878 Severe combined immune deficiency (SCID) is a fatal, het- erogeneous group of immune disorder, characterized by T-cell lymphopenia, a profound lack of cellular (T-cell) and humoral (B-cell) immunity and, in some cases, decreased NK-cell number and function. The incidence of SCID is estimated to be 1/100,000 live births.
GENETICS/BASIC DEFECTS
1. A heterogeneous syndrome of varied genetic origins a. X-linked type SCID (X-SCID)
i. The most common type (50% of all patients with SCIDs)
ii. A combined cellular and humoral immunodefi- ciency resulting from lack of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes
iii. Caused by a mutation in the X-linked gene IL2RG, which encodes the common γ chain, γc (mapped on Xq13), of the leukocyte receptors for interleukin-2 and multiple other cytokines a) Significant frequency of de novo mutations
accounting for 1/3rd of the cases
b) Occurrence of maternal germline mosaicism iv. Atypical X-SCID: less frequently seen in patients with mutations that result in production of a small amount of gene product or a protein with residual activity
b. Autosomal recessive type SCID
i. Formerly known as Swiss-type agammaglobu- linemia
ii. Causes
a) Adenosine deaminase deficiency (10–20%
of all cases of SCID): the ADA gene mapped on chromosome 20q13.11
b) Purine nucleoside phosphorylase (PNP) deficiency: the PNP gene mapped on 14q13 c) Janus-associated kinase 3 (JAK3) deficiency causing autosomal recessive T–B + SCID:
the JAK3 gene mapped on 19p13 d) Interleukin (IL)-2 deficiency
e) ZAP-70 protein tyrosine kinase (PTK) defi- ciency: ZAP-70 mapped on 2q12
f) Bare lymphocyte syndrome g) Reticular dysgenesis h) Omenn syndrome 2. Pathophysiology
a. Varies among various forms of SCID b. Common endpoint in all forms of SCID
i. Lack of T-cell function ii. Lack of B-cell function
c. Cellular hallmarks differentiating various forms of SCID
i. X-linked SCID
a) Absence or near absence of T cells (CD3
+) and natural killer (NK) cells leading to lymphopenia
b) Variable levels of B cells that produce no functional antibodies
ii. JAK3 deficiency
a) Absence or near absence of T cells (CD3
+) and natural killer (NK) cells leading to lymphopenia
b) Normal or high levels of B cells that produce no functional antibodies
iii. ADA deficiency
a) Death of T cells secondary to the accumula- tion of toxic metabolites in the purine salvage pathway leading to lymphopenia
b) Decreased or absence of functional antibodies iv. PNP deficiency
a) Death of T cells secondary to the accumula- tion of toxic metabolites in the purine sal- vage pathway leading to lymphopenia b) Normal number of circulating B cells with
poor B-cell function, evidenced by the lack of antibody formation
v. IL-2 deficiency
a) Normal or near normal numbers of T cells (both CD4
+and CD8
+)
b) Decreased production of functional antibody vi. ZAP-70 PTK deficiency
a) Absence of CD8
+T cells leading to lym- phopenia
b) No antibody formation vii. Bare lymphocyte syndrome
a) Normal or mildly reduced lymphocyte count b) Decreased CD4
+T cells
c) Normal or mildly increased CD8
+T cell numbers
d) Normal or mildly decreased B-cell numbers with decreased antibody production viii. Reticular dysgenesis
a) Absence of myeloid cells in the bone mar- row leading to lymphopenia
b) Presence of functioning red blood cells and platelets
ix. Omenn syndrome
a) Presence of normal or elevated T-cell num- bers of maternal origin
b) Usually undetectable B cells c) Presence of NK cells
d) Markedly low total immunoglobulin level with poor antibody production
e) Elevated eosinophils and total serum
immunoglobulin E (IgE) level
3. Molecular defects a. X-linked SCID
i. Mutation of the common gamma chain of the IL receptors (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R) resulting in loss of cytokine function
ii. Loss of IL-2R function leading to the loss of a lymphocyte proliferation signal
iii. Loss of IL-4R function leading to the inability of B cells to class switch
iv. Loss of IL-7R function leading to the loss of an antiapoptotic signal resulting in a loss of T-cell selection in the thymus and also associated with the loss of a T-cell receptor
v. Loss of IL-15R function leading to the ablation of NK cell development
b. JAK3 deficiency
i. JAK, a protein tyrosine kinase that associates with the common gamma chain of the IL receptors ii. Deficiency of JAK3 resulting in the same
clinical manifestations as those of X-linked SCID
c. ADA and PNP deficiencies
i. Associated with enzyme deficiencies in the purine salvage pathway
ii. Toxic metabolites responsible for the destruction of lymphocytes that cause the immune deficiency d. IL-2 deficiency
i. Molecular defect unknown
ii. Often associated with other cytokine production defects
e. ZAP-70 PTK deficiency: caused by a mutation in the gene coding for this tyrosine kinase, which is impor- tant in T-cell signaling and is critical in positive and negative selection of T cells in the thymus
f. Bare lymphocyte syndrome
i. Deficiency of major histocompatibility complex (MHC)
ii. Absent or decreased MHC type I levels
iii. Decreased MHC type II levels on mononuclear cells
g. Omenn syndrome: believed to be caused by a mutation impairing the function of immunoglobulin and TCR recombinase genes, such as RAG1 and RAG2 genes
CLINICAL FEATURES
1. Age of onset: 3–6 months of life
2. Usual presentation with infections due to lack of T-cell function
a. Opportunistic organisms
i. Pneumocystis carinii pneumonia ii. Systemic candidiasis
iii. Atypical mycobacterium iv. Cryptosporidium
v. Pneumococcus b. Recurrent infections
c. Persistence of infections despite conventional treatment 3. Failure to thrive
4. Oral or diaper candidiasis
5. Dehydration from chronic diarrhea
6. Fevers 7. Rashes
8. Cough and congestion
9. Increased reparatory rate and effort 10. Absence of tonsils and lymph nodes
11. Absence of lymphadenopathy or increased tonsillar tissue despite serious infections
12. Pneumonias 13. Sepsis
14. Disseminated infections a. Salmonella
b. Varicella c. Cytomegalovirus d. Epstein-Barr virus e. Herpes simplex virus
f. BCG
g. Vaccine strain (live) polio virus 15. Recurrent sinopulmonary infections 16. Recurrent skin infections
17. Abscesses
18. Poor wound healing
19. Transplacental transfer of maternal lymphocytes to the infant prenatally or during parturition causing graft-vs-host disease (GVHD), characterized by:
a. Erythematous skin rashes b. Hepatomegaly
c. Lymphadenopathy
20. ADA deficiency and PNP deficiency with later onset and miler or atypical clinical presentation
a. Diagnosis suspected in patients with:
i. Unexplained T-cell lymphopenia
ii. Late manifestations of immunodeficiency a) Chronic pulmonary insufficiency
b) History of autoimmunity and neurologic abnormalities
c) Onset during the first two decades of life and even later
b. Diagnosis confirmed by finding absent or very low enzyme activity in erythrocytes or in nucleated blood cells
21. Lymphadenopathy or hepatosplenomegaly in Omenn syn- drome or bare lymphocyte syndrome
22. Prognosis
a. Fatal if untreated
b. Bone marrow transplantation or enzyme replacement to reconstitute the immune system compatible with long survival
DIAGNOSTIC INVESTIGATIONS
1. Blood workup
a. Complete blood cell count with differential to detect lymphopenia
b. Lymphocyte markers to obtain percentages and absolute counts
i. CD3
+T cells ii. CD4
+T cells iii. CD8
+T cells iv. CD19
+T cells
v. NK cell markers (CD16 and CD56)
c. Immunoglobulin concentrations i. Low IgA and IgM
ii. IgG
a) Generally normal at birth
b) Declines as maternally transferred IgG dis- appears by three months of age
d. Lymphocyte functional tests
i. Absence of responses to vaccines and infectious agents
ii. Lacking T-cell responses to mitogens 2. Chest X-ray
a. Absent to small thymus shadow b. Pneumonia
c. Typical cupping and flaring of the costochondral junction in patients with ADA deficiency
3. Lymph node biopsy a. Paucity of T and B cells b. Lack of germinal centers
4. Consider X-SCID in male infants with:
a. Severe recurrent or persistent infections b. Infections not responding to ordinary treatment c. Infections caused by opportunistic pathogens d. Failure to thrive
5. Confirmatory tests
a. Determination of the ADA and PNP levels i. Lymphocytes
ii. Erythrocytes iii. Fibroblasts
b. X-inactivation studies to determine whether the SCID is X-linked
c. Molecular genetic testing i. X-SCID
a) Sequence analysis of the IL2RG coding region detecting a mutation in >99% of affected individuals
b) Mutation analysis 6. Carrier testing of X-SCID
a. Testing for known family-specific IL2RG mutations b. Sequence analysis of the IL2RG coding region and
splice regions
c. Southern blot analysis used to detect large deletions and complex mutations if the family-specific muta- tion is not known and sequence analysis is uninforma- tive
d. X-chromosome inactivation studies on lymphocytes for at-risk females in whom sequence analysis and/or mutation analysis are not an option for carrier testing or are not informative, provided presence of the fol- lowing two conditions:
i. Skewed X-chromosome inactivation in lym- phocytes
ii. Nonskewed X-chromosome inactivation in another blood lineage such as granulocytes
GENETIC COUNSELING
1. Recurrence risk a. X-SCID
i. Female germline mosaicism present if a woman has more than one affected son and the
disease-causing mutation in the IL2RG gene cannot be detected in her leukocytes
ii. Over 50% of affected males do not have family history of early deaths in maternal male relatives iii. Patient’s sib if the mother is a carrier
a) 50% of males sibs affected b) 50% of females sibs carriers
iv. Patient’s sib is still at increased risk even if the dis- ease-causing mutation has not been identified in the mother’s leukocytes since germline mosaicism has been demonstrated in this condition
v. Patient’s offspring (offspring of affected males) a) 100% of daughters carriers
b) None of sons affected b. Autosomal recessive SCID
i. Patient’s sib: 25%
ii. Patient’s offspring: not increased unless the spouse is a carrier in which case 25% of the off- spring will be affected
2. Prenatal diagnosis a. X-SCID
i. Determination on fetal cells obtained by CVS or amniocentesis
ii. Analysis of DNA from fetal cells for the known disease-causing mutation, provided:
a) Karyotype revealing 46,XY
b) The disease-causing IL2RG mutation has been identified in a family member
iii. Fetal blood sampling for immunological evalua- tion when the family-specific mutation is not known
a) Lymphocytopenia b) Low numbers of T cells
c) Poor T cell blastogenic responses to mitogens b. Autosomal recessive SCID
i. JAK3 deficient SCID
a) Immunophenotypic evaluation of cord blood cells at 18–20 weeks of gestation
b) Direct gene analysis using chorionic villus sampling derived DNA in the first trimester ii. ADA deficiency: prenatal diagnosis established
by measuring ADA enzyme activity in amniotic cells or chorionic villi
3. Management
a. X-linked SCID and JAK3 PTK deficiency
i. Fatal disease unless cured by bone marrow trans- plantation (BMT)
a) The best results achieved by using an HLA-matched sibling as a donor (success rates of 97%)
b) Using haploidentical T-cell depleted BMT from a parent (haploidentical family donors resulting in lower success rates of 52%):
lifesaving for the majority of X-SCID patients who lack matched sibling
ii. Monthly intravenous immunoglobulin replace- ment therapy required if B cells do not engraft iii. Report of in utero transplantation of hematopoi-
etic progenitor cells allowing immune reconsti-
tution in a fetus
iv. Gene therapy
a) Using autologous bone marrow stem/pro- genitor cells retrovirally transduced with a therapeutic gene
b) Successful in reconstituting the immune sys- tem in patients with X-SCID
c) Youngest two of the first ten infants treated in a French study developed leukemia due to retroviral insertional mutagenesis
d) Currently a consideration only for those who are not candidates for bone marrow transplantation or have failed bone marrow transplantation
b. ADA deficiency
i. Usually fatal unless:
a) Keeping affected children in protective iso- lation, or
b) Reconstituting the immune system by bone marrow transplantation from a human leuko- cyte antigen (HLA)-identical sibling donor (therapy of choice but only available for a minority of patients)
ii. Exogenous enzyme replacement primarily with polyethylene glycol-conjugated ADA replace- ment (PED-ADA) therapy
a) Providing noncurative, life-saving treatment for ADA- SCID patients
b) Increased peripheral T cell counts providing a source of T cells for gene correction not available without enzyme therapy
c) Weight gain and decreased opportunistic infections in most patients
d) Improved T cell function as measured by in vitro mitogen responses in most patients e) Recovery of consistent immune responses to
specific antigens in fewer patients
iii. The first genetic disorder treated by gene thera- py: a clinical trial using retroviral mediated transfer of the adenosine deaminase (ADA) gene into the T cells of children with ADA- SCID a) Normalization of the number of blood T cells
as well as many cellular and humoral immune responses
b) Successful gene transfer into long-lasting progenitor cells, producing a functional mul- tilineage progeny
c) Safe and effective addition to treatment for some patients
iv. Combined treatment with PEG-ADA and gene therapy
c. PNP deficiency and bare lymphocyte syndrome: pri- marily with bone marrow transplantation when an appropriate donor is available
d. IL-2 production defects:
i. Primarily with intravenous IL-2 replacement ii. Alternatively with bone marrow transplantation
when an appropriate donor is available e. Omenn syndrome
i. Primarily with bone marrow transplantation when an appropriate donor is available
ii. Pretreatment ablative chemotherapy necessary because of maternal cell engraftment
f. Bone marrow transplantation from a related donor: a life-saving and life-sustaining treatment for patients with any type of severe combined immune deficiency, even when there is no HLA-identical donor
g. Two fetuses successfully treated with gene therapy in utero by an injection of haploidentical CD34
+cells for the γ chain deficiency
h. Psychosocial support for the affected family i. Avoid live vaccines
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Fig. 1. A healthy 9-year-old boy with ADA deficient SCID who has been receiving bi-weekly Adagen (Pegademase) injections since early infancy.
