INTRODUCTION — The T cell-negative, B cell-negative, natural killer cell-positive severe combined immunodeficiency (T-B-NK+ SCID) phenotype accounts for approximately one-quarter to one-half of all cases of SCID. Unless identified by newborn screening (NBS) or a positive family history, children with T-B-NK+ SCID present early in life with serious to life-threatening infections, failure to thrive, low to absent T and B cell numbers and function, and normal numbers and relatively normal function of NK cells.
This form of SCID can result from autosomal recessive defects in any of several genes that encode proteins involved in antigen receptor gene V(D)J recombination. The recombination process randomly combines variable, diversity, and joining gene segments that encode T cell receptor (TCR) and immunoglobulin genes in T and B cells, respectively. NK cells do not have rearranged antigen receptors and therefore develop relatively normally in patients with impaired V(D)J recombination. Some of the proteins encoded by genes involved in V(D)J recombination are also involved in deoxyribonucleic acid (DNA) repair in all cells of the body. Defects in these genes are associated with extra-immune phenotypes including increased sensitivity to ionizing radiation and alkylating chemotherapy and may also have growth and developmental abnormalities.
The pathogenesis, clinical manifestations, and diagnosis of T-B-NK+ SCID are reviewed here. The treatment of T-B-NK+ SCID is discussed separately. An overview of SCID and the different forms of SCID are also presented separately. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects" and "T-B-NK+ SCID: Management".)
EPIDEMIOLOGY — T-B-NK+ SCID accounts for approximately 20 percent of all cases of SCID in Western countries such as the United States, France, and Germany but up to 53 percent in some countries such as Morocco and Saudi Arabia, where consanguineous mating is common [1-4]. The overall estimated incidence of SCID in the United States is approximately 1:60,000 live births based upon data from universal newborn screening (NBS) in 10 states plus the Navajo Nation over a four-year period  and in California over seven years . In these studies, the X-linked form of SCID accounted for 19 to 29 percent of the identified cases, while the remainder comprised autosomal recessive forms of SCID. Based upon these data, it appears that the true incidence for autosomal recessive SCID is closer to 1:72,500, with significantly higher rates in certain founder populations. As an example, the estimated incidence of Athabascan SCID (SCID-A) in the Navajo and Apache Native American populations is approximately 1:2000 live births . (See "Severe combined immunodeficiency (SCID): An overview" and "Newborn screening for inborn errors of immunity".)
PATHOGENESIS — All known causes for T-B-NK+ SCID (table 1) involve defects in V(D)J recombination of antigen receptor genes in T and B cells (figure 1) [6-15] (see "Severe combined immunodeficiency (SCID): Specific defects", section on 'T-B-NK+ SCID'). V(D)J recombination is the process by which the immune system generates a vastly diverse repertoire of T and B cell receptors capable of recognizing a huge number of potential pathogens [16,17]. These receptors contain variable domains that represent the recognition portion of each specific receptor molecule. The biology underlying V(D)J recombination and T cell receptor (TCR) genetics are reviewed briefly here.
T cell receptor generation — There are two types of heterodimeric TCRs (see "Normal B and T lymphocyte development"):
●Alpha beta TCR – The majority (85 percent or more) of peripheral blood T cells bear this form of TCR, made up of an alpha and a beta chain (figure 2).
●Gamma delta TCR – The minority of circulating T cells bear a TCR made up of a gamma and a delta chain . However, gamma delta T cells may predominate in some tissues (eg, intestinal mucosa).
As with immunoglobulins, each TCR chain is encoded by multiple rearranging gene segments. The rearrangement process leads to diversification of the assembled genes, with each cell undergoing its own unique rearrangement events. The alpha locus, analogous to immunoglobulin light chains, contains three gene clusters: V (variable) alpha, J (joining) alpha, and C (constant) alpha (figure 3) . The TCR beta chain is encoded by four gene segments (V, J, and C, as above, plus D [diversity]), similar to the immunoglobulin heavy chain (figure 4) [19,20]. TCR gamma genes, like TCR alpha genes, are composed of three rearranging segments (figure 5) . Delta chains are made up of four gene segments (figure 6) . (See "Structure of immunoglobulins".)
The orderly progression of TCR gene segment rearrangement is regulated in a complex manner by chromatin structure determining accessibility to gene segments and signal sequences, as well as a variety of promoters, enhancers, and other associated DNA sequences that recruit a variety of transcription and binding factors [21,22].
TCR genes rearrange via the same mechanisms and according to the same rules as immunoglobulin genes [19,21] (see "Immunoglobulin genetics"). However, the organization and rearrangement of immunoglobulin and TCR genes also have important differences:
●TCR gene loci tend to have fewer V region segments and a greater number of J segments.
●Junctional diversity with the addition of N regions at gene segment junctions and with utilization of D genes in multiple reading frames plays a greater role in generating diversity in the TCR repertoire.
●TCR genes do not undergo somatic hypermutation following initial rearrangement in the thymus. Expressed TCR genes are stable during T cell development and subsequent mature T cell clonal expansion in the periphery.
TCR gene rearrangement does not occur prior to entry of T cell progenitors from bone marrow into the thymus. The gamma and delta genes are the first to be recombined and expressed during fetal thymic T cell development. The beta genes are next expressed in the fetus. The alpha genes are expressed last. Subsequently, T cells bearing the alpha-beta and gamma-delta TCRs develop contemporaneously. T cells expressing alpha beta do not express gamma delta and vice versa. (See "Normal B and T lymphocyte development".)
The mechanisms of gene rearrangement ultimately yield a large repertoire of distinct TCR specificities. The predominant population of T cells in the human periphery, cells expressing alpha-beta TCRs, contains approximately 107 to 108 different molecular species of TCR . These include cells having low affinity for their targets as well as cells with high affinity. The affinity of the TCR for its peptide-major histocompatibility complex (MHC) target determines the consequences of interaction: activation, anergy, memory cell formation, etc . The determinants of what constitutes an adequate repertoire for effective antimicrobial immunity have not yet been characterized. (See "The adaptive cellular immune response: T cells and cytokines".)
Immunoglobulin generation — Membrane-bound immunoglobulin molecules, Igalpha and Igbeta, in association with signal transducing molecules, serve as receptors for antigen on the surface of B cells (BCRs). Immunoglobulin gene organization and rearrangement is similar to that for the TCR. An immunoglobulin light chain gene is assembled from three types of gene segments, the light chain variable region (VL), joining region (JL), and constant region (CL) (figure 7). The immunoglobulin heavy chain is made up of four types of gene segments: the variable (VH), joining (JH), and constant (CH) regions and another type of gene segment called D (diversity) (figure 8). Immunoglobulin gene rearrangement is regulated by complex interactions between special DNA sequences, DNA-binding factors, and DNA-modifying enzymes. Immunoglobulin receptor diversity is accomplished through several mechanisms. The genetics and structure of immunoglobulins are reviewed in greater detail separately. (See "Immunoglobulin genetics" and "Structure of immunoglobulins".)
Recombination mechanisms — The coding regions of DNA for the variable domains of TCR and BCR genes are assembled during the early stages of T and B cell maturation. This process involves site-specific DNA rearrangement to select one of each of a large tandem array of alternate variable (V), diversity (D), and joining (J) segments of DNA, although it is known that proximal sites of the TCR and BCR gene segments are used for recombination more frequently than distal ones .
For every specific antigen receptor, there is a V and J gene segment and sometimes a D gene segment that are randomly selected and ligated together via a process called V(D)J recombination. Highly conserved sequences of DNA, termed recombination signal sequences (RSSs), flank all V, D, and J coding regions and facilitate this process. The RSS consists of a highly conserved heptamer motif and a conserved nonamer sequence separated by poorly conserved spacer sequences of 12 or 23 nucleotides. The IgH and J fragments use the 23-bp spacer while the D fragment has a 12-bp spacer. Efficient recombination only occurs between RSSs with different space lengths such that D can combine with J and V while V cannot combine with J. Thus, D-J recombines first, followed by V-DJ.
In the initial step of V(D)J rearrangement, remodeling of the local chromatin structure brings the gene segments together into a complex (figure 9). This is followed by the generation of precise DNA double-strand breaks (DSBs) at RSSs. These resulting signal ends (SEs) are rejoined into what is termed a signal joint (SJ), while the coding ends (CEs) are rejoined into a coding joint (CJ) (figure 10). The excised SJ fragments of DNA form what are called T cell receptor excision circles (TRECs), which are an indicator of T cell production in the thymus. Similarly, generation of diverse BCR light chains results in kappa-deleting recombination excision circles (KRECs). Neither TRECs nor KRECs can replicate in the cell, but they are stable and are found in peripheral blood of healthy infants. The absence of TRECs in newborn dried blood spots is used for newborn screening (NBS) for SCID, and measurement of KRECs may also identify infants with absent B cells. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects' and "Newborn screening for inborn errors of immunity", section on 'Screening for B cell defects'.)
RAG complex (initiation of recombination) — V(D)J recombination is initiated by the recombination-activating gene complex (RAG1/2) (figure 9) . The RAG1 and RAG2 proteins recognize RSSs that flank the V, D, and J segments in developing T and B cells, forming a stable protein-DNA complex termed the stable cleavage complex (SCC) that introduces DNA DSBs by a coordinated cleavage reaction. Cleavage at the SCC sites leaves a blunt SE and covalently sealed hairpin CE.
RAG proteins are expressed in all lymphoid progenitors as well as immature T and B cells. Thus, careful regulation is necessary to restrict access of RAG proteins to only specific recombination substrates . For B cell development, the IgH locus is rearranged at the pro-B cell stage prior to recombination of Ig kappa and Ig lambda genes in pre-B cells. For T cells, TCR-beta genes are rearranged in double-negative pro-T cells, while TCR-alpha genes are rearranged in double-positive T cells in the thymus. The lineage specificity and ordering of rearrangements are caused by sequential opening of local chromatin regions that permit specific RSSs access to the V(D)J recombinase. This is controlled by many processes including subnuclear relocation, DNA demethylation, chromatin remodeling, histone modification, intergenic antisense ribonucleic acid (RNA) expression, and germline transcription. When recombination is prevented by the absence of any number of essential proteins including RAG1 or RAG2, pro-B and pro-T cells fail to mature, resulting in the T-B-NK+ SCID immunophenotype.
Nonhomologous DNA end joining (recombination and DNA repair) — The rejoining of both CEs is accomplished by a process that is also involved in DNA DSB repair [26,27]. The pathway of repair of these DSBs in eukaryotic organisms is called nonhomologous DNA end joining (NHEJ) (figure 10). NHEJ requires the modification of the two broken ends of DNA so that they are compatible with each other prior to rejoining. DNA-dependent protein kinase catalytic subunit (DNA-PKcs); the endonuclease Artemis; the Ku heterodimer (Ku70 and Ku80); the x-ray cross-complementing group 4 (XRCC4); DNA ligase IV; Cernunnos/XRCC4-like factor (XLF); and nibrin are essential factors involved in V(D)J recombination/DNA repair [28-32].
There are two levels of V(D)J recombination required to generate an effective and efficient diverse immune repertoire. The first is the diverse rearrangement of V, D and J genes. The second involves the joining mechanism of the coding segments in which there is a loss or addition of extra nucleotides. This is accomplished, in part, by the terminal deoxynucleotidyl transferase, which adds random nucleotides at the V-D and D-J junctions, significantly adding to the diversity of the immune repertoire . Only recombinant TCR genes with in-frame rearrangements can generate mature TCR molecules. As a result, only one-in-three recombinants with integer numbers of 3-nucleotide codons are "productive."
Ku proteins — Ku70/80 is thought to be the first complex to attach to the double-stranded break . The Ku proteins constitute the major DNA end-binding activity in nuclear extracts from mammalian cells. There is a Ku:DNA complex at each end of the two DNA ends being joined, which protects the DNA ends from digestion . The complex recruits DNA-PKcs and Artemis, generating a DNA protein kinase by stimulating DNA-PKcs. Ku also functions in stabilizing broken DNA ends and bringing them together, as well as recruiting other components (terminal deoxytransferase [TdT] and the DNA ligase IV/XRCC4 complex) to the DNA ends to facilitate end joining [16,34].
DNA-PKcs — DNA-dependent protein kinase catalytic subunit (DNA-PKcs) alone possesses certain DNA-binding and kinase activities and is associated with the NHEJ process of DNA repair. However, DNA-PKcs requires the involvement of Ku proteins to recruit it and Artemis to DNA ends and stabilize its binding so that it is efficiently activated. DNA-PKcs undergoes autophosphorylation and activates Artemis, which then acquires 5' and 3' endonuclease activity and hairpin opening activity [34,36]. DNA-PKcs also aids in recruitment of a ligation complex including LigIV, XRCC4, and XLF. PAXX, a protein that is structurally similar to XRCC4 and XLF, helps in DSB repair through its interaction with Ku .
Artemis — Artemis is encoded by the DNA cross-link repair protein 1C gene (DCLRE1C) . The Artemis nuclease activity ensures that the two DNA ends are compatible by resecting end groups that are damaged or cannot be ligated. Artemis is required for the maintenance of a normal DNA damage-induced cell cycle arrest . The radiosensitivity and chromosomal instability seen in Artemis-deficient cells may be due to defects in cell cycle responses after DNA damage. In addition, Artemis is essential for CJ formation [8,40]. Finally, Artemis is involved in the later stages of class switch recombination (CSR) by resolution of the intermediate switch region complexes that are generated during CSR [41,42]. (See 'Radiation-sensitive SCID due to DNA repair defects' below and 'Athabascan (SCID-A) phenotype' below.)
XRCC4 and DNA ligase IV — DNA ligase IV couples with x-ray cross-complementing group 4 (XRCC4) to execute the final ligation of SJ and CJ ends . XRCC4 has no known enzymatic activity but functions as a scaffolding protein that helps attract other repair proteins to the DNA break. XRCC4 stabilizes DNA ligase IV and enhances its activity . DNA ligase IV is capable of ligating one DNA strand at a time. The targeted deletion in mice of either XRCC4 or LIG4 (the DNA ligase IV gene) leads to a pleiotropic phenotype including late embryonic lethality, severely impaired lymphocyte development, and massive apoptosis of newly generated neurons .
Cernunnos/XLF — Cernunnos/XRCC4-like factor (XLF) protein plays a critical role in V(D)J recombination/DNA repair [46,47]. It enhances the DNA ligation activity of the XRCC4/DNA ligase IV complex by promoting its readenylation. This protein appears to play an essential role in gap filling that is required prior to ligation in the process of DNA DSB repair via the NHEJ pathway . XRCC4 and XLF interact to form long, helical protein filaments that protect and align the DSB ends without requiring long complementary DNA ends.
Nibrin — Nibrin is part of the meiotic recombination 11 (MRE11) complex, which has a role in the end-processing step in NHEJ along with Artemis and several other proteins described above. Nibrin is encoded by the Nijmegen breakage syndrome 1 (NBS1) gene. Defects in this gene result in a combined immunodeficiency called Nijmegen breakage syndrome . Absence of nibrin in T cell precursors results in premature T cell development due to abnormal TCR beta coding and SJs . (See "Nijmegen breakage syndrome".)
Genetic defects and radiation sensitivity — The two principal types of T-B-NK+ SCID associated with V(D)J recombination are those with and without radiation/chemotherapy sensitivity. The type depends upon whether the defective gene is involved in both V(D)J recombination and DNA repair or recombination alone. All forms of T-B-NK+ SCID are autosomal recessive. (See 'Pathogenesis' above and 'Recombination mechanisms' above.)
T-B-NK+ SCID without radiation sensitivity due to RAG defects (includes most cases of Omenn syndrome) — Severe pathogenic variants in recombination activating gene 1 or 2 (RAG1 or RAG2) result in T-B-NK+ SCID without radiation/chemotherapy sensitivity [6,7,50]. This is expected since RAG1 and RAG2 are only involved in V(D)J recombination but not DNA repair. Certain RAG hypomorphic pathogenic variants result in partial protein expression and limited production of T and B cells with fairly distinct clinical manifestations known as Omenn syndrome [51,52]. (See 'RAG complex (initiation of recombination)' above.)
Omenn syndrome is usually a T-B-NK+ SCID, although it is a "leaky" SCID with production of nonfunctioning T and B cells and therefore may appear to be T+B+NK+ SCID or a milder combined immunodeficiency . Some hypomorphic pathogenic variants of other SCID genes, including those encoding Artemis, the interleukin 2 common gamma chain receptor (IL2RG), DNA ligase IV, and interleukin 7 receptor alpha (IL7R-alpha) proteins, can also result in a clinical and immunologic phenotype that is indistinguishable from RAG-related Omenn syndrome [53,54]. (See 'Clinical variants' below.)
The majority of patients with Omenn syndrome have one nonfunctional RAG allele and a second, poorly functioning allele or are homozygous for a poorly functional allele [50,55]. These hypomorphic pathogenic variants in either RAG1 or RAG2 preserve some ability to accomplish V(D)J recombination. In a study of RAG1/2 variants, the amount of recombinase activity correlated with diversity of the TCR and BCR repertoire (the TCR repertoire is very restricted in most patients) . The residual RAG activity allows for production of oligoclonal T cells that are poorly regulated and cause adenopathy, infiltrative erythroderma skin rash, and eosinophilia. Later-onset phenotypes are seen when more RAG function is preserved, including those with autoimmune phenomena and T cell granulomatous skin lesions , common variable immunodeficiency , and even lupus erythematosus and autoimmune blood cytopenias such as autoimmune hemolytic anemia and thrombocytopenia [56,58].
The unique clinical features of Omenn syndrome appear to be a result of activated T cells with a limited repertoire and dysregulated B cells  suggestive of graft-versus-host disease (GVHD), although skin histology is not consistent with GVHD and there is no evidence of maternal engraftment [60,61]. (See 'Clinical variants' below.)
There are several families with hypomorphic RAG pathogenic variants in which one child had Omenn syndrome, while a sibling had typical SCID with a T-B-NK+ phenotype . Molecular analysis of RAG1 and RAG2 in these children revealed identical pathogenic variants, illustrating phenotypic diversity known as variable expressivity . These results suggest that the theory of a "leaky" defect  caused by a partially functioning RAG protein cannot completely explain the Omenn syndrome phenotype. (See 'Omenn syndrome phenotype' below.)
Radiation-sensitive SCID due to DNA repair defects — The other type of T-B-NK+ SCID is radiation-sensitive SCID (RS-SCID). A single founder pathogenic variant in the Artemis gene, DCLRE1C, causes Athabascan SCID (SCID-A), found in Athabascan-speaking Apache and Navajo Native Americans [38,40,63-70]. However, it should not be assumed that a Native American child with suspected SCID has SCID-A, since Navajo and Apache children are susceptible to other types of SCID including RAG1 SCID, IL-7R-alpha-deficient SCID, and X-linked SCID [71,72]. Patients from other populations have also been identified with DCLRE1C pathogenic variants and RS-SCID (called Artemis-deficient SCID [ART-SCID]) [3,73]. Other causes of RS-SCID include abnormalities of PRKDC (the gene that codes for DNA-dependent protein kinase catalytic subunit [DNA-PKcs]), the DNA ligase IV gene (LIG4), and the nonhomologous end-joining factor 1 (NHEJ1) gene (encodes Cernunnos/XRCC4-like factor [XLF]) [9,15,46,74-77]. (See 'Nonhomologous DNA end joining (recombination and DNA repair)' above and 'Athabascan (SCID-A) phenotype' below and 'Other radiation-sensitive SCID' below.)
Hypomorphic pathogenic variants in genes for LIG4, DNA-PKcs (PRKDC), Cernunnos/XLF (NHEJ1), and nibrin (NBS1) result in a combined T and B cell immunodeficiency phenotype (CID) in which the clinical phenotype is less severe than typical SCID and can present as marrow failure without a significant infectious history [13,15,32,46,53,75,76,78,79]. Fibroblasts from patients with these conditions have increased sensitivity to radiation, suggesting an associated defect in DNA repair. Some PRKDC pathogenic variants result in DNA-PKcs that is still expressed but is defective in recruiting Artemis to the site of DNA damage [13,78].
Overview — In general, children with T-B-NK+ SCID present early in life with features typical of all children with SCID, including serious infections and failure to thrive, unless they are identified by newborn screening (NBS) before the onset of these complications. In addition, many of the specific defects are accompanied by unique clinical features. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations'.)
Clinical variants — Children with Omenn syndrome and Athabascan-speaking Navajo and Apache Indian children with Athabascan SCID (SCID-A) have unique clinical variants.
Omenn syndrome phenotype — Children with Omenn syndrome generally have early onset (less than three months old) diffuse, exudative erythroderma; lymphadenopathy; hepatosplenomegaly; chronic persistent diarrhea; and failure to thrive [80,81].
RAG1 and RAG2 are located in close proximity to each other and two genes associated with aniridia, paired box gene 6 (PAX6) and Wilms tumor 1 gene (WT1) . One case was reported of a child who presented with aniridia in association with the Omenn syndrome phenotype due to a point mutation in one RAG1 allele with a contiguous gene deletion of RAG2, RAG1, WT1, and PAX6 genes on the other allele . Omenn syndrome was also seen in a patient with reticular dysgenesis due to an adenine kinase 2 (AK2) pathogenic variant and can be associated with hypomorphic or incomplete defects in numerous genes that, when completely knocked out, cause typical SCID .
Athabascan (SCID-A) phenotype — Another distinct clinical form of T-B-NK+ SCID is found in Athabascan-speaking Native Americans with SCID (SCID-A) who have Artemis-deficient SCID (ART-SCID) [64,84,85]. In the absence of NBS, SCID-A infants develop symptoms within three months of birth. Chronic diarrhea and failure to thrive occur in virtually all affected infants who are not diagnosed at birth or prenatally because of a positive family history or by NBS. (See 'Artemis' above and 'Radiation-sensitive SCID due to DNA repair defects' above and "Newborn screening for inborn errors of immunity".)
A unique clinical feature of SCID-A is the presence of Noma-like ulcers (picture 1A-B), which have not been reported in patients with ART-SCID from other populations [86,87]. In 18 patients with SCID-A that were followed at a single institution, 12 developed deep and painful ulcerative lesions of the oral mucosa and/or genitalia . Extensive studies of biopsy tissue and exhaustive culturing attempts failed to explain the etiology or pathogenesis of the lesions, although restoration of T cell immunity post-hematopoietic cell transplantation (HCT) was associated with complete resolution [84,86,87]. (See "T-B-NK+ SCID: Management", section on 'Outcomes'.)
Another unique feature seen in some patients with SCID-A is failure to develop secondary teeth, which is now understood to be related to their underlying radiation/alkylator sensitivity combined with pretransplant conditioning chemotherapy (and, in some instances, ionizing radiation) .
Other radiation-sensitive SCID — Patients with radiation-sensitive SCID (RS-SCID) other than ART-SCID (eg, defects in LIG4, NHEJ1 [also called Cernunnos], and PRKDC) often have clinical manifestations outside of the immune system, including microcephaly, developmental and growth delay, and dysmorphic facial features. They can also present with a marrow failure syndrome and share some features of Fanconi anemia [15,76,89-91].
Malignancy — There is a theoretical increased risk of malignancy for patients with defects that involve DNA repair. Increased incidence of malignancy has not been observed yet in children with the classic phenotype of ART-SCID , although Epstein-Barr virus (EBV) associated lymphoma was reported in two children with ART-SCID and pathogenic variants of the distal exon of DCLRE1C that left a partially functioning protein and the presence of B cells . Further long-term follow-up of posttransplant survivors is essential to determine if there is an increased risk of malignancy.
Characteristic findings — Characteristic laboratory findings in patients with T-B-NK+ SCID include [61,62] (see "Severe combined immunodeficiency (SCID): An overview", section on 'Laboratory abnormalities'):
●Lymphopenia (<1000/microL as detected by complete blood count and differential count)
●Low-to-absent T cells (<300/microL) with low-to-absent proliferative responses to mitogens and alloantigens (<10 percent the lower end of the of normal range for the laboratory)
●Absent B cells (<50/microL) with absent immunoglobulin M (IgM) isohemagglutinin titers (<1:8) and no response to immunizations
●Normal number and function of NK cells (at least 100 to 200/microL)
●Absent or very low T cell receptor excision circles (TRECs), as performed in newborn screening (NBS) for SCID
Additional features — However, not all affected patients display these findings, and other patients have additional features:
●Some patients have maternal chimerism, in which maternal T cells are found in the infant. These maternal cells generally have a memory phenotype (bearing the marker CD45RO+), in contrast to the naïve (CD45RA+) T cells seen in a newborn, and impaired proliferation to mitogens such as phytohemagglutinin (PHA).
●Patients with Omenn syndrome have elevated immunoglobulin E (IgE) levels and hypereosinophilia (500 to 10,000/microL) [61,80,81,93]. In addition, they have low-to-normal (or even elevated) autologous T cell numbers with oligoclonal T cells (more than 80 percent of their CD4+ cells are CD45RO+ memory T cells). These cells are host in origin, lack the normal diverse T cell repertoire , have poor-to-absent proliferation to antigens in vitro, and have low-to-no antibody responses to immunizations [55,61,62]. The finding of activated T cells with increased production of interleukin (IL) 4, IL-5, and IL-10 may explain, at least in part, some of the clinical and laboratory manifestations of this syndrome . Patients with Omenn syndrome do not have maternal chimerism.
Defects in peripheral and central tolerance may explain some of the autoimmune features of Omenn syndrome. Regulatory T cells fail to suppress proliferation of CD4+ responder T cells . Expression of autoimmune regulator (AIRE) protein is decreased, leading to reduced elimination of autoreactive T cells . Finally, autoantibodies and elevated B cell-activating factor (BAFF) levels have been found in patients with Omenn syndrome and "leaky" SCID, suggesting that the generation of an autoreactive B cell repertoire associated with defective central and peripheral checkpoints of B cell tolerance is also important in the pathogenesis of this disorder .
●Lymphopenia with a median absolute lymphocyte count of 500/microL (range 40 to 1400) is present in all patients with Athabascan SCID (SCID-A), including those with maternal engraftment . In children with SCID-A without maternal engraftment, the absolute number of CD3+ T cells and CD19+ B cells is very low (12±9/microL and 5±4/microL, respectively). Approximately 20 percent of patients with SCID-A have evidence of maternal engraftment at diagnosis, which is associated with graft-versus-host disease (GVHD) in some cases.
●Patients with radiation-sensitive SCID (RS-SCID) other than Artemis-deficient SCID (ART-SCID) may also have aspects of marrow failure including thrombocytopenia, anemia, and/or neutropenia, in some cases without a history of infections or a SCID phenotype . T cells are absent, except for memory T cells, in patients with defects in the NHEJ1 gene that codes for the protein Cernunnos, also named XRCC4-like factor (XLF) . In addition, these patients have a progressive loss of B cells. Finally, these patients often have microcephaly and dysmorphic features noted at birth and may have growth retardation and short stature.
Initial approach to diagnosis — The majority of children with T-B-NK+ SCID who are not identified by newborn screening (NBS) present with signs and symptoms typical of all children with SCID (ie, failure to thrive, chronic mucocutaneous fungal infections, and/or opportunistic infections). However, SCID is increasingly detected in presymptomatic infants by NBS in regions and countries that perform this screening. The diagnosis of T-B-NK+ SCID can be made if the child with a consistent history and/or positive NBS test has laboratory manifestations with a lymphocyte phenotype that is characteristic plus demonstrated impaired proliferation to the mitogen phytohemagglutinin (PHA), with the specific genetic etiology to be determined by mutation analysis. The general diagnosis of SCID is reviewed in detail separately. Establishing the specific molecular diagnosis is reviewed here. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Diagnosis' and "Newborn screening for inborn errors of immunity".)
A skin biopsy to establish a fibroblast cell line for radiation sensitivity testing should be initiated as soon as the T-B-NK+ SCID phenotype is identified and while genetic testing is ongoing since establishing the cell line and performing the assay can take several weeks. Delays that result in later diagnosis and transplantation can lead to poorer survival outcomes. (See 'Evaluation for radiation sensitivity' below.)
Children with an atypical phenotype who have eczematous rashes, particularly of the scalp, may have Omenn syndrome. Those with deep ulcerative lesions in the mouth or perianal or genital area may have Artemis-deficient SCID (ART-SCID). In addition, those with growth retardation, neurocognitive impairment, dysmorphic features, thrombocytopenia/anemia/neutropenia, and/or microcephaly may have DNA-dependent protein kinase catalytic subunit (DNA-PKcs), DNA ligase IV, or Cernunnos/XRCC4-like factor (XLF) deficiency. (See 'Genetic defects and radiation sensitivity' above and 'Clinical variants' above and 'Additional features' above.)
If the lymphocyte phenotype is not characteristic of T-B-NK+ SCID (ie, T and/or B cells are present, but lymphocyte proliferative tests and antibody responses, providing the patient has not been started on immune globulin replacement therapy and is at least two months old, are low to absent), then the T cell receptor (TCR) repertoire should be evaluated, looking for skewing with oligoclonal bands. These patients should also be evaluated for maternal engraftment. Children with Omenn syndrome (in particular, those with RAG1 or RAG2 defects) characteristically do not have detectable maternal T cell engraftment, while those with Artemis defects can have maternal engraftment. The "leaky" SCID phenotype (ie, T [low or +] B [low or +] NK+) is seen in a number of the defects associated with V(D)J recombination including RAG1, RAG2, DCLRE1C, LIG4, PRKDC, and nonhomologous end-joining factor 1 (NHEJ1), as well as other SCID genes (eg, IL7R, IL2RG, and AK2) [83,98]. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Detection of maternal T cell engraftment'.)
Genetic testing — The lymphocyte profile does not always correspond to genotype, and treatment options and transplantation protocols may require adjustment depending upon genotype. Thus, determining the specific etiology for T-B-NK+ SCID by mutation analysis of the RAG1, RAG2, DCLRE1C, LIG4, PRKDC, and NHEJ1 genes (table 1) is an important diagnostic step. Any patient with T-B-NK+ SCID who does not have pathogenic variants in one of these genes should be evaluated for adenosine deaminase (ADA) deficiency and other defects in other SCID genes, as the T, B, and NK profiles are not always predictive of genotype. Primary immunodeficiency gene panels that encompass all the known SCID genes are available through a number of companies. These full SCID panels are cost and time efficient and are covered by most third-party payors. A full gene panel is not necessary for initial genetic testing in a patient with a known family history of SCID (eg, sequence for IL2GR pathogenic variants if there is a family history of X-linked T-B-NK+ SCID) or if the patient is Apache or Navajo (sequence for the Athabascan DCLRE1C pathogenic variant).
If pathogenic variants cannot be found, next steps may include performing radiation sensitivity testing as well as whole exome or whole genome sequencing (WES/WGS). Not all SCID patients have clearly deleterious homozygous or compound heterozygous defects in a known SCID gene. WES/WGS may identify the underlying gene defect in patients whose pathogenic variants were not found by panel sequencing. (See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)
Evaluation for radiation sensitivity — Increased radiation sensitivity is of clinical importance because children with SCID who are undergoing preparation for allogeneic related or unrelated donor hematopoietic cell transplantation (HCT) are frequently treated with alkylating agents to increase the chance of engraftment [84,99-101]. The significantly increased morbidity and mortality in patients with the T-B-NK+ phenotype who are not RAG1 or RAG2 deficient is due to the inability to efficiently repair alkylator chemotherapy-induced double-strand breaks (DSBs).
A rapid test for chemotherapy and radiation sensitivity would be ideal in the evaluation of newly diagnosed children with SCID prior to conditioning for HCT, particularly in patients with "leaky" or nonnull mutations who may appear to have T+B+NK+ SCID or a milder immunodeficiency and therefore might not be suspected to have radiation sensitivity [53,79]. A flow cytometry-based assay for radiation sensitivity in T, B, and NK cells has been developed and may avoid the need for a skin biopsy, especially once it is validated for all of the DNA repair defects . Until then, the gold standard for assessing radiation sensitivity requires a fibroblast cell line from the patient. Once the fibroblast cell line is generated, the test is relatively straightforward and can detect patients with possible Artemis, DNA ligase IV, or other DNA-repair protein defects. However, it generally takes two to four weeks to obtain an adequate fibroblast culture, and the assay requires another one to two weeks.
For children with autosomal-recessive SCID and the T-B-NK+ phenotype, genotyping for RAG1, RAG2, LIG4, NHEJ1, and DCLRE1C pathogenic variants should be performed through commercial laboratories prior to any conditioning for HCT. Particular clinical features are associated with specific defects leading to radiation-sensitive SCID (RS-SCID) and can aid in the identification of children with the T-B-NK+ immunophenotype who are radiation sensitive in the absence of a rapid test.
Prenatal diagnosis — In families with prior affected individuals with SCID and documented gene defects, prenatal diagnosis for SCID due to RAG1, RAG2, or DCLRE1C pathogenic variants as well as other DNA repair genes is available, using either chorionic villous samples (at approximately 10 to 11 weeks gestation) or amniotic fluid fibroblasts (at 14 to 19 weeks gestation) . T-B-NK+ SCID can also be diagnosed in utero by lymphocyte phenotyping of fetal blood samples. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Preimplantation and prenatal diagnosis'.)
Newborn screening — NBS for SCID is reviewed in detail separately. (See "Newborn screening for inborn errors of immunity", section on 'Screening for SCID and other T cell defects'.)
DIFFERENTIAL DIAGNOSIS — Children with an atypical immune cell phenotype should be evaluated for all other etiologies of SCID, including adenosine deaminase (ADA) deficiency, purine nucleoside phosphorylase deficiency, and interleukin 7 receptor (IL-7R) alpha deficiency among others . Males should be evaluated for IL2RG defects regardless of the phenotype since some patients with X-linked SCID can have a "leaky" SCID T+B+NK+ phenotype. (See "Severe combined immunodeficiency (SCID): Specific defects" and "X-linked severe combined immunodeficiency (X-SCID)", section on 'Laboratory abnormalities'.)
The differential diagnosis of children with this presentation also includes neonatal human immunodeficiency virus (HIV) infection and Letterer-Siwe disease (histiocytosis). Polymerase chain reaction (PCR) testing for the HIV viral genome in the blood should be performed on all children undergoing evaluation for SCID. The skin rash and systemic illness seen with histiocytosis can mimic Omenn syndrome. Biopsy of the skin and the finding of characteristic granuloma should distinguish histiocytosis from leaky SCID/Omenn syndrome. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis" and "Diagnostic testing for HIV infection in infants and children younger than 18 months".)
The differential diagnosis of SCID is discussed in greater detail separately. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Differential diagnosis'.)
SUMMARY AND RECOMMENDATIONS
●Epidemiology and pathogenesis – T cell-negative, B cell-negative, natural killer cell-positive severe combined immunodeficiency (T-B-NK+ SCID) accounts for approximately 20 percent of all cases of SCID. All the known causes for T-B-NK+ SCID involve defects in V(D)J recombination that randomly combines variable, diverse, and joining gene segments in lymphocytes to generate a diverse repertoire of T and B cell receptors (TCRs and BCRs) capable of recognizing a huge number of potential pathogens. Defects in several of these genes are associated with radiation/chemotherapy sensitivity because some of the proteins encoded by these genes are also involved in deoxyribonucleic acid (DNA) repair. (See 'Epidemiology' above and 'Pathogenesis' above.)
●Types of T-B-NK+ SCID – The two principal types of T-B-NK+ SCID associated with V(D)J recombination defects are those with and without radiation/chemotherapy sensitivity (see 'Genetic defects and radiation sensitivity' above):
•Radiation-sensitive SCID (RS-SCID) includes Athabascan SCID (SCID-A), found in Athabascan-speaking Native Americans. RS-SCID is primarily due to DNA cross-link repair protein 1C (DCLRE1C) pathogenic variants but can also be seen in variants involving PRKDC (the gene that codes for DNA-dependent protein kinase catalytic subunit [DNA-PKcs]), the genes for DNA ligase IV (LIG4), nonhomologous end-joining factor 1 (NHEJ1), and Nijmegen breakage syndrome 1 (NBS1), all of which are essential for NHEJ DNA repair. (See 'Nonhomologous DNA end joining (recombination and DNA repair)' above.)
•Severe pathogenic variants in recombination-activating gene 1 or 2 (RAG1 or RAG2) result in T-B-NK+ SCID without radiation sensitivity. Hypomorphic pathogenic variants in RAG genes and in other SCID genes such as DCLRE1C, interleukin 2 receptor common gamma chain (IL2RG), interleukin 7 receptor-alpha (IL7RA), and adenine kinase 2 (AK2) result in partial protein expression and limited production of nonfunctioning T and B cells ("leaky" SCID). This leads to partial impairment of V(D)J recombination and distinct clinical manifestations with a spectrum of autoimmune and immunodeficiency disorders known as Omenn syndrome. (See 'RAG complex (initiation of recombination)' above.)
●Clinical features – Unless detected by newborn screening (NBS) prior to the development of symptoms, children with T-B-NK+ SCID present early in life with failure to thrive, chronic mucocutaneous fungal infections, and/or opportunistic infections. Several unique features are seen in children with Omenn syndrome and SCID-A. Children with Omenn syndrome generally have early onset (less than three months) of diffuse, exudative erythroderma; lymphadenopathy; hepatosplenomegaly; and chronic, persistent diarrhea. They also have elevated immunoglobulin E (IgE) levels and hypereosinophilia. A unique clinical feature seen in over half of patients with SCID-A is the presence of Noma-like ulcers, deep and painful ulcerative lesions of the oral mucosa or genitalia.(See 'Genetic defects and radiation sensitivity' above and 'Clinical variants' above and 'Additional features' above.)
●Laboratory findings – Characteristic laboratory manifestations include lymphopenia, hypogammaglobulinemia, absent B cells with absent isohemagglutinin titers and no response to immunizations, absent T cells with low-to-absent proliferative responses to mitogens and alloantigens, and normal number and function of NK cells. Some patients with defects in LIG4 or NHEJ1 may also present with thrombocytopenia, anemia, and/or neutropenia and have fewer T and B cell immune abnormalities. (See 'Laboratory findings' above.)
●Diagnosis – The diagnosis of T-B-NK+ SCID can be made in a child who presents with a positive NBS (abnormally low number of T cell receptor excision circles [TRECs]) or later with signs and symptoms typical of SCID) and who has the characteristic lymphocyte phenotype and laboratory findings. Additional studies may include examining the TCR repertoire for skewed oligoclonal bands, determining the number and percent of CD4+CD45RA+ T cells, and evaluating for maternal engraftment. The specific etiology is determined by gene sequencing, with radiation sensitivity testing as a backup when pathogenic disease-causing variants are not identified. Radiation sensitivity testing should begin as soon as possible when the T-B-NK+ phenotype is identified and while genotyping is underway since preparative regimens are modified for RS-SCID. (See 'Diagnosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
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