Table 1 Comparison of the ALPID syndromes
Disease | ALPS | CTLA-4 haploinsufficiency and LRBA deficiency | STAT3 GOF | NF-kB1 haploinsufficiency | APDS |
|---|---|---|---|---|---|
Genes | FAS, FASLG, FADD | CTLA4, LRBA | STAT3 | NFKB1 | PIK3CD, PIK3R1 |
Pattern of heredity | Variable inheritance, somatic variants (LOF) | CTLA4: autosomal-dominant, LRBA: autosomal-recessive (LOF) | Autosomal-dominant, somatic variants (GOF) | Autosomal-dominant (LOF) | Autosomal dominant, gain-of-PI3Kδ-activity |
Genetic heterogeneity | High | High | High | High | Low (E1021K hotspot in PIK3CD—90% of cases) |
Penetrance | Incomplete | CTLA-4: incomplete, LRBA: complete | Incomplete | Incomplete | Almost complete |
Mechanism | Defective extrinsic apoptotic pathway | Lack of CTLA-4 and decreased Treg function | Increased STAT3-dependent transcription, decreased function of other STATs | Reduced levels of p105/p50 subunit | Increased activity of PI3Kδ with mTORC1 activation and FOXO1 inhibition |
Age of onset | Variable, majority in childhood | CTLA-4: median 11 years, LRBA: infancy | Median 2,3 years | Highly variable, median 12 years | Median 1 year |
Most common first symptom(s) | Lymphoproliferation | Immune dysregulation | Immune dysregulation | Infections | Infections |
Autoimmunity | Cytopenia | Cytopenia, enteropathy, encephalitis | Cytopenia, enteropathy, diabetes, growth failure | Cytopenia, inflammatory disease | Cytopenia, enteropathy |
Lymphoproliferation | Splenomegaly, lymphadenopathy +  +  | Splenomegaly, lymphadenopathy | Splenomegaly, lymphadenopathy | Splenomegaly, lymphadenopathy | Splenomegaly, lymphadenopathy +  +  + , mucosal lymphoid hyperplasia |
Immunoglobulins | Hyper-IgG, 5–10% hypogammaglobulinemia | Frequent hypogammaglobulinemia | Sometimes hypogammaglobulinemia | Frequent hypogammaglobulinemia | Increased IgM, sometimes hypogammaglobulinemia |
Recurrent infections | Not prominent | Yes, interstitial lung disease | Yes, interstitial lung disease | Yes | Yes, early-onset bronchiectasis |
Immunological findings | Expansion of DNT, sometimes low class-switched B cells | Increased Tfh, increased CD21low, decreased class-switched B cells | Increased CD21low B cells, reduced Treg | Increased CD21low B cells, decreased T cell function | Increased transitional, reduced class-switched B cells, increased senescent T cells |
Disease-specific assay | ALPS biomarkers | Trans-endocytosis assay | STAT3 reporter assay | NF-kB1 reporter assay | S6 phosphorylation |
Targeted therapy | mTOR inhibitor | CTLA-4 fusion protein | JAK inhibitor, anti-IL-6R monoclonal antibody | - | PI3Kδ inhibitor |