Combined immunodeficiencies: Specific defects

INTRODUCTION — The combined immunodeficiency (CID) defects reviewed here include monogenic inborn errors of immunity (IEI; primary immunodeficiency [PID]) associated with severe T cell quantitative or functional defects but without other syndromic or nonimmunologic features [1]. Many of them can be sorted mechanistically, including impaired T cell receptor (TCR) signaling, cytokine signaling, cellular immunity by disruption of actin rearrangement, or cellular immunity by disruption of regulation and activity of critical transcription factors.

Some of the more common disorders are described in dedicated topic reviews; others are described in this topic or, if only reported in a few patients, in the table (table 1). A separate topic gives a broad overview of the clinical presentation, diagnosis, and management of CID. (See "Combined immunodeficiencies: An overview".)

CID that are discussed in greater detail separately include:

●CD40 and CD40 ligand deficiencies (see "Hyperimmunoglobulin M syndromes")

●CD3 gamma-chain deficiency (see "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'CD3 deficiency')

●Serine threonine kinase 4 deficiency (see "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'STK4 deficiency')

●Interleukin (IL) 2-inducible T cell kinase (ITK) deficiency (see "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'ITK deficiency')

●Zeta chain-associated protein (ZAP) 70 deficiency (see "ZAP-70 deficiency")

●Major histocompatibility complex (MHC) class I and II deficiencies (see "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'MHC (HLA) class I deficiency' and "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'MHC (HLA) class II deficiency')

●Ras homolog gene family member H (RHOH) deficiency (see "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'RHOH deficiency')

●TCR alpha subunit constant (TRAC) deficiency (see "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'TRAC deficiency')

●Lymphocyte-specific protein-tyrosine kinase (p56lck) deficiency (see "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'Lck deficiency')

Syndromic immunodeficiencies are also reviewed separately. (See "Syndromic immunodeficiencies".)

DISORDERS OF T CELL RECEPTOR SIGNALING

CD8 deficiency — CD8 is a T cell receptor (TCR) accessory molecule that binds to class I major histocompatibility complex (MHC). CD8 is primarily expressed on cytotoxic T cells but is also found on natural killer (NK) cells. It plays an important role in the antigen-specific activation and function of cytotoxic T cells. (See "CD3/T cell receptor complex disorders causing immunodeficiency".)

CD8 deficiency due to a homozygous pathogenic variant in the gene for the CD8 alpha chain (CD8A) on chromosome 2p12 (MIM #608957) was reported in three offspring of consanguineous parents [2]. Only one of them, a 25-year-old male, was symptomatic. He had recurrent sinopulmonary infections beginning at approximately age five years, which suggested a humoral deficiency. However, his immunoglobulin levels and specific antibody titers were normal. CD4+ T cell, B cell, and NK cell percentages and absolute counts were normal, but CD8+ T cells were completely absent. He had two younger sisters who also had absent CD8+ T cells but were asymptomatic at the time of the report. Genetic defects were not described in these patients. CD8A pathogenic variants were identified in several additional patients with variable disease severity (recurrent respiratory tract infections with or without pulmonary parenchymal damage) [3,4]. The differential diagnosis for this phenotype is defects of the ZAP-70 kinase, MHC class I expression, or CD8. (See "ZAP-70 deficiency" and "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'MHC (HLA) class I deficiency'.)

There are no published data regarding therapy for these patients. Management is directed toward infectious complications and may include immune globulin replacement.

ICOS and ICOSL deficiency — The ICOS gene, located at chromosome 2q33.2, encodes inducible T cell costimulator, which is similar in structure to CD28 and cytotoxic T lymphocyte-associated 4 (CTLA4). As the name implies, this T cell surface marker is only expressed in activated T cells [5]. It is not constitutively expressed. It functions to induce interleukin (IL) 10 synthesis and also impacts follicular recruitment of activated CD4 cells, leading to germinal center defects when absent [6]. ICOS is important in the development of T helper type 1 (Th1), T helper type 2 (Th2), and T helper type 17 (Th17) based immunity [7,8]. ICOS ligand, encoded by the ICOSL gene on chromosome 21q22.3, is expressed on B cells and enhances germinal center interactions between follicular T cells and B cells. In the absence of ICOSL, the selection of high-affinity B cells within the germinal center is impaired.

Several case series of patients have been described [9,10]. Both ICOS and ICOSL deficiency are inherited in an autosomal recessive pattern. Patients develop clinical symptoms from infancy through adulthood. Patients with ICOS deficiency have demonstrated normal levels of T cells, B cells, and immunoglobulin levels but manifest with symptoms of recurrent infections, autoimmunity, gastroenteritis, and granulomas [1,10]. In contrast, patients with ICOSL deficiency have demonstrated lower T and B cells with lower immunoglobulin levels and clinically manifest with recurrent bacterial and viral infections, as well as neutropenia.

DISORDERS OF CYTOKINE SIGNALING

IL-21 and IL-21 receptor deficiencies

●Role of IL-21 – Interleukin (IL) 21 is a common gamma chain-related cytokine that signals primarily through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. This cytokine plays a critical role in immune cell development, differentiation, proliferation, function, and survival. Deficiencies of IL-21 or its receptor (IL-21R) cause an immunodeficiency similar to common variable immunodeficiency (CVID) [11-13]. (See "Common variable immunodeficiency in children" and "Pathogenesis of common variable immunodeficiency", section on 'Genetics'.)

●Clinical manifestations – Most patients with IL-21R deficiency (MIM #615207) present in early childhood with recurrent sinopulmonary and gastrointestinal infections with both common and opportunistic organisms [11,13-15]. The most notable of these is cryptosporidial infections associated with chronic cholangitis, biliary fibrosis, liver disease, and chronic diarrhea. Fungal infections, lymphoproliferation, inflammatory skin disease, and anaphylaxis have also been reported. Another presented with recurrent sinopulmonary infections (recurrent otitis media at two years of age, severe interstitial pneumonia with acute respiratory distress syndrome at five years of age, and then Pneumocystis jirovecii pneumonia [PJP] with bronchiectasis at six years of age) but no liver or gastrointestinal disease [16]. A patient with IL-21 deficiency (MIM #615767) had recurrent sinopulmonary infections and very-early-onset inflammatory bowel disease (VEO-IBD) with chronic nonbloody diarrhea, failure to thrive, and recurrent aphthous stomatitis [12]. The child's two siblings also had early-onset IBD and died in infancy. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Very early-onset inflammatory bowel disease'.)

●Laboratory findings – T, B, and natural killer (NK) cell numbers are normal in patients with IL-21R deficiency, but they have defects in B cell proliferation and immunoglobulin class switching, decreased T cell proliferation to recall antigens and cytokine production, and variable impairment of NK cell cytotoxicity [11,13]. Immunoglobulin E (IgE) levels are elevated, specific antibody responses to immunizations are reduced, and some patients have decreased immunoglobulin G (IgG) levels. Elevated IgE, decreased IgG, and reduced antibody responses to immunizations were also seen in the patient with IL-21 deficiency [12]. In addition, B cells were decreased, with a reduction in marginal zone and class-switch B cells but an increase in transitional B cells, and T cell proliferation was impaired.

●Treatment – Four of the seven patients with IL-21R deficiency in one report underwent hematopoietic cell transplantation (HCT), but three died due to complications [13]. The remaining patients were receiving immune globulin replacement therapy. Another patient with IL-21R deficiency underwent successful HCT after developing lymphoma [14]. One patient with IL-21 deficiency was receiving prophylactic antibiotics in addition to immune globulin replacement therapy and treatment for IBD [12]. Administration of recombinant IL-21 is a potential therapeutic option for this patient.

DISORDERS INVOLVING THE ACTIN CYTOSKELETON

DOCK2 deficiency

●Genetics – Dedicator of cytokinesis 2 (DOCK2) deficiency is due to biallelic (homozygous or compound heterozygous) pathogenic variants in DOCK2 on chromosome 5q35 (MIM #616533). DOCK2 deficiency was first identified through whole exome sequencing in five unrelated patients with early-onset invasive bacterial and viral infections, lymphopenia, and defective T, B, and natural killer (NK) cell responses [17]. The pathogenic variants included missense and nonsense point mutations, as well as insertions leading to frameshift and premature termination. Four siblings with leaky severe combined immunodeficiency (SCID) or Omenn syndrome due to a homozygous splice-site mutation in DOCK2 resulting in complete loss of DOCK2 expression were also identified [18]. (See "Combined immunodeficiencies: An overview", section on 'Genotypes and immunophenotype severity'.)

●Pathogenesis and laboratory findings – DOCK2 is expressed in peripheral blood leukocytes, as well as in the thymus, spleen, and liver. DOCK2 activates Ras-related C3 botulinum toxin substrate 1 (RAC1; a small GTP-binding protein), which is involved in actin polymerization and cell proliferation. DOCK2 deficiency results in impaired RAC1 activation, with defective actin polymerization and chemokine-mediated migration in T, B, and NK cells; impaired NK cell degranulation after stimulation; decreased circulating natural killer T (NKT) cells; diminished interferon (IFN) alpha, beta, and lambda production in peripheral blood mononuclear cells in response to viral infections; and enhanced levels of viral replication and virus-induced cell death in fibroblasts. Partial impairment of cytoskeletal rearrangement and production of reactive oxygen species is also seen, leading to symptoms of dysfunctional neutrophils that are also observed in affected patients [18]. Mitochondrial dysfunction in T cells contributes to T cell lymphopenia [19]. Elevated serum immunoglobulin M (IgM) was reported in one patient [20] and elevated IgE with slightly low IgM in another [21]. Reduced T cell receptor excision circle (TREC) levels at birth was documented in one patient [17].

●Clinical manifestations – Most patients presented in the first three to four months of life with recurrent viral and bacterial respiratory tract infections [17]. Other early findings included chronic or recurrent diarrhea and growth failure. Disseminated vaccine-strain varicella, local lesion at the site of Bacillus Calmette-Guérin (BCG) vaccination, oral moniliasis, and severe infections with Mycobacterium avium, human herpesvirus-6, mumps, parainfluenza virus type 3, adenovirus, cytomegalovirus (CMV), and Klebsiella pneumoniae were also reported. Additional documented clinical features included thrombocytopenia, hepatomegaly, colitis, and rectal fistula.

●Treatment, complications, and prognosis – Two of the initial identified patients died in early childhood. The other three patients underwent successful hematopoietic cell transplantation (HCT). In vitro studies showed normalization of fibroblast defects after treatment with IFN-alfa-2b or lentiviral-mediated expression of wild-type DOCK2. Another patient developed hemophagocytic lymphohistiocytosis (HLH) due to Epstein-Barr virus (EBV) infection after HCT [22].

DOCK8 deficiency

●Genetics – Over 200 patients have been identified with pathogenic variants in the dedicator of cytokinesis 8 (DOCK8) gene that is predominantly expressed in white blood cells [23-33]. Most of these mutations are loss-of-function (LOF) homozygous or compound heterozygous point mutations, although some deletions have been identified. DOCK8 deficiency (MIM #243700) was initially classified as type 2 hyperimmunoglobulin E syndrome (HIES) with autosomal recessive inheritance, although approximately 40 percent of patients do not have HIES [30]. (See "Autosomal dominant hyperimmunoglobulin E syndrome".)

●Pathogenesis – The susceptibility to cutaneous infections in patients with DOCK8 deficiency may be due to an inability of CD8 cells to effectively enter into the skin [34]. DOCK8 function is required for proper cytoskeletal organization, an integral part of leukocyte activation. As a result of impaired cytoskeletal function in DOCK8 deficiency, CD8 T cells (and NK cells) cannot migrate into tissues with dense collagen structure, such as the skin. Instead, they die by a particular form of apoptosis that has been named "cytothripsis" and cannot populate the skin with resident memory CD8 cells [34].

●Laboratory findings – Most patients have low absolute lymphocyte counts, with low T cells. B and NK cells are also low in many patients. NK cell function [35], CD8 T cell survival and function [36], peripheral B cell tolerance [37], and regulatory T (Treg) cell function are impaired. Most patients also have eosinophilia and elevated IgE. IgM levels are low, but many patients have increased IgG levels. IgG antibody responses to bacterial and viral antigens are variable.

●Clinical manifestations – Common clinical features include recurrent respiratory tract infections (otitis media, sinusitis, pneumonia), bronchiectasis, extensive cutaneous viral infections (herpes simplex virus, herpes zoster, molluscum contagiosum, human papillomavirus [HPV]), Staphylococcus aureus skin infections, mucocutaneous candidiasis, atopic disease (atopic dermatitis, severe food and environmental allergies, asthma), failure to thrive, chronic diarrhea, hepatic disorders (sclerosing cholangitis, hepatitis), cancer (vulvar, facial, and anal squamous cell dysplasia and carcinomas, T cell lymphoma-leukemia, and Burkitt and non-Hodgkin lymphomas), and autism spectrum disorders [23-25,27,29,38-42].

●Differential diagnosis (STAT3 LOF HIES and severe atopic dermatitis) – Almost all of the features associated with autosomal dominant signal transducer and activator of transcription (STAT) 3 LOF HIES (type 1) can also be seen in patients with DOCK8 deficiency. Thus, it can be difficult to assign patients to one category or another based upon clinical features alone. However, there are five clinical features that have good predictive value for distinguishing the two groups: Parenchymal lung abnormalities, retained primary teeth, and fractures with minimal trauma are seen more often with STAT3 defects, while frequent upper respiratory infections and eosinophilia are more prominent in patients with DOCK8 deficiency [40].

Mucocutaneous candidiasis and herpes infection are common in DOCK8 deficiency but infrequently seen in severe atopic dermatitis [43]. However, they otherwise have overlapping features that can make it difficult to differentiate between the two disorders without specialized diagnostic testing (eg, immunoblot, flow cytometry [44], and deoxyribonucleic acid [DNA] sequencing). The profile of low percentages of CD3+, CD4+, and naïve CD8+ T cells along with a normal total B cell percentage but low percentages of switched memory B cells (IgM-IgD-CD27+) is strongly associated with DOCK8 deficiency (odds ratio 26.3, 95% CI 9.4-73.4, in favor of a DOCK8 deficiency diagnosis versus severe atopic dermatitis) [45]. These lymphocyte biomarkers are a potential tool to screen patients with severe eczema for DOCK8 deficiency to determine which patients should have more extensive diagnostic testing.

●Somatic reversion – In one series of 34 patients with germline DOCK8 pathogenic variants, one-half had variable degrees of somatic reversion with restoration of DOCK8 expression mainly within antigen experience T cells or NK cells [46]. These patients were older and had less severe allergic disease. However, they continued to have recurrent cutaneous and sinopulmonary infections and still required HCT for a cure. In another series of three patients, somatic reversion occurred in multiple lymphocyte subsets with complete resolution of clinical manifestations of the disease [47].

●Treatment – Over 100 patients with DOCK8 deficiency have received HCT [29,34,40-42,48-56]. Survival has been excellent with generally rapid and complete immune reconstitution and resolution of infections and other clinical features. Several patients with severe herpes or papilloma virus skin infections refractory to antiviral therapy have responded to systemic IFN-alfa-2b [57-59]. Dupilumab, an IL-4 receptor antagonist, has been used successfully as bridge therapy to treat the severe atopic dermatitis before HCT [60]. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity", section on 'DOCK8 deficiency'.)

FCHO1 deficiency — The Fer/Cip4 homology (FCH) and mu domain-containing endocytic adaptor 1 (FCHO1) gene, located at chromosome 11p13.11, encodes the FCHO1 protein, which is involved in the ability to make clathrin-coated pits that are critically important for endocytosis. This inborn error of immunity (IEI) is inherited in an autosomal recessive pattern. Affected patients have low T cells, with poor proliferation and increased activation-induced T cell death, while B cell number and function are variable. Clinically, the patients described have experienced recurrent infections and failure to thrive. Additionally, several patients have been diagnosed with B cell lymphoma. Five patients have had clinical improvement following hematopoietic cell transplantation [1,61,62].

Moesin deficiency — The MSN gene, located on chromosome Xq12, encodes moesin protein, which is part of the ezrin-radixin-moesin (ERM) family of proteins that function together to stabilize the submembranous cytoskeleton. Moesin is particularly critical in the development of filopodia and cell membrane protrusions that are needed for cell movement and communication between cells. The role of moesin is essential for the development of a functional immunologic synapse.

Several patients with hemizygous pathologic variants in MSN have been described (MIM 300988) and at least two of whom were identified via TREC-based SCID newborn screening [63-66]. Clinical features include recurrent infections of the respiratory, gastrointestinal, and genitourinary tracts with bacterial, as well as varicella and newborn CMV infections. Both T cells and B cells have are present in lower-than-normal numbers, with defective proliferation and migration. Specifically, both CD4+ and CD8+ are low, with lower-than-expected naïve T cell populations (CD45RA+CD32+CD4+ and CD45RA+CCR7+CD8+) for age. Neutropenia is variably present. Immunoglobulin levels can decline with time. In some cases, the clinical presentation may resemble SCID, and HCT has been described in these patients [65].

The severity of the phenotype is variable and may include autoimmune features such as antiphospholipid syndrome, Hashimoto thyroiditis, leg ulcers, and juvenile tooth loss [66]. Therapies can be targeted to autoimmune symptoms; immunologic supportive therapies may not be required.

DEFECTS OF TRANSCRIPTION FACTORS CRITICAL TO T CELL FUNCTION

Disorders of the CBM signalosome complex — The CBM signalosome complex comprises the intracellular molecules caspase recruitment domain-containing protein 11 (CARD11; ie, CARMA1), B cell chronic lymphocytic leukemia (CLL)/lymphoma 10 (BCL10), and mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1). The CBM complex functions to regulate the activity of nuclear factor kappa B (NFkB) signaling in T and B cells after the stimulation of the T cell receptor (TCR) or B cell receptor. CARD11 is a membrane-associated protein, which, when phosphorylated, links to BCL10. BCL10 and MALT1 are constitutively linked. The formation of the CBM allows for regulation of I-kappa-B kinase (IKK) mediated NFkB activation [67].

BCL10 deficiency — Autosomal recessive, complete B cell chronic lymphocytic leukemia (CLL)/lymphoma 10 (BCL10) deficiency (MIM #616098) was reported in a child with a history of recurrent and severe respiratory tract and gastrointestinal infections of viral and bacterial origin, leading to death in the fourth year of life [68]. A homozygous BCL10 splice-site mutation was shown to abrogate protein expression. Analysis of lymphocyte subsets demonstrated a marked decrease of memory T and B cells and regulatory T (Treg) cells, and in vitro proliferative response to CD3/CD28 stimulation was absent. The defect was not confined to adaptive immunity; the patient's fibroblasts failed to respond to Toll-like receptor (TLR) 4, TLR2/6, and dectin-1 agonists.

A second patient homozygous for a different pathogenic variant also had recurrent respiratory infections and similar laboratory findings but did not have gastrointestinal disease [69]. A third patient, also with a novel pathogenic variant, had decreased natural killer (NK), gamma-delta T, and T follicular helper (Tfh) cells in addition to previously reported near absence of Treg cells and memory B and T cells and was cured with hematopoietic cell transplantation (HCT) [70].

CARD11 deficiency

●Role of CARD11 – Caspase recruitment domain-containing protein 11 (CARD11) is a member of the membrane-associated guanylate kinase (MAGUK) family. It plays a role in differentiation of immunologic and neuronal tissues and is involved in activation of the NFkB pathway [71-73].

●Autosomal recessive LOF CARD11 deficiency – CARD11 deficiency (MIM #615206) due to a homozygous mutation resulting in autosomal recessive loss of function (LOF) was reported in a 13-month-old girl with consanguineous parents [74]. She presented with Pneumocystis jirovecii pneumonia (PJP) and hypogammaglobulinemia. She had an older sister who had failed to thrive and died at three months of age from progressive respiratory failure. An older brother had meningitis and recurrent pneumonias by 6 months of age and died at 15 months of age after he developed a high fever and progressive respiratory distress in the setting of panhypogammaglobulinemia. Several other patients have presented with PJP or viral pneumonia in infancy [67,75-77]. Two of these patients had severe inflammatory gastrointestinal disease, and another had severe eczema [77]. Recurrent sinopulmonary bacterial infections are also reported.

All reported patients with this deficiency had hypogammaglobulinemia (one went from isolated reduced IgG levels to panhypogammaglobulinemia over a three-month period) [67,74-77]. Total numbers of CD19+ B cells and CD4+ and CD8+ T cells were normal, but B cell differentiation was blocked at the late transitional stage, and regulatory, effector memory, follicular helper, and terminally differentiated T cell counts were reduced. Activation of the NFkB pathway was abrogated, and upregulation of OX40, an inducible T cell costimulatory, was impaired. Lymphocyte proliferation to T cell mitogens was impaired, but proliferation to a B cell mitogen was nearly normal.

●Dominant-negative LOF CARD11 deficiency – A heterozygous, dominant-negative CARD11 mutation (R30W protein defect with loss-of-function) was reported in four affected members from a single family [78,79]. Patients manifested recurrent respiratory tract infections, asthma, and atopic dermatitis since childhood. Immunologic evaluation showed a normal T cell count but a skewed T cell repertoire and reduced in vitro T cell proliferation to mitogens and antigens. Immunoglobulin levels were low or borderline low in two patients and normal in the remaining two.

●Overlapping features – Severe atopic disease, particularly atopic dermatitis (90 percent of patients), and eosinophilia (80 percent of patients) is a unifying feature of patients with either autosomal recessive inherited LOF or dominant-negative variants.

●Treatment – Described management is generally supportive, with immune globulin replacement due to poor antibody function and PJP prophylaxis. Due to severe atopy, several of the described patients required systemic immunomodulatory therapies including glucocorticoids and/or methotrexate. At least four patients with autosomal recessive LOF CARD11 deficiency have successfully undergone HCT [74,75,77].

●Other CARD11 defects – A CARD11 gain-of-function that leads to a humoral immunodeficiency is discussed separately. (See "Primary humoral immunodeficiencies: An overview", section on 'Isotype, light chain, or functional deficiencies with generally normal numbers of B cells'.)

MALT1 deficiency

●Role of MALT1 – The mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) encodes a caspase-like cysteine protease that is part of a signalosome complex essential for NFkB activation [73].

●Genetics and clinical manifestations – MALT1 deficiency (MIM #615468) due to a homozygous mutation was first reported in a 15-year-old girl and 13- and 7-year-old siblings, both with consanguineous parents [80,81]. Clinical presentations included a longstanding history of failure to thrive, severe eczema, recurrent bacterial and viral skin and lung infections with resultant chronic inflammatory lung disease and bronchiectasis, meningitis, inflammatory gastrointestinal disease, long bone fractures, recurrent production of granulation tissue, and severe periodontal disease. The 13-year-old girl and 7-year-old boy had persistent infections and died of respiratory failure. MALT1 deficiency was also reported in a male infant who presented with generalized skin rash, intestinal inflammation, and persistent cytomegalovirus (CMV) infection [82]. This patient had normal T cell receptor excision circle (TREC) levels at birth. Other patients have had an immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) like [83] or Netherton/Omenn syndrome-like picture [84], and autoimmunity is common [85,86].

●Laboratory findings – In the first reported patients, lymphocyte numbers were normal, with normal T and NK cell numbers. T cell proliferation to mitogens and TCR-mediated activation of NFkB were absent. IgG, immunoglobulin A (IgA), and IgM levels and production of protective antibody titers were normal. Phenotypic variability has been observed in the B cell compartment. The B cell count was markedly reduced in one patient but normal in another. Likewise, serum IgE was chronically elevated in one patent and normal in another. Other patients have had lymphocytosis, low to normal immunoglobulin levels, low T helper type 17 (Th17) cells, absent Treg cells, variable proliferative response to mitogens, and an abnormal TCR gamma chain repertoire [83]. Eosinophilia is common [86]. Progressive depletion of B cells was also reported [87].

●Treatment – Several patients were successfully treated with HCT [83,86,88].

c-Rel deficiency — c-Rel deficiency is inherited in an autosomal recessive fashion due to pathologic variants in the REL proto-oncogene, NFkB subunit (REL) gene located on chromosome 2p16.1 and has been described in two kindreds. This gene encodes c-Rel, a transcription factor that is part of the NFkB signaling complex. c-Rel is critical to the development of several lymphocyte subsets and functional T and B cells due to deleterious impacts on the ability to produce interleukin (IL) 2, IL-12, and interferon (IFN) gamma [1,89,90]. NK cell cytotoxic function also is impaired [91]. Affected patients have normal to elevated overall numbers of T cells, with reduced proportions of memory CD4 cells and impaired proliferative capacity. B cells may be reduced in number with a predominantly naïve phenotype, impaired proliferation, and low immunoglobulin production, including a poor ability to make specific antibody to vaccine challenge. NK cell populations are also reduced. Clinically, patients have recurrent bacterial, mycobacterial, Salmonella, and opportunistic infections. Management is supportive, with immune globulin replacement therapy and antimicrobial prophylaxis.

Ikaros protein family deficiencies

●Genetics and pathogenesis – The Ikaros family of proteins includes Ikaros, Helios, Aiolos, Eos, and Pegasus. The Ikaros family zinc finger 1 (IKZF1) gene, located at chromosome 7p12.2, encodes the Ikaros protein, a zinc finger transcription factor that is critical to lymphocyte development. The Ikaros family zinc finger 2 (IKZF2) gene, located at chromosome 2q34, encodes the Helios protein, a member of the Ikaros family of transcription factors that mediates protein dimerization (OMIM 606234). The Ikaros family zinc finger 3 (IKZF3) gene, located at chromosome 17q17, encodes the Aiolos protein, a hematopoietic transcription factor critical to lymphoid cell differentiation (OMIM 606221, 619437).

The proteins mediate DNA binding through the N-terminus zinc finger domain and multimerization via the C-terminus zinc finger domain. More than 30 pathologic variants have been identified, and nearly half impact the DNA-binding domain. Ikaros deficiency is associated with the following molecular mechanisms: dominant-negative, LOF, haploinsufficiency, and defective dimerization. Autosomal dominant haploinsufficiency of Ikaros is associated with a common variable immunodeficiency (CVID) phenotype. Of note, gain-of-function in Ikaros has also been described in a limited number of patients and is categorized by the International Union of Immunological Societies (IUIS) to be within the group of Treg cell defects.

●Clinical features of Ikaros deficiency – Patients with Ikaros deficiency due to LOF as well as autosomal dominant-negative defects have been described to have early-onset CID disease starting in the first year of life, with recurrent sinopulmonary infections and pneumocystis, although dominant-negative variants seem to be the most severe [92]. The dominant-negative variant effects most commonly impact the amino acid at position 159 within the DNA binding domain. The clinical laboratory phenotype in these patients manifests with an absence of memory B cells and little to no immunoglobulin production. The T cell immunophenotype is variable across reports, with some reporting absence of memory T cells and others with skewing of CD8+ T cells towards a naïve phenotype, while CD4+ skew towards a memory phenotype. Reduced numbers of neutrophils have also been described. Additionally, autoimmune features, particularly immune thrombocytopenia (ITP), are frequently seen, and B cell acute lymphoblastic leukemia (ALL) has also been described in a number of these patients. Management included immune globulin replacement therapy and close monitoring for development of autoimmune, lymphoproliferative, and malignant complications. In patients with the N195 dominant-negative defects as well as patients with B cell ALL and somatic or germline IKZF1 deletions, HCT was successful in correcting the immune dysfunction and improving survival in those with B cell ALL [93-95].

●Clinical features of Helios deficiency – Defects in Helios lead to abnormalities in Tfh cell, Treg cell, and NK cell physiology [1,96-99]. Affected patients with pathologic variants in either an autosomal dominant or autosomal recessive pattern have been described, and their clinical laboratory phenotype includes increased numbers of activated T cells, reduced memory B cells, and lower-than-expected immunoglobulin levels. Symptoms included features of both immunodeficiency and immunodysregulation. Infections included recurrent upper respiratory tract infections, pneumonia, and thrush. Symptoms of immunodysregulation included lymphoproliferation, lymphoma, oral ulcers, autoimmune cytopenias, hemophagocytic lymphohistiocytosis (HLH), and lupus.

●Clinical features of Aiolos deficiency – An autosomal dominant missense variant in the DNA binding domain of IKZF3 in patients from a single kindred manifests with increased Epstein-Barr virus (EBV) susceptibility leading to HLH and lymphoma. Laboratory abnormalities were noted in the CD4 population being skewed toward naïve T cells, in addition to an overall reduction in the number of circulating B cells [100]. In another kindred, several affected patients were also noted to have hypogammaglobulinemia and PJP [101].

IKBKB deficiency — I-kappa-B kinase (IKK) beta chain (IKBKB, also known as I-kappa-B kinase 2 [IKK2]) activates transcription factor NFkB, which results in activation of genes involved in inflammatory and other immune responses.

A series of patients from Canada who were of Northern Cree ancestry were found to have IKBKB deficiency (MIM #615592) due to homozygous null mutations [102]. These patients presented in early infancy with oral candidiasis. They went on to develop more severe infections in the first year of life, including parainfluenza pneumonia and bacterial sepsis (Escherichia coli, Listeria, Serratia, Klebsiella). One patient also had a nontuberculous mycobacterial infection. Another series of four patients from two consanguineous families in Qatar were identified with a homozygous nonsense mutation in IKBKB and recurrent viral, bacterial, and fungal infections [103]. Four children from two related Saudi families also had a novel homozygous nonsense pathogenic variant and presented with delayed umbilical cord separation in addition to severe infections [104]. The largest series of patients reported includes 16 subjects [105]. Bacterial, fungal, mycobacterial, and viral infections were present since early in life and were associated with failure to thrive. Bacterial and mycobacterial meningitis or brain abscesses were documented in six patients. Disseminated Bacillus Calmette-Guérin (BCG) infection was observed in all four infants who received BCG immunization at birth. One patient successfully underwent HCT without conditioning from a fully matched sibling donor [104]. Eight patients in the series discussed above also underwent HCT, but only three survived [105].

NIK deficiency — The mitogen-activated protein kinase kinase 14 (MAP3K14) gene, located at chromosome 17q21.31, encodes the NFkB-inducing kinase (NIK) protein, a participant in the NFkB signaling pathway. In two reported patients, loss of NIK activity was associated with impaired activation of canonical and noncanonical NFkB signaling [106]. These patients demonstrated low B cell counts, with decreased switched memory B cells and poor production of immunoglobulin. While overall T cell counts were normal, the expression of IL7R on CD8+ cells was impaired, and the proliferative response to recall antigens was also lower than expected. Finally, NK cell counts were also low. Clinically, these patients presented with symptoms of infection including CMV, cryptosporidium, BCGosis, candidiasis, and recurrent bacterial and viral respiratory tract infections. Both patients were treated with HCT, but only one survived. Of note, the patient who did not survive was first treated with an unconditioned transplant followed by a second transplant.

DEFECTS IN OTHER PATHWAYS CRITICAL TO T CELL DEVELOPMENT AND FUNCTION

Polymerase delta deficiency — Polymerase delta deficiency is associated with defects in the DNA polymerase delta 1, catalytic subunit (POLD1) and DNA polymerase delta 2, accessory subunit (POLD2) genes, located on chromosomes 19q13.33 and 7p13, respectively. These genes encode proteins that are components of the polymerase delta complex, critical to DNA repair. POLD1 protein is the catalytic component of the complex and supports synthesis of the lagging DNA strand, while POLD2 is an accessory subunit, involved in regulation of the polymerase delta complex activity and regulation of the cell cycle. Biallelic pathologic variants in both of these genes demonstrating an autosomal recessive mode of inheritance have been described in association with CID [107,108]. In addition, at least one patient with POLD1-associated immunodeficiency was identified via T cell receptor excision circle (TREC) based severe combined immunodeficiency (SCID) newborn screening [109].

Described patients suffered from recurrent bacterial and viral infections, including recurrent respiratory infections, persistent molluscum, warts, and skin abscesses. In addition, severe neurologic impairments and growth deficiency have been described [107,108]. Patients were found to have reduced T, B, and natural killer (NK) cell populations. T cells were skewed toward a memory phenotype, with expansion of T effector memory CD45RA+(T_EMRA) CD4+CD8+ cells increased in some patients. A restricted T cell receptor (TCR) variable beta chain (Vbeta) repertoire and decreased proliferative capacity have also been described. B cells, although reduced in number, appear able to develop into class-switched memory cells. Despite this, lower-than-normal immunoglobulin levels have been noted in affected patients. All described patients have been managed supportively with immune globulin replacement therapy as well as antibacterial and antifungal prophylaxis.

Transferrin receptor 1 defect — The transferrin receptor 1 (TfR1, also CD71), encoded by the gene TFRC, is involved in the cellular uptake of iron. A missense mutation that disrupts the TfR1 internalization motif results in defective receptor endocytosis and markedly increased cell surface expression of TfR1. Patients homozygous for this mutation (MIM #616740) have severe, recurrent childhood infections, chronic diarrhea, and failure to thrive [110,111]. Less common findings included skin abscesses, developmental delay, optic nerve atrophy, goiter, vitiligo, conjunctivitis, and hemophagocytic lymphohistiocytosis (HLH) like features. Laboratory findings include hypo- or agammaglobulinemia; normal T and B cell counts but a decreased percentage of memory B cells and defective T cell proliferation to stimulation; and intermittent neutropenia and thrombocytopenia. In addition, patients have mild anemia resistant to iron supplementation. Six of 15 patients in one series had died, and eight had undergone hematopoietic cell transplantation (HCT) [110,112]. In another series of eight patients, two received HCT, five were on prophylactic treatment, and one had died [111].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

●Overview – The combined immunodeficiency (CID) defects reviewed in this topic include monogenic inborn errors of immunity (IEI) associated with severe T cell quantitative or functional defects but without other syndromic or nonimmunologic features (table 1). These disorders can be grouped based upon the mechanistic process affected by the underlying defect, including impaired T cell receptor (TCR) signaling, cytokine signaling, cellular immunity by disruption of actin rearrangement, and cellular immunity by disruption of regulation and activity of critical transcription factors. (See "Combined immunodeficiencies: An overview" and 'Introduction' above.)

●Disorders of T cell receptor signaling – Many of the CID involve impaired T cell receptor (TCR) signaling. These include CD3, which is important in transducing the signal that initiates T cell activation and differentiation; class I or II major histocompatibility complex (MHC I or MHC II) molecules, which function to distinguish self from non-self and are involved in antigen processing and presentation; and CD8, which is a TCR accessory molecule that binds to MHC I and plays an important role in the antigen-specific activation and function of cytotoxic T cells. Management is directed toward infectious complications and may include immune globulin replacement. Hematopoietic cell transplantation (HCT) can be curative, but experience is limited. (See "CD3/T cell receptor complex disorders causing immunodeficiency" and 'Disorders of T cell receptor signaling' above and "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

●Disorders of cytokine signaling – Interleukin (IL) 21 is a common gamma chain-related cytokine that plays a critical role in immune cell development, differentiation, proliferation, function, and survival. Deficiencies of IL-21 or its receptor (IL-21R) cause an immunodeficiency similar to common variable immunodeficiency (CVID). (See 'Disorders of cytokine signaling' above and "Common variable immunodeficiency in children".)

●Disorders involving the actin cytoskeleton – Dedicator of cytokinesis (DOCK) 2 and 8 function is required for proper cytoskeletal organization, an integral part of leukocyte activation. Common clinical features include recurrent viral and bacterial respiratory tract infections, chronic diarrhea, and growth failure. Patients with DOCK8 deficiency also have extensive atopic disease. Patients commonly undergo HCT. (See 'Disorders involving the actin cytoskeleton' above and "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

●Defects of transcription factors critical to T cell function – Caspase recruitment domain-containing protein 11 (CARD11), B cell chronic lymphocytic leukemia/lymphoma 10 (BCL10), and mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) comprise the CBM signalosome complex that is a key modulator of lymphocyte signaling through several pathways. The Ikaros family of proteins are critical to lymphocyte differentiation. Patients with defects in these and other transcription factors can present with severe atopic disease, malignancy, autoimmunity, and inflammatory disease in addition to immunodeficiency, depending upon the specific defect. Management is primarily supportive, with immune globulin replacement therapy and antimicrobial prophylaxis. HCT has been performed, with mixed results. (See 'Defects of transcription factors critical to T cell function' above.)