Table 3.
Mutations associated with peculiar clinical features of IPEX.
| Mutation | Location | Mut Type | Mutation effect | Enteropathy | Mild | Late onset | Relevant clinical features | Notable Lab features | Definitive Treatment | References | N of Pts reported |
|---|---|---|---|---|---|---|---|---|---|---|---|
| c.210+1G>A | N term | SP | var | no | no | T1DM, dermatitis, nephropathy, AIH, thyroiditis | HSCT | (44) | 2 | ||
| c.210+1G>C | N term | SP | Low FOXP3 | yes | no | yes | T1DM, nephropathy, lymphadenopathy, FTT | Rapa | (6) | 1 | |
| c.694T>G, p.C232G | LZ | MS | Normal/low FOXP3, normal/poor Treg suppression | yes | var | var | Recurrent sinopulmonary infections, cutaneous candidiasis, arthritis, T1DM, dermatitis, AIHA, FTT | HGG, B cell class switching defect, Th1/Th17 skewing of cTFH | Variable: no IS, Rapa + ster, HSCT | (18, 51) | 7 |
| c.736-2A>C | Intron 7 | SP | Skipping ex 7, low FOXP3 | var | var | no | Membranous nephropathy, MCN, T1DM, dermatitis, infections, hypothyroidism, AIHA, ITP, FTT | CsA, Tacrolimus, Rituximab, ster | (37, 52) | 3 | |
| c.751_753del, p.E251del | LZ | IFD | Absent FOXP3 | yes | no | var | Late-onset enteropathy with depletion of goblet cells, T1DM, dermatitis, nephropathy, AIHA, ITP, neutropenia, hypothyroidism, CIDP, AIH, FTT | Anti-goblet cells Abs | HSCT | (19, 29, 54) | 4 |
| c.816+ 3G>C | downstream ex 7 | SP | Low FOXP3 | yes | no | no | Dermatitis, nephropathy, thrombosis, fractures, infections, FTT | HSCT | (24) | 1 | |
| c.816+5G>A | downstream ex 7 | SP | Normal FOXP3, normal Treg suppression | yes | no | no | Thyroiditis, adrenal insufficiency, seizures, infections, nephropathy, HSM, lymphadenopathy, lung involvement, AIH, arthritis, neutropenia, T1DM, dermatitis, FTT | HGG, high IgE | Variable: CsA, Rapa, IVIG, ster, AZA, HSCT | (24, 39) | 6 |
| c.816+7G>C | downstream ex 7 | SP | Skipping ex 7, Normal FOXP3 | yes | no | no | T1DM, dermatitis, membranous nephropathy, ILD, seizures, GH deficiency, hypothyroidism, infections, FTT | HGG, high IgE | HSCT | (24, 29, 55) | 4 |
| c.1110 G>A, p.M370I | FKH | MS | Low FOXP3 Treg | yes | no | no | Dermatitis, HSM, lymphadenopathy, nephropathy, lung involvement, AIHA, ITP, neutropenia, AIH, FTT | na | (24, 56) | 2 |
Mut, Mutation; LZ, leucine Zipper domain; FKH, Forkhead domain; SP, Splicing; MS, Missense; IFD, In-frame deletion; ex, exon; var, variable; T1DM, Type 1 diabetes mellitus; FTT, Failure to thrive; AIHA, Autoimmune hemolytic anemia; ITP, Immune thrombocytopenic purpura; CIDP, Chronic inflammatory demyelinating polyneuropathy; AIH, autoimmune hepatitis; HSM, hepatosplenomegaly; ILD, Interstitial lung disease; GH, Growth hormone; HGG, Hypogammaglobulinemia; IS, Immunosuppression; Rapa, Rapamycin/Sirolimus; ster, Steroid; HSCT, Hematopoietic Stem Cell Transplantation; CsA, Cyclosporin A; 6-MP, Mercaptopurine; IVIG, Intravenous immunoglobulins; AZA, Azathioprine; na, not available. Clinical features considered most noteworthy are in bold.