Purine Nucleoside Phosphorylase Deficiency

Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive combined immunodeficiency in which T cells fail progressively while B cell function is relatively preserved early. Low serum uric acid and neurological disease distinguish it.

Pathophysiology. Loss of PNP lets deoxyguanosine build up and be converted to deoxyguanosine triphosphate in T cells, which is toxic to developing T lymphocytes. Uric acid is low because PNP acts just before uric acid is formed in purine breakdown.

It is rare. Onset is usually in the first year, but can be as late as early childhood.

Two thirds have neurological disease, and autoimmunity and lymphoma are common.

• Recurrent respiratory infection and chronic diarrhoea in infancy, including Pneumocystis pneumonia
• Opportunistic infection: CMV, EBV, varicella (severe), candidiasis
• Complications of live vaccines (BCG, measles, varicella)
• Neurological disease: developmental delay, hypotonia, spasticity, ataxia, tremor
• Autoimmunity: haemolytic anaemia, thrombocytopenia, neutropenia, lupus, vasculitis
• Lymphoma and other malignancy
• Failure to thrive

• Serum uric acid: very low (under 1 mg/dL, or under 60 micromol/L), the key clue.
• PNP enzyme activity in red cells (absent or under 5% of normal), with raised plasma and urine inosine, guanosine, deoxyinosine and deoxyguanosine.
• Lymphocyte subsets: progressive T lymphopenia (low CD4 and CD8), with normal B cells and NK cells at first.
• Immunoglobulins: normal early, with falling antibody function later.
• Genetic testing of PNP, with family testing.
• Infection workup: viral PCR, Pneumocystis PCR, cultures.
• Neurological assessment: MRI brain, developmental testing.
• Autoimmune workup: full blood count, direct antiglobulin test.

Differential diagnosis.

• Adenosine deaminase deficiency and other combined immunodeficiencies
• Severe combined immunodeficiency
• DiGeorge syndrome
• Xanthine oxidase deficiency and other causes of low uric acid (renal tubular loss, drugs)
• HIV infection
• Cerebral palsy and mitochondrial disease (neurological features)

• Haematopoietic stem cell transplantation is the only cure. It corrects the immune defect but does not reliably reverse neurological damage, so transplant early.
• Pneumocystis prophylaxis from diagnosis: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week (adults 960 mg three times weekly).
• Immunoglobulin replacement for poor antibody function: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Antifungal prophylaxis: fluconazole 3 to 6 mg/kg orally daily (maximum 400 mg); check liver enzymes.
• Viral infection: CMV disease with ganciclovir 5 mg/kg intravenously every 12 hours (adjust to renal function), then valganciclovir. Herpes zoster or varicella: aciclovir 10 mg/kg intravenously every 8 hours (adjust to renal function).
• Autoimmunity: prednisolone 1 mg/kg orally daily (maximum 60 mg) with taper, and early transplant referral. Rituximab 375 mg/m2 intravenously weekly for 4 doses for refractory cytopenia, after hepatitis B screening.
• Spasticity: baclofen start 5 mg orally three times daily in older children and adults, increased every 3 days to the lowest effective dose (maximum 100 mg daily), withdrawn slowly.
• Infection control: avoid live vaccines. Give only irradiated, leukodepleted, CMV-safe blood products.
• Lymphoma: early biopsy of new nodes, with oncology input.

Special groups.

• Infants with a sibling affected: measure uric acid and lymphocyte subsets early, and delay live vaccines.

Monitoring. Lymphocyte subsets and trough IgG every 3 months. Full blood count, liver enzymes and creatinine monthly while unwell. Neurodevelopment and growth at each visit.

Referral and escalation. Refer urgently to a paediatric immunology and transplant centre. Emergency for respiratory distress, sepsis, severe cytopenia or rapidly progressive neurological signs.