LRBA Deficiency

LRBA deficiency is an autosomal recessive immune dysregulation disorder from biallelic loss-of-function variants in LRBA (lipopolysaccharide responsive beige like anchor protein). It presents in early childhood with hypogammaglobulinaemia, autoimmunity and enteropathy.

Pathophysiology. LRBA normally keeps CTLA-4 from being degraded in lysosomes. Without it, CTLA-4 is lost from the cell surface, so regulatory T cell function fails and T and B cells overreact.

It is rare and is more frequent where consanguinity is common.

Severity varies even within families, and some patients present as a common variable immunodeficiency like disease.

• Recurrent sinopulmonary infection and bronchiectasis
• Autoimmune cytopenias: immune thrombocytopenia, autoimmune haemolytic anaemia
• Chronic diarrhoea and failure to thrive (enteropathy)
• Lymphadenopathy, splenomegaly and hepatomegaly
• Type 1 diabetes, thyroid disease and arthritis
• Interstitial lung disease
• Neurological disease: seizures or focal lesions
• Lymphoma in some

• Immunoglobulins: low IgG, IgA and/or IgM; poor vaccine response.
• Lymphocyte subsets: low B cells and class switched memory B cells, reduced regulatory T cells, and CD4 lymphopenia.
• LRBA protein expression by flow cytometry or immunoblot (absent), with reduced CTLA-4 on regulatory T cells.
• Genetic testing of LRBA (biallelic variants), with parental testing.
• Autoimmune workup: full blood count, direct antiglobulin test, glucose and HbA1c, thyroid function, autoantibodies.
• Imaging: high resolution CT chest, abdominal ultrasound, MRI brain with neurological signs.
• Endoscopy with biopsy for enteropathy.

Differential diagnosis.

• CTLA-4 haploinsufficiency
• Common variable immunodeficiency
• Autoimmune lymphoproliferative syndrome
• IPEX syndrome
• Activated PI3K delta syndrome
• Very early onset inflammatory bowel disease
• Coeliac type enteropathy and food allergy

• Abatacept (off label): 10 mg/kg intravenously (maximum 1000 mg) every 2 weeks for the first 4 doses and then every 4 weeks. It improves enteropathy, cytopenias and lung disease in many patients. Screen for hepatitis B and tuberculosis first and avoid live vaccines.
• Sirolimus for lymphoproliferation or cytopenia: children 1 mg/m2 orally once daily, adults 1 to 2 mg once daily, adjusted to a trough of 5 to 10 microgram/L. Monitor lipids, creatinine, urine protein, mouth ulcers and wound healing.
• Corticosteroids for flares: 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 for refractory cytopenia, after hepatitis B screening.
• 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.
• 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). Azithromycin 500 mg three times weekly in adults (children 10 mg/kg three times weekly, maximum 500 mg) for bronchiectasis, after ECG shows QTc under 450 ms.
• Enteropathy: nutritional support, with parenteral nutrition for severe malabsorption, and exclusion of infection first.
• Haematopoietic stem cell transplantation is the only cure, and is offered early when disease is severe or refractory to abatacept. Control inflammation and infection before conditioning.

Special groups.

• Children: weight based dosing and growth monitoring. Genetic counselling for parents, since each sibling has a 1 in 4 risk.

Monitoring. Full blood count, liver enzymes and creatinine every 3 months. Trough IgG every 3 months. Glucose, HbA1c and thyroid function every 6 months. CT chest and abdominal ultrasound yearly. Growth and weight at every visit.

Referral and escalation. Refer to paediatric or adult immunology and a transplant centre. Urgent for severe cytopenia, neurological signs, uncontrolled diarrhoea, or sepsis.