Combined B-Cell and T-Cell Disorders Clinical Presentation

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,^[6] 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:^[7]

• 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

The following is a summary of history and physical features that are associated with various forms of SCIDs:

• 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 al^[8] ; 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.^[9] 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 patientsbecauseoftheirinabilitytorejectforeignantigens.
• 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.

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.

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.^[10] 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