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To date, less than 70 cases have been reported in the world literature. PNP deficiency accounts for approximately 4% of patients with severe combined immunodeficiency (SCID; see this term).

PNP deficiency typically manifests after the 1st year of life, with recurrent, opportunistic infections caused by bacterial, viral (such as varicella zoster virus), and fungal (such as Pneumocystis carinii) pathogens. The susceptibility to infections is variable ranging from classical SCID in infancy to infrequent infections during childhood. Failure to thrive has also been reported. Up to 2/3 of patients have neurologic involvement including motor system dysfunction, hyper/hypotonia, spastic paresis, ataxia, hyperactivity, and behavioral problems. Cerebrovascular accidents and sensorineural deafness are less commonly observed. The neurologic involvement often precedes immune abnormalities. Autoimmune diseases are reported in 1/3 of cases and the most common manifestation of this is autoimmune hemolytic anemia. Immune thrombocytopenic purpura and systemic lupus erythematosus have also been reported (see these terms).

PNP deficiency is caused by loss-of-function mutations in the PNP gene (14q11.2) which encodes a key enzyme (PNP) in the purine salvage pathway. PNP is vital for removal of metabolites of DNA breakdown and promotes recycling of purine bases. Lack of PNP allows intracellular accumulation of such metabolites which are particularly toxic to immature lymphoid cells, leading to lymphopenia and impaired cell-mediated immunity. Intracellular accumulation of purine bases has been suggested to cause neuronal cell apoptosis.

Diagnosis is based on the clinical examination and on laboratory findings showing leucopenia, severe lymphopenia (low CD3, CD4, and CD8 counts and variable B cell function and immunoglobulin levels), and neutropenia. Hallmark diagnostic markers of PNP deficiency include hypouricemia, complete or near complete absence of PNP activity in red blood cell lysate and increased urine or blood levels of inosine, guanosine and their deoxy forms. Diagnosis is confirmed by genetic screening of PNP.

Differential diagnosis includes aplastic anemias, SCID, severe combined immunodeficiency due to adenosine deaminase deficiency, ataxia-telangiectasia (see these terms), and viral meningoencephalitis.

Measurement of T cell receptor excision circles during newborn screening for SCID can detect some patients suffering from PNP deficiency, although removal of metabolites by maternal PNP may delay the deleterious effects on PNP-deficient lymphocytes.

Transmission is autosomal recessive and genetic counseling is recommended.

Specific enzyme replacement is not available for PNP deficiency, although frequent red blood cells transfusions rich in PNP have been shown to provide temporary benefit. Hematopoietic stem cell transplantation (HSCT) is the only treatment option for the severe immune deficiency. Transplanted cells deliver the missing enzyme, thereby restoring purine homeostasis. Supportive treatment, including intravenous immunoglobulin therapy, prophylaxis for Pneumocystis carinii, and physical, occupational, and speech therapy, reduces the risk of infection and may encourage optimal neurologic development for patients.

If left untreated, prognosis is poor and patients usually die in the first decade of life, often succumbing to infections. After HSCT from family or unrelated donors, patients may achieve successful immune reconstitution and are free from infections. Nevertheless, even with HSCT, improvement of neurological deficits is not definite.