Purine Nucleoside Phosphorylase Deficiency Clinical Presentation

  • Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD   more...
 
Updated: Aug 29, 2011
 

History

Most patients with purine nucleoside phosphorylase (PNP) deficiency have a history of recurrent viral, bacterial, fungal, mycobacterial, and protozoal infections, similar to patients with severe combined immunodeficiency (SCID).[1, 2] Oral candidiasis that is recalcitrant to therapy occurs in approximately 85% of patients with severe T-cell immunodeficiency. In addition, the presenting infections are often those caused by opportunistic microorganisms, such as Pneumocystis jiroveci pneumonia.

Neurologic problems are commonly associated with purine nucleoside phosphorylase and adenosine deaminase (ADA) deficiencies and have therapeutic implications. More than 50% of patients with purine nucleoside phosphorylase deficiency have neurologic impairments that may predate the onset of infections. Neurologic problems include developmental delay, hypertonia, spasticity, tremors, ataxia, retarded motor development, behavioral difficulties, and varying degrees of mental retardation.[6] Patients with adenosine deaminase deficiency may also have neurologic problems, principally neurodevelopmental delays. Of importance, polyethylene glycol (PEG) adenosine deaminase therapy does not correct the neurodevelopmental problems in adenosine deaminase deficiency, although immune reconstitution does occur. Likewise, bone marrow transplantation does not correct neurological deficits in purine nucleoside phosphorylase or adenosine deaminase deficiencies.

Autoimmune disorders are also frequent in purine nucleoside phosphorylase immunodeficiency.[6] These include autoimmune hemolytic anemia (AHA), idiopathic thrombocytopenia (ITP), autoimmune neutropenia, lupus, thyroiditis, and central nervous vasculitis.

Lymphoma and lymphosarcoma has also been reported in children with purine nucleoside phosphorylase immunodeficiency.

Purine nucleoside phosphorylase immunodeficiency

Patients with purine nucleoside phosphorylase deficiency may have recurrent sinopulmonary infections that may result in a delay in diagnosis until late childhood.

Patients with purine nucleoside phosphorylase deficiency, similar to patients with serious T-cell immune deficiency, are susceptible to herpes infections (eg, varicella).

Patients with purine nucleoside phosphorylase deficiency are also susceptible to recurrent urinary tract infections.

Adenosine deaminase immunodeficiency

Infections typically appear in infancy. However, T-cell function can fluctuate and might not be completely absent. Therefore, a spectrum of T-cell immune deficiency is reported in patients with adenosine deaminase deficiency.

Major clinical phenotypes of adenosine deaminase deficiency have been described, as follows:

  • Neonatal or infantile onset - Indistinguishable from other forms of SCID; bony abnormalities in 50%
  • Delayed - Onset at age 0-2 years; retention of immunoglobulin (Ig) with later attrition, susceptibility to infection similar to that of adenosine deaminase SCID
  • Late onset - Onset at age 3-15 years; may present with recurrent bacterial sinopulmonary infections typical for antibody immunodeficiency, lymphopenia (measure adenosine deaminase and purine nucleoside phosphorylase activity), hyper-IgE, eosinophilia, autoimmunity; may be misdiagnosed as common variable immunodeficiency (CVID) or IgG2-subclass deficiency/specific antibody deficiency
  • Adult onset - Same as late onset, but in adolescents or young adults, plus persistent warts, recurrent herpes zoster, idiopathic thrombocytopenic purpura, lymphopenia; may be misdiagnosed as CVID or IgG2-subclass deficiency/specific antibody deficiency
  • Somatic mosaicism (de novo or revertant mutations) - May show improvement over time without treatment

Both partial adenosine deaminase deficiency and somatic mosaicism have no confirmed immunodeficiency. Some individuals may have very low levels of adenosine deaminase activity in lymphocytes but retain 55-80% normal adenosine deaminase activity in RBCs. These children were healthy in childhood. In addition, revertant mutations of inherited ADA gene mutations have been described.[14]

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Physical

Physical examination reveals a paucity of peripheral lymphoid tissue, such as lymph nodes, tonsillar tissue, and adenoids. The liver and spleen are usually normal in size but can be enlarged in patients with accompanying hemolytic anemia or lymphoma. In neonates, the thymic shadow is typically small on chest radiography. Neurologic symptoms, consisting of developmental delay, hypertonia, spasticity, and tremors, may be present. Patients may fail to thrive.

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Causes

Purine nucleoside phosphorylase deficiency is a genetic disorder caused by a deficiency of the enzyme purine nucleoside phosphorylase. The PNP gene has been localized to band 14q13. Missense mutations have been identified in some patients. The purine nucleoside phosphorylase protein is a trimer with a molecular weight of 84-94 kDa, with the highest levels in lymphoid tissue. The mechanism by which purine nucleoside phosphorylase deficiency causes neurologic disease is unknown.

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Contributor Information and Disclosures
Author

Alan P Knutsen, MD  Professor of Pediatrics, Director of Pediatric Allergy and Immunology, Director Jeffrey Modell Diagnostic & Research Center for Primary Immuodeficiences (CGCMC), Director of Pediatric Clinical Immunology Laboratory, Department of Pathology, St Louis University Health Sciences Center

Alan P Knutsen, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, and Clinical Immunology Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Ann O'Neill Shigeoka, MD †  Former Clinical Associate Professor, Department of Pediatrics, Division of Immunology-Rheumatology, University of Utah School of Medicine

Ann O'Neill Shigeoka, MD † is a member of the following medical societies: American Federation for Medical Research, Clinical Immunology Society, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David J Valacer, MD  Consulting Staff, Hoffman La Roche Pharmaceuticals

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences

Disclosure: Nothing to disclose.

David Pallares, MD  Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville School of Medicine

David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD  Associate Professor, Division of Pulmonary, Allergy/Immunology, and Infectious Diseases, Department of Pediatrics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

References

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  20. O'Reilly RJ, Keever C, Kernan NA, et al. HLA nonidentical T cell depleted marrow transplants: a comparison of results in patients treated for leukemia and severe combined immunodeficiency disease. Transplant Proc. Dec 1987;19(6 Suppl 7):55-60. [Medline].

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  24. Kohn DB, Hershfield MS, Carbonaro D, et al. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA- deficient SCID neonates. Nat Med. Jul 1998;4(7):775-80. [Medline].

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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.
Table 1. Immunologic Studies and Findings in Adenosine Deaminase Deficiency
StudyInfantile OnsetLate OnsetAdult Onset
LymphopeniaMarkedly decreasedDecreasedDecreased
CD3+ cellsAbsent or traceMarkedly reducedMarkedly reduced
CD4/CD8 ratioToo few to test< 1< 1
Phytohemagglutinin responseAbsentReducedReduced
Antigen responseAbsentTraceTrace
Mixed lymphocyte culture responseReduced......
Ig responseAbsentLow to absentNormal (low IgG2)
IgELowElevatedElevated
Antibody responseAbsentAbsent to lowLow to polysaccharides antigens
EosinophiliaRareCommonCommon
InfectionsPredominantly viral, fungal, opportunistic, bacterialBacterial sinopulmonaryBacterial sinopulmonary, varicella-zoster, herpes simplex, candidal
Table 2. Intravenous Immunoglobulin[28, 29, 30]
Brand (Manufacturer)Manufacturing ProcesspHAdditives*Parenteral Form and Final ConcentrationIgA Content (mcg/mL)
Carimune NF (CSL Behring)Kistler-Nitschmann fractionation; pH 4, nanofiltration6.4-6.86% solution: 10% sucrose < 20 mg NaCl/g proteinLyophilized powder 3%, 6%, 9%, 12%Trace
Flebogamma (Grifols USA)Cohn-Oncley fractionation, polyethyline glycol (PEG) precipitation, ion-exchange chromatography, pasteurization5.1-6Sucrose-free, contains 5% D-sorbitolLiquid 5%< 50
Gamunex (Talecris Biotherapeutics)Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation4-4.5Contains no sugar, contains glycineLiquid 10%46
Iveegam EN (Baxter Bioscience)Cohn-Oncley fraction II/III; ultrafiltration; pasteurization6.4-7.25% solution: 5% glucose, 0.3% NaClLyophilized 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 6.4-7.25% solution: 0.3% albumin, 2.25% glycine, 2% glucoseLyophylized 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 4.6-5.10.25M glycineReady-for-use Liquid 10%37
Octagam (Octapharma USA)Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization5.1-610% maltoseLiquid 5%200
Panglobulin (Swiss Red Cross for the American Red Cross)Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration6.6Per gram of IgG: 1.67 g sucrose, < 20 mg NaClLyophilized 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 filtration4.6-5L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizersReady-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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