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Purine Nucleoside Phosphorylase Deficiency: Differential Diagnoses & Workup
Updated: May 21, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Differential Diagnoses
Severe Combined Immunodeficiency
Other Problems to Be Considered
Because multiple genetic and metabolic disorders can cause common combined immunodeficiency (CID), purine nucleoside phosphorylase (PNP) deficiency should be included in the evaluation when the patient's clinical history and physical findings suggest severe combined T-cell and B-cell immunodeficiency.
Purine nucleoside phosphorylase deficiency may be misdiagnosed as thymic dysplasia (Nezelof syndrome). In both disorders, lymphopenia is observed, with decreased T-cell numbers but normal numbers of B cells, and specific antibody deficiency with normal serum immunoglobulin (Ig) levels is present. However, autoimmune complications and neurologic symptoms are more likely to occur in patients with purine nucleoside phosphorylase deficiency than in those with Nezelof syndrome.
Because of the recurrent bacterial sinopulmonary infections, purine nucleoside phosphorylase deficiency may also be misdiagnosed as B-cell immunodeficiencies, such as common variable immunodeficiency (CVID), hyper–immunoglobulin M (IgM) syndrome, or Bruton agammaglobulinemia. However, in contrast to purine nucleoside phosphorylase deficiency, these primary B-cell immunodeficiencies are typically characterized by profound decrease in serum Ig levels. In variants of adenosine deaminase (ADA) and purine nucleoside phosphorylase deficiency, in which the clinical picture resembles predominant B-cell immunodeficiency (eg, CVID, Bruton agammaglobulinemia), the presence of lymphopenia may provide a clinical clue.
Lymphopenia should prompt an evaluation for both adenosine deaminase and purine nucleoside phosphorylase deficiency. DiGeorge anomaly (DGA) also causes variably decreased numbers of T cells, normal B-cell numbers, and normal serum Ig levels with variably deficient antibody responses. Physical examination usually reveals facial dysmorphism, including low-set ears, hypognathia, and hypertelorism. Conotruncal cardiac defects may or may not be present in DGA. Monosomic deletion of 22q11.2 is present in more than 95% patients with DGA and can be identified by fluorescence in situ hybridization (FISH) analysis.
Workup
Laboratory Studies
- Patients often have autoimmune cytopenias, such as autoimmune hemolytic anemia, idiopathic thrombocytopenia, or autoimmune neutropenia. Patients with purine nucleoside phosphorylase (PNP) deficiency may develop other autoimmune diseases, such as systemic lupus erythematosus (SLE) and thyroiditis.
- Immunoglobulin (Ig)G autoantibodies should be measured when warranted.
- Autoantibodies (eg, antinuclear antibodies [ANA], antibodies to double-stranded DNA [dsDNA], thyroid antibodies) should be measured when clinically indicated.
- Purine nucleoside phosphorylase deficiency
- In purine nucleoside phosphorylase deficiency, immunologic evaluation reveals lymphopenia and markedly decreased CD3+ T cells (<15%), but the percentages and number of B cells are normal. T-cell function may be normal at birth but progressively decreases with age. T-cell function may also fluctuate.
- Serum Ig levels may be decreased but are often normal. Antibody responses to immunizations and infectious pathogens are depressed.
- Diagnosis is confirmed by low purine nucleoside phosphorylase activity in erythrocytes, lymphocytes, and fibroblasts. Low levels of serum uric acid suggest purine nucleoside phosphorylase deficiency but not adenosine deaminase (ADA) deficiency.
- Adenosine deaminase deficiency
- In infantile-onset adenosine deaminase deficiency, lymphopenia and attrition of T-cell, B-cell, and natural killer (NK)-cell function occurs (see Table 1). Profound lymphopenia of less than 500 cells/mcL, is typical of adenosine deaminase severe combined immunodeficiency (SCID) and distinguishes it from other genetic causes of SCID. Percentages of T cells and numbers of CD3+, CD4+, and CD8+ T cells are markedly decreased. Percentages of CD19+ B-cells and CD16+/CD56+ NK-cells vary, but numbers of B and NK cells are markedly decreased, resulting in a T-, B-, NK- phenotype of SCID. T-cell function as measured by lymphoproliferative responses to mitogens, antigens, and alloantigens are absent. Hypogammaglobulinemia and antibody deficiency complete the immune profile of SCID.
- In late-onset adenosine deaminase deficiency, serum Ig levels are low or absent with decreased antibody deficiencies. Lymphopenia and reduced CD3+ and CD4+ T cells are present. Although T-cell responses may be decreased, they are not so suppressed as to predispose patients to intracellular and opportunistic infections. This form may be misdiagnosed as common variable immunodeficiency (CVID). Lymphopenia in a patient with CVID warrants consideration of possible adenosine deaminase deficiency. Eosinophilia and elevated serum IgE levels are present.
- In adult-onset adenosine deaminase, IgG2-subclass deficiency with decreased antibody responses to polysaccharide antigens may be present, predisposing patients to sinopulmonary infection by encapsulated bacteria. Lymphopenia, decreased numbers of CD3+ and CD4+ T cells, elevated serum IgE levels, and eosinophilia are present, as is seen in late-onset ADA deficiency. Recurrent varicella-zoster, herpes simplex, and Candida infections may be present.
- Several immunologic studies may be helpful in assessing adenosine deaminase deficiency, including those seen in the following table: Table 1. Immunologic Studies and Findings in Adenosine Deaminase Deficiency
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[ CLOSE WINDOW ]Table
Study Infantile Onset Late Onset Adult Onset Lymphopenia Markedly decreased Decreased Decreased CD3+ cells Absent or trace Markedly reduced Markedly reduced CD4/CD8 ratio Too few to test <1 <1 Phytohemagglutinin response Absent Reduced Reduced Antigen response Absent Trace Trace Mixed lymphocyte culture response Reduced ... ... Ig response Absent Low to absent Normal (low IgG2) IgE Low Elevated Elevated Antibody response Absent Absent to low Low to polysaccharides antigens Eosinophilia Rare Common Common Infections Predominantly viral, fungal, opportunistic, bacterial Bacterial sinopulmonary Bacterial sinopulmonary, varicella-zoster, herpes simplex, candidal Study Infantile Onset Late Onset Adult Onset Lymphopenia Markedly decreased Decreased Decreased CD3+ cells Absent or trace Markedly reduced Markedly reduced CD4/CD8 ratio Too few to test <1 <1 Phytohemagglutinin response Absent Reduced Reduced Antigen response Absent Trace Trace Mixed lymphocyte culture response Reduced ... ... Ig response Absent Low to absent Normal (low IgG2) IgE Low Elevated Elevated Antibody response Absent Absent to low Low to polysaccharides antigens Eosinophilia Rare Common Common Infections Predominantly viral, fungal, opportunistic, bacterial Bacterial sinopulmonary Bacterial sinopulmonary, varicella-zoster, herpes simplex, candidal
Imaging Studies
- The thymic shadow is absent on chest radiography. Adenoid tissue is absent on lateral airway radiographs.
- In adenosine deaminase deficiency, the characteristic radiographic finding of bony structures are sometimes observed and correlate with bony histologic abnormalities.
- These findings include cupping or flaring of the ribs, similar to the appearance seen in rickets.
- In addition, abnormalities of the vertebral transverse processes and scapula may be observed.
Other Tests
- Genetic studies to examine mutations of genes that encode for ADA and PNP are readily available and should be performed.
- In purine nucleoside phosphorylase deficiency, Grunebaum et al identified “hot spots” at codons 58 and 234 with increased frequency of mutations in the gene that encodes PNP.10,1
Histologic Findings
- In adenosine deaminase deficiency, if thymic biopsy is performed (which is usually not necessary), the results demonstrate marked loss of corticomedullary differentiation; absence of Hassall corpuscles; and depletion of thymocytes, especially in the thymic cortex and medulla.
- In purine nucleoside phosphorylase deficiency, histopathology of lymphoid tissue reveals abnormalities, predominantly in T-cell dependent areas. The thymus is markedly reduced in size, with depleted thymocytes. Hassall corpuscles are present but poorly formed. By comparison, Hassall corpuscles are usually absent in patients with classical SCID. In the lymph nodes and spleen, paracortical regions are reduced or absent. Germinal centers are reduced; however, plasma cells can be identified.
More on Purine Nucleoside Phosphorylase Deficiency |
| Overview: Purine Nucleoside Phosphorylase Deficiency |
 Differential Diagnoses & Workup: Purine Nucleoside Phosphorylase Deficiency |
| Treatment & Medication: Purine Nucleoside Phosphorylase Deficiency |
| Follow-up: Purine Nucleoside Phosphorylase Deficiency |
| Multimedia: Purine Nucleoside Phosphorylase Deficiency |
| References |
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References
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Further Reading
Keywords
purine nucleoside phosphorylase deficiency, PNP deficiency, severe combined immunodeficiency, SCID, adenosine deaminase deficiency, ADA deficiency, purine metabolism, combined immunodeficiency, CID, common variable immunodeficiency, CVID, lymphopenia, autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia, thyroiditis, lupus, failure to thrive, lymphoma, oral candidiasis, Pneumocystis jiroveci pneumonia, developmental delay, hypertonia, herpes, recurrent herpes zoster, idiopathic thrombocytopenic purpura, mental retardation, candidiasis, treatment, diagnosis
