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

Severe Combined Immunodeficiency

Workup

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Media Gallery

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.

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Table 1. Immunologic Studies and Findings in Adenosine Deaminase Deficiency

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

Table 2. Intravenous Immunoglobulin ^{[39, 40, 41]}

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).