Diagnostic Considerations
Because multiple genetic and metabolic disorders can cause combined immunodeficiency (CID), 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.
PNP 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 PNP deficiency than in those with Nezelof syndrome.
Because of the recurrent bacterial sinopulmonary infections, PNP 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 PNP deficiency, these primary B-cell immunodeficiencies are typically characterized by profound decrease in serum Ig levels. In variants of ADA and PNP deficiencies, in which the clinical picture resembles predominant B-cell immunodeficiency (eg, CVID, Bruton agammaglobulinemia), the presence of lymphopenia, especially T lymphopenia, may provide a clinical clue.
Lymphopenia should prompt an evaluation for both ADA and PNP deficiencies. 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 in DGA patients. 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 or microarray analysis.
Differential Diagnoses
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Severe Combined Immunodeficiency
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Biochemical pathway of purine metabolism. AMP = adenosine monophosphate, APRT = adenine phosphoribosyltransferase, GMP = guanosine monophosphate, HGPRT = hypoxanthine-guanine phosphoribosyltransferase, IMP = inosine monophosphate, NP = nucleoside phosphorylase, PPriboseP = 5-phosphorylribose-1-pyrophosphate.
Tables
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 |
Brand (Manufacturer) |
Manufacturing Process |
pH |
Additives* |
Parenteral Form and Final Concentration |
IgA Content (mcg/mL) |
Carimune NF (CSL Behring) |
Kistler-Nitschmann fractionation; pH 4, nanofiltration |
6.4-6.8 |
6% solution: 10% sucrose < 20 mg NaCl/g protein |
Lyophilized powder 3%, 6%, 9%, 12% |
Trace |
Flebogamma (Grifols USA) |
Cohn-Oncley fractionation, polyethyline glycol (PEG) precipitation, ion-exchange chromatography, pasteurization |
5.1-6 |
Sucrose-free, contains 5% D-sorbitol |
Liquid 5% |
< 50 |
Gamunex (Talecris Biotherapeutics) |
Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation |
4-4.5 |
Contains no sugar, contains glycine |
Liquid 10% |
46 |
Iveegam EN (Baxter Bioscience) |
Cohn-Oncley fraction II/III; ultrafiltration; pasteurization |
6.4-7.2 |
5% solution: 5% glucose, 0.3% NaCl |
Lyophilized powder 5% |
< 10 |
Gammagard S/D, Polygam S/D (Baxter Bioscience for the American Red Cross) |
Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation |
6.4-7.2 |
5% solution: 0.3% albumin, 2.25% glycine, 2% glucose |
Lyophylized powder 5%, 10% |
< 1.6 (5% solution) |
Gammagard Liquid 10% (Baxter Bioscience) |
Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation |
4.6-5.1 |
0.25M glycine |
Ready-for-use Liquid 10% |
37 |
Octagam (Octapharma USA) |
Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization |
5.1-6 |
10% maltose |
Liquid 5% |
200 |
Panglobulin (Swiss Red Cross for the American Red Cross) |
Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration |
6.6 |
Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl |
Lyophilized powder 3%, 6%, 9%, 12% |
720 |
Privigen Liquid 10% (CSL Behring) |
Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration |
4.6-5 |
L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers |
Ready-for use liquid 10% |
< 25 |
*IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors (eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs). |
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