What are the clinical presentations and treatment options for a patient with LRBA (Lymphoid Regulatory Barrier A) syndrome?

LRBA Syndrome Clinical Presentation

Core Clinical Features

LRBA (Lipopolysaccharide Responsive Beige-like Anchor protein) deficiency presents as a triad of immune deficiency, autoimmunity, and lymphoproliferation, with autoimmunity being the dominant feature in 80-100% of cases. 1, 2

Primary Clinical Manifestations

Autoimmune Disease (80-100% of patients):

• Autoimmune cytopenias are the most common presentation, occurring in 80% of cases 3
• Evans syndrome (combined autoimmune hemolytic anemia and thrombocytopenia) affects 26.6% of patients 3
• Autoimmune thyroiditis occurs in 20% of cases 3
• Refractory single or multilineage cytopenias may be the initial presenting feature 4

Organomegaly (57-100% of patients):

• Splenomegaly is nearly universal, present in 57-93% of cases 5, 2, 3
• Hepatomegaly frequently accompanies splenomegaly 1
• Lymphadenopathy occurs in 36.4% of patients 1

Gastrointestinal Manifestations (53-63% of patients):

• Chronic diarrhea is a hallmark feature, present in 53-63% of cases 5, 2
• Enteropathy with inflammatory bowel disease-like features 2
• CMV colitis can occur and may be life-threatening 1

Infectious Complications (49-64% of patients):

• Recurrent upper respiratory tract infections occur in 93.3% of cases 3
• Pneumonia affects 49% of patients 2
• Lower respiratory tract infections occur in 53.3% of cases 3
• Opportunistic infections may develop, particularly in severely affected patients 1

Immunologic Phenotype

Hypogammaglobulinemia (54% of patients):

• Progressive decrease in IgG levels occurs in 54.2% of evaluated patients 2
• Notably, hypogammaglobulinemia may be absent at initial presentation 5
• Progressive B cell decline develops over time 3

B Cell Abnormalities:

• Switched-memory B cells are reduced in 73.5% of patients 2
• CD21low B cells are increased in 77.8% of patients 2
• Total B cell percentage/numbers are low in 60% of patients at presentation 3

T Cell Abnormalities:

• CD4+ T cell reduction occurs in 21.6% of patients 2
• Regulatory T cells (Tregs) are decreased in 65.6% of evaluated patients 2
• Double negative T cells (TCRαβ+CD4-CD8-) are increased in 80% of patients 3
• Naive and recent thymic emigrant (RTE) T helper cells are decreased 3
• Effector memory/TEMRA T helper cells are markedly increased 3

ALPS-Like Phenotype

LRBA deficiency can present with features indistinguishable from autoimmune lymphoproliferative syndrome (ALPS), creating diagnostic confusion. 1, 3

• Lymphadenopathy and hepatosplenomegaly with autoimmune cytopenia mimic ALPS 1
• Double negative T cells are elevated in 80% of cases, similar to ALPS 3
• The key distinguishing feature is progressive hypogammaglobulinemia and B cell decline, which develops over time in LRBA deficiency but not in ALPS 3

Additional Clinical Features

Malignancy Risk:

• Lymphoma develops in 26.6% of patients, reflecting impaired immune surveillance 3

Hematologic Abnormalities:

• Lymphopenia occurs in 33% of cases 3
• Intermittent neutropenia affects 27% of patients 3
• Eosinophilia is present in 27% of cases 3

Other Autoimmune Manifestations:

• Autoimmune endocrinopathy may occur 4
• Multiple organ systems can be affected simultaneously 5

Critical Diagnostic Considerations

Genetic confirmation requires identification of biallelic mutations in the LRBA gene, with 85% having homozygous mutations and 15% having compound heterozygous mutations. 2

• Most deleterious missense mutations are located in the DUF1088 and BEACH domains 3
• Protein expression analysis by Western blot or flow cytometry is required when missense variants of uncertain significance are identified 3
• Whole exome sequencing is recommended when clinical suspicion is high 6, 1

Variable expressivity exists even within families with identical mutations—one sibling with a homozygous LRBA defect remained completely asymptomatic while their sibling was severely affected. 3

Common Diagnostic Pitfalls

Do not exclude LRBA deficiency based on normal immunoglobulin levels at presentation, as hypogammaglobulinemia develops progressively over time. 5

In patients initially diagnosed with ALPS, progressive decrease in B cells and IgG levels, along with development of inflammatory bowel disease symptoms during follow-up, should immediately raise suspicion for LRBA deficiency. 3

LRBA deficiency should be included in the differential diagnosis for any patient with autoimmune disease affecting multiple organs, chronic diarrhea, and organomegalies, even without overt immunodeficiency. 5, 2