Summary of clinical and immunological phenotypes of IKZF-associated IEI
| . | IKAROS deficiency . | IKAROS-GOF disease . | HELIOS deficiency . | AIOLOS deficiency . |
|---|---|---|---|---|
| Mechanisms | LOF, HI, DD, DN | GOF | LOF, altered protein interaction, DD | LOF, DN, heteromeric interference, HI, DD |
| Causative gene | IKZF1 | IKZF1 | IKZF2 | IKZF3 |
| Inheritance | AD | AD | AD or AR | AD |
| Reported frequency | 1–2% to 10% within CVID cohort (45, 46, 47) | Unknown | Unknown | Unknown |
| Immunological abnormalities | ||||
| B cell phenotype | B cell deficiency ∼ B lymphopenia (often progressive, mild in DD) | Occasional B lymphopenia | Occasional B lymphopenia | ↓ memory B, occasional B lymphopenia |
| Immunoglobulin levels | Agammaglobulinemia ∼ hypoimmunoglobulinemia | Dysgammaglobulinemia | Occasional hypoimmunoglobulinemia | Agammaglobulinemia ∼ normal range |
| T cell phenotype | Variable, ↓ memory T in DN | ↑ CD4+ TEM and CD8 TEMRA, Th2 skewing, ↓ Treg | CD4+ T and CD8+ T skewing toward memory. Occasional ↓ number or ↓ suppressive function of Treg | Variable, ↓ naïve CD4+ T (other than DN), occasional CD4+ T skewing toward naïve in DN |
| Clinical manifestations | ||||
| Infections | ++ (mild in DD), +++ (DN) | + | ++ | ++, +++ (DN) |
| Immune dysregulation | + | ++ | ++ | ++ (HI and DD) |
| Malignancy | + | +++ | + | + |
| Cytopenias | + | − (occasional AIC) | − (frequent AIC) | + |
| Syndromic manifestation | − | − | + (ICHAD syndrome) | − |
| . | IKAROS deficiency . | IKAROS-GOF disease . | HELIOS deficiency . | AIOLOS deficiency . |
|---|---|---|---|---|
| Mechanisms | LOF, HI, DD, DN | GOF | LOF, altered protein interaction, DD | LOF, DN, heteromeric interference, HI, DD |
| Causative gene | IKZF1 | IKZF1 | IKZF2 | IKZF3 |
| Inheritance | AD | AD | AD or AR | AD |
| Reported frequency | 1–2% to 10% within CVID cohort (45, 46, 47) | Unknown | Unknown | Unknown |
| Immunological abnormalities | ||||
| B cell phenotype | B cell deficiency ∼ B lymphopenia (often progressive, mild in DD) | Occasional B lymphopenia | Occasional B lymphopenia | ↓ memory B, occasional B lymphopenia |
| Immunoglobulin levels | Agammaglobulinemia ∼ hypoimmunoglobulinemia | Dysgammaglobulinemia | Occasional hypoimmunoglobulinemia | Agammaglobulinemia ∼ normal range |
| T cell phenotype | Variable, ↓ memory T in DN | ↑ CD4+ TEM and CD8 TEMRA, Th2 skewing, ↓ Treg | CD4+ T and CD8+ T skewing toward memory. Occasional ↓ number or ↓ suppressive function of Treg | Variable, ↓ naïve CD4+ T (other than DN), occasional CD4+ T skewing toward naïve in DN |
| Clinical manifestations | ||||
| Infections | ++ (mild in DD), +++ (DN) | + | ++ | ++, +++ (DN) |
| Immune dysregulation | + | ++ | ++ | ++ (HI and DD) |
| Malignancy | + | +++ | + | + |
| Cytopenias | + | − (occasional AIC) | − (frequent AIC) | + |
| Syndromic manifestation | − | − | + (ICHAD syndrome) | − |
+, occasional; ++, frequent; +++, frequent and severe. AIC, autoimmune cytopenia; AD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; TEM, effector memory T cells; TEMRA, effector memory T cells re-expressing CD45RA.