ZAP70 Deficiency

ZAP70 deficiency is an autosomal recessive combined immunodeficiency from biallelic variants in ZAP70, with absent CD8 T cells and non-functional CD4 T cells. It presents in infancy like severe combined immunodeficiency, although immunoglobulins can be normal.

Pathophysiology. ZAP70 is a kinase downstream of the T cell receptor. Without it, CD8 T cells fail to develop in the thymus, and CD4 T cells that develop cannot respond to antigen. Selection defects can also release autoreactive T cells.

It is very rare. Most cases present in the first year, with some milder and later presentations.

Because CD4 cell counts are normal, the disorder can be missed on a simple lymphocyte count.

• Recurrent severe respiratory infection, including Pneumocystis pneumonia
• Chronic diarrhoea and failure to thrive
• Oral candidiasis and viral infection (CMV, adenovirus, respiratory syncytial virus)
• Complications after BCG or other live vaccines
• Autoimmunity and Omenn like features: erythroderma, eosinophilia, lymphadenopathy
• Milder phenotype later in childhood: skin disease, cytopenias, colitis

• Lymphocyte subsets: absent or very low CD8 T cells, normal or raised CD4 T cells, normal B and NK cells.
• T cell function: poor proliferation to T cell receptor stimulation (anti-CD3, antigens), with normal response to mitogens that bypass the receptor (phorbol ester and ionomycin).
• ZAP70 protein expression by flow cytometry and sequencing of ZAP70 (biallelic variants).
• Immunoglobulins: normal or variable, with poor specific antibody responses.
• TREC screen at birth may be low where it is performed.
• Infection workup: viral PCR, Pneumocystis PCR, cultures, chest imaging.
• Skin and gut biopsy when Omenn like disease is suspected.

Differential diagnosis.

• Severe combined immunodeficiency, other types
• MHC class I deficiency
• Omenn syndrome
• CD8 deficiency from CD8A variants
• DiGeorge syndrome
• HIV infection (infants)
• Secondary lymphopenia

• Haematopoietic stem cell transplantation is the definitive treatment and should be done early, ideally in infancy.
• Protective environment: infection control, breast milk from CMV-negative mothers or screened feeds, and up-to-date vaccination of household contacts.
• Pneumocystis prophylaxis: co-trimoxazole with trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week.
• Antifungal prophylaxis: fluconazole 3 to 6 mg/kg orally daily (maximum 400 mg); check liver enzymes.
• Immunoglobulin replacement for poor antibody function or infection: 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.
• Viral infection: treat CMV disease with ganciclovir 5 mg/kg intravenously every 12 hours (adjust to renal function), then valganciclovir.
• Autoimmunity and Omenn like disease: prednisolone 1 mg/kg orally daily (maximum 60 mg) as a bridge, with early transplant referral.
• Live vaccines (BCG, rotavirus, oral polio, measles-mumps-rubella, varicella) are contraindicated. Use irradiated, leukodepleted, CMV-safe blood products.

Special groups.

• Infants with a positive newborn screen or a sibling with the disorder: flow cytometry in the first weeks, and delay of live vaccines until immunity is checked.

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

Referral and escalation. Refer urgently to a paediatric immunology and transplant centre. Emergency for respiratory distress, sepsis, or erythroderma.