Table of Contents
Types of T-Cell Deficiencies
Complete T-cell deficiency results from genetic conditions like severe combined immunodeficiency (SCID) and cartilage-hair hypoplasia. T-cell function is completely insufficient in this type.
Partial T-cell disorders typically have limited T-cell defects that predispose patients to more frequent or extensive infections; these disorders often include immune dysregulation that allows autoimmune phenomena, lymphoproliferation, and malignancies. Examples include acquired immune deficiency syndrome (AIDS), ataxia-telangiectasia, chromosomal breakage syndromes, Wiskott-Aldrich syndrome, and DiGeorge syndrome. Partial T-cell defects commonly cause abnormalities of immune regulation.
- Glucocorticoid therapy
Signs and symptoms
The initial manifestations are often hemorrhagic (usually bloody diarrhea), followed by recurrent respiratory infections, eczema, and thrombocytopenia. Cancers, especially Epstein-Barr virus lymphomas and acute lymphoblastic leukemia, develop in about 10% of patients > 10 years of age.
Common manifestations are:
- Viral infections
- Erythrodermatous rash
- Failure to thrive
The following tests can be used to ascertain the diagnosis:
- Hypersensitivity skin test
- T-cell count
- Culture in the case of infection
- Immunoglobulin levels
- Platelet count and volume assessment
- WBC function tests (e.g., neutrophil chemotaxis, T-cell function)
Diagnosis is based on the following:
- Decreased T-cell count and function
- Elevated IgE and IgA levels
- Low IgM levels
- Low or normal IgG levels
- Decreased natural killer cell cytotoxicity
- Impaired neutrophil chemotaxis
Severe Combined Immunodeficiency
Severe combined immunodeficiency is a genetic disorder. There is disturbed development of functional B and T cells due to several genetic mutations. Multiple mutations result in heterogeneous symptoms. The prevalence of SCID is 1 in 100,000 births. Severe combined immunodeficiency involves defective antibody response due to either direct involvement with B lymphocytes or through improper B-lymphocyte activation due to non-functional T-helper cells. Severe combined immunodeficiency is the most severe form of primary immunodeficiencies. There are now at least 9 different known genes in which mutations lead to a form of SCID.
- Glanzmann-Riniker syndrome
- Severe mixed immunodeficiency syndrome
- Thymic alymphoplasia
Types of SCID
- X-linked severe combined immunodeficiency: Most cases of SCID are due to mutations in the gene encoding the common gamma chain (γc), a protein that is shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.
- Adenosine deaminase deficiency: the 2nd most common form of SCID after X-SCID is caused by a defective enzyme, adenosine deaminase (ADA), necessary for the breakdown of purines.
- Purine nucleoside phosphorylase deficiency: an autosomal recessive disorder involving mutations of the purine nucleoside phosphorylase (PNP) gene
- Reticular dysgenesis: inability of granulocyte precursors to form granules secondary to mitochondrial adenylate kinase-2 malfunction
- Omenn syndrome: The manufacture of immunoglobulins requires recombinase enzymes derived from the recombination activating genes RAG-1 and RAG-2.
- Bare lymphocyte syndrome: There are 2 types of this condition: (1) MHC class 1, which is not expressed on the cell surface; and (2) MHC class 2, which is expressed on the cell surface.
- JAK3: Janus Kinase-3 (JAK3) is an enzyme that mediates transduction downstream of the γc signals.
The disease typically presents in early childhood (2–6 months). Severe opportunistic infections are seen in affected individuals:
- Viral infections
- CBC: reduced T cells
- T-cell morphology: abnormal
- Flow cytometry: T-cell subpopulation deficiency
- Chest X-ray: absent thymus in some cases
- Bone marrow transplantation within the first 3 months of birth
- Intravenous immunoglobulin infusion
- Pneumocystis pneumonia (PCP) prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX)
- Reverse isolation
- Supportive care using immune globulin replacement therapy, antibiotics, and antifungals
- Hematopoietic stem cell transplantation
- Enzyme replacement for ADA deficiency
An autosomal recessive disease, it is a combined deficiency of T cells, immunoglobulins, and neurocutaneous findings. It is due to a defect in the gene encoding ataxia-telangiectasia mutated protein (ATM). The hallmarks of this syndrome are poor coordination and dilatation of small blood vessels.
- Ataxia-telangiectasia syndrome
- Louis-Bar syndrome
Affected individuals have various symptoms presenting at different stages of life. It is usually diagnosed during the 1st year of life. Important features are:
- Ataxia: presents at an early age and worsens with time
- Truncal ataxia by 2 years of age
- Wheelchair-bound by school-age
- Involuntary movements
- Marked telangiectasia on sclera and sun-exposed areas of skin. It is first seen after the age of 5. Skin telangiectasia presents at the age of 7.
- Chronic lung disease
- Disoriented sounds
- Diabetes by adolescence
- Otitis media
- Oculomotor apraxia: the lack of coordination between the head and eye movement while shifting gaze from 1 object to another
- Increased risk of cancers, especially lymphomas and leukemias
- Incomplete pubertal development
- Retarded growth
- Early menopause
- Premature changes in hairs
- Vitiligo and warts are seen in some cases.
- Dysphagia during the 2nd decade of life
- Symptomatic and supportive treatment
- Physical therapy
- Occupational therapy
- Speech therapy
- Anti-Parkinson drugs
- Anti-epileptic drugs
Wiskott-Aldrich Syndrome (WAS)
- Eczema-thrombocytopenia-immunodeficiency syndrome
- Immunodeficiency 2
- Wiskott syndrome
Wiskott-Aldrich syndrome is a disorder of B- and T-cell deficiency. It is caused by WAS gene mutation, which results in a lack of functional Wiskott-Aldrich syndrome protein (WASp).
A lack of WASp leads to impaired actin cytoskeleton, phagocytosis and chemotaxis, and impaired platelet development.
It also causes defective T-cell signaling and interactions with antigen-presenting cells (APCs), and loss of humoral and cellular responses.
Wiskott-Aldrich syndrome has X-linked recessive inheritance. The prevalence of Wiskott-Aldrich syndrome is 1–10 cases per million males. It is rare in females.
Individuals affected with Wiskott-Aldrich syndrome present with recurrent infections (viral, bacterial, and fungal). The frequency of these infections increases with age. The most common bacterial infections are due to Streptococcus pneumonia, Neisseria meningitides, and Haemophilus influenza. Common viral agents are cytomegalovirus and varicella.
Candidiasis is a frequent fungal infection seen in these individuals. Hepatosplenomegaly, eczema, and thrombocytopenia are common. Bruising, hematemesis, hematuria, petechiae, purpura, and epistaxis are frequent, especially in the early days of life.
Thirty percent of individuals have the triad of:
- Chronic otitis media
- Serology: decreased T- and B-cell count
- Immunoglobulins: decrease in IgG and IgM
- Increased levels of IgE and IgA
- Platelet count: 20,000/mm3–50,000/mm3
Gene sequence analysis of WAS confirms the diagnosis.
- Intravenous immunoglobulin
- Hematopoietic stem cell transplantation
Individuals with Wiskott-Aldrich syndrome usually die before the of age 10.
DiGeorge syndrome results from a microdeletion in a small segment of chromosome 22.
The deletion is heterozygous and involves the long arm, q, of chromosome 22, hence the name 22q11.2 deletion syndrome. Up to 50 genes may be affected as a result of such deletions. About 93% of cases are de novo mutations during early fetal development, while 7% are inherited in an autosomal dominant pattern from affected parents. The frequency of DiGeorge Syndrome is 1 in 4,000 births.
Signs and symptoms
There are various symptoms related to DiGeorge Syndrome and marked variability in clinical expression among different individuals. Commonly associated signs and symptoms include the following.
Congenital heart disease
Congenital heart disease is found in around 40% of individuals. Common anomalies are:
- Interrupted aortic arch
- Patent truncus arteriosus
- Tetralogy of Fallot
- Ventricular septal defect
- Poor circulation of oxygenated blood results in palatal defects, particularly cleft palate, and velopharyngeal incompetence.
Affected individuals have characteristic features such as:
- Tubular nose
- Hooded eyes
- Learning difficulties (90% of cases). Attention deficit disorders and cognitive deficits are common.
- Deficiency of growth hormone
- Hypoparathyroidism (50% of the cases). Hypoparathyroidism leads to hypocalcemia.
- Skeletal abnormalities
- Problems related to feeding
- Thymic aplasia due to failure to develop the 3rd and 4th pharyngeal pouches
- Conductive and sensorineural hearing loss
- Seizures, which may be due to hypocalcemia
- Anomalies of respiratory and digestive tracts (laryngotracheoesophageal problems)
- Renal anomalies (up to 37% of patients)
- Autoimmune diseases such as Graves disease and rheumatoid arthritis
- Poor immunity due to reduced T cell
- Psychiatric disorders such as depression, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and schizophrenia
Variations in the phenotypes of DiGeorge syndrome make the diagnosis difficult. Patients who have 1 or more deletion signs are more likely to have 22q11.2 deletion syndrome.
- Genetic testing is used for prenatal diagnosis using BACs-on-Beads or fluorescence in situ hybridization.
- Karyotyping may not detect microdeletions.
- Array-comparative genomic hybridization is used to detect deletions or duplications through screening the entire genome.
- The latest diagnostic methods include quantitative polymerase chain reaction and multiplex ligation-dependent probe amplification assay.
Other lab work and procedures include:
- Cardiac echocardiography (ECHO)
- Serum calcium and phosphorus
- Thyroid profile test
- Chest X-rays to look for thymus
- Immunoglobulin levels
- Renal ultrasound
There is no cure for 22q11.2 deletion syndrome. Management is aimed at treating the associated features of the disease. Treatment revolves around a multidisciplinary approach with the aim of improving the function of affected organ systems.
Immune problems due to the absence of thymus must be identified in the early stages. Blood transfusions and live attenuated vaccines are used with caution in affected individuals. In rare cases, thymus transplantation is also possible. Antibiotics are used to treat frequent bacterial infections. Lifelong calcium and vitamin D supplementation are required to address hypocalcemia resulting from hypoparathyroidism. Surgery can be used to treat structural abnormalities such as congenital heart abnormalities. Early intervention and developmental evaluation are key.