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- van der Burg, M. & Gennery, A.R. Eur J Pediatr (2011) 170: 561. doi:10.1007/s00431-011-1452-3
Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency characterized by absence of functional T lymphocytes. It is a paediatric emergency, which is life-threatening when recognized too late. The clinical presentation varies from the classical form of SCID through atypical SCID to Omenn syndrome. In addition, there is a considerable immunological variation, which can hamper the diagnosis. In this educational review, we describe the immunopathological background, clinical presentations and diagnostic process of SCID, as well as the therapeutic possibilities.
KeywordsSevere combined immunodeficiencies Diagnosis Lymphocytes Therapy Primary immunodeficiencies
Graft versus host disease
Hematopoietic stem cell transplantation
Non-homologous end joining
Severe combined immunodeficiency
Severe combined immunodeficiency (SCID) is an inherited primary immunodeficiency, which is characterized by the absence or dysfunction of T lymphocytes affecting both cellular and humoral adaptive immunity . It is one of the most severe forms of primary immunodeficiency (PID), which is life-threatening when recognized too late. Seven percent of PID patients suffer from a T cell deficiency, including SCID . Depending on the genetic defect, B and natural killer (NK) cells may be present or absent. Conventionally, SCID can be classified as T−B+ and T−B− SCID with further subdivision based on the presence or absence of NK cells. However, the presentation is not always classic, and the presence or absence of NK cells may be misleading. Therefore, a phenotype describing NK cells no longer forms a part of the classification system of the International Union of Immunological Societies . It has become clear that clinical presentation has wide phenotype variability with considerable immunological variation . These aspects can impede the diagnosis of SCID. In this review, we address the immunological and clinical spectrum of SCID and provide some clues and tools for diagnosing SCID.
Clinical presentations of SCID
Presenting features of classical and atypical severe combined immunodeficiency and Omenn syndrome
Present in infancy
Present in infancy
Present >12 months of age
Persistent viral respiratory +/− gastrointestinal infection
Recurrent, severe, prolonged viral infection
Pneumocystis jiroveci pneumonitis
Disseminated BCG infection
Failure to thrive
Failure to thrive
Granulomatous cutaneous lesions
Maternofoetal graft versus host disease
Absent lymphoid tissue
Partial or restricted antigen-specific antibody responses
Absent T lymphocytes
Bacterial infections are less common in part because of the presence of maternal IgG in early infancy. However, prolonged otitis media and invasive bacterial infections, such as staphylococcal or pseudomonas septicaemia and pneumonia, may occur, which may respond poorly to appropriate treatment. However, patients with associated agranulocytosis, such as those with reticular dysgenesis due to adenylate kinase 2 (AK2) deficiency, generally present in the first few days of life with omphalitis or invasive bacterial sepsis .
Severe invasive fungal infection is rare, but often fatal. Extensive persistent superficial candidiasis is more common. Disseminated BCGosis occasionally may be the presenting feature in immunised infants. Skin lesions demonstrate acid fast bacilli on histological analysis. A mild reticular skin rash, which may be thickened and lichenoid, with or without slightly deranged liver function tests may be seen in maternofoetal graft versus host disease. As SCID infants lack functional T cells, they cannot reject foreign lymphocytes acquired from the mother in utero, and so the skin is infiltrated by abnormal maternal T lymphocyte clones . A similar clinical picture may occur in patients who have received an unirradiated blood transfusion, due to viable donor lymphocytes in the red cell donation, although in these cases, the rash is more severe and lymphadenopathy and hepatosplenomegaly may be present.
Examination usually reveals a wasted child who has dropped through the weight centiles—head circumference is usually preserved. There may be abdominal distension and muscle wasting due to malabsorption and malnutrition. Respiratory signs may include tachypnoea, nasal flaring, subcostal and intercostal recession, with widespread crepitations and rales, and cyanosis. There may be evidence of oral or perineal candidiasis and other superficial infections. There is no clinically detectable lymphoid tissue, although detecting this in young infants is not easy because lymph nodes and tonsils in normal infants are often very small. There may be hepatomegaly, with or without splenomegaly, particularly when disseminated Bacille Calmette–Guerin (BCG) infection is present. Rare presentations include Hodgkin-like polymorphous lymphoproliferative disorder, with rapidly growing extranodal tumours . Very rarely, erythrophagocytosis has been described, in association with maternal T lymphocyte engraftment.
Patients may present with atypical forms of SCID or Omenn syndrome. Previously described as profound combined immunodeficiency, these patients usually survive beyond 12 months of age. Increasingly, hypomorphic mutations in genes normally associated with classical SCID are identified, thus retaining some protein function. Alternative mechanisms of demonstrating partial immunity include spontaneous gene reversion in early lymphoid progenitors [52, 59, 60, 74]. Such patients present with severe, prolonged infection, which may slowly resolve. Partial antibody responses can be demonstrated to restricted antigens. Other presentations include autoimmune manifestations, particularly with autoimmune cytopenias, and EBV-driven lymphoproliferative tumours. Rarely, cutaneous granulomatous lesions have been described [16, 19, 30, 32, 55]. It is important to consider atypical SCID presentations in children presenting beyond the first year of life so that appropriate antimicrobial treatment can be commenced and the patient considered for curative therapy (vide infra).
Other forms of SCID
In addition to SCID caused by developmental defects, SCID can also be caused by mutations affecting lymphocyte survival, as seen in patients with reticular dysgenesis due to mutations in AK2  and in the enzyme deficiencies ADA and purine nucleoside phosphorylase (PNP), involved in nucleotide metabolism and salvage [3, 12]. As a result of the deficiency, toxic metabolites are formed, to which lymphocytes are exquisitely sensitive. Consequently, ADA and PNP deficiencies usually lead to profound lymphopenia . Finally, several deficiencies have been described that can give rise to a clinical phenotype of SCID, but only affect a subset of T cells, e.g. MHC class II deficiency, ZAP 70 kinase deficiency  ( #1755). Additionally, defects in CD154 (CD40 ligand) and CD40 may present in infancy with P. jiroveci pneumonia. These types of SCID will not be further discussed in this review.
Stepwise diagnostics for SCID
Flow cytometric immunophenotyping of peripheral blood
Interpretation of results is more complicated in Omenn syndrome or atypical SCID. These patients present with high numbers of oligoclonal T cells , the presence of which may be misleading, and so detailed analysis of T cells in patients clinically suspected for typical or atypical SCID is of utmost importance .
Gene defects and disease mechanisms in T−B+ SCID
T−B+ SCID is caused by mutations in cytokine-mediated signalling. The majority of patients have X-linked SCID caused by mutations in the IL2RG gene encoding the common γ chain (γc). The γc chain is shared by the IL2, IL4, IL7, IL9, IL15 and IL21 cytokine receptors . Cytokines mediate oligomerization of the γc chain with the appropriate cytokine receptor chain, which leads to Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3) activation and phosphorylation of critical tyrosine residues in the receptor chains (Fig. 4) [23, 36]. JAK1 and JAK3 phosphorylate each other and phosphorylate STAT5. Upon phosphorylation, STAT5 dimerizes and translocates to the nucleus where it activates multiple genes . Autosomal recessive forms of T−B+ SCID are less frequent and have been shown to be caused by mutations in the JAK3 or IL7RA genes [38, 50]. Mutations in the IL7RA gene abrogate T cell development, but do not interfere with NK cell development.
Gene defects and disease mechanisms in T−B− SCID
Detailed analysis of T cells potentially present in patients suspected for having typical or atypical SCID
There are several reasons for the presence of T cells in SCID patients. First, T cells can be engrafted transplacentally from the mother. In 50% of B− SCID and in 80% of B+ SCID, maternal T cells can be detected . These T cells can be present at low frequencies, but can also exceed the upper limit of reference. The immunophenotype of these T cells can be diverse. Most have a mature (CD45RO+) phenotype, but this cannot be regarded as a golden rule. They may have a disturbed CD4/CD8 ratio or aberrant CD3 expression (van der Burg, unpublished observation). To prove that T cells are maternal, they can be analysed by human leukocyte antigen (HLA) typing or the origin determined by XY FISH in case of boys, or short tandem repeat analysis can be performed [41, 68].
Patients with Omenn syndrome have hypomorphic mutations resulting in the presence of T cells that expanded in the periphery . These T cells are autologous and generally oligoclonal. The clonality of the T cells can be determined by flow cytometry, e.g. by using a Vβ analysis kit . Molecular clonality assays by heteroduplex analysis or spectratyping are alternative methods which reliably determine whether the T cells present are oligoclonal, polyclonal or oligoclonal in a polyclonal background [34, 35]. The latter would be predominantly due to infections.
A much rarer explanation for the presence of autologous T cells in SCID patients is the occurrence of somatic reversion mutations . These reversion mutations have been described in a few X-linked SCID cases, in a single RAG deficiency and in patients with a CD3Z deficiency [52, 59, 60, 74]. In these patients, somatic reversion mutation occurred, probably in early T cells, and corrected the genetic defect. If somatic reversion occurs, the T cells have a selective growth advantage and the potential to develop normal function. The mechanism by which this somatic reversion arises is as yet unknown.
T cells in patients with suspected typical or atypical SCID should always be typed in detail. Analysis of TCR expression can be particularly helpful. In some patients with a partial V(D)J recombination defect, a high frequency of TCRγδ T cells is detected .
Analysis of protein expression of candidate genes
In T−B+ SCID, analysis of CD132 expression on lymphocytes and measurement of STAT5 phosphorylation upon IL2 stimulations and informative screening tests are advanced [25, 75]. If CD132 expression is absent, this is indicative of X-linked SCID, and in virtually all cases without CD132 expression, a mutation is found in the IL2RG gene. The same holds true for the analysis of IL7RA expression. This is somewhat more complicated because IL7Rα is mainly expressed on T cells, which are typically absent in these patients. Aberrant results in STAT5 phosphorylation  point toward defects downstream of the γc chain, and if aberrant, sequence analysis of JAK3 is a logical choice for molecular analysis.
Flow cytometric analysis of precursor B cell compartment in bone marrow
In the case of T−B− SCID, analysis of the precursor B cell compartment in bone marrow can give information whether or not there is an underlying defect in the V(D)J recombination process. A typical SCID patient with a V(D)J recombination defect due to mutations in RAG1, RAG2, Artemis or DNA–PKcs has a full block in precursor B cell differentiation before the cytoplasmic Igμ-positive pre-B-II cell stage (Fig. 3b) [44, 45, 64]. In a hypomorphic mutation, the differentiation block can be incomplete, implying that low frequencies of pre-B-II can be present. Alternatively, an incomplete precursor B cell differentiation block can be due to the type of gene defect. LIG4 and XLF deficiencies give rise to the presence of pre-B-II and immature B cells and even mature B cells in XLF deficiency [30, 65].
Sequence analysis of candidate genes
Infants suspected of having a severe immunodeficiency disorder should be placed in protected isolation, limiting the numbers of persons involved with care; specifically, individuals with respiratory or gastrointestinal symptoms of infection should avoid contact. If the mother is cytomegalovirus (CMV)-negative, breastfeeding should be encouraged—otherwise, it should be discontinued to prevent neonatal CMV infection from being transmitted through breast milk. Strict handwashing procedures are critical to prevent infection. Blood products should be CMV-negative and irradiated to avoid the risk of transfusion GVHD . Appropriate imaging of chest, abdominal organs and brain should be considered, guided by the clinical features. For those diagnosed later, particular attention needs to be paid to nutritional status and the management of dietary intolerances secondary to infectious or inflammatory gastrointestinal problems. Advice from paediatric gastroenterologists should be sought early, to minimise the impact of the disease on the gut and to institute modular formula milk feeds or parenteral nutrition as appropriate. Respiratory paediatricians should be consulted early to maximise supportive therapy and prevent further lung damage. Imaging to detect focal infiltration is important and may guide subsequent biopsy. Infection should be sought aggressively, and biopsy material may be required to demonstrate infection. Culture of appropriate tissue specimens, including bronchoalveolar lavage fluid, and PCR may be needed to identify infecting pathogens—serology is generally unhelpful. Infections should be vigorously treated—broad spectrum multi-agent antimicrobial therapy may be required. Co-trimoxazole as prophylaxis against P. jiroveci should be given. Antifungal prophylaxis should also be used, and antiviral prophylaxis with aciclovir is used in patients with a previous herpes simplex infection. Supporting the emotional needs of the family is also very important.
Hematopoeitic stem cell transplantation (HSCT) is the treatment of choice for patients with SCID. If HSCT with conditioning chemotherapy is embarked upon, isolation in facilities with positive-pressure-filtered air supply is necessary, mainly to reduce the risk of aspergillosis and droplet-borne viral infections. European data regarding outcome of HSCT for SCID Patient data are collected in the Stem Cell Transplantation for Immunodeficiencies in Europe registry, giving data on almost 700 patients, and have recently been published . A broad repertoire of stem cell sources are used, including stem cells from marrow, mobilised peripheral blood stem cells or those harvested from umbilical cord blood. Best results are obtained using HLA-matched sibling donors, with survival of around 90% in the best circumstances. The molecular defect has a bearing on outcome, with B− SCID patients having an overall worse outcome than B+ forms of SCID . The outcome is better in the absence of infection, arguing for the early identification of patients through neonatal screening programmes . New chemotherapy conditioning regimens are increasingly utilised, with improved outcome. A successful procedure is generally curative, with patients leading normal lives off medication, but few long-term studies have demonstrated long-term sequelae for some patients [39, 58]. Particular problems relate to ongoing thymopoiesis, with failure leading to T lymphocyte senescence in the long term [7, 10]. Long-term immunoglobulin therapy is necessary for some B lymphocyte dysfunction or failure of donor engraftment. Chemotherapy may lead to infertility. Hypothyroidism, secondary to chemotherapy, affects about 10% of patients. Some sequelae relate to the specific genetic defect, for instance, human papillomavirus-associated warts in IL2RG/JAK3 SCID  and neurodevelopmental disorders in ADA deficiency .
For ADA deficiency, enzyme replacement therapy with polyethelyne-glycosylated ADA is an alternative treatment . Treatment is required lifelong, is expensive and results in only partial immune reconstitution. Sequalae include the development of autoimmunity, but in the short term, it may allow some immune reconstitution and clearance of infection before proceeding to definitive therapy.
Gene therapy has been used for ADA- and IL2RG-deficient SCID [1, 6, 11]. Advantages include removal of the necessity for chemotherapy conditioning and available treatment despite lack of a matched donor. Earlier ADA trials were only partially successful, and the majority of patients required ongoing PEG-ADA therapy. More recently, the procedure has been more successful, although low doses of chemotherapy give the best results . Some patients have an ongoing requirement for immunoglobulin replacement. XL-SCID gene therapy does not require chemotherapy and has led to complete immune reconstitution, but insertion of the retroviral vector close to oncogenes has led to the development of lymphoproliferation in some patients . Development of new, probably safer, vectors and directed insertion of the mutated gene away from oncogenes promise improved outcome, and clinical trials are ongoing . Treatment of other forms of SCID is at a pre-clinical phase.
SCID is one of the most severe forms of primary immunodeficiency and is a paediatric emergency, which is life-threatening if recognized too late. Therefore, early diagnosis and good clinical management are crucial. The clinical and immunological spectrum of SCID is broader than initially described, so (atypical) SCID should be considered as a potential diagnosis more often. Improved supportive care, detection of infection by molecular means and less toxic chemotherapy conditioning regimens have significantly improved survival, and patients should be referred urgently to centres specializing in the diagnosis and treatment of such patients to optimize outcome.
▪ SCID is one of the most severe forms of PID and is a life-threatening paediatric emergency.
▪ The molecular basis of most forms of SCID is now recognized.
▪ Early careful liaison with the immunology laboratory will enable the most appropriate investigations to be performed.
▪ Atypical, later presentation of patients with partial gene function is increasingly described.
▪ Atypical SCID should be considered in patients presenting with unusual, severe or recurrent infections.
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