Pediatrics

SCID Syndromes

OVERVIEW: What every practitioner needs to know

Severe Combined Immune Deficiency (SCID) syndromes are a heterogeneous group of disorders that lead to profound immune impairment and dysregulation. If unrecognized and treated in early infancy, most forms of SCID will result in death during early childhood. The most common causes of death are opportunistic infections, although children with SCID disorders are highly susceptible to malignancy and autoimmune disease.

The majority of severe cases are due to single gene defects that lead to early arrested development of precursor cells of the adaptive immune system. Therefore, SCID can be cured with hematopoietic stem cell transplantation, and in some cases, gene therapy. SCID due to adenosine deaminase (ADA) deficiency was the first human condition successfully treated with gene delivery to correct a genetic defect.

Are you sure your patient has SCID ? What are the typical findings for this disease?

Clinical presentations generally involve overwhelming, chronic, or recurrent infections with viral, fungal, or bacterial pathogens. Importantly, patients with SCID will often present with opportunistic infections due to organisms that do not generally cause severe disease, such as Pneumocystis jiroveci pneumonia, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Candida, or atypical Mycobacteria pneumonia. Even relatively benign viruses such as adenovirus, respiratory syncytial virus, and parainfluenza virus can induce fatal pneumonia in patients with SCID. Pulmonary infections commonly have clinical presentations consisting of interstitial pneumonitis with hyperaeration and hypoxia, manifestations that mimic severe viral bronchiolitis.

On the other hand, in some cases the clinical manifestations can be indolent, consisting of failure to thrive (FTT), intestinal malabsorption due to chronic viral or parasitic infections, or persistent rash and hepatitis due to either chronic viral infection or graft-versus-host-disease (GVHD).

Approximately 20% of patients with SCID will exhibit maternally derived GVHD, the result of transplacental transfer of maternal lymphocytes that are able to proliferate freely in the immune incompetent host. These infants display chronic inflammatory dermatitis, hepatitis, and diarrhea.

However, most infants with SCID appear normal at birth with no obvious physical findings or signs that would raise clinical suspicion.

Some forms of SCID, such as Omenn syndrome, display erythroderma and eosinophilia that are manifestations of immune dysregulation. Patients with Wiscott-Aldrich syndrome, a form of combined immune deficiency, have a distinct clinical phenotype of eczema, thrombocytopenia and recurrent infections. Infants with ectodermal dysplasia with immune deficiency have abnormal hair and malformed conical teeth, in addition to recurrent infections.

What other disease/condition shares some of these symptoms?

There are several primary immune deficiencies that share clinical features of SCID. The most common include defects in B cell development, including X-linked agammaglobulinemia (XLA), X-linked hyper IgM (XLHIGM), or chronic granulomatous disease (CGD). Antibody deficiencies generally become apparent in older infants following the decay of transplacentally derived maternal IgG, but these patients can also have viral and bacterial infections that mimic SCID. Pneumocystis pneumonia is common in XLHIGM. CGD is characterized by infections with catalase positive organisms such as Staphylococcus aureus and Aspergillus, although infections with atypical Mycobacteria and Nocardia can be seen in either CGD or SCID.

The most common T cell deficiency in children worldwide remains perinatally acquired HIV infection, and children with AIDS have clinical courses very similar to SCID.

Many inborn errors of metabolism and genetic conditions such as cystic fibrosis have clinical characteristics similar to SCID because of the common association of FTT with recurrent infections. Malnutrition and parental neglect can also mimic the clinic manifestations of SCID.

A focused laboratory evaluation often quickly differentiates SCID syndromes from these other conditions.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Any infant or child who has clinical conditions suggestive of SCID can be easily screened, and in most cases laboratory results will quickly lead to a diagnosis. However, SCID must be specifically suspected because common laboratory testing, such as complete blood counts, comprehensive metabolic panels, and urinalysis, often will produce normal or near-normal results. A caveat is that some subsets of patients with SCID have severe lymphopenia, thus providing a clue to the diagnosis based on a complete blood count (CBC) that shows an absolute lymphocyte count of less than 1000 cells/μL.

The most effective screening test for SCID is a lymphocyte subset analysis using flow cytometry to enumerate the proportion of T cells, B cells and natural killer (NK) cells in the peripheral blood. This test can be performed using small volumes of blood (<3 mL), and is readily available in most commercial labs and hospitals. All forms of SCID need to be recognized quickly, and expeditiously referred to a center where hematopoietic stem cell transplantation can be performed in order to assure optimal outcomes.

Many of the different forms of SCID can be differentiated based on the results of lymphocyte flow cytometry. These are summarized in Table I.

Table I.

Distribution of lymphocyte subsets in different forms of SCID and their inheritance.

Adenosine deaminase (ADA) deficiency demonstrates profound lymphopenia with no detectable T cells, B cells or NK cells. Mutations that impact the Recombinase Activating Gene (RAG) and Artemis deficiency also produce severe lymphopenia, because cells of both B and T cell lineage fail to develop, but NK cell numbers are normal. All of these conditions have an autosomal recessive inheritance and are very rare.

In contrast, other forms of SCID have detectable blood lymphocytes by CBC, but flow cytometry analysis shows absent T cells with the presence of normal numbers of circulating B cells. Different forms of SCID with B cells can be differentiated based on the presence or absence of NK cells. Subsets of SCID with circulating NK cells and B cells include mutations in the IL-7á receptor and the CD3 δεζ chain of the T cell receptor.

Complete DiGeorge syndrome and CHARGE syndrome (coloboma, heart anomalies, atresia of the choanae, retardation of growth and development, genital and/or urinary defects, and ear anomalies) are associated with thymic aplasia, and these patients also have absent T cells with B cells and NK cells present.

The most common form of SCID is X-linked and due to a mutation of the γc chain of the IL-2 receptor (γcIL-2R). This form of SCID has absent T cells and absent NK cells, but B cells are present. An identical phenotype is also seen in children with a defect in the T signaling protein Jak3.

Other forms of SCID and severe T cell defects can be recognized by their distinct patterns of lymphocyte subsets using flow cytometry (Table II). Zap70 deficiency and MHC class I deficiency have characteristic elevated CD4/CD8 T cell ratios due to their low numbers of total CD8 T cells. Infants with Omenn syndrome (a subset of RAG deficiency) have oligoclonal T cell expansion, with 90% of circulating T cells expressing the memory T cell marker CD45RO. A recently characterized defect in a magnesium transporter gene results in isolated CD4 T cell lymphopenia.

Table II.

Laboratory findings in other forms of SCID and conditions that mimic SCID

Immunoglobulin (Ig) profiles, which include measures of serum IgG, IgA, IgM and IgE, are also important in the evaluation of infants suspected of having SCID. In infants under 12 months of age, IgG levels generally reflect passively acquired maternal IgG. IgA is absent in normal newborn infants and is slowly acquired over the first few years of life. IgM is generally low, but not absent in healthy newborns.

Very low immunoglobulin levels may suggest SCID or congenital agammaglobulinemia, where flow cytometry analysis will reveal normal T cells but absent B cells.

Immunoglobulin profiles can be helpful in detecting T cell deficiencies associated with immune dysregulation conditions associated with combined immune deficiency. For example, children with Wiscott-Aldrich syndrome have normal IgG levels, elevated IgA and IgE, and low IgM. Patients with IPEX sydrome, (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) do not have increased susceptibility to infections, but rather, FTT due to chronic enteritis and type 1 diabetes in infancy are common early manifestations. The Ig profiles of these patients show markedly elevated IgA and IgE for age.

Patients with Omenn syndrome have low total T and B lymphocyte counts, elevated IgE levels and eosinophilia. Testing of T cell function using mitogen-induced T cell proliferation studies is helpful in confirming their diagnosis of T cell deficiency, such as SCID, but these tests are not readily available in all medical centers. Transport of blood specimens to referral laboratories is often difficult, and many days are required to obtain the results. These tests are necessary to evaluate T cell function to confirm the diagnosis of defective lymphocyte signaling.

Recently, newborn screening has become available for SCID. The assay can be performed as part of the standard newborn screening (NBS) program and is currently used throughout the United States for the diagnosis of many inborn errors of metabolism.

For this screening, a single blood drop from a heel stick is added to a Guthrie card, the filter paper used for NBS; this is all that is needed for the assay. After extraction of the DNA from the dried blood spot (Figure 1), T cell receptor excision circles (TRECs), circular pieces of DNA formed during rearrangement of the T cell receptor genetic complex during T cell development, are amplified using a quantitative PCR method. Beta-actin is used as a control for input DNA.

T cell recombinant excision circle (TREC) assay for newborn screening for SCID

The TREC level is a molecular marker of recent thymic emigrants; a low TREC level (<25 copies/3 μL blood) identifies multiple potential T cell deficiencies, including most forms of SCID (ADA deficiency, RAG, γc IL-2R, Jak3, Zap70, Artemis, and reticular dysgenesis) as well as other conditions associated with low T cell numbers. An abnormal result should be confirmed quickly using flow cytometry assessment of peripheral blood lymphocytes.

Recently (2010), both the Centers for Disease Control and Prevention (CDC) and the United States Department of Health and Human Services (HHS) recommended that TREC analysis be added to the Newborn Screening panel in all states.

TREC Assay for Newborn Screening for SCID is outlined in Figure 1.

Newborn Screening (NBS) for SCID involves screening all newborns via a heel stick with a drop of blood (3 μL) applied to a Guthrie filter paper card. The dried blood spot (DBS) is removed from the card by a 3.2 mm punch and placed in DNA extraction buffer. The TRECs (shown as circles) are amplified by a reverse transcriptase quantitative PCR (RT-qPCR) using primers specific for δRecΨJαTREC. Beta-actin is amplified as a control to verify the integrity of the DNA. After 40 cycles of amplification, the median TREC number from normal newborns is 827 copies. The cutoff for infants with suspected T cell deficiency that requires further evaluation is < 25 copies.

Would imaging studies be helpful? If so, which ones?

Imaging studies are generally unhelpful in establishing the diagnosis of SCID, but chest imaging is valuable in assessing the presence of opportunistic infections, as well as many viral or fungal infections such as Pneumocystis interstitial pneumonitis. Other abnormalities that can be seen on chest x-ray that point to the diagnosis of immune deficiency include absent thymic shadow (DiGeorge syndrome) or rib abnormalities (ADA deficiency). Imaging should be used cautiously because some forms of SCID, such as Artemis, are associated with radiosensitivity, raising the risk for malignancy with repeated exposure to ionizing radiation.

Confirming the diagnosis

Clinical evaluation is warranted based on either clinical signs and symptoms suggestive of SCID or a Newborn Screen (NBS) TREC assay result of <25 copies (Figure 2).

Algorithm for management of a child with suspected SCID.

Infants with low TREC numbers are referred for confirmatory testing consisting of flow cytometry to enumerate T cells, B cells, and NK cells. While awaiting results, the child should be started on oral trimethoprim/sulfamethoxazole prophylaxis, and all live immunizations should be withheld.

If the results of flow cytometry studies are normal, then prophylaxis is discontinued and no further evaluation is needed.

If the results confirm SCID, then further testing is carried out to assay antibody levels and function, and T cell function; and replacement immunoglobulin is started for prophylaxis. Referral to a hematopoietic stem cell (HSC) transplant center should be done as quickly as possible for HLA typing and HSC transplant. Genetic confirmation should be obtained, but should not delay definitive therapy.

If you are able to confirm that the patient has SCID, what treatment should be initiated?

When the diagnosis of SCID is confirmed or highly suspected, definitive therapy needs to be initiated as quickly as possible. Opportunistic infections generally begin to develop within the first few months of life, and death occurs prior to the age of 2 years.

All children with suspected SCID should begin prophylaxis for Pneumocystis with trimethoprim/sulfamethoxazole. Live immunizations, including rotavirus, measles, mumps, rubella, varicella, and BCG vaccines, should not be administered.

Diagnostic assessment for occult viral infection using antigen-based assay (culture or PCR) should be carried out for EBV, CMV, BK, HSV, parainfluenza, respiratory syncytial virus (RSV), adenoviruses, and enteroviruses in blood and secretions. Because of the risk of acquisition of EBV, CMV and graft-versus host disease, all blood transfusions should be done with leukocyte-depleted or irradiated blood products. Immune prophylaxis with gamma globulin should be administered at a dose of 400-600 mg/kg every two to three weeks to maintain IgG levels in the therapeutic range. Any infections should be treated aggressively.

Hematopoietic stem cell transplantation (HSCT) is considered the definitive therapy for SCID. If HSCT is carried out prior to the age of 3.5 months, the overall survival rate is >90%. If transplantation is delayed past 6 months of age, the survival rate falls to <50%, generally due to opportunistic infections or non-engraftment. Therefore, SCID should be considered an immunologic emergency, requiring rapid referral to a medical center where therapy can be initiated.

The approach to HSCT is dependent on the availability of a suitable HSC donor and the subtype of SCID.

An HLA identical first degree relative offers the best chance of HSC engraftment with the lowest risk of graft-versus-host disease. An HLA-matched, unrelated donor is the next best option, followed by mismatched umbilical cord blood as the HSC source. If these options are not available, then a haplo-identical HSC transplant from the mother or father may be the only alternative.

The source of HSC must be manipulated ex vivo to remove T cells that would cause fatal graft-versus-host disease. HSC engraftment is facilitated by the use of pre-conditioning chemotherapy to ablate recipient immunity and provide a better milieu in the bone marrow for engraftment. Factors that influence the choice of conditioning regimens are the degree of T cell and NK function in the recipient. The presence of NK function generally requires some degree of conditioning to assure engraftment. If there is complete absence of immune function (T cell and NK cell), then HSC can be given without conditioning chemotherapy and still have a good chance of engraftment within 90 days of the transplant.

HSCT is curative, but late graft failure has occurred many years after the initial transplant in some patients.

Some forms of SCID (ADA deficiency in particular) can be treated with polyethylene glycol (PEG)-adenosine deaminase given as a regular subcutaneous injection, but treatment is lifelong. This can be administered in lieu of HSCT if T cell function can be restored. This form of SCID can also be treated successfully with gene therapy. In this situation, the child's HSCs are transduced ex vivo with a retroviral vector that carries the ADA gene. The normal gene is inserted into the HSC nucleus and produces normal ADA levels. HSC lymphoid progeny that carry the normal gene are able to function normally and survive. This approach is also curative.

What are the adverse effects associated with each treatment option?

All HSC transplants carry a risk of graft-versus-host disease (GVHD) which can be acute or chronic, involving the gastrointestinal system, liver, skin, and pulmonary system. When the risk of GVHD is high, prophylaxis with immune suppressive medications such as tacrolimus or cyclosporine is necessary. When GVHD develops, it must be treated aggressively with systemic immune suppression. In the case of haplo-identical transplantation, the risk of GVHD correlates with the number of donor T cells in the grafted cells.

The presence of infection, particularly viral infections such as CMV and EBV, increases the risk for GVHD and non-engraftment. EBV is also associated with a risk of EBV-driven lymphoproliferative disease and malignancy. The risk of non-engraftment is higher if the HSC dose is low or if there is presence of maternal T cells. Older children have a higher non-engraftment rate. A greater degree of HLA mismatch and intact NK cell function are also associated with lower engraftment rates.

The type of conditioning used prior to transplantation impacts the outcome. More potent chemotherapy agents, such as busulfan or cyclophosphamide, cause prolonged cytopenias and end-organ damage in the liver, lung and mucus membranes. These chemotherapeutic agents are also associated with bacterial fungal infections. Busulfan and other chemotherapies place recipients with underlying liver disease at risk for veno-occlusive disease, a severe vasculopathy seen in HSC transplant recipients. On the other hand, reduced conditioning regimens carry the risk of non-engraftment.

A unique feature of HSCT for SCID is non-B cell engraftment, where T cells and NK cells engraft but functional B cells do not. These children require lifelong immunoglobulin replacement therapy. This outcome generally occurs in infants who do not receive preconditioning chemotherapy. Gene therapy carries a risk of insertional mutogenesis, where the gene and its viral products can induce malignancies in the HSC lineages that are transduced by the vector. This problem soon became apparent in the gene therapy trial to treat X-linked SCID.

What are the possible outcomes of SCID?

Death, due either to opportunistic infections or malignancy, occurs in essentially all infants with SCID who do not receive definitive therapy. Isolation within a germ free environment has proven ineffective and impractical.

While early HSCT offers the best chance for cure, adverse transplant outcomes include GVHD, non-engraftment, or graft loss. GVHD can be chronic and require long-term treatment with immune suppression. It can also lead to chronic pulmonary, cutaneous, and gastrointestinal conditions. Non-engraftment or graft failure must be treated with repeat transplantation. Chemotherapy conditioning can result in pancytopenia, end-organ damage, developmental delay, and infection. B cell non-engraftment requires chronic replacement therapy with gamma globulin.

What causes this disease and how frequent is it?

SCID is predominantly a collection of single gene disorders that impact the development of the adaptive immune system. Its overall incidence is estimated to be 1:40,000 births, but many cases go unrecognized.

The most common form of SCID is X-linked, but even in this type of SCID, up to 40% of cases are the result of new mutations, showing that a family history for SCID is unreliable.

ADA deficiency makes up about 16% of cases. It is a defect in the purine salvage pathway, when deoxyadenosine cannot be converted to non-toxic deoxyinosine and accumulates in rapidly dividing cells such as T cells, B cells and NK cells, causing cell death.

RAG deficiency and Artemis deficiency are due to mutations in key cellular proteins involved in gene recombination that form the T cell and B cell antigen receptors. Abnormalities in these proteins lead to maturational arrest early in the development of the adaptive immune response. The common γ chain of cytokine receptors IL-2, 4, 7, 9, 21, and 15 (X-linked SCID) share signaling pathways that are critical to T cell and B cell activation and differentiation. Defects in this common chain and its downstream companion Jak3 result in early failure of T cell development. Other defects in T cell signaling include mutations in the IL-7á receptor, CD3 δεζ chain, and Zap70.

A form of SCID associated with ectodermal dysplasia is due to a mutation within the nuclear signaling pathway of NFkB. MHC class I deficiency is due to a mutation in Tap, a protein responsible for expression of the MHC I complex on the surface of all cells.

Are additional laboratory studies available; even some that are not widely available?

Commercial laboratory tests for specific, single gene forms of SCID by DNA sequencing analysis are available and can be used for the suspected diagnosis of RAG deficiency, Artemis, X-linked γc IL-2R mutations, Jak3, and ZAP70. Studies can be carried out using whole blood specimens or buccal swabs for genomic DNA.

Screening for multiple conditions simultaneously is not practical and may delay definitive therapy. Therefore, understanding the different clinical and laboratory phenotypes is an essential rational use of genetic confirmation. However, it should not be used in clinical decision-making, because receiving the results may take many months and unnecessarily delay definitive therapy.

Genetic testing is essential for genetic counseling.

How can SCID be prevented?

In general, SCID is a genetic condition that is not the result of an environmental toxin or induced by a pathogen. Single gene mutations are sporadic and occur in essentially every ethnic group. Consanguinity increases the risk for SCID, but many forms are also the result of spontaneous mutations.

What is the evidence?

Treatment of SCID is a rapidly evolving field. Studies of long-term outcomes are hampered by changes in the management of opportunistic infections and better methods for early diagnosis. Clinical trials for the treatment of SCID tend to involve few subjects, but the results are often compelling.

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Ongoing controversies regarding etiology, diagnosis, treatment

Beyond HSC transplantation, there is currently no consensus with regard to the optimal treatment regimen for SCID. Due to the heterogeneity among patients receiving treatment, HSC source and conditioning regimens vary among centers and are often determined on a case-by-case basis, depending on the sub-type of SCID, donor source, concurrent infections, and patient age.

These issues may be resolved as newborn screening becomes available and patients are more clinically stable at the time of transplantation. However, some states continue to question the cost of universal screening compared to the benefits of early diagnosis. However, most experts agree that the relatively low cost of screening ($4 to $5 per assay) compared with the high costs of late diagnosis with poor outcomes makes the case for newborn screening compelling.

Gene therapy continues to be controversial because of its associated risk for therapy induced-malignancy. As gene delivery systems improve and the malignancy risk falls, gene therapy is likely to become the accepted mode of therapy for the most common forms of SCID, ADA deficiency and X-linked SCID.

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