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fact
sheet
IL2RG
and
Severe Combined Immunodeficiency (SCID),
a Primary Immunodeficiency Disease (PID)
Lisa Kalman, Mary
Lou Lindegren, Lisa Kobrynski, Robert
Vogt
HuGE Review
Published July, 2002
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IL2RG
Gene |
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The
IL2RG gene, located at Xq13, encodes the gc-chain of the
IL2, 4, 7, 9, and 15 cytokine receptors that are essential for the
development of T and NK lymphocyte subsets. Mutations in the IL2RG
gene cause the X-linked form of Severe Combined Immunodeficiency Disorder
(SCID), a subset of the PID disorders. |
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Prevalence of
Gene Variants |
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A
total of 264 mutations of the IL2RG gene have been sequenced, of
which 169 are unique (8). Each of these mutations has resulted in gc
deficiency with varying degrees of immune deficiency (5). The
penetrance of each of the identified IL2RG mutations is unknown.
The mutations are distributed throughout the eight exons of the gene, as
well as in the regions necessary for proper transcription and translation.
Exons 5 and 7 have mutation hot spots. The types of mutations
identified include missense, nonsense, insertions, deletions, splice
mutations, and mutations that affect RNA processing and translation.
No population based data exists to describe the frequency of mutations in IL2RG. |
Disease
Burden |
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SCID,
an inevitably fatal form of PID that presents in infancy, is caused by
mutations in a number of genes, including the IL2RG gene. In
two clinical series, patients with mutations in IL2RG represent 28%
to 45% of all SCID cases (2, 6). The estimated incidence of SCID is
1:100,000 live births. SCID resulting from mutations in IL2RG (XSCID)
is characterized by profound deficiencies of T and NK cells but normal to
elevated levels of B cells. These patients usually present as
infants, often with diarrhea and failure to thrive. They also are
susceptible to severe and often fatal infections with organisms such as Candida
albicans; Pneumocystis carinii; Pseudomonas; and Salmonella
species, as well as viruses such as respiratory syncytial virus and herpes
viruses (5). Infants with SCID have undetectable tonsils and usually
undetectable peripheral lymph nodes. The thymus gland is small and
poorly differentiated (5). On rare occasions, mutations in IL2RG
have caused an atypical mild combined immunodeficiency that presented
beyond infancy (5).
Successful treatment of XSCID involves
immune reconstitution by transplantation of either HLA-identical
unfractionated bone marrow or haploidentical T-cell-depleted bone marrow.
Bone marrow transplantation is also the treatment of choice for SCID
caused by mutations in other genes. Transplantation is more
successful if done early in infancy, before the onset of life threatening
infections. In a series from one clinical center, infants who
received transplants in the first three and a half months had a 95%
survival rate while infants receiving transplants after three and a half
months had a survival rate of 76% (1). Post-transplant recipients
may require ongoing immunoglobulin replacement and antibiotics.
Recently, gene therapy as a treatment for
XSCID has been tested in five patients at another clinical center (3).
Autologous CD34+
bone marrow cells were transduced ex vivo with a replication incompetent
retroviral vector containing a gene encoding a normal gc-chain.
Initial results (two and a half years post-treatment) in four patients
indicate that they have nearly normal T-cell numbers and phenotypes.
These T cells also had nearly normal repertoires of T-cell receptors and
in vitro proliferative responses to antigens. Although the frequency
of transduced B cells was low, these children did not require
immunoglobulin replacement (3). One patient underwent stem-cell
transplantation eight months after gene therapy due to the failure of
T-cell reconstitution (3).
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Laboratory
Tests
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Ninety-five percent of patients with mutations in IL2RG have lymphopenia,
with total lymphocyte counts less than 2,000/mm3
(normal 4,000-13,500/mm3),
based on clinical case series. All patients have very low or absent
T cells, and approximately 88% have low or absent NK cells (5).
Lymphopenia can be detected prenatally or after birth by obtaining a white
cell count and differential; however subset analysis by flow
cytometry is necessary to enumerate T, B and NK cells. Abnormal
lymphocyte counts and analysis of T-cell function using in vitro responses
of peripheral blood lymphocytes to phytomitogens and common antigens are
currently used to diagnose this disorder (7). The diagnosis can be
confirmed by sequence analysis of the IL2RG gene. Female
carriers of IL2RG mutations can be identified by nonrandom X chromosome
inactivation in lymphoid cells or by sequence analysis if the mutation is
known. Prenatal diagnosis involves collection of fetal cells by
amniocentesis or chorionic villus biopsy to look for known mutations or by
fetal blood sampling to examine for lymphopenia, low T-cell counts, and
poor T-cell blastogenic responses to mitogens (5).
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Population
Testing |
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Specific
testing for SCID is currently done only on symptomatic individuals and in
families with affected individuals. Some cases are also identified
as a result of blood analysis performed for unrelated reasons.
Although recent data shows that intervention shortly after birth (before
the onset of symptoms) clearly improves outcome (1, 4), there is currently
no program to detect infants with SCID. Testing for
lymphopenia using a cord blood total lymphocyte count and a subset
analysis using flow cytometry immediately after birth has been suggested,
but the sensitivity and specificity has not been evaluated and thus may
not be practical on a large scale. Detection of T-cell
lymphopenia from the dried blood spots (DBS) currently collected from each
newborn would allow the integration of SCID screening into the existing
newborn screening system. If a DBS test could be developed and
validated through large population pilot studies, it could potentially be
incorporated into the current newborn screening programs.
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References |
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- Buckley RH, Schiff SE, Schiff RI, Markert ML,
Williams LW, Roberts JL, Myers LA, Ward FE. Hematopoietic stem-cell
transplantation for the treatment of severe combined immunodeficiency.
N Engl J M 1999;340:508-16.
- Buckley RH, Schiff RI, Schiff SE, et al.
Human severe combined immunodeficiency: Genetic, phenotypic, and functional
diversity in one hundred eight infants. J Pediatr 1997;130:378-87.
- Hacein-Bey S, Le Deist F, Carlier F et al.
Sustained correction of X-linked severe combined immunodeficiency by ex vivo
gene therapy. N Engl J M 2002; 346:1185-93.
- Myers LA, Patel DD, Puck JM, Buckley RH.
Hematopoietic stem cell transplantation for severe combined immunodeficiency
in the neonatal period leads to superior thymic output and improved
survival. Blood 2002;99:872-8.
- Puck JM. X-Linked severe combined
Immunodeficiency. In: Ochs HD, Smith CIE, Puck JM, eds.
Primary Immunodeficiency Diseases-- A Molecular and Genetic Approach.
Oxford University Press; 1999.
- Stephan JL, Vlekova V, Le Deist F, et al.
Severe combined immunodeficiency: a retrospective single-center study of
clinical presentation and outcome in 117 cases. J Pediatr
1993;123:564-72.
- Primary Immunodeficiency Diseases.
Report of an IUIS Committee. Clinical Exp Immunol. 1999;118 (suppl.
1):1-28.
- National
Human Genome Research Institute. X-linked SCID mutation database (no
date provided).
Accessed June 18, 2002.
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Web sites |
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National
Human Genome Research Institute. X-linked SCID mutation database
The SCID Homepage
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