eMedicine Specialties > Hematology > Disorders of Lymphocytic Function

Combined B-Cell and T-Cell Disorders

Author: Francisco J Hernandez-Ilizaliturri, MD, Assistant Professor, Departments of Medicine and Immunology, Roswell Park Cancer Institute, State University of New York at Buffalo
Coauthor(s): Mohammad Muhsin Chisti, MD, Staff Physician, Department of Internal Medicine, Sisters of Charity, University at Buffalo State University of New York (SUNY) School of Medicine and Biomedical Sciences; Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences; David Claxton, MD, Assistant Professor, Department of Internal Medicine, Section of Hematology-Oncology, Hershey Medical Center, Pennsylvania State University; James O Ballard, MD, Kienle Chair for Humane Medicine, Professor, Departments of Humanities, Medicine, and Pathology, Division of Hematology/Oncology, Milton S Hershey Medical Center, Pennsylvania State University College of Medicine
Contributor Information and Disclosures

Updated: Jun 24, 2008

Introduction

Background

Immunodeficiency is the genetic or acquired failure of the patient's innate or adaptive immunity, resulting in an increased frequency and severity of infections that may lead to catastrophic morbidity, early death, or both.

There has been a considerable gain in knowledge of the pathologic conditions of the immune system since the recognition of primary immunodeficiency as an entity in 1950, highlighted by the discovery of X-linked agammaglobulinemia, congenital neutropenia, and severe combined immunodeficiency (SCID). The description of over 200 diseases with more than 100 genetic etiologies has been described, which has provided opportunities for diagnosis and genetic counseling. Moreover, an understanding of the pathogenesis of primary immunodeficiencies has paved the way for immunologic interventions and new treatments, such as immunoglobulin G (IgG) replacement, bone marrow transplantation, and gene therapy.

Combined B-cell and T-cell immunodeficiencies, or SCID, is a group of medical disorders that are the result of genetic defects in both cellular and humoral immunity. The defects in humoral and cellular immunity have an early clinical presentation and, if untreated, result in a fatal outcome in the first few years of life. This article focuses only on SCID disorders and outlines recent advances in therapeutics options for patients.

The profound degree of immune compromise in SCID leads to infections with bacterial, viral, and fungal pathogens that cause significant morbidity and eventually mortality in patients.

For excellent patient education resources, visit eMedicine's Immune System Center, Bacterial and Viral Infections Center, and Yeast and Fungal Infections Center. Also, see eMedicine's patient education articles HIV/AIDS and Pneumonia.

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Pathophysiology

B and T cells, type 2 dendritic cells, and natural killer (NK) cells share a common ancestor: the common lymphoid progenitor (CLP). CLP differentiates into 2 intermediate progenitors, termed early B cells and T/NK/DC trilineage cells. Both intermediate progenitors continue their development in the bone marrow through primary lymphopoiesis, which is an antigen-independent process. Secondary B-cell lymphopoiesis is an antigen-dependent process that occurs in the germinal centers of peripheral lymphoid organs with specific antibody production. Secondary T-cell lymphopoiesis is also antigen-dependent and occurs in the thymus.

The earlier the defect, the more devastating the effect on lymphopoiesis. Defects occurring at the CLP stage or those affecting processes common to B- and T-cell development result in SCID involving B, T, and NK cells. According to the type of defect that leads to a SCID phenotype, Combined B- and T-cell disorders can be divided into specific groups with unique pathophysiologies that invariably result in an absence of nonfunctional B cells and absence of T cells (see Table 1).

Table 1.  Classification of SCID

Open table in new window

In other circumstances, the defect can affect later events in lymphopoiesis; a major loss or dysfunction in T cells can cause secondary B-cell deficiency, resulting in a clinical disorder that manifests as a combined B- and T-cell deficiency.

There are 4 characterized pathways that can result in SCID are the following:

• Premature cell death caused by the accumulation of purine metabolites (seen in adenosine deaminase (ADA) deficiency)
• Defective V(D)J rearrangements of the TCR and B-cell receptor genes (BCR) (accounts for 30% of SCID cases)
• Defective cytokine-dependent survival signaling in T-cell precursors and sometimes NK-cell precursors (accounts for more than 50% of SCID cases)
• Defective pre-TCR and TCR signaling. Pure T-cell deficiencies are caused by defects in either a CD3 subunit (such as CD3δ, CD3ε, or CD3ζ) or in CD45 tyrosine phosphatase, key proteins involved in pre-TCR and/or TCR signaling at the positive selection stage.

Defects in purine pathway enzymes that result in buildup of metabolites toxic to lymphocytes

ADA is an enzyme of the purine salvage pathway that is responsible for adenosine deamination to inosine and deoxyadenosine deamination to deoxyinosine. The deficiency of this enzyme leads to the accumulation of deoxyadenosine triphosphate (dATP) and 2'-deoxyadenosine. An increase in the intracellular levels of dATP is toxic to lymphocytes because it inhibits the enzyme ribonucleotide reductase, leading to suppression of DNA synthesis, whereas 2'-deoxyadenosine inhibits the enzyme S- adenosyl-L-homocysteine (SAH) hydrolase, which results in accumulation of SAH, a potent inhibitor of all cellular methylation reactions. Both B and T cells are affected, leading to SCID.

Defects in recombination of the antigen receptor genes (RAG) of B-cells and T-cells

Immunoglobulin gene rearrangement begins with heavy-chain gene rearrangement, which is followed by light-chain gene rearrangement. Once the rearrangement process is finished, recombination signal sequences that served to approximate the different genes from each other are removed with the help of the RAG1 and RAG2 proteins. RAG1/RAG2 deficiency is responsible for the B- and T-cell maturation defects in some persons with SCID.

Omenn syndrome is a rare, inherited disorder with a pooly understood pathogenesis. This condition produces a paradoxical combination of immunodeficiency and immune dysregulation, which is the result of mutations in the genes coding for the recombinases (ie, RAG1 and RAG2) t hat cause a defect in the VDJ rearrangement that is needed for mature B-and T-cells to develop.  

In study by Khiong et al, the authors identified a C57BL/10 mouse with a spontaneous mutation in and reduced activity of RAG1.² Mice bred from this animal exhibited major symptoms of Omenn syndrome, including having high numbers of memory-phenotype T cells, experiencing hepatosplenomegaly and eosinophilia, having oligoclonal T cells, and demonstrating elevated levels of IgE. When the CD4+ T cells in the mice were depleted, a reduction in their IgE levels resulted. Thus, Khiong et al concluded the these "memory mutant" mice may be a model for human Omenn syndrome, and many symptoms of the murine disease were direct results of the RAG hypomorphism, whereas some were caused by malfunctions of their CD4+ T-cells.²

Artemis deficiency (with mutations in the Artemis protein that result in defective VDJ recombination) decreases both B and T cells and can be considered part of a subset of SCIDs. DNA ligase IV deficiency likewise results in defective circulating T- and B-cells and serum immunoglobulins.

Bloom syndrome, or congenital telangiectatic erythema, results from a mutation in the helicase enzyme called BLM RecQ. This mutation leads to defects in DNA repair and is characterized by an increased risk of malignancy and radiation sensitivity.

Defects in cytokine receptors and/or cytokine signaling (B cells are generally present but nonfunctional)

An extensive number of disorders with SCID manifestations belong to this category in which Defects in cytokine receptors and/or cytokine signaling are present. Many cytokine receptors (eg, interleukin [IL], IL-2, IL-4, IL-7, IL-9, IL-15) share a common gamma chain, which is necessary for the normal signaling from the receptors after binding with their ligands.³

After binding of IL-2 to its receptor (ie, IL-2R), JAK3 is recruited to the cytoplasmic tail of the receptor and then phosphorylated. In turn, JAK3 phosphorylates a docking site for src homology-containing (SHC) signal transducer and activator of transcription (STAT) proteins. Subsequent phosphorylation and dimerization of STAT with its translocation into the nucleus results in gene transcription and/or activation.

The gene that encodes the gamma chain is located on band Xq13. Approximately 100 mutations have been described in this gene, resulting in an abnormal (two thirds of cases) or absent (one third of cases) gamma C-chain. The absence of the gamma-C chain or the presence of aberrant forms affect signaling events that are mediated via various cytokine receptors, thus explaining the multiple cell types that are affected in X-linked SCID, which include T, NK, and B cells.

X-linked SCID is characterized by the absence of T and NK cells but a normal number of dysfunctional B cells (T– B+ NK– SCID). The development of T cells is dependent on functional IL-7/IL-7R, and that of NK cells is dependent on functional IL-15/IL-15R, whereas the abnormalities of IL-2 and IL-4 pathways affect the function of B cells.

The gene encoding JAK3 is located on band 19p13. JAK3 deficiency results in a rare SCID syndrome that is also associated with absent T and NK cells but a normal number of dysfunctional B cells (T–B+NK–SCID).

The Wiskott-Aldrich syndrome protein (WASP) is encoded by a gene located on band Xp11.22–11.23. This protein has a dual role: (1) it affects immune cell motility and trafficking through its binding with CDC42H2 and rac, members of the Rho family of GTPases, which then results in changes in actin polymerization; and (2) it relays external signals into the nucleus. The mutated gene encodes a WASP that lacks the hydrophobic transmembrane domain and results in defective immune cell trafficking and motility. The abnormality affects all immune cells, including dendritic cells, macrophages, and B and T cells, leading to abnormal initiation and regulation of the immune response and, ultimately, to ineffective secondary lymphopoiesis.

In common variable immunodeficiency (CVID), mature B cells are normal in number and morphology, but they fail to differentiate into plasma cells because of defective interaction between the B and T cells, mostly caused by a T-cell defect. This defect is thought to be related to a decreased number and/or function of CD4⁺ T lymphocytes or, occasionally, to an increased number of CD8+ T lymphocytes; however, abnormal responses of B cells to many usual stimuli have also been identified in vitro.

The underlying abnormality in selective IgM deficiency is a defect of helper T cells and excessive suppressor T-cell activity. The condition is characterized by a low IgM level. IgG) levels are normal, but the IgG response is usually decreased.

T-helper lymphocyte deficiency has been incriminated in the pathogenesis of transient hypogammaglobulinemia of infancy (THI) and immunodeficiency with thymoma.

Primary B-cell disorders result in a complete or partial absence of one or more immunoglobulin isotypes. Regardless of the primary cause, the symptoms depend on the type and severity of the immunoglobulin deficiency and the association of cell-mediated immunodeficiency. In general, severe immunoglobulin deficiency results in recurrent infections with specific microorganisms at certain anatomic sites.

Immunoglobulins play a dual role in the immune response by recognizing foreign antigens and triggering a biologic response that culminates in the elimination of the antigen. Their role in the fight against bacterial infections has been recognized for many years. Emerging evidence from animal and clinical studies suggests a more important role for humoral immunity in the response to viral infections than was initially thought.

IgM plays a pivotal role in the primary immune response. IgG represents the major component of serum antibodies (ie, approximately 85%). By binding to the Fc receptors, they mediate many functions, including antibody-dependent cell-mediated cytotoxicity, phagocytosis, and clearance of immune complexes. IgG1 is the major component of the response to protein antigens (eg, antitetanus/diphtheria antibodies); IgG2 is produced in response to polysaccharide antigens (eg, antipneumococcal antibodies); and IgG3 seems to play an important role in the response to respiratory viruses.

Complement fixation and activation is carried out by IgG1, IgG3, IgM, and, to a lesser degree, IgG2. IgA and, to a lesser extent, IgM, produced locally and secreted in the secretions of mucous membranes, are the major determinants of mucosal immunity.

IgG antibodies are the only immunoglobulin class that crosses the placenta and provides the infant with effective humoral immunity during the first 7-9 months of life.

Deficiency of the expression of major histocompatibility complex (MHC) class I and II cellular proteins also commonly manifests in early infancy with classic symptoms of SCID. Symptoms in affected patients indicate the crucial involvement of MHC proteins in the immune recognition of self and non-self.

In other B- and T-cell disorders, additional anomalies may predominate, and clinical manifestations suggestive of immunodeficiency may occur late in life. Patients with short-limbed skeletal dysplasia with cartilage-hair hypoplasia (CHH) can also have either a T-cell or combined defect.

Combined immunodeficiency due to caspase-8 deficiency presents with recurrent sinopulmonary bacterial infections, poor growth, lymphadenopathy and splenomegaly, ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS). These are part of various mutations of DNA proteins. AT is a rare, autosomal recessive, neurodegenerative disorder in which the diagnosis is based on the presence of both ataxia and telangiectasia; combined immunodeficiency can be quite variable in this condition. Other multisystemic manifestations of AT include motor impairments secondary to a neurodegenerative process, oculocutaneous telangiectasia, sinopulmonary infections, and hypersensitivity to ionizing radiation.

NBS is also an autosomal recessive chromosomal instability syndrome in which patients have increased susceptibility to infection or lymphatic tumor development due to defects in humoral and cellular immune functions. NBS is also characterized by microcephaly with growth retardation, normal or impaired intelligence, and birdlike facies. Nearly all patients with NBS are homozygous for the same founder mutation, ie, deletion of 5 bp (657del5) in the NBS1 gene, which encodes the protein nibrin.

Both AT and NBS are associated with decreased circulating levels of T cells and often decreased levels of the IgA, IgE, and IgG subclasses, whereas circulating levels of B cells are normal.

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Frequency

United States

The accurate incidence of SCID in the United States is unknown, but it has been estimated to be in 1 per 50,000-100,000 births across all ethnic groups. A postulated reason for the lack of exact epidemiologic information is that infants with SCID may die of infections without having been diagnosed with the condition.

X-linked SCID is the most common form of this disorder (approximately 42%), followed by autosomal recessive SCID (22%), ADA deficiency (approximately 15%), and JAK3 deficiency (6%).

The incidence of reticular dysgenesis and CHH are less than 1% each. In approximately 14% of cases, the etiology remains unknown.⁴

International

Estimates for Europe are thought to approximate those in the United States. CHH may be more frequent in Finland. SCID is underreported, but several countries now maintain registries of patients with primary immunodeficiency diseases.

The estimated prevalence of SCID in Australia is 0.15 cases per 100,000; in Norway, 0.045 cases per 100,000; in Switzerland, 0.47 cases per 100,000; in Sweden, 2.43 of every 100,000 live births.⁵

Mortality/Morbidity

SCID is a devastating disease with a high risk of early death in infancy or childhood: a large number of patients die during their first year of life, and most do not survive beyond their second year.

The condition is notable for recurrent failure to thrive and common infections (eg otitis media, diarrhea, mucocutaneous candidiasis). Moreover, if infants are not diagnosed by age 6 months, opportunistic infections follow, especially Pneumocystis carinii pneumonia and invasive fungal infections, and mortality may ensue from common viral illnesses (eg, infections with varicella (VZV), respiratory syncytial virus (RSV), rotavirus, parainfluenza virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), enterovirus, adenovirus).⁴

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Race

Although there is no racial predilection for combined B-cell and T-cell disorders, some forms of combined immunodeficiency have been reported more in some ethnic groups, such as the following⁴ :

• JAK3 mutations in Italy
• MHC class II deficiency of North African origin
• ZAP70 mutations in the Mennonite population
• Artemis gene product–deficiency in Navaho Indians of Athabasca descent
• RAG1/RAG2 –deficient SCID in Europe
• CHH in the Finnish population and the old Amish order in the United States

Sex

The disorders associated with the X chromosome manifest only in males, whereas females are carriers. Approximately 50% of SCID cases are X-linked.

Age

Most patients with these disorders become symptomatic with recurrent infections, failure to thrive, or both in the first months of life.

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Clinical

History

The clinical manifestation landmarks of SCID are secondary to the profound degree of immune compromise leading to repetitive and frequent bacterial, viral, and fungal infections that persist despite standard medical treatment.

Patients with primary T-cell deficiency or SCID begin having infections soon after birth (ie, age 3-4 mo) compared with those that have pure B-cell disorders, who do not have an increased incidence of bacterial infections until 7-9 months after birth, when placental antibodies fall to undetectable levels.

Clinicians should focus attention on the family history, site of infection, type of microorganisms, and any adverse reactions to transfusion of blood products, which may provide clues to the significance and type of immune deficiency. It is also important to inquire about consanguineous relationships because consanguinity increases the risk of immune disorders that have autosomal recessive inheritance patterns (eg, some forms SCID or chronic granulomatous disease [CGD]). In addition, a careful family history of risk factors for human immunodeficiency virus (HIV) should be obtained to rule out secondary forms of immunodeficiency.

Upper and lower respiratory tract infections, skin infections, meningitis, bacteremias, and abscesses are common in persons with B-cell disorders. Pneumonia with P carinii or CMV, disseminated bacille Calmette-Guerin (BCG) infection, or atypical mycobacterial infection and recurrent or persistent skin candidiasis are suggestive of T-cell disorders or SCID. Diarrhea with failure to thrive in children with SCID is usually related to infections with viruses such as rotaviruses and adenoviruses. Although antibody deficiency is associated with recurrent encapsulated bacteria infections, T-cell disorders or SCID are associated with opportunistic infections with fungi, viruses, or intracellular bacteria.

Reactions to blood products or vaccines should raise the suggestion of an underlying immunodeficiency, particularly IgA deficiency. Transfusion with blood products can result in significant graft versus host disease (GVHD) in SCID patients.

After a detailed inquiry, a SCID disorder should be suspected if the patient falls into one of the following groups:

• Prenatal diagnosis
• Neonate with a family history of a known immunologic disorder
• Failure to thrive
• Recurrent upper and lower respiratory tract infections that do not respond to appropriate antibiotics
• Recurrent skin infections and delayed wound healing

• X-linked immunodeficiency with hyper IgM syndrome (XHM)
  • XHM is a part of the hyper-IgM syndromes that includes a group of disorders characterized by recurrent bacterial infections, low serologic levels of IgG, IgA, and IgE, with relatively elevated levels of IgM.
  • XHM affects only boys and is the result of mutations in the gene that encodes the CD40 ligand (CD40L or CD154) located on chromosome X.
  • Patients with XHM present with recurrent infections of the upper and lower respiratory tracts beginning during the first 2 years of life. The susceptibility to P carinii and Clostridium parvum, both opportunistic infections controlled by cellular immunity, may be explained by the nature of the defect underlying this disease, involving T-cell CD40L.
  • These patients have a high incidence of liver disease and sclerosing cholangitis (approximately 20% of patients in a series reported by Levy et al⁶ ; others report 80% by age 20 y), as well as liver and gastrointestinal malignancies.
  • Oral and rectal ulcers are common in patients with chronic neutropenia (approximately 50% of cases).
  • Autoimmune diseases such as arthritis, nephritis, and hematologic disorders have also been reported.
• X-linked severe combined immunodeficiency (XSCID)
  • XSCID is by far the most common form of SCID, accounting for almost 50% of the cases. As the affected gene is located in the X chromosome (X13q band), the disease is limited to males.Because of a defective common gamma chain (a component of cytokine receptors for IL-2, IL-4, IL-7, IL-9, and IL-15), signal transduction cannot proceed normally, which results in SCID characterized by absent T and NK cells and dysfunctional B cells. The phenotype is T–B+NK–. Infections begin in the first months of life, affecting the upper and lower respiratory tracts, gastrointestinal tract, and skin, whereas symptoms in patients with X-linked agammaglobulinemia (XLA) do not manifest symptoms until the second half of an infant's first year of life.Persistent opportunistic infections with Candida albicans or P carinii and viral infections with VZV, CMV, and EBV are common.The risk of GVHD is high in these patients because of their inabilityto reject foreign antigens.
• ADA deficiency
  • ADA is an enzyme of the purine salvage pathway. Deficiency leads to the accumulation of dATP and 2'-deoxyadenosine. dATP is lymphocytotoxic because of its ability to inhibit DNA synthesis via inhibition of ribonucleotide reductase. The nucleoside 2'-deoxyadenosine inhibits the enzyme SAH hydrolase, which results in accumulation of SAH, a potent inhibitor of all cellular methylation reactions. Both B and T cells are affected. The phenotype is T–B–NK–.
  • ADA deficiency is an autosomal recessive disorder in which the age at presentation varies. Failure of the immune system is progressive and may not fully manifest in certain individuals until adulthood.
  • This disease has the same symptoms of XSCID, that is, recurrent infections, persistent opportunistic infections, and GVHD susceptibility. Clinically, ADA deficiency differs from XSCID by (1) the presence of skeletal and chest wall abnormalities involving the vertebral bodies and the chondrocostal junctions and (2) the possible presence of thymic differentiation with rare Hassall concentric corpuscles.
• JAK3 deficiency
  • JAK3 is an intracellular enzyme that is activated as a result of the binding of cytokines with their cognate receptors. The gene encoding JAK3 is located on band 19p13, and the disorder is autosomal recessive. The phenotype is T–B+NK–.
  • The symptoms of this condition are similar to those observed in persons with XSCID and include upper and lower respiratory tract infections, persistent infections with opportunistic microorganisms, and increased susceptibility to GVHD.
• RAG1 and RAG2 deficiency
  • In patients deficient in the RAG proteins 1 and 2, the lymphocytes cannot rearrange the antigen receptors, thus leading to B- and T-lymphocyte deficiency.
  • Phenotypically, the numbers of B and T cells are decreased, whereas the number of NK cells is normal.
  • Clinically, these patients present with increased susceptibility to infection with encapsulated and intracellular bacteria, viruses, and fungi.
  • This syndrome is characterized by high serum IgE levels, decreased levels of the other immunoglobulins, and hypereosinophilia.
  • RAG1 deficiency is observed in patients with CHH. This condition is characterized by short hands; metaphysial chondroplasia; hyperextensibility of the distal joints of hands and feet; and fine, light hair.
• CHH
  • CHH manifests in early infancy with chronic diarrhea, failure to thrive, and an erythematous rash with desquamation. Hepatosplenomegaly is common. Patients die in the first few months of life unless successful allogeneic bone marrow transplantation is performed.
• Reticular Dysgenesis
  • This is a rare disorder that is characterized by an almost complete lack of granulocytes and lymphocytes.
  • Most patients die in early infancy or the newborn period because of severe and overwhelming infection.
  • The molecular basis of the disease is not known
• Wiskott-Aldrich Syndrome
  • WAS affects only males because it is transmitted by an X-linked recessive gene that encodes for the WAS protein (WASP). WASP is a key regulator of actin polymerization in hematopoietic cells. Structural studies of the WASP protein have identified 5 domains that are involved in signaling, cell locomotion, and immune synapse formation. WASP regulates the nuclear factor kappaB (NF-KB) activity by promoting the nuclear translocation of NF-KB. In addition, WASP plays not only an important role in lymphoid development, but also in the maturation of myeloid monocytic cells.
  • Clinically, the syndrome is characterized by the triad of thrombocytopenic purpura, eczema, and increased susceptibility to infections.
  • Symptoms begin in the first year of life, with recurrent upper and lower respiratory tract infections with encapsulated bacteria. P carinii and herpes infections become a problem later in life
  • Most patients die of serious infections at approximately age 11 years. If these patients survive to adulthood, they are at high risk for autoimmune diseases, such as cytopenias and vasculitis, and for cancer, particularly non-Hodgkin lymphomas. The discovery of the Wiskott-Aldrich gene made possible the identification of carriers of the gene in families of WAS patients with an incomplete syndrome. Some of these patients have only the thrombocytopenia (X-linked thrombocytopenia) with no skin involvement or immunodeficiency despite inheriting the same gene mutation.

Physical

The physical examination may identify nonspecific signs of acute or chronic infections and those more specifically related to certain disease entities.

• Growth and development may be delayed as a result of recurrent infections. Dysmorphic syndromes such as short-limbed dwarfism may occur. Hair abnormalities are observed in persons with CHH.
• Lymphoid tissue and organs such as the tonsils, adenoids, and peripheral lymph nodes are underdeveloped in persons with XLA and those with various forms of SCID. Diffuse lymphadenopathy is observed in persons with CVID, XHM, and Omenn syndrome.
• Permanent cutaneous scars are observed following skin infections. A desquamating erythematous rash is observed in persons with Omenn syndrome.
• Evidence of past perforations, scarring, and dull tympanic membranes are observed after recurrent episodes of otitis media. Purulent nasal discharge, a cobblestone pattern of the pharyngeal mucosa, and postnasal exudate may be evident. Note the presence or absence of tonsillar tissue.
• Evaluate for signs such as a loud pulmonic heart sound, right ventricular heave, and tricuspid regurgitation murmur. If present, these signs support the diagnosis of pulmonary hypertension. Jugular venous distention, tender hepatomegaly, and lower-extremity edema suggest cor pulmonale. Pulmonary rales, rhonchi, wheezing, and digital clubbing may be encountered.
• Paralytic poliomyelitis may be present in patients with antibody deficiency following vaccination.
• Deep sensory loss with decreased vibratory sense and position of limb segments are observed in persons with pernicious anemia.

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Causes

SCID disorders are the result of specific genetic alterations in key regulators of B-, T- and/or NK-cell activation, proliferation, or differentiation. The genetic alterations had been identified in some of these disorders, which has led to the investigation of gene therapy as an attractive intervention to treat such conditions.

• XSCID – Genetic defects in the gamma C gene, leading to defects in various cytokine receptors
• ADA deficiency – Genetic mutations in the ADA enzyme
• JAK3 deficiency – Defects in the Janus signaling kinase that interacts with the intracellular portion of the common gamma chain of various cytokine receptors
• RAG1 and RAG2 deficiency – Specific mutations and genetic defects in the RAG1 and RAG2 enzyme
• Omenn syndrome
• CHH – Mutations in RMRP, the RNA component of the ribonucleoprotein complex. RNase MRP consists of an RNA molecule bound to several proteins (as described by Ridanpaa et all, it has at least 2 functions: cleavage of RNA in mitochondrial DNA synthesis and nucleolar cleaving of pre-rRNA.⁷ This group of investigators recently identified several mutations in RMPR in patients with CHH.)
• Reticular dysgenesis
• WAS - Rare X-linked disorder with variable clinical phenotypes that correlate with the type of mutations in the WAS protein (WASP) gene

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