CTLA-4 Haploinsufficiency

CTLA-4 haploinsufficiency is an autosomal dominant immune dysregulation disorder from heterozygous loss-of-function variants in CTLA4. It combines hypogammaglobulinaemia, lymphoproliferation and multi-organ autoimmunity.

Pathophysiology. CTLA-4 normally limits T cell activation by binding CD80 and CD86 on antigen presenting cells and by removing these ligands. With less CTLA-4, regulatory T cells fail and effector T cells infiltrate tissue.

Penetrance is incomplete (about 70%), and the pattern varies, even within one family. Onset is from early childhood to adulthood.

Hypogammaglobulinaemia and autoimmune cytopenias are the most frequent, and lymphoma and gastric cancer are recognised risks.

• Recurrent sinopulmonary infection from low immunoglobulins
• Autoimmune cytopenias: immune thrombocytopenia, autoimmune haemolytic anaemia
• Lymphadenopathy and splenomegaly
• Enteropathy with diarrhoea and weight loss
• Granulomatous lymphocytic interstitial lung disease
• Neurological disease: lymphocytic infiltration of the brain, with headache, seizures or focal deficits
• Endocrine autoimmunity: type 1 diabetes, thyroid disease, adrenal insufficiency
• Hepatic, renal and joint involvement
• Lymphoma and gastric cancer

• Immunoglobulins: low IgG, with low IgA and/or IgM, and poor vaccine response.
• Lymphocyte subsets: progressive CD4 lymphopenia, low B cells and class switched memory B cells, and raised CD21-low B cells.
• CTLA-4 expression by flow cytometry on stimulated regulatory T cells (reduced), with genetic testing of CTLA4 for confirmation.
• Autoimmune workup: full blood count, direct antiglobulin test, thyroid function, glucose and HbA1c, morning cortisol, autoantibodies.
• Organ imaging: high resolution CT chest, MRI brain with neurological symptoms, abdominal imaging.
• Endoscopy with biopsy for enteropathy.

Differential diagnosis.

• Common variable immunodeficiency
• LRBA deficiency
• Autoimmune lymphoproliferative syndrome
• Activated PI3K delta syndrome
• IPEX syndrome and other regulatory T cell disorders
• STAT3 gain-of-function disease
• NFKB1 deficiency

• Abatacept (CTLA-4 immunoglobulin fusion protein, off label for this use): 10 mg/kg intravenously (maximum 1000 mg) every 2 weeks for the first 4 doses and then every 4 weeks. Adults may use 125 mg subcutaneously weekly. Screen for hepatitis B and tuberculosis before starting. Monitor for infection. Avoid live vaccines.
• Immunoglobulin replacement: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Flares of cytopenia or organ inflammation: prednisolone 1 mg/kg orally daily (maximum 60 mg) with taper over 4 to 8 weeks; rituximab 375 mg/m2 intravenously weekly for 4 doses; sirolimus 1 to 2 mg orally once daily in adults, adjusted to a trough of 5 to 10 microgram/L; mycophenolate mofetil 1 g orally twice daily. Check blood count, creatinine and liver enzymes regularly.
• Antibiotic prophylaxis: azithromycin 500 mg orally three times weekly in adults (children 10 mg/kg three times weekly, maximum 500 mg), after ECG shows QTc under 450 ms. Pneumocystis prophylaxis during immunosuppression: co-trimoxazole 960 mg orally three times weekly in adults (children trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week).
• Neurological involvement: early abatacept or rituximab with corticosteroids, under neurology.
• Cancer surveillance: lymph node biopsy for new or asymmetric nodes, gastroscopy at intervals, and cross-sectional imaging for symptoms.
• Haematopoietic stem cell transplantation for refractory disease.

Special groups.

• Family members who carry the variant without disease need clinical review and immunoglobulin measurement, since penetrance is incomplete and disease can appear later.
• Pregnancy: IgG replacement is continued; weigh abatacept continuation with immunology.

Monitoring. Full blood count, liver enzymes and creatinine every 3 months. Trough IgG every 3 months. Thyroid function and glucose every 6 to 12 months. CT chest and abdomen yearly.

Referral and escalation. Refer to immunology. Urgent for new neurological signs, severe cytopenia, rapid lymphadenopathy, or uncontrolled diarrhoea.