Severe Combined Immunodeficiencies 1

Definition and History

The first description of severe combined immunodeficiencies (SCID) dates back to 1950, when Glanzmann and Riniker described infants who died with overwhelming infections, intractable diarrhea, thrush, and profound lymphophenia.26 The SCID phenotype represents a heterogeneous group of genetic disorders that are characterized by a severe impairment of T-lymphocyte development and function (Fig. 82–1).27–29 Depending on whether the development of B and/or NK lymphocytes is also affected, SCID can be classified into four distinct immunologic phenotypes: (1) T–B+NK– SCID (the most common variant); (2) T–B+NK+ SCID; (3) T–B–NK+ SCID; or, (4) T–B–NK– SCID. The term “combined immune deficiency” (CID) is used to define disorders with residual development and/or function of T lymphocytes. Unless treated by allogeneic hematopoietic stem cell transplantation or, in selected cases, by gene therapy or enzyme replacement therapy, SCID is inevitably fatal.


SCIDs are mendelian disorders, and their overall prevalence is estimated to be 1:50,000 births. In Western countries, the most common form of SCID is inherited as an X-linked trait; however, a variety of autosomal recessive forms are also known. SCID can be grouped in different categories that illustrate the various pathogenetic mechanisms involved in T-cell development.

SCID as a Result of Increased Apoptosis of Lymphocyte Precursors

Adenosine Deaminase Deficiency

Approximately 5 to 10 percent of infants with SCID have a deficiency of adenosine deaminase (ADA), the enzyme that converts adenosine and deoxyadenosine into inosine and deoxyinosine, respectively.30 In the absence of ADA, high intracellular levels of adenosine, deoxyadenosine, and their toxic phosphorylated metabolites cause apoptosis of lymphoid precursors, and hence result in the virtual absence of T lymphocytes, that is usually associated with marked reduction of B and NK lymphocytes (T–B–NK–SCID).31,32 ADA-SCID is inherited as an autosomal recessive trait, and its clinical manifestations extend beyond the immune system, reflecting the fact that ADA is a general housekeeping enzyme.

Purine Nucleoside Phosphorylase Deficiency

Purine nucleoside phosphorylase (PNP) is another enzyme of the purine salvage pathway. PNP catalyzes the phosphorylation of inosine, guanosine, and deoxyguanosine.30 In the absence of PNP, high intracellular levels of deoxyguanosine triphosphatase cause lymphoid and neuronal toxicity. Immature thymocytes are particularly susceptible to PNP deficiency.33 Accordingly, the immunologic phenotype of PNP deficiency is characterized by decreased T-cell counts, whereas B and NK lymphocytes are often unaffected.34 PNP deficiency accounts for 1 to 2 percent of all forms of SCID, and is inherited as an autosomal recessive trait.

Adenylate Kinase 2 Deficiency

Another rare variant of autosomal recessive SCID, reticular dysgenesis, is characterized by extreme lymphopenia, absence of neutrophils, and sensorineural deafness.35 The disease is caused by mutations of adenylate kinase 2 that result in apoptosis of myeloid precursors of neutrophils, and of lymphoid progenitor cells.36,37

SCID as a Result of Defects of Cytokine-Mediated Signaling

Thymic T-cell progenitors depend on interleukin (IL)-7 for cell proliferation. The IL-7 receptor (IL-7R) is composed of an chain (encoded by the IL7R gene) and a common chain (c), that is shared also by IL-2R, IL-4R, IL-9R, IL-15R, and IL-21R,38 and is encoded by the IL2RG gene, located on the X chromosome. Cytokine-mediated signaling through c—containing receptors involves activation of Janus-associated tyrosine kinase 3 (JAK3).39 In humans, defects of IL-7–mediated signaling abrogate T-cell development, whereas impaired signaling through IL-15R affects development of NK cells.38 X-linked SCID, caused by IL2RG mutations,40 represents approximately 40 percent of all cases of SCID, and is characterized by lack of T and NK lymphocytes but normal development of B cells (T–B+NK– SCID). B-lymphocyte function, however, is severely compromised by both the lack of T-cell help and nonfunctional c. JAK3 deficiency is inherited as an autosomal recessive trait, and its phenotype is identical to that of X-linked SCID (T–B+NK– SCID).41,42 In contrast, autosomal recessive IL-7R deficiency caused by mutation of the chain is characterized by the selective lack of T cells (T–B+NK+ SCID).43

SCID as a Result of Defective Signaling through the T-Cell Receptor

One of the distinctive features of developing thymocytes is the expression of the pre–T-cell receptor (TCR), that is composed of a pre-T chain, a TCR chain, and the CD3 , , , and chains. Signaling through the pre-TCR permits rearrangement of the TCR chain and expression of a mature TCR. Alternatively, thymocytes may express the chains of the TCR. Rearrangement of the TCR loci is accomplished by means of the V(D)J recombination, whereby the lymphoid specific RAG1 and RAG2 proteins mediate DNA cleavage at the variable (V), diversity (D), and joining (J) elements of the TCR loci. The DNA double-strand break of the coding ends is initially sealed as a hairpin, that is resolved by Artemis (encoded by the DCLRE1C gene). Eventually, joining of coding (and signal) elements is mediated by a series of proteins, that include the Ku70/80 heterodimer, XRCC4, DNA ligase IV (LIG4), DNA-protein kinase catalytic subunit, and Cernunnos/XLF. Defects in V(D)J recombination affect both T- and B-cell development and hence cause T–B–NK+ SCID, because this process is also essential to mediate rearrangement of the immunoglobulin genes, a key step in B-cell development. RAG1 or RAG2 deficiencies account for 3 to 20 percent of all SCID cases in different series.27,44 Artemis (DCLRE1C),45 DNA-protein kinase catalytic subunit,46 LIG4,47,48 and Cernunnos/XLF49 deficiencies are less frequent and their cellular and clinical phenotype extends beyond impaired T and B cells development, because enzymes that mediate DNA double-strand break repair are ubiquitously expressed, and their deficiency results in increased cellular radiosensitivity.45–49 The phenotype of LIG4 deficiency can be extremely variable, from T–B–NK+ SCID to mild or no immunodeficiency whereas Cernunnos/XLF deficiency is characterized by significant T-cell lymphopenia and progressive decrease in the number of B cells.

Defects of the CD3 , , or chains affect signaling through the pre-TCR and the TCR and hence cause autosomal recessive T–B+NK+ SCID.50–52 In contrast, CD3 deficiency is associated with mild T-cell lymphopenia and a variable clinical phenotype.53,54

Mutations of CD45, a pan-leukocyte tyrosine phosphatase that has been implicated in signaling through the TCR and the B-cell receptor, have been reported in few patients with T–B+NK+ SCID.55,56

Clinical Features of Severe Combined Immunodeficiency Syndromes

Despite genetic heterogeneity, SCID is characterized by a consistent clinical phenotype. Interstitial pneumonia, often sustained by P. jiroveci, cytomegalovirus (CMV), adenovirus, parainfluenza 3 virus, respiratory syncytial virus, chronic diarrhea, failure to thrive, and persistent candidiasis are common features. Typically, infections develop in the first months of life. Skin manifestations (maculopapular rash, erythroderma, alopecia) are also common, especially in infants with maternal T-cell engraftment. Hypoplastic lymphoid tissue (tonsils, lymph nodes), and absence of a thymic shadow on chest radiography are characteristic.57,58

Because of the inability to control replication of live microorganisms, administration of live-attenuated vaccines often leads to severe, life-threatening complications in infants with SCID.59–61

T-cell engraftment from maternal transplacentally derived cells occurs in more than 50 percent of infants with SCID. Most often asymptomatic, it may cause skin rash or, less frequently, typical graft-versus-host disease with generalized rash, liver disease, profuse diarrhea, jaundice, and severe hematologic abnormalities (thrombocytopenia, anemia, leukopenia) that are indicative of marrow damage.62,63 Transfusion of unirradiated blood products often leads to fatal graft-versus-host disease.

Laboratory Features of Severe Combined Immunodeficiency Syndromes

An absolute lymphocyte count less than 2000/L should prompt immediate investigation for SCID, regardless of the severity of clinical symptoms.27 However, a normal absolute lymphocyte count does not rule out SCID, if suggestive clinical features are present. Typically, infants with SCID have markedly reduced or absent circulating T cells, hence circulating CD3+ cells should be determined in infants suspected of having SCID, and values should be compared to healthy age-matched controls.64 Lymphocytes fail to proliferate in vitro to mitogens and specific antigens.27,57

Normal absolute lymphocyte counts in SCID may reflect maternal T-cell engraftment, hypomorphic mutations, or somatic reversions that allow for some autologous T-cell development.65,66 Maternal T-cell engraftment and “leaky” SCID with residual development of autologous T cells are characterized by the expression of the CD45R0 memory/activation antigen on the surface of circulating T lymphocytes (whereas most T cells in normal infants have a naïve CD45RA+ phenotype) and failure to respond in vitro to mitogens.

T-cell receptor excision circles, consisting of circularized signal joints, are a byproduct of V(D)J recombination and are exported to the blood by recent thymic emigrants. Levels of T-cell receptor excision circles in circulating lymphocytes are particularly high in newborns and infants, and progressively decline with age. Because T-cell receptor excision circles cannot be detected in infants with SCID, assessment of T-cell receptor excision circle levels by polymerase chain reaction has been proposed for newborn screening for SCID67; two pilot studies of this approach have started in the United States.

Although the number of circulating B lymphocytes can vary, depending on the nature of the genetic defect, serum immunoglobulin levels are low in infants with SCID. Normal serum IgG levels early in life reflect transplacental passage of maternal immunoglobulins. Antibody response to immunization antigens is abolished. PNP deficiency represents an exception, as in this disease humoral immunity is often spared.

Eosinophilia and elevated IgE levels are common in SCID. Anemia, thrombocytopenia, and neutropenia, caused by infections or marrow damage, may also be present. Autoimmune hemolytic anemia is frequent in PNP deficiency.34 Marrow abnormalities (dysplasia or aplasia) can be observed in ADA,68 PNP,69 Cernunnos/XLF,70,71 and LIG472 deficiencies.

The diagnosis of ADA and PNP deficiency is facilitated by the demonstration of increased levels of deoxyadenosine triphosphate and deoxyguanosine triphosphate, respectively, in red blood cells.

Differential diagnosis of SCID includes secondary forms of immunodeficiencies, especially HIV infection, congenital rubella, and CMV infections, severe malnutrition, marrow failure syndromes,73 and defects of vitamin B12 and folate metabolism.74,75

Therapy, Course, and Prognosis of Severe Combined Immunodeficiency Syndromes

SCID is a medical emergency and is inevitably fatal if untreated. Confirmation of diagnosis by appropriate laboratory assays, referral to a tertiary care center, and aggressive treatment of infections should be immediately initiated in infants with possible SCID. High-dose intravenous sulfamethoxazole/trimethoprim (20 mg/kg) is effective in treating P. jiroveci pneumonia. CMV or adenoviral infections should be treated with ganciclovir or cidofovir, respectively. Infants who have received bacillus Calmette-Guerin vaccination at birth should receive isoniazid and rifampicin, regardless of the presence of overt signs of mycobacteriosis. Administration of intravenous immunoglobulins and antimicrobial prophylaxis are necessary to reduce the risk of infections. Parenteral nutrition may be necessary, especially if chronic diarrhea and failure to thrive are present.

Survival, however, is ultimately dependent on immune reconstitution. Allogeneic stem cell transplantation was first performed in 1968 in an infant with X-linked SCID,76 and is the treatment of choice. Survival following stem cell transplantation from an human leukocyte antigen (HLA)-identical sibling is currently as high as 90 percent.27,77,78 T-cell–depleted transplantation from haploidentical donors results in excellent results if the transplantation is performed in the neonatal period79 or in the first 3.5 months of life,27 but survival is only 50 to 65 percent if performed at a later age.77 Haploidentical transplantation is more successful in B+ SCID than in B– SCID,77 but is problematic in patients with the Artemis gene mutation or ADA deficiency, or with reticular dysgenesis. Although graft rejection should in theory be impossible in patients with SCID (making the use of pretransplantation chemotherapy unnecessary), full and durable immune reconstitution is more easily achieved following pretransplantation nonmyeloablative conditioning, which favors engraftment of donor stem cells. Promising results have been achieved with stem cell transplantation from matched-unrelated donors and unrelated cord blood.78,80

Failure to achieve sufficient T- and B-cell reconstitution is associated with prolonged morbidity after transplantation, but most patients with SCID enjoy good quality of life after transplantion,81 except for those with ADA or PNP deficiency and SCID with increased cellular radiosensitivity, who often develop neurologic deterioration and developmental problems even after transplantation.82–84

Enzyme replacement therapy offers rapid normalization of the toxic metabolites in ADA deficiency in those who do not have a matched donor, and may result in immune reconstitution and significant clinical improvement in patients with ADA deficiency,85 although T-cell counts often remain low.86

A proof of principle that gene therapy may cure SCID has been achieved in X-linked SCID87,88; however, some of the patients have developed leukemia because of insertional mutagenesis.89,90 In contrast, efficacy of gene therapy without adverse events has been reported in ADA deficiency.91