashed line.
To facilitate the evaluation of the function of this patient's
IFN-R1, we derived an Epstein Barr virus-transformed B-cell line
from peripheral blood. The response of these cells to IFN- was
assessed by monitoring the nuclear translocation of Signal Transducers
and Activators of Transcription 1 (STAT1) by using an
electrophoretic mobility shift assay. The intensity of the radioactive bands are an indirect measure of the nuclear translocation of STAT1. Markedly reduced STAT1 nuclear translocation was observed after exposure to IFN- (Fig 3),
indicating a significantly impaired signal transduction through the
IFN-R1 in this patient. The methods used for molecular analysis,
surface expression, and signaling were performed as previously
described.8,14
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DISCUSSION |
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Abstract
Discussion
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M avium complex most commonly causes infection in
patients with human immunodeficiency virus, chronic lung disease, and
prolonged use of corticosteroid.15-17 Additionally and
recently, several patients with mycobacterial infection have been
determined to be homozygous for a mutation of the
IFN-R1.6-14 Although M avium has been the
major pathogen, other severe infections have occurred in these
patients.7 This immune defect seems to translate
phenotypically to a selective susceptibility to intramacrophagic
organisms and, perhaps, uncovers a part of the immune system that lacks
a redundant host response. In addition, this deficiency may allow the
patient to be open to severe viral infections such as herpes viruses,
parainfluenza virus type 3, and respiratory syncytial virus, as shown
by Dorman et al.13
Jouanguy et al8 investigated 18 patients with infections
with bacille Calmette-Guerin and mycobacteria. In this study, however, only 4 of 18 patients had MAC disease limited to bone
alone.8 They were able to identify 14 mutations at a
single site on the IFNR1 gene in these patients. All of the
mutations isolated occurred at the 818 residue position and produced a
reading frame shift that resulted in a premature stop codon downstream
that halted transcription of the receptor protein. The resulting
incomplete IFN-R1 lacked the intracellular component on the R1
subunit responsible for cell signaling, with 1 normal wild-type allele
and 1 mutant allele. Dominant inheritance was inferred in the kindreds
reported.
Analysis of our patient's IFN-R1 revealed a unique mutation at
position 832. This mutation was a substitution of T for G that
immediately led to translation of a premature stop codon and resulted
in a similarly truncated IFN-R1 (Fig 1). This mutation at 832, designated E278X, has 9 intracytoplasmic residues (YIKKINPLK), whereas
the 818delT consisted of 6 (YIKKIH) and the 818del4 consisted of 7 (YIKKIIH). The substitution/mutation was not found in other family
members. Therefore, in the genetic differential diagnosis of patients
with these reported clinical symptoms and hyperexpression of the
IFN-R1, the search for the mutation cannot be limited only to 818T
and 818del4, but must also include E278X.
In our patient's case, because some of the cell surface IFN-R1 are
functionally present, it is, therefore, conceivably possible to
administer exogenous IFN- to flood the existing functional and
nonfunctional receptor sites during an episode of osteomyelitis. This
would then ensure an optimal immunologic response from the patient's
cells, potentially expediting infectious resolution.
This case stresses the importance of analyzing and coupling not just the immediate past medical history involving a patient's chief complaint, but also history that may span several years. It also exemplifies the fact that genetic mutations need not affect the host directly at birth, and care must be taken not to immediately eliminate genetic mutations from the differential diagnosis. In addition, individual differences in susceptibility to the same pathogens may be caused by subtle defects in the immune system that remain unrecognized. With the aid of modern technology in the laboratory and the explosion of knowledge in the field of genetics, these immune disorders can be increasingly uncovered by the observant clinician with access to a sophisticated laboratory.
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FOOTNOTES |
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Received for publication Jul 11, 2000; accepted Nov 17, 2001.
Address correspondence to Robert W. Hostoffer, DO, FACOP, FAAP, University Suburban Health Center, Suite 231, 1611 South Green Rd, South Euclid, OH 44121. E-mail: k.hostoffer{at}worldnet.att.net
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ABBREVIATIONS |
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MAC, Mycobacterium avium complex;
IFN-R, interferon- receptor;
Ig, immunoglobin;
STAT1, Signal
Transducers and Activators of Transcription 1.
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REFERENCES |
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Abstract
Discussion
References
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This article has been cited by other articles:
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  S. Okada, N. Ishikawa, K. Shirao, H. Kawaguchi, M. Tsumura, Y. Ohno, S. Yasunaga, M. Ohtsubo, Y. Takihara, and M. Kobayashi The novel IFNGR1 mutation 774del4 produces a truncated form of interferon-{gamma} receptor 1 and has a dominant-negative effect on interferon-{gamma} signal transduction J. Med. Genet., August 1, 2007; 44(8): 485 - 491. [Abstract] [Full Text] [PDF]
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 S. D. Rosenzweig, S. E. Dorman, G. Uzel, S. Shaw, A. Scurlock, M. R. Brown, R. H. Buckley, and S. M. Holland A Novel Mutation in IFN-{gamma} Receptor 2 with Dominant Negative Activity: Biological Consequences of Homozygous and Heterozygous States J. Immunol., September 15, 2004; 173(6): 4000 - 4008. [Abstract] [Full Text] [PDF]
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), a
child with partial dominant IFN-