INTRODUCTION — Several genetic mutations lead to variable immune defects of humoral and cell-mediated immunity (table 1) [1-3]. Combined immunodeficiency syndromes are somewhat arbitrarily distinguished from severe combined immunodeficiency (SCID) in that they do not characteristically lead to death from overwhelming infection in the first year of life. In addition, combined immunodeficiency syndromes frequently have associated clinical features.
Mutations of a particular gene may lead to SCID or to milder combined immunodeficiency, depending upon whether the gene defect is fully penetrant or on the functional consequences of the specific mutation: amorphic (complete defect) or hypomorphic (partial defect). Genetic defects in which the mutations primarily lead to a SCID phenotype are discussed separately. (See "Severe combined immunodeficiency (SCID): Specific defects" and "CD3/T cell receptor complex disorders causing immunodeficiency".)
The following combined immunodeficiency syndromes are discussed separately:
●CD40 and CD40 ligand deficiencies (see "Hyperimmunoglobulin M syndromes")
●Wiskott-Aldrich syndrome (see "Wiskott-Aldrich syndrome")
●Ataxia-telangiectasia (see "Ataxia-telangiectasia")
●DiGeorge syndrome (see "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis" and "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis")
●Nijmegen breakage syndrome (see "Nijmegen breakage syndrome")
●Purine nucleoside phosphorylase deficiency (see "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis")
●DNA ligase IV deficiency (see "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis")
●Cernunnos deficiency (see "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis")
●Omenn syndrome (see "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis")
●Zeta chain-associated protein 70 (ZAP-70) deficiency (see "ZAP-70 deficiency")
●T cell receptor (TCR) alpha subunit constant (TRAC) deficiency (see "CD3/T cell receptor complex disorders causing immunodeficiency")
●CD3 gamma-chain deficiency (see "CD3/T cell receptor complex disorders causing immunodeficiency")
●Lymphocyte-specific protein-tyrosine kinase (p56lck) deficiency (see "CD3/T cell receptor complex disorders causing immunodeficiency")
●Ras homolog gene family member H (RHOH) deficiency (See "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'RHOH deficiency'.)
●Macrophage stimulating 1 (MST1, or serine threonine kinase 4, STK4) deficiency (See "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'MST1 (STK4) deficiency'.)
●Interleukin 2-inducible T cell kinase (ITK) deficiency (See "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'ITK deficiency'.)
●Major histocompatibility complex (MHC) class I and II deficiencies (see "CD3/T cell receptor complex disorders causing immunodeficiency")
●Signal transducer and activator of transcription 1 (STAT1) deficiency (see "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'Dominant negative LOF STAT1 deficiency')
●X-linked lymphoproliferative syndrome (see "X-linked lymphoproliferative disease")
●X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) (see "Malignancy in primary immunodeficiency", section on 'XMEN disease')
●Cartilage-hair hypoplasia/short-limbed dwarfism (see "Cartilage-hair hypoplasia")
●Syndromic immunodeficiencies (see "Syndromic immunodeficiencies")
The following disorders are described here:
SCID variants:
●Interleukin 2 receptor alpha (IL-2RA) chain (CD25) deficiency (see 'Interleukin 2 receptor alpha chain (CD25) deficiency' below)
●Signal transducer and activator of transcription 5b (STAT5b) deficiency (see 'Signal transducer and activator of transcription 5b deficiency' below)
●Winged-helix nude (also called forkhead box N1 [FOXN1]) deficiency (see 'Winged-helix nude (FOXN1) deficiency' below)
●Calcium release-activated calcium modulator 1 (ORAI1/CRACM1) and stromal interaction molecule 1 (STIM1) deficiencies (see 'ORAI1/CRACM1 and STIM1 deficiencies' below)
Defects of nuclear factor (NF)-kappa-B regulation:
●NF-kappa-B inhibitor alpha (NFKBIA, also called I-kappa-B alpha [IKBA]) deficiency (see 'IKK complex and NFKBIA (IKBA) deficiencies' below)
●Defects in the I-kappa-B kinase (IKK) complex: IKK 2/beta and NF-kappa-B essential modifier (NEMO or IKK 3/gamma) deficiencies (see 'IKK complex and NFKBIA (IKBA) deficiencies' below)
●Caspase recruitment domain-containing protein 11 (CARD11) deficiency (see 'Caspase recruitment domain-containing protein 11 deficiency' below)
●Mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) deficiency (see 'MALT1 deficiency' below)
●B cell chronic lymphocytic leukemia (CLL)/lymphoma 10 (BCL10) deficiency (see 'BCL10 deficiency' below)
Other combined immunodeficiencies:
●Serine threonine kinase 4 (STK4/MST1) deficiency (see 'Serine threonine kinase 4 deficiency' below)
●Caspase 8 deficiency (see 'Caspase 8 deficiency' below)
●CD8 deficiency (see 'CD8 deficiency' below)
●CD27 deficiency (see 'CD27 deficiency' below)
●CD70 deficiency (see 'CD70 deficiency' below)
●Dedicator of cytokinesis 2 (DOCK2) deficiency (see 'Dedicator of cytokinesis 2 deficiency' below)
●Dedicator of cytokinesis 8 (DOCK8) deficiency (see 'Dedicator of cytokinesis 8 deficiency' below)
●Phosphoglucomutase 3 (PGM3) deficiency (see 'Phosphoglucomutase 3 deficiency' below)
●Activated PI3K-delta syndrome (APDS) (see 'Activated PI3K-delta syndrome' below)
●IL-21 and IL-21 receptor deficiencies (see 'Interleukin 21 and IL-21 receptor deficiencies' below)
●IL-2 inducible T cell kinase (ITK) deficiency (see 'Interleukin 2-inducible T cell kinase (ITK) deficiency' below)
●Cytidine 5' triphosphate (CTP) synthase 1 deficiency (see 'CTP synthase 1 deficiency' below)
●Gain-of-function mutation in the transferrin receptor 1 (TfR1) gene (TFRC) (see 'Transferrin receptor 1 (TfR1) defect' below)
●Hypomorphic recombinase activating gene 1 or 2 (RAG1, RAG2) mutations (see 'Hypomorphic RAG1 and RAG2 mutations' below)
●Late-onset combined immunodeficiency (LOCID) (see 'Late-onset combined immunodeficiency' below)
OVERVIEW — Although specific combined T and B cell immunodeficiencies are rare disorders, collectively they are not uncommon and make up approximately one-half of the patients with combined immunodeficiencies reported in immunodeficiency registries, which include the severe combined immunodeficiencies (SCID). The severity of the immunodeficiency and the spectrum of associated abnormalities depend upon which gene is mutated and the extent of the genetic defect. Thus, each syndrome associated with a particular gene(s) can have a wide variation in clinical manifestations and the age at presentation.
Presentation — Patients with combined immunodeficiency often present in the first two years of life with recurrent infections and specific findings associated with the different syndromes. However, patients with milder defects may not present until later in childhood or even early adulthood.
Combined immunodeficiencies may not be identified by SCID newborn screening if thymic output is only mildly or moderately depressed. (See "Newborn screening for primary immunodeficiencies" and "Newborn screening for primary immunodeficiencies", section on 'Diseases not identified by TREC testing'.)
Evaluation — The diagnosis of combined immunodeficiency should be suspected in children with any of the following:
●Chronic or recurrent respiratory tract infections (eg, more than eight upper respiratory tract infections or more than one lower respiratory tract infection yearly)
●Chronic viral disease
●Opportunistic infections
●Failure to thrive
●Chronic diarrhea
●Autoimmunity and other manifestations of immune dysregulation, such as granuloma formation
●Epstein-Barr virus (EBV)-driven lymphoproliferative disease
●A family history of immunodeficiency
●Chronic lymphopenia (total lymphocyte count <1500 cells/microL in children over five years of age, <2500 cells/microL in younger children)
Many of the presenting features are similar in adults with combined immunodeficiency. Additional features that suggest a combined immunodeficiency in adults are:
●Unexplained weight loss
●New onset of an autoimmune disease
●Development of lymphopenia either de novo or in a patient with a childhood history of an immunodeficiency
An overview of the conditions and infections that should alert a clinician to the possibility of immunodeficiency in general is discussed separately. (See "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)
The patient suspected of having combined immunodeficiency requires complete evaluation of specific humoral and cellular immunity. Studies include the measurement of immunoglobulin levels (table 2), specific antibody titers, absolute numbers and percentages of lymphocyte subsets (T, B, and natural killer [NK]), and assessment of T cell function. Algorithms for evaluation of patients with suspected immunodeficiency are published [1]. All patients suspected of having one of these disorders should be referred to an immunology specialist for evaluation and an attempt to determine a definitive diagnosis. The most specific diagnosis possible (preferably molecular) is desirable for the most accurate prognosis, therapy, and genetic counseling. (See "Laboratory evaluation of the immune system" and "Severe combined immunodeficiency (SCID): An overview".)
Many of the combined immunodeficiency syndromes have characteristic-associated clinical and laboratory features that suggest a particular defect and help direct the diagnostic evaluation. As examples:
●Eczema and thrombocytopenia in Wiskott-Aldrich syndrome. (See "Wiskott-Aldrich syndrome".)
●Conical or absent teeth; frontal bossing; fine, sparse hair; and hypohidrosis in defects of nuclear factor (NF)-kappa-B signaling. (See 'Defects of NF-kappa-B regulation' below.)
●Cardiac and facial anomalies in DiGeorge syndrome. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis".)
●Neurologic abnormalities and oculocutaneous telangiectasias in ataxia-telangiectasia. (See "Ataxia-telangiectasia".)
●Short stature, short limbs, other skeletal anomalies, and fine hair in cartilage-hair hypoplasia. (See "Cartilage-hair hypoplasia".)
●Many patients with complete or incomplete DiGeorge syndrome and mucocutaneous candidiasis have antibody defects in addition to their cellular immunodeficiency. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis" and "Chronic mucocutaneous candidiasis".)
●Clinical features that suggest a genetic syndrome with undue susceptibility to infection. (See "Syndromic immunodeficiencies".)
Diagnostic algorithms are of value for the diagnosis of immunodeficiency syndromes [1].
It is often useful to determine the genetic defect since it influences the clinical phenotype and may impact the course of the disease and its treatment. It is most important to recognize if a child has one of the defects associated with SCID as this would require urgent clinical intervention. (See "Severe combined immunodeficiency (SCID): Specific defects".)
Management — The choice of treatment depends upon the type and severity of the immune defect. Live vaccines and nonirradiated blood transfusions should be avoided. Immune globulin replacement therapy is given to almost all patients with combined immunodeficiency since they have a component of diminished antibody production by definition. Palivizumab, a humanized monoclonal antibody against respiratory syncytial virus (RSV), is often also given to severely immunodeficient patients during RSV season [4]. Patients with increased susceptibility to opportunistic bacterial or other infections are treated with prophylactic antimicrobial agents. Aggressive antimycobacterial therapy and sometimes interferon gamma are used in patients with increased susceptibility to mycobacterial infections. Hematopoietic cell transplantation (HCT) or possibly gene therapy is indicated for defects that lead to a more severe clinical phenotype and fatality in early childhood if untreated. (See "Primary immunodeficiency: Overview of management" and "Mendelian susceptibility to mycobacterial diseases: Specific defects" and "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Preventing initial infection'.)
SEVERE COMBINED IMMUNODEFICIENCY VARIANTS — A severe combined immunodeficiency (SCID) variant is a combined immunodeficiency that may or may not meet strict criteria for SCID based upon a variable amount of residual T cell function. Some patients with these defects may have classical SCID features, but many may not.
Interleukin 2 receptor alpha chain (CD25) deficiency — At least five patients have been described with lesions in the interleukin 2 receptor alpha (IL2RA) gene located on chromosome 10p15.1 (MIM #147730), encoding the alpha chain (CD25) of the IL-2R [5-10]. One patient had an increased susceptibility to bacterial, viral, and fungal infections due to a homozygous mutation in the IL2RA gene [5,6]. Another patient had a phenotype resembling the syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX), a syndrome which is more often associated with mutations of the transcription factor forkhead box P3 (FOXP3) [7]. A third patient had recurrent infections and primary biliary cholangitis [8]. A fourth patient had follicular bronchiolitis with lymphocyte hyperplasia, eczema, and recurrent infections [9]. A fifth patient presented in the first year of life with severe diarrhea with villous atrophy and eczema and went on to develop cytomegalovirus (CMV) infection, bullous pemphigoid, autoimmune thyroiditis, eczema, alopecia, and lymphadenopathy [10]. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)
The IL-2R alpha and beta chains combine with the common gamma chain to form the high-affinity IL-2R on T cells, B cells, natural killer (NK) cells, and monocytes. IL-2 production and expression of IL-2R are stimulated by antigen binding to the T cell receptor (TCR). IL-2 is involved in the growth and differentiation of cytotoxic and regulatory T cells and NK cells and optimization of T cell help to B cells for antibody production. (See "Normal B and T lymphocyte development".)
The described SCID-like patient presented at six months of age with CMV pneumonia and persistent oral and esophageal candidiasis. He had failure to thrive, partly due to chronic diarrhea from adenoviral gastroenteritis. He developed extensive infiltration and inflammation of several tissues with autoreactive T cells. Lymphadenopathy and hepatosplenomegaly became more prominent with age. He had extremely few T and B cells in the circulation, and the T cells did not respond to mitogens in vitro. He underwent successful allogeneic hematopoietic cell transplantation (HCT) at three years of age.
The reported IPEX-like patient had onset of chronic diarrhea and diabetes mellitus and CMV pneumonia at six weeks of age. Serum immunoglobulins were elevated, and lymphocyte populations initially appeared normal. Over the ensuing eight years, he exhibited asthma, recurrent otitis media, sinusitis and pneumonia, eczema, lymphadenopathy and hepatosplenomegaly, hypothyroidism, and autoimmune anemia and neutropenia.
Signal transducer and activator of transcription 5b deficiency — Several patients have been identified with mutations in the signal transducer and activator of transcription 5b (STAT5B) gene that cause a defect in the signaling pathways of receptors for IL-2, IL-4, colony-stimulating factor 1 (CSF1, also called macrophage colony-stimulating factor [M-CSF]), and growth hormone (MIM #245590) [11-17].
CD4+CD25+ regulatory T cells are decreased in number in patients with STAT5b deficiency [12,13]. Other immunologic parameters are variable, including T, B, and NK cell levels, and T cell proliferation.
Patients present with signs of growth hormone insensitivity, including short stature, a prominent forehead and saddle nose, and a high-pitched voice. Some patients also have pruritic skin lesions. One patient was diagnosed with eczema and another with congenital ichthyosis. Manifestations of the associated immunodeficiency include recurrent respiratory tract infections, viral infections (including hemorrhagic varicella and herpes zoster), and Pneumocystis jirovecii (Pneumocystis carinii) pneumonia.
Winged-helix nude (FOXN1) deficiency — Two sisters were described who had congenital alopecia, nail dystrophy, and severe infections consistent with T cell immunodeficiency (MIM #601705) [18]. They had a homozygous defect in the forkhead box N1 (FOXN1) gene, which is the gene mutated in "nude" SCID mice [19]. Subsequently, additional patients have been reported with the same phenotype and biallelic FOXN1 mutations [20-23].
FOXN1 (also called winged-helix nude) is a member of the winged-helix domain family of transcription factors [24]. This protein is involved in the development of the thymus, as well as the formation of hair and nails. It also may be involved in brain and neural tube development.
The two sisters with defects in this gene described in the original report [18] had decreased circulating T cells, mainly due to low levels of CD4+ T cells. T cell proliferative responses to mitogens were abnormal. One of the sisters died from infection at one year of age. The other was successfully transplanted at five months of age [19]. Four additional children from the same village were identified who had congenital alopecia and died in early childhood from severe infections [25]. A fetus with the same genetic defect was identified during population screening in the village [24]. This fetus lacked a thymus and had grossly abnormal skin. It also had additional defects, including spina bifida and anencephaly. Two additional, unrelated patients were reported, one who presented with disseminated Bacillus Calmette–Guérin (BCG) disease and the other with human herpes virus 6 (HHV6) infection and cytopenias [20]. Both infants attained immune reconstitution after thymus transplantation. Besides T cell lymphopenia (with marked reduction of CD4+ T cells in particular), patients with FOXN1 deficiency may also exhibit an increased proportion of CD4- CD8- TCR-alpha-beta+ "double-negative" T cells and of FOXP3+ regulatory T cells [21].
ORAI1/CRACM1 and STIM1 deficiencies — Lymphocyte activation after antigen stimulation is dependent upon store-operated entry of Ca2+ (eg, entry triggered by intracellular depletion of Ca2+) across the plasma membrane via Ca2+ release-activated Ca2+ (CRAC) channels [26]. Orai1 or calcium release-activated calcium modulator 1 (CRACM1) is the pore-forming subunit of the CRAC channel [27]. Stromal interaction molecule 1 (STIM1) senses release of Ca2+ from endoplasmic reticulum stores and activates CRAC channels in the plasma membrane. Sustained Ca2+ influx leads to translocation of the transcription factor nuclear factor of activated T cells (NFAT) to the nucleus, where it induces expression of IL-2 and other cytokines.
Mutations in ORAI1 on chromosome 12q24 (MIM #612782) and STIM1 on chromosome 11q15.5 (MIM #605921) lead to a primary immunodeficiency with increased susceptibility to bacterial and viral infections [28-31]. Both mutations appear to have autosomal recessive inheritance.
The laboratory findings are similar for both of these defects [28,29]. Lymphocyte counts are normal to slightly reduced, and immunoglobulin levels are normal to elevated. However, T cell proliferative response to mitogens and antigens is compromised, and specific antibody response to vaccination is impaired.
The two deficiencies have similarities and differences in their clinical manifestations [28,29]. Two siblings reported with ORAI1 deficiency presented at two weeks of age with fever and failure to thrive. The first child died from sepsis at 11 months of age. The younger sibling was successfully transplanted at 16 weeks of age. Three siblings with STIM1 deficiency developed infections within the first two months of life. The eldest survived until nine years of age, dying from HCT complications. The younger sister died at 18 months from encephalitis. The third sibling, a boy, was successfully transplanted at 15 months of age.
Nonprogressive muscular hypotonia and abnormalities in dental enamel are seen in both ORAI1 and STIM1 deficiencies [28-30]. Two surviving patients with ORAI1 deficiency have more extensive ectodermal defects (ectodermal dysplasia and anhidrosis). The three siblings with STIM1 deficiency all had autoimmune disorders, and the two who were not transplanted had lymphoproliferative disorders. A unique feature of STIM1 deficiency is partial iris hypoplasia.
DEFECTS OF NF-KAPPA-B REGULATION
IKK complex and NFKBIA (IKBA) deficiencies — Hypomorphic gene defects that result in partial function of the inhibitor of nuclear factor-kappa-B (NF-kappa-B) or the kinase that inactivates the inhibitor (I-kappa-B kinase [IKK]) cause a combined immunodeficiency with variable associated features.
Pathogenesis — NF-kappa-B is a transcription factor that regulates expression of a large number of genes with roles in immune and inflammatory responses to pathogens. Examples include genes encoding acute phase proteins, adhesion molecules, and the cytokines interleukin (IL) 1, IL-2, IL-6, IL-8, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF) [32,33]. NF-kappa-B also regulates development of other tissues such as skin, hair, and teeth.
The activity of NF-kappa-B is controlled by NF-kappa-B inhibitor proteins alpha and beta (NFKBIA and NFKBIB), also called the inhibitor of kappa B (I-kappa-B alpha and beta [IKBA and IKBB]). These inhibitors inactivate NF-kappa-B by trapping it in the cytoplasm [32,33]. NF-kappa-B is active when the inhibitor is degraded after phosphorylation by IKK. IKK is a heterotrimer of alpha, beta, and gamma chains. Mutations in NFKBI or IKK lead to decreased NF-kappa-B activity.
The IKK beta chain (IKBKB, IKK-beta, or IKK2) is encoded on chromosome 8p11.21 (MIM *603258). The IKK gamma chain (IKBKG, IKK-gamma, or IKK3, also called NF-kappa-B essential modifier [NEMO], MIM *300248) is encoded by a gene on the X chromosome. The NFKBIA (also called I-kappa-B alpha or IKBA, MIM #164008) is encoded on chromosome 14q13. Mutations in NFKBIA lead to constitutive activity of the inhibitor and a partial block of NF-kappa-B signaling.
Clinical manifestations — Hypomorphic mutations that allow partial function of NEMO typically cause an X-linked syndrome of antibody deficiency, increased susceptibility to infection with nontuberculous mycobacteria, and ectodermal dysplasia (MIM #300291) [32-40]. Ectodermal dysplasia is characterized by conical or absent teeth; fine, sparse hair; and hypohidrosis due to decreased sweat glands. (See "Ectodermal dysplasias", section on 'Hypohidrotic ectodermal dysplasia with immune deficiency'.)
Individuals with NEMO mutations experience severe bacterial or viral infections early in life and atypical mycobacterial infections. Failure to thrive, recurrent gastrointestinal infections with chronic diarrhea, bronchiectasis secondary to recurrent respiratory tract infections, and recurrent skin infections are common findings [41]. Other Mendelian susceptibility to mycobacterial diseases (MSMD) disorders are discussed separately. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)
Some patients with NEMO mutations also have osteopetrosis and lymphedema associated with ectodermal dysplasia and immunodeficiency. Thus, these syndromes are sometimes distinguished as "ectodermal dysplasia with immunodeficiency" (EDA-ID) and "osteopetrosis and lymphedema with ectodermal dysplasia and immunodeficiency" (OL-EDA-ID) [41,42].
While all NEMO mutations result in immunodeficiency, they do not all result in ectodermal dysplasia [34,35,43]. Thus, male patients with atypical mycobacterial infections and immunologic laboratory findings consistent with NEMO mutation should be evaluated for NEMO deficiency.
A mutation in the 5' untranslated region of NEMO causing decreased expression of normal protein was reported in two brothers with a history of recurrent sinopulmonary infections and dysgammaglobulinemia [44].
Null (amorphic) mutations of NEMO lead to the X-linked dominant disorder incontinentia pigmenti, which is usually lethal in males prenatally. Survival in males is possible if the mutation is hypomorphic, the karyotype is abnormal, or there is somatic mosaicism, but these infants can have severe combined immunodeficiency (SCID) [45-50]. (See "Incontinentia pigmenti".)
Several patients have been described with an autosomal dominant form of anhidrotic ectodermal dysplasia with T cell immunodeficiency due to mutations in the gene for NFKBIA (MIM #612132) [51-54]. The phenotype is very similar to NEMO deficiency [39]. These patients generally present in infancy with failure to thrive, recurrent respiratory and gastrointestinal tract infections, and chronic diarrhea. These patients are also prone to atypical mycobacterial infections.
One patient with IKK-beta deficiency due to a homozygous nonsense mutation has been identified [55]. She was the second child of first-degree consanguineous parents and presented in early infancy with delayed separation of the umbilical cord and omphalitis. She went on to develop severe recurrent infections (including disseminated Bacillus Calmette–Guérin [BCG]), chronic diarrhea, and generalized rash and died at 25 months of age. Four other family members had died in infancy with febrile illnesses.
A series of patients from Canada who were of Northern Cree ancestry were found to have homozygous null mutations in IKBKB [56]. 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 [57]. The largest series of patients reported includes 16 subjects [58]. 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 BCG infection was observed in all four infants who received BCG immunization at birth.
Laboratory findings — Immunologic findings in NEMO deficiency include hypogammaglobulinemia with poor specific antibody production (particularly in response to polysaccharide antigens), either elevated immunoglobulin M (IgM) or immunoglobulin A (IgA), and low natural killer (NK) cell function [32-34,41]. Some consider NEMO deficiency a form of the hyperimmunoglobulin M (HIGM) syndrome [59]. However, this is misleading since patients with NEMO deficiency more often have elevated serum IgA rather than IgM. Cellular responses to T cell mitogens and recall antigens in vitro are variable.
Persistent lymphocytosis, generally with a normal distribution of T, B, and NK cells; normal T cell responses to mitogens; and impaired production of cytokines regulated by NFKBIA are common laboratory findings in patients with NFKBIA (IKBA) deficiency [51-54]. However, immunoglobulin levels and T cell responses to antigens are variable [51-54].
Typical laboratory findings in patients with IKBKB deficiency are hypogammaglobulinemia or agammaglobulinemia and normal T and B cell counts in the peripheral blood [56,57]. However, most T and B cells are naïve, regulatory T cells, and gamma-delta T cells are absent, NK cells numbers are low, and both adaptive and innate immune responses are impaired.
Diagnosis — Analysis of Toll-like receptor function may reveal defects due to impaired NF-kappa-B signaling in patients with characteristic clinical and laboratory features. The gene structure should be determined if Toll-like receptor function is abnormal. Establishing the molecular diagnosis is important for definitive therapy and genetic counseling.
Treatment — Immune globulin replacement is indicated in patients with IKBKB, NEMO, or NFKBIA deficiency [34,51,56]. In some patients, significant bacterial infections may still occur, in spite of immune globulin therapy. Treatment of active mycobacterial infections is adjusted according to disease severity and antimicrobial sensitivity. Young patients who have not yet been diagnosed with Mycobacterium avium infection can be treated with antimycobacterial prophylaxis. Surgical treatment of foci of infection may be necessary, particularly for mycobacterial infections. Chronic herpes antiviral prophylaxis is often used in patients who have herpesvirus infections. (See "Primary immunodeficiency: Overview of management" and "Immune globulin therapy in primary immunodeficiency" and "Mendelian susceptibility to mycobacterial diseases: Specific defects".)
Survival ranges from early infancy to late adolescence, with many patients dying in early childhood. The severe course of many patients should lead to consideration of hematopoietic cell transplantation (HCT), especially in patients who have a human leukocyte antigen (HLA)-identical sibling donor and have not yet experienced mycobacterial infection. HCT will not ameliorate ectodermal dysplasia, if present. One patient with NFKBIA deficiency was treated successfully with HCT, but another died from transplant complications [51,54,60]. Patients with NEMO deficiency have also been transplanted successfully, but may not have resolution of all of the clinical manifestations of the disease [61]. In an initial report, two patients with IKBKB deficiency were transplanted successfully, but another died after graft rejection and continued opportunistic infections [56]. Among the 16 patients included in the largest series of cases with IKBKB deficiency [58], eight died of overwhelming infection, and the remaining eight were treated by HCT. Of these, four patients who received unconditioned or reduced-intensity transplantation experienced primary or secondary graft failure. The remaining four received a busulfan-based myeloablative conditioning regimen and attained full or mixed chimerism; three of them were alive at the time of the report. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)
Caspase recruitment domain-containing protein 11 deficiency — 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 NF-kappa-B pathway [62-64].
CARD11 deficiency due to a homozygous mutation was reported in a 13-month-old girl with consanguineous parents [65]. She presented with P. jirovecii pneumonia 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 six 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. Another girl born to consanguineous parents presented at six months of age with P jirovecii pneumonia [66].
Both confirmed patients with this deficiency had hypogammaglobulinemia (one went from isolated reduced immunoglobulin G [IgG] levels to panhypogammaglobulinemia over a three-month period) [65,66]. 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, and terminally differentiated T cell counts were reduced. Activation of the NF-kappa-B 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.
Two patients have successfully undergone HCT [65,66].
A heterozygous, dominant-negative CARD11 mutation (R30W protein defect with loss of function) was reported in four affected members from a single family [67]. 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.
MALT1 deficiency — 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 NF-kappa-B activation [64].
MALT1 deficiency due to a homozygous mutation was reported in a 15-year-old girl and 13- and 7-year-old siblings, both with consanguineous parents [68,69]. 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 [70]. This patient had normal T cell receptor (TCR) excision circles (TREC) levels at birth.
Lymphocyte numbers were normal, with normal T and NK cell numbers. T cell proliferation to mitogens and TCR-mediated activation of NF-kappa-B were absent. IgG, 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 immunoglobulin E (IgE) was chronically elevated in one patent and normal in another.
BCL10 deficiency — Autosomal recessive, complete B cell chronic lymphocytic leukemia (CLL)/lymphoma 10 (BCL10) deficiency 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 [71]. 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 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 4 (TLR4), TLR2/6, and dectin-1 agonists.
OTHER COMBINED IMMUNODEFICIENCY SYNDROMES
Serine threonine kinase 4 deficiency — Serine threonine kinase 4 (STK4, also called mammalian sterile 20-like protein 1 [MST1], MIM #604965) is part of a signaling pathway that controls cell growth, apoptosis, and tumorigenesis [72].
Seven patients from three consanguineous families have been described with STK4 deficiency due to homozygous mutations in STK4 [73,74]. The age at presentation of these patients ranged from the first 1 to 2 years of life to 10 years of age. Two siblings in one of the families died in the first year of life from septicemia (STK4 deficiency suspected but not documented in these patients). Common clinical features reported were recurrent skin and respiratory tract infections (bacterial and viral), bronchiectasis, mucocutaneous candidiasis, extensive molluscum contagiosum, eczematous skin lesions, Epstein-Barr virus (EBV)-associated lymphoproliferative syndrome and lymphoma, and asymptomatic structural cardiac abnormalities. Growth was normal in all patients.
Patients had progressive T cell lymphopenia [73,74]. B and natural killer (NK) cell numbers were low to normal. Hypergammaglobulinemia (IgG, IgA, and IgE) was reported in most patients, while IgM was low to normal. Specific antibody levels were low to normal. Intermittent neutropenia was also reported. A higher rate of lymphocyte apoptosis was seen.
One patient was successfully treated with hematopoietic cell transplantation (HCT) [74]. Her two older siblings died from graft-versus-host disease (GVHD) and infectious complications post-HCT.
Caspase 8 deficiency — Caspases are a family of proteases that play roles in signal transduction by inflammatory cytokine receptors (eg, interleukin [IL] 1 and IL-18), as well as in pathways leading to programmed cell death (apoptosis) [75].
Four patients with caspase 8 deficiency (MIM #697271) due to a mutation in the CASP8 gene have been described to date [76,77]. In the original description, two siblings presented at 11 and 12 years of age with recurrent sinopulmonary bacterial infections and herpes simplex virus infections, poor growth, lymphadenopathy and splenomegaly, eczema, and asthma. Two adult siblings subsequently were reported: one who presented with pulmonary hypertension and the other with a complex neurologic disease with cranial nerve palsies [77]. Both had multiorgan lymphocytic infiltration and granulomas. Caspase 8 deficiency is also referred to as autoimmune lymphoproliferative syndrome type IIB (ALPS2B).
Immunoglobulin levels were normal, although in vivo antibody responses to S. pneumococcus and in vitro production of IgG and IgM were diminished in the first two patients. All four patients had a low CD4 T cell count. T cells showed decreased proliferation and IL-2 production in vitro with mitogens, and NK cell function was also impaired.
Management is directed toward infectious complications and may include immune globulin replacement. The adult patient with pulmonary hypertension required lung transplantation. She developed a fatal Nocardia asteroides meningoencephalitis while on immunosuppression to prevent graft rejection. Her brother with neurologic manifestations and immune dysregulation was treated with glucocorticoids and mofetil mycophenolate [77]. Caspase 8 is ubiquitously expressed, and, therefore, one cannot predict that HCT would be curative.
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 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 mutation in the gene for the CD8 alpha chain (CD8A) on chromosome 2p12 (MIM #608957) was reported in three offspring of consanguineous parents [78]. 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. This phenotype could be consistent with defects of the zeta chain-associated protein 70 (ZAP-70) kinase, defects of MHC class I expression, or defects of CD8 itself. (See "ZAP-70 deficiency" and "CD3/T cell receptor complex disorders causing immunodeficiency".)
There are no published data regarding therapy for these patients. Management is directed toward infectious complications and may include immune globulin replacement.
CD27 deficiency — CD27 is a member of the tumor necrosis factor receptor superfamily (TNFRSF7), and its ligand, CD70 (TNFSF7), is expressed on activated T and B cells. CD27 plays a role in T, B, and NK cell differentiation, function, and survival. (See "Normal B and T lymphocyte development".)
Approximately 20 cases of CD27 deficiency have been identified [79,80]. Most patients have homozygous mutations, although heterozygous mutations have been reported. The predominant clinical features include severe EBV infections with EBV-associated lymphoproliferative disease/hemophagocytic lymphohistiocytosis, uveitis, and Hodgkin lymphoma, as well as other recurrent infections (viral, bacterial, and fungal). The first patient identified was initially thought to have common variable immunodeficiency (CVID). Most patients had onset of symptoms in the first eight years of life. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Common variable immunodeficiency in children".)
Hypogammaglobulinemia is common but is often secondary to treatment with rituximab or other immunosuppressive drugs [80]. The index patient had no CD27+ T or memory B cells [79]. Plasmablast formation via T cell-dependent stimulation was absent, and antibody production was impaired. A reduced T cell response was seen to mitogens that strongly depend upon CD27, but response to recall antigens was normal. NK cell numbers, differentiation, and cytotoxic function were all normal.
Management is directed toward infectious complications and may include immune globulin replacement. The mortality rate is high. Three patients have successfully undergone HCT [80].
CD70 deficiency — CD70 is the counter-receptor of CD27, and autosomal recessive CD70 deficiency has been described in patients whose clinical and immunologic phenotype mirrors that reported in patients with CD27 deficiency [81-83]. (See 'CD27 deficiency' above.)
Dedicator of cytokinesis 2 deficiency — Biallelic (homozygous or compound heterozygous) mutations in dedicator of cytokinesis 2 (DOCK2) gene were identified through whole-exome sequencing in five unrelated patients with early-onset invasive bacterial and viral infections, lymphopenia, and defective T, B, and NK cell responses [84]. Elevated serum IgM was reported in one patient [85]. The mutations included missense and nonsense point mutations, as well as insertions leading to frameshift and premature termination.
DOCK2 is expressed in peripheral blood leukocytes, as well as in the thymus, spleen, and liver. DOCK2 activates RAC1 (Ras-related C3 botulinum toxin substrate 1, 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 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. Reduced T cell receptor excision circle (TREC) levels at birth were documented in one of these patients.
Most patients presented in the first three to four months of life with recurrent viral and bacterial respiratory tract infections [84]. Other early findings included chronic or recurrent diarrhea and growth failure. Disseminated vaccine-strain varicella, local lesion at the site of Bacille Calmette-Guérin (BCG) vaccination, oral moniliasis, and severe infections with M. 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. Two of the identified patients died in early childhood. The other three patients underwent successful HCT. In vitro studies showed normalization of fibroblast defects after treatment with interferon alfa-2b or lentiviral-mediated expression of wild-type DOCK2.
Dedicator of cytokinesis 8 deficiency — Several patients have been identified with mutations in the DOCK8 gene that is predominantly expressed in white blood cells [86-92]. Most of these mutations are loss-of-function homozygous or compound heterozygous point mutations, although some deletions have been identified. DOCK8 deficiency has also been classified as type 2 hyperimmunoglobulin E syndrome (HIES) with autosomal recessive inheritance. (See "Autosomal dominant hyperimmunoglobulin E syndrome".)
Most patients have low absolute lymphocyte counts, including low T cells. B and NK cells are also low in many patients. NK cell function [93], CD8 T cell survival and function [94], peripheral B cell tolerance [95], and regulatory T 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.
Common clinical features include recurrent respiratory tract infections (otitis media, sinusitis, pneumonia), extensive cutaneous viral infections (herpes simplex virus, herpes zoster, molluscum contagiosum, HPV), Staphylococcus aureus skin infections, mucocutaneous candidiasis, atopic disease (atopic dermatitis, severe food and environmental allergies, asthma), hepatic disorders (sclerosing cholangitis, hepatitis), and cancer (vulvar, facial, and anal squamous cell dysplasia and carcinomas, T cell lymphoma-leukemia, and Burkitt and non-Hodgkin lymphomas) [86-88,90,92,96-99].
Almost all of the features associated with autosomal dominant signal transducer and activator of transcription 3 (STAT3) loss-of-function 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 [98].
Distinguishing DOCK8 deficiency from severe atopic dermatitis can also be difficult without specialized diagnostic testing (eg, immunoblot, flow cytometry [100], and 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 memory B cells 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) [101]. 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.
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 [102]. 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 [102].
In one series of 34 patients with germline DOCK8 mutations, one-half had variable degrees of somatic reversion with restoration of DOCK8 expression mainly within antigen experience T cells or NK cells [103]. 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.
Nearly a hundred patients with DOCK8 deficiency have received HCT [92,98,99,102,104-111]. 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 interferon alpha 2b [112-114]. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity", section on 'DOCK8 deficiency'.)
Phosphoglucomutase 3 deficiency — Phosphoglucomutase 3 (PGM3) deficiency causes a hyperimmunoglobulin E-like syndrome with glycosylation defects [115,116] in some patients and a T-B-NK+ severe combined immunodeficiency (SCID) with neutropenia in others [117,118]. PGM3 encodes an enzyme in the biosynthesis of N-glucans. Congenital disorders of glycosylation often lead to immunodeficiencies (eg, leukocyte-adhesion deficiency) because many proteins of the immune system, such as immunoglobulins, adhesion molecules, complement, and cytokines, are glycosylated and glycosylation is required for their function.
The initial patients identified with autosomal recessive PGM3 deficiency were noted to have elevated IgE, eczema, recurrent respiratory tract infections, pneumonias, candidiasis, and abscesses, but no characteristic facies or chemotaxis defects [115,116]. Laboratory findings included neutropenia, T and B cell lymphopenia, and progressive bone marrow failure. Two additional patients have skeletal anomalies, including short stature and dysmorphic facial features [117]. Motor and neurocognitive impairment were also reported in some patients [116]. Four siblings were previously reported with recurrent infections (abscesses, upper and lower respiratory tract infections, severe viral infections), eczema, neutropenia, lymphopenia, eosinophilia, normal IgE, and elevated IgA [119]. None had skeletal or neurologic abnormalities. The one surviving sibling and DNA from one of the deceased siblings had a homozygous PGM3 mutation that results in an unstable protein with decreased enzyme activity [120]. (See "Autosomal dominant hyperimmunoglobulin E syndrome".)
Activated PI3K-delta syndrome — Phosphatidylinositol 3-kinase (PI3K, also called phosphoinositide 3-kinase) activates mammalian target of rapamycin (mTOR) and AKT (a murine thymoma viral oncogene homolog and protein kinase) signaling pathways that control T cell metabolism, proliferation, and effector function [121]. Activation of these pathways shifts intracellular metabolism from beta-oxidation of fatty acids to aerobic glycolysis in effector T cells. T cells switch back to beta-oxidation when they transition from the effector to memory cell state. PI3K also plays a role in B cell development, class-switch recombination (CSR), and survival of mature B cells [122]. p85-alpha, p55-alpha, and p50-alpha are regulatory subunits of PI3K that negatively control PI3K activation.
Activated PI3K-delta syndrome (APDS) or PASLI disease (p110-delta-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency; MIM #615513) is due to heterozygous gain-of-function mutations of the phosphatidylinositol 3-kinase, catalytic, delta (PIK3CD) gene that encodes the p100-delta subunit of PI3K [123-126]. Some patients identified with this defect were previously diagnosed with hyperimmunoglobulin M syndrome (HIGM). A similar disorder is observed in families with heterozygous splice-site mutation of the phosphatidylinositol 3-kinase, regulatory subunit 1 (PIK3R1) gene that encodes the p85-alpha negative regulatory subunit of PI3K, termed APDS2 [127,128]. These syndromes have autosomal dominant inheritance, although sporadic occurrence due to de novo mutations is also possible in both conditions. Null mutations of PIK3R1 are associated with agammaglobulinemia and a block in B cell development [129]. (See "Hyperimmunoglobulin M syndromes".)
Most patients with APDS have low IgA and IgG levels (particularly IgG2), high IgM levels, low specific antibody titers, decreased circulating T and B cells, and impaired CD8+T and NK cell cytotoxicity [123-126]. The proportion of transitional B cells (CD21low CD38hi) is increased, and there are reduced numbers of memory B cells (CD27+), especially those that are class switched. The number of naïve CD4+ and CD8+ T cells is reduced, and there is an increased proportion of effector memory T cells and of T cells expressing markers of senescence (CD57+). In addition, there is increased activation-induced cell death of T cells. In vitro T and B cell proliferation is impaired.
Patients present with recurrent respiratory and ear infections in early childhood and go on to develop progressive airway damage with bronchiectasis.
Patients with APDS/PASLI disease have recurrent sinopulmonary infections with progressive airway damage and bronchiectasis, lymphadenopathy, nodular lymphoid hyperplasia in mucosal tissues, increased incidence of EBV and CMV viremia and EBV-related lymphoma, progressive lymphopenia, elevated serum IgM, and impaired antibody responses [123-125,127,128]. Skin and oral abscesses, splenomegaly, and herpes group virus infections have also been reported [123,130]. Primary sclerosing cholangitis was reported in two adult patients [131]. A similar phenotype is observed in patients with APDS2 [127,128].
Sustained PI3K signaling causes increased activation of the mTOR signaling pathway. Thus, patients with APDS/PASLI or with APDS2 may benefit from treatment with sirolimus (rapamycin), an mTOR inhibitor, that can partially restore NK cell cytotoxicity [124,126]. In addition, specific inhibitors of PI3K p110-delta that are used in the treatment of cancer are also under investigation for the treatment of APDS/PASLI [123,132]. Immune globulin replacement therapy, antimicrobial prophylaxis, surveillance of CMV and EBV viremia, and use of anti-CMV drugs and of rituximab, when indicated, are also part of the mainstays of treatment. HCT is an option in patients who have life-threatening lymphoproliferation and/or infections. Nine of 26 patients in one series underwent HCT with reduced-intensity conditioning, with all but one patient eventually achieving donor engraftment despite frequent complications and initial engraftment failure in a third of patients [133].
The prognosis of APDS/PASLI and of APDS2 is largely determined by the severity and progression of lung disease and by the occurrence of EBV-related lymphoma. Patients can survive into adulthood. However, most patient have persistent symptoms and life-threatening lymphoproliferation, and/or infections are common [133].
Another immunodeficiency due to a defect in the same PI3K subunit has been reported [134]. This mutation results in a nonfunctioning kinase. The patient presented at six years of age with chronic diarrhea and polyarticular arthritis. He had normal numbers of T, B, and NK cells but low IgG and IgA levels. He died from severe pneumonia and sepsis at 14 years of age. An older sibling had died from sepsis at six months of age.
Interleukin 21 and IL-21 receptor deficiencies — 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 CVID [135-137]. (See "Common variable immunodeficiency in children".)
Patients with IL-21R deficiency present in early childhood with recurrent sinopulmonary and gastrointestinal infections with both common and opportunistic organisms [135,137]. The most notable of these is cryptosporidial infections associated with chronic cholangitis, biliary fibrosis, liver disease, and chronic diarrhea. One patient also had fungal infections, lymphoproliferation, and inflammatory skin disease. A patient with IL-21 deficiency had recurrent sinopulmonary infections and very early onset inflammatory bowel disease with chronic nonbloody diarrhea, failure to thrive, and recurrent aphthous stomatitis [136]. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)
T, B, and 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 [135,137]. IgE levels are elevated, specific antibody responses to immunizations are reduced, and some patients have decreased IgG levels. Elevated IgE, decreased IgG, and reduced antibody responses to immunizations were also seen in the patient with IL-21 deficiency [136]. 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.
Three of the seven patients with IL-21R deficiency have died due to complications related to HCT [137]. One additional patient has undergone HCT. The remaining patients are receiving immune globulin replacement therapy. One patient with IL-21 deficiency is receiving prophylactic antibiotics in addition to immune globulin replacement therapy and treatment for inflammatory bowel disease. Administration of recombinant IL-21 is a potential therapeutic option for this patient.
Interleukin 2-inducible T cell kinase (ITK) deficiency — ITK deficiency causes an EBV-associated lymphoproliferative disorder similar to X-linked lymphoproliferative (XLP) disease. This combined immunodeficiency is discussed in greater detail separately. (See "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'ITK deficiency'.)
CTP synthase 1 deficiency — Synthesis of cytidine 5' triphosphate (CTP), which is required for the metabolism of DNA, RNA, and phospholipid, involves two enzymes, CTP synthase 1 and 2 (CTPS1 and CTPS2). CTPS1 is required for proliferation, but not differentiation, of T cells in response to TCR-CD3 activation by antigens. Proliferation of B cells is also dependent upon CPTS1.
Several patients have been identified with a homozygous mutation in CTPS1 that ablates protein expression [138]. Symptoms begin in infancy to early childhood. All patients reported have had severe chronic viral infections and recurrent encapsulated bacterial infections. Two patients had non-Hodgkin lymphoma associated with EBV infection. Three of the eight patients reported in this series had died, and six had undergone HCT. No patients had extra-hematopoietic manifestations.
Most patients had lymphopenia of varying degrees that worsened during infections [138]. The CD4:CD8 T cell ratio was inversed. Proliferation to antigens and mitogens was impaired. Immunoglobulin levels were normal to increased (particularly IgG), although antibody titers to Streptococcus pneumoniae were low.
Transferrin receptor 1 (TfR1) 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 [139]. 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 this series had died, and eight had undergone HCT.
Hypomorphic RAG1 and RAG2 mutations — Mutations in recombination activating genes 1 and 2 (RAG1 and RAG2) can cause SCID. However, "leaky" hypomorphic mutations with partial protein function can have a variable presentation, including Omenn syndrome, granulomatous skin disease, disseminated infection with nontuberculous mycobacteria, autoimmune disease, isolated T cell lymphopenia with late onset of infections, or a clinical phenotype similar to HIGM syndrome or CVID [140-143]. These patients may present beyond early childhood with autoimmune and autoinflammatory complications in addition to chronic recurrent infections [144]. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "Hyperimmunoglobulin M syndromes".)
Late-onset combined immunodeficiency — In the French national study of adults with primary hypogammaglobulinemia, 28 of 313 patients (9 percent) with CVID had late-onset combined immunodeficiency (LOCID), with severe opportunistic infections and/or a CD4 count <200 cells/microL [145]. These patients had a higher incidence of gastrointestinal tract disease, splenomegaly, lymphomas, and granulomas than other patients with CVID. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)
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
●Several genetic mutations lead to variable defects of humoral and cell-mediated immunity (table 1). Combined immunodeficiency syndromes are somewhat arbitrarily distinguished from severe combined immunodeficiency (SCID) in that they do not characteristically lead to death from overwhelming infection in the first year of life. In some cases, mutations of a particular gene may lead to SCID or to milder combined immunodeficiency, depending upon the extent of the gene defect. (See 'Introduction' above.)
●Patients with combined immunodeficiency often present in the first two years of life with recurrent infections and specific findings associated with the different syndromes. However, patients with milder defects may not present until later in childhood or even early adulthood. Many of the combined immunodeficiency syndromes have characteristic-associated clinical features that suggest a particular defect and help direct the diagnostic evaluation. The choice of treatment depends upon the type and severity of the immune defect. (See 'Overview' above.)
●Defects of nuclear factor (NF)-kappa-B regulation, including mutations in NEMO (I-kappa-B kinase gamma chain [IKBKG]) and NF-kappa-B inhibitor protein alpha (NFKBIA; I-kappa-B alpha [IKBA]) cause a combined immunodeficiency usually associated with ectodermal dysplasia. Patients experience severe bacterial or viral infections early in life. Those with NEMO defects also have increased susceptibility to infection with nontuberculous mycobacteria. (See 'Defects of NF-kappa-B regulation' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Francisco A Bonilla, MD, PhD, who contributed as an author to earlier versions of this topic review.
The editorial staff at UpToDate would also like to acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.
