Version December 2023
INTRODUCTION — Combined immunodeficiency syndromes encompass a rapidly expanding heterogeneous group of disorders arising from a disturbance in the development and function of both T cell and B cell (cellular and humoral) arms of the adaptive immune system (figure 1 and table 1 and table 2). These disorders are termed "severe" (eg, severe combined immune deficiency [SCID]) when there is a complete absence of T cell function, which leads to early death from overwhelming infection, typically in the first year of life [1]. Pathogenic variants of a particular gene may either lead to SCID or to a milder immunodeficiency, depending upon whether the defect is complete or partial. Gene defects that lead to partial function of the gene product are called "hypomorphic," whereas complete defects are called "null" or "amorphic." Based upon the 2019 International Union of Immunology Societies (IUIS) report, there are 18 genetically defined forms of SCID that are generally categorized based upon the presence or absence of B and/or natural killer (NK) cells in addition to an absence of T cells [2]. In the 2017 IUIS report, a mobile application, "PID Classification," was also introduced, which can be used to aid the evaluation and diagnosis of patients with combined immunodeficiency [3], and this has been updated with the 2019 report.
Brief synopses are given for the molecular types of SCID that are discussed in detail separately:
●X-linked SCID (see "X-linked severe combined immunodeficiency (X-SCID)")
●Adenosine deaminase (ADA) deficiency (see "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis")
●Artemis, recombination-activating gene 1 (RAG1), recombination-activating gene 2 (RAG2), and DNA protein kinase catalytic subunit (DNA-PKcs) deficiencies (see "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "T-B-NK+ SCID: Management")
●Janus kinase 3 (JAK3) deficiency (see "Severe combined immunodeficiency (SCID) with JAK3 deficiency")
●Deficiencies in CD3 complex components (see "CD3/T cell receptor complex disorders causing immunodeficiency")
A general overview of SCID is also presented separately. (See "Severe combined immunodeficiency (SCID): An overview".)
Combined immunodeficiencies that are not considered "severe" are discussed separately (table 1). (See "Combined immunodeficiencies: An overview" and "CD3/T cell receptor complex disorders causing immunodeficiency" and "Purine nucleoside phosphorylase deficiency" and "ZAP-70 deficiency".)
T-B+NK- SCID — Gene pathogenic variants affecting the integrity of the gamma-c/Janus kinase 3 (JAK3) signaling pathway result in T cell-negative, B cell-positive, natural killer-negative (T-B+NK-) SCID and include X-linked SCID and JAK3 deficiency.
X-linked SCID — X-linked SCID (MIM #300400), the most common form of typical SCID, is due to defects in interleukin 2 receptor subunit gamma (IL2RG), which encodes the common gamma chain of the interleukin (IL) 2 receptor shared by five other cytokine receptors (IL-4, -7, -9, -15, and -21). These male patients usually have the classic clinical SCID phenotype, presenting in the newborn period with recurrent severe infections, chronic diarrhea, and failure to thrive if they are not diagnosed via newborn screening (NBS) for SCID. Gene therapy has been developed and used in clinical trials with some early success for this form of SCID. However, late development of leukemia in some patients receiving gamma retroviral-based therapy led to a need to develop safer vectors, which are available only on a research basis [4]. This form of SCID is discussed in greater detail separately. (See "X-linked severe combined immunodeficiency (X-SCID)".)
JAK3 deficiency — Janus kinase 3 (JAK3; encoded on chromosome 19p12-13.1) mediates cytokine signal transduction via gamma-c. This autosomal-recessive form of T-B+NK- SCID (MIM #600802) is identical to X-linked SCID in cellular and clinical phenotypes. Rarely, partial JAK3 defects associated with low amounts of functional protein can present with mild immunodeficiency. SCID due to JAK3 deficiency is discussed in greater detail separately. (See "Severe combined immunodeficiency (SCID) with JAK3 deficiency".)
T-B+NK+ SCID — The T cell-negative, B cell-positive, natural killer-positive (T-B+NK+) SCID syndromes include defects in IL-7 receptor alpha chain (IL7RA; also called CD127); CD45 (also called protein-tyrosine phosphatase, receptor-type, C [PTPRC]); the CD3 chains: CD3 delta (CD3D), CD3 epsilon (CD3E), and CD3 zeta (CD3Z); linker for activation of T cells (LAT); and coronin 1A (CORO1A).
Interleukin 7 receptor alpha chain (CD127) deficiency — The IL7RA chain gene (IL7R, encoded on chromosome 5p13) plays a critical role in cytokine signaling that is necessary for T cell development. Deficiency of the IL7RA chain (MIM #608971) is among the most common types of SCID, and these patients have a typical SCID phenotype [5-7]. Pathogenic variants in the IL7R gene can also present with an Omenn syndrome phenotype [8]. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Omenn syndrome phenotype' and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T-B-NK+ SCID without radiation sensitivity due to RAG defects (includes most cases of Omenn syndrome)'.)
CD45 deficiency — CD45, the leukocyte common antigen (also called protein-tyrosine phosphatase, receptor-type, C [PTPRC]), is encoded on chromosome 1q31-q32. CD45 is a transmembrane tyrosine phosphatase involved in T cell receptor (TCR) signaling and T cell development in the thymus. Only a few patients with classic SCID due to CD45 deficiency (MIM #608971) have been described [9-11].
CD3 complex component deficiencies — The CD3 complex plays a major role in signaling through the TCR. Pathogenic variants in the genes encoding CD3 chains (CD3D, CD3E, and CD3Z) lead to SCID (MIM #615617, #615615, #610163). Patients with CD3 gamma deficiency have varying phenotypes, with some having SCID-like symptoms and some having a more benign course, often marked by immune dysregulation. CD3 chain deficiencies are discussed in greater detail separately. (See "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'CD3 deficiency'.)
Actin-regulating protein coronin 1A deficiency — CORO1A (encoded on chromosome 16p11.2) is involved in actin cytoskeleton regulation and is essential for T cell egress from the thymus. Autosomal-recessive defects in CORO1A lead to absence of normal peripheral T cells and a typical T-B+NK+ SCID phenotype (MIM #615401) with a visible thymus on chest radiograph [12-17]. Other reported features include Epstein-Barr virus-induced B cell lymphoproliferative syndrome and B cell lymphoma at an early age and attention deficit hyperactivity disorder.
LAT deficiency — Autosomal-recessive pathogenic variants in the linker for activation of T cells (LAT) gene lead to a T-B+NK+ SCID phenotype (MIM #617514). The LAT protein plays a crucial role in the process of linking TCR activation to downstream intracellular T cell responses. In addition to immunodeficiency, affected patients also experience severe autoimmune disease, particularly cytopenias. (See "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'LAT deficiency'.)
T-B-NK+ SCID — Genetic defects that disrupt both T and B cell development with preservation of natural killer (NK) cells result in T cell-negative, B cell-negative, NK cell-positive SCID (T-B+NK+ SCID). These SCID syndromes include the VDJ recombination defects due to autosomal-recessive defects in recombination-activating genes 1 and 2 (RAG1 and RAG2); DNA cross-link repair protein 1C (DCLRE1C, the gene for Artemis); protein kinase, DNA-activated, catalytic subunit (PRKDC, also called DNA protein kinase catalytic subunit [DNA-PKcs]); nonhomologous end-joining factor 1 (NHEJ1, also called Cernunnos or XRCC4-like factor [XLF]); and DNA ligase IV (LIG4). These defects are reviewed briefly here and discussed in greater detail separately. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "T-B-NK+ SCID: Management".)
RAG1/RAG2 deficiency — Recombination-activating gene 1 (RAG1) and recombination-activating gene 2 (RAG2) are expressed exclusively in lymphocytes and mediate the creation of double-strand DNA breaks at the sites of recombination and signal sequences during T and B cells receptor gene rearrangement. There has been an increased detection of SCID caused by RAG1/RAG2 defects (MIM #601457), particularly leaky forms of SCID, since the widespread use of SCID newborn screening (NBS) was implemented in the United States [1]. Nonhomologous end joining is normal in individuals with RAG1 or RAG2 deficiency. Autosomal-recessive pathogenic variants in RAG1 and RAG2 are not associated with radiation sensitivity, which has implications for the types of conditioning used prior to hematopoietic cell transplantation for these patients.
DCLRE1C (Artemis) deficiency — Artemis deficiency (MIM #602452) is also known as Athabascan SCID (SCIDA) since a founder pathogenic variant in DNA cross-link repair 1C (DCLRE1C) is found with increased frequency in Native Americans speaking one of the Athabascan family languages (eg, Apache, Navajo). Pathogenic variants in DCLRE1C lead to T-B-NK+ SCID because the Artemis protein is critical to the end-processing step of nonhomologous end joining necessary for V(D)J recombination in T and B cell receptor development. Patients with this form of SCID also demonstrate increased sensitivity to ionizing radiation and alkylator-based chemotherapy used in many preparative regimens for hematopoietic cell transplantation since Artemis is also required for repair of double-strand DNA breaks caused by these insults. A clinical trial of gene therapy for Artemis SCID is available in the US [4].
DNA protein kinase catalytic subunit (DNA-PKcs) deficiency — DNA-PKcs has a role in rejoining double-strand breaks in DNA critical to nonhomologous end joining necessary for V(D)J recombination in T and B cell receptor development. Autosomal-recessive pathogenic variants in PRKDC, the gene for DNA-PKcs, lead to an inability to develop T and B cells (MIM #615966). These patients also demonstrate radiosensitivity and sensitivity to alkylator-based conditioning regimens, similar to patients with SCIDA.
Cernunnos/XLF deficiency — Nonhomologous end-joining factor 1 protein (NHEJ1, also called Cernunnos or XRCC4-like factor [XLF]) is involved in the end-bridging and ligation steps of nonhomologous end joining necessary for V(D)J recombination in T and B cell receptor development. Autosomal-recessive pathogenic variants in NHEJ1 cause Cernunnos/XLF deficiency (MIM #611291). In addition to T-B-NK+ SCID, patients with this genetic defect demonstrate microcephaly and poor growth. These patients also demonstrate radiosensitivity and sensitivity to alkylator-based conditioning regimens, similar to patients with SCIDA.
DNA ligase IV deficiency — DNA ligase IV plays a role in rejoining double-strand breaks in DNA critical to nonhomologous end joining necessary for V(D)J recombination in T and B cell receptor development. Autosomal-recessive pathogenic variants in LIG4, the gene for DNA ligase IV, lead to an inability to develop T and B cells (MIM #611291). Other commonly associated features are microcephaly and growth failure, similar to patients with Cernunnos/XLF deficiency, and radiosensitivity and sensitivity to alkylator-based conditioning regimens, similar to patients with SCIDA.
Activated RAC2 defect — Raas-related C3 botulinum toxin substrate 2 (RAC2) has a role in neutrophil superoxide production as well actin remodeling. Autosomally dominant inherited gain-of-function pathogenic variants in RAC2 have led to T and B cell lymphopenia as well as excessive neutrophil superoxide production in patients (MIM #618986) [18-21]. Some patients were diagnosed following abnormal T cell receptor excision circle (TREC) based NBS for SCID, while others presented with clinical symptoms of recurrent bacterial and viral infections, lymphoproliferation, and neutropenia.
T-B-NK- SCID — T cell-negative, B cell-negative, natural killer cell-negative (T-B-NK-) SCID syndromes include adenosine deaminase (ADA) deficiency and reticular dysgenesis.
Adenosine deaminase deficiency — ADA deficiency (MIM #102700) accounts for approximately 10 to 15 percent of SCID. Approximately 90 percent of patients with ADA deficiency have a classic severe SCID phenotype, and they develop severe infections in the first months of life. Most of the remainder have a "delayed" or "late-onset" form that presents in late infancy or early childhood. Definitive treatments included hematopoietic cell transplantation and gene therapy. Gene therapy using a gamma retroviral-based vector was approved for use in Europe in 2016 and demonstrated good ability to correct the genetic defect. Unfortunately, in late 2020, there was concern for development of T cell lymphoproliferation five years after treatment, and this form of gene therapy was put on hold pending further safety evaluations. Gene therapy with lentiviral vectors is under investigation, but there are not commercially available gene therapy products for ADA-SCID in the US [4]. Polyethylene glycol (PEG) ADA is a reasonably effective therapeutic agent to use as a bridge to definitive therapy. (See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis" and "Adenosine deaminase deficiency: Treatment and prognosis" and "Overview of gene therapy for inborn errors of immunity", section on 'Adenosine deaminase deficiency SCID'.)
Reticular dysgenesis — Reticular dysgenesis (MIM #267500) is one of the rarest and most severe forms of SCID [22-33]. Infants with reticular dysgenesis are often born prematurely and are small for gestational age. Severe infections occur earlier than in other forms of SCID due to profound neutropenia in addition to markedly decreased T and NK cells and absent to low normal B cells. Neutrophil counts do not increase with granulocyte colony-stimulating factor (G-CSF) treatment. Other features include bilateral sensorineural deafness and skeletal abnormalities (squaring of scapular tips and cupping and fraying of the anterior rib costochondral junctions). This autosomal-recessive SCID is caused by pathogenic variants in the mitochondrial adenylate kinase 2 (AK2) gene.
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
●Combined immunodeficiency syndromes are a heterogeneous group of disorders arising from pathogenic variants in genes whose products are essential for the normal development and function of T and B cells (cellular and humoral immunity) (figure 1 and table 1 and table 2). These disorders are termed "severe" (eg, severe combined immune deficiency [SCID]) when there is a complete absence of immune function that typically leads to death from overwhelming infection in the first year or so of life. (See 'Introduction' above.)
●The classic approach has been to classify SCID syndromes as T-B+NK+, T-B+NK-, T-B-NK+, or T-B-NK- based upon the presence of defects affecting T cells and with or without defects also affecting B and/or natural killer (NK) cells (table 2). This paradigm is gradually being replaced by naming these conditions based upon their specific molecular causes. (See 'T-B+NK- SCID' above and 'T-B+NK+ SCID' above and 'T-B-NK+ SCID' above and 'T-B-NK- SCID' above.)
●Knowledge of the gene responsible for the expressed phenotype can have important implications for treatment, especially in the case of T-B-NK+, where radiosensitivity may or may not be present, and in consideration of gene therapy. (See 'T-B-NK+ SCID' above and 'Adenosine deaminase deficiency' above and "Overview of gene therapy for inborn errors of immunity".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.
The UpToDate editorial staff also acknowledges Francisco A Bonilla, MD, PhD, who contributed as an author to earlier versions of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
