Clinical and laboratory feature in patients with heterozygous IKZF1 dimerization defective mutations
| . | A.I.1 (g-mother) . | A.II.1 (father) . | A.III.1 (index pt) . | B.I.1 (mother) . | B.II.1 (index pt) . | C.I.1 (g-mother) . | C.II.1 (mother) . | C.II.2 (aunt) . | C.II.3 (aunt) . | C.III.1 (index pt) . | C.III.2 (sister) . | D.I.1 (father) . | D.II.1 (index pt) . | Reference . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mutation | p.R213* | p.R213* | p.R213* | p.S427* | p.S427* | p.C467R | p.C467R | p.C467R | p.C467R | p.C467R | p.C467R | p.R502L | p.R502L | % of total lymphocytes |
| Age, y; sex | 74; F | 48; M | 17; M | 74; F | 31; M | 66; F | 44; F | 36; F | 38; F | 18; F | 21; F | 50; M | 15; M | |
| Age at onset, y; diagnosis | 9; ITP | 2.5; T-ALL | 9; ITP | 9; Burkitt lymphoma | ||||||||||
| Lymphocyte phenotyping | ||||||||||||||
| CD3 T, ALC | 812 | 1384 | 970 | 797 | 1348 | 2510 (H) | 1196 | 1821 | 1004 | 1394 | 1556 | 2095 | 4181 (H) | 714-2266 |
| CD3 T, % | 81.2 | 87.6 (H) | 85.8 (H) | 57 (L) | 89.3 (H) | 91.6 (H) | 87.3 (H) | 80.2 | 85.8 (H) | 91.1 (H) | 77.4 | 77.6 | 88.2 (H) | 60-83.7 |
| CD4 T, ALC | 346 (L) | 272 (L) | 421 | 558 | 477 | 1121 | 523 | 742 | 580 | 915 | 824 | 1450 | 2176 (H) | 359-1565 |
| CD4 T, % | 34.7 | 17.2 (L) | 37.3 | 39.9 | 31.6 (L) | 40.9 | 38.2 | 32.7 | 49.6 | 59.8 | 41 | 53.7 | 45.9 | 31.9-62.2 |
| CD4+CD62L+CD45RA+, % | n.d. | 3.8 (L) | 11.6 | n.d. | 3.4 (L) | 3.2 (L) | 7.7 | 4.9 (L) | 14.2 | 20.4 | 8.5 | 18.2 | 25.6 | 7.6-37.7 |
| CD4+CD62L+CD45RA−, % | n.d. | 10.2 (L) | 21.5 | n.d. | 24.7 | 34 (H) | 23 | 25 | 31.3 (H) | 33.9 (H) | 25.4 | 22.8 | 15.1 | 10.4-30.7 |
| CD4+CD62L−CD45RA−, % | n.d. | 3.1 | 4 | n.d. | 3.5 | 3.7 | 6.8 | 2.7 | 4 | 5.2 | 6.6 | 11.7 | 4.6 | 2.3-15.6 |
| CD4+CD62L−CD45RA+, % | n.d. | 0.2 | 0.3 | n.d. | 0 | 0 | 0.6 | 0 | 0.1 | 0.3 | 0.5 | 1.1 | 0.6 | 0-1.5 |
| CD8 T, ALC | 441 | 1063 (H) | 483 | 230 | 808 | 1145 (H) | 564 | 826 | 335 | 412 | 607 | 508 | 1673 (H) | 178-853 |
| CD8, % | 44.1 (H) | 67.3 (H) | 42.7 (H) | 16.5 | 53.5 (H) | 41.8 (H) | 41.2 (H) | 36.4 (H) | 28.6 | 26.9 | 30.2 | 18.8 | 35.3 (H) | 11.2-34.8 |
| CD8+CD62L+CD45RA+, % | n.d. | 26.8 (H) | 20.7 (H) | n.d. | 22 (H) | 18.8 | 11.3 | 16.2 | 16.4 | 20.2 (H) | 16 | 7.2 | 26.2 (H) | 5.7-19.7 |
| CD8+CD62L+CD45RA−, % | n.d. | 6.9 | 6.1 | n.d. | 9.1 | 11.5 (H) | 5.2 | 14 (H) | 7.7 | 1.9 | 6.1 | 3.1 | 2.3 | 1.5-10.3 |
| CD8+CD62L−CD45RA−, % | n.d. | 4.7 | 7.2 | n.d. | 3.2 | 3.1 | 5.4 | 5.2 | 2.6 | 2.3 | 3 | 6 | 3.8 | 1.1-9.2 |
| CD8+CD62L−CD45RA+, % | n.d. | 28.8 (H) | 8.7 (H) | n.d. | 19.2 (H) | 8.4 (H) | 19.3 (H) | 1 | 1.9 | 2.5 | 5.1 | 2.4 | 3 | 0.7-7.8 |
| CD4/CD8 ratio | 0.79 (L) | 0.26 (L) | 0.87 (L) | 2.42 | 0.59 (L) | 0.98 (L) | 0.93 (L) | 0.9 (L) | 1.73 | 2.22 | 1.36 | 2.86 | 1.3 | 1.11-5.17 |
| CD4+CD45RA+CD31+, % | n.d. | n.d. | 8.6 | n.d. | 2.1 | n.d. | 4.8 | n.d. | n.d. | 13.9 | 4.6 | 9.5 | 18.6 | 1.6-20.2 |
| CD4+CD45RA−CXCR5+, % | n.d. | n.d. | 3.4 | n.d. | 5 | n.d. | 7.3 | n.d. | n.d. | 7.6 | 8.5 | 3.2 | 2.9 | 1.8-8.9 |
| CD4+CD25+FOXP3+, % | n.d. | n.d. | 2 | n.d. | 2 | n.d. | 0.6 (L) | n.d. | n.d. | 1.6 | 0.9 (L) | 2.3 | 1.7 | 1.6-4.3 |
| CD20 B, ALC | 76 | 38 (L) | 35 (L) | 247 | 27 (L) | 121 | 92 | 118 | 41 (L) | 44 (L) | 217 | 154 | 351 (H) | 59-329 |
| CD20 B, % | 7.6 | 2.4 (L) | 3.1 | 17.7 | 1.8 (L) | 4.4 | 6.7 | 5.2 | 3.5 | 2.9 (L) | 10.8 | 5.7 | 7.4 | 3-19 |
| CD20+CD27−IgM+ % | n.d. | 78.8 | 84.5 | n.d. | 39.2 (L) | 84.2 | 91.2 | 84.8 | 98.7 (H) | 98.8 (H) | 89.3 | 53.3 (L) | 86.6 | 56.2-91.5 (% of B cells) |
| CD20+CD27+IgM+, % | n.d. | 12.0 | 12.5 | n.d. | 45.19 (H) | 4.3 (L) | 3.9 (L) | 5.7 | 0.5 (L) | 0.9 (L) | 6.9 | 29.9 | 7.9 | 4.8-38.5 (% of B cells) |
| CD20+CD27+IgM−, % | n.d. | 6.6 | 2 (L) | n.d. | 6.5 | 6.1 | 3.2 (L) | 6.2 | 0 (L) | 0.2 (L) | 2.7 (L) | 15.4 | 2.6 (L) | 4.3-19.9 (% of B cells) |
| CD19+CD24++CD38++, % | n.d. | 6.1 | 18.7 | n.d. | 0 (L) | 16.8 | 7.7 | 4.9 | 11.1 | 3.2 (L) | 10.6 | 4.2 (L) | 4.1 (L) | 4.7-18.7 (% of B cells) |
| CD19+CD24−CD38+, % | n.d. | 0.6 | 0.3 | n.d. | 0 (L) | 0.1 (L) | 0.1 (L) | 0.4 | 0 (L) | 0 (L) | 0.1 (L) | 1.5 | 0.7 | 0.3-3.6 (% of B cells) |
| NK, ALC | 106 (L) | 158 | 130 | 353 | 134 | 104 (L) | 85 (L) | 336 | 125 (L) | 95 (L) | 233 | 454 | 209 | 126-729 |
| NK, % | 10.61 | 10 | 11.5 | 25.2 | 8.9 | 3.8 (L) | 6.2 | 14.8 | 10.7 | 6.2 | 11.6 | 16.8 | 4.4 (L) | 6.2-34.6 |
| Immunoglobulins, mg/dL | ||||||||||||||
| IgG | n.d. | 516 (L) | 1001* | 672.7 (L) | 349 (L) | 1147 | n.d. | n.d. | 59.8 (L) | 984* | n.d. | n.d. | 740 | 700-1600 |
| IgA | n.d. | 36 (L) | 49 (L) | 90.5 | 28 (L) | 98 | n.d. | <10 (L) | 12 (L) | n.d. | n.d. | 112 | 70-400 | |
| IgM | n.d. | 15 (L) | 14 (L) | 54.3 | <7 (L) | <10 (L) | n.d. | n.d. | <10 (L) | 6 (L) | n.d. | n.d. | 98 | 40-230 |
| Autoantibodies | n.d. | n.d. | Anti-platelet Ab positive, Coombs negative | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | Coombs positive | n.d. | n.d. | ANA positive, anti-dsDNA negative, Coombs negative | |
| ANA positive | ||||||||||||||
| Vaccine response | n.d. | n.d. | Progressive loss of protective titers toward pneumococcal and HiB antigens | n.d. | Positive to 1/14 pneumococcal serotypes, nonprotective titers to tetanus toxoid, diphtheria toxoid, measles, mumps, rubella or varicella | Positive to 5/23 pnemococcal serotypes prevaccination and 8/23 postvaccination, tetanus protective | n.d. | n.d. | n.d. | Positive to 2/14 pnemococcal serotypes, protective to diphtheria and tetanus | n.d. | n.d. | n.d. | |
| Clinical history | Asymptomatic | 1 pneumonia (age 25 y), pernicious anemia | ITP, progressive hypogammaglobulinemia | Type 2 diabetes, hypothyroidism | T-ALL, recurrent diarrhea, hypogammaglobulinemia | Pneumonia (×2, starting in her 50s) | Asymptomatic | Asymptomatic | Recurrent URIs, hypogammaglobulinemia, fibromyalgia | ITP, AIHA, hypogammaglobulinemia s/p rituximab | Hashimoto’s | Asymptomatic | Burkitt lymphoma, lymphadenopathy, ITP, neutropenia |
| . | A.I.1 (g-mother) . | A.II.1 (father) . | A.III.1 (index pt) . | B.I.1 (mother) . | B.II.1 (index pt) . | C.I.1 (g-mother) . | C.II.1 (mother) . | C.II.2 (aunt) . | C.II.3 (aunt) . | C.III.1 (index pt) . | C.III.2 (sister) . | D.I.1 (father) . | D.II.1 (index pt) . | Reference . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mutation | p.R213* | p.R213* | p.R213* | p.S427* | p.S427* | p.C467R | p.C467R | p.C467R | p.C467R | p.C467R | p.C467R | p.R502L | p.R502L | % of total lymphocytes |
| Age, y; sex | 74; F | 48; M | 17; M | 74; F | 31; M | 66; F | 44; F | 36; F | 38; F | 18; F | 21; F | 50; M | 15; M | |
| Age at onset, y; diagnosis | 9; ITP | 2.5; T-ALL | 9; ITP | 9; Burkitt lymphoma | ||||||||||
| Lymphocyte phenotyping | ||||||||||||||
| CD3 T, ALC | 812 | 1384 | 970 | 797 | 1348 | 2510 (H) | 1196 | 1821 | 1004 | 1394 | 1556 | 2095 | 4181 (H) | 714-2266 |
| CD3 T, % | 81.2 | 87.6 (H) | 85.8 (H) | 57 (L) | 89.3 (H) | 91.6 (H) | 87.3 (H) | 80.2 | 85.8 (H) | 91.1 (H) | 77.4 | 77.6 | 88.2 (H) | 60-83.7 |
| CD4 T, ALC | 346 (L) | 272 (L) | 421 | 558 | 477 | 1121 | 523 | 742 | 580 | 915 | 824 | 1450 | 2176 (H) | 359-1565 |
| CD4 T, % | 34.7 | 17.2 (L) | 37.3 | 39.9 | 31.6 (L) | 40.9 | 38.2 | 32.7 | 49.6 | 59.8 | 41 | 53.7 | 45.9 | 31.9-62.2 |
| CD4+CD62L+CD45RA+, % | n.d. | 3.8 (L) | 11.6 | n.d. | 3.4 (L) | 3.2 (L) | 7.7 | 4.9 (L) | 14.2 | 20.4 | 8.5 | 18.2 | 25.6 | 7.6-37.7 |
| CD4+CD62L+CD45RA−, % | n.d. | 10.2 (L) | 21.5 | n.d. | 24.7 | 34 (H) | 23 | 25 | 31.3 (H) | 33.9 (H) | 25.4 | 22.8 | 15.1 | 10.4-30.7 |
| CD4+CD62L−CD45RA−, % | n.d. | 3.1 | 4 | n.d. | 3.5 | 3.7 | 6.8 | 2.7 | 4 | 5.2 | 6.6 | 11.7 | 4.6 | 2.3-15.6 |
| CD4+CD62L−CD45RA+, % | n.d. | 0.2 | 0.3 | n.d. | 0 | 0 | 0.6 | 0 | 0.1 | 0.3 | 0.5 | 1.1 | 0.6 | 0-1.5 |
| CD8 T, ALC | 441 | 1063 (H) | 483 | 230 | 808 | 1145 (H) | 564 | 826 | 335 | 412 | 607 | 508 | 1673 (H) | 178-853 |
| CD8, % | 44.1 (H) | 67.3 (H) | 42.7 (H) | 16.5 | 53.5 (H) | 41.8 (H) | 41.2 (H) | 36.4 (H) | 28.6 | 26.9 | 30.2 | 18.8 | 35.3 (H) | 11.2-34.8 |
| CD8+CD62L+CD45RA+, % | n.d. | 26.8 (H) | 20.7 (H) | n.d. | 22 (H) | 18.8 | 11.3 | 16.2 | 16.4 | 20.2 (H) | 16 | 7.2 | 26.2 (H) | 5.7-19.7 |
| CD8+CD62L+CD45RA−, % | n.d. | 6.9 | 6.1 | n.d. | 9.1 | 11.5 (H) | 5.2 | 14 (H) | 7.7 | 1.9 | 6.1 | 3.1 | 2.3 | 1.5-10.3 |
| CD8+CD62L−CD45RA−, % | n.d. | 4.7 | 7.2 | n.d. | 3.2 | 3.1 | 5.4 | 5.2 | 2.6 | 2.3 | 3 | 6 | 3.8 | 1.1-9.2 |
| CD8+CD62L−CD45RA+, % | n.d. | 28.8 (H) | 8.7 (H) | n.d. | 19.2 (H) | 8.4 (H) | 19.3 (H) | 1 | 1.9 | 2.5 | 5.1 | 2.4 | 3 | 0.7-7.8 |
| CD4/CD8 ratio | 0.79 (L) | 0.26 (L) | 0.87 (L) | 2.42 | 0.59 (L) | 0.98 (L) | 0.93 (L) | 0.9 (L) | 1.73 | 2.22 | 1.36 | 2.86 | 1.3 | 1.11-5.17 |
| CD4+CD45RA+CD31+, % | n.d. | n.d. | 8.6 | n.d. | 2.1 | n.d. | 4.8 | n.d. | n.d. | 13.9 | 4.6 | 9.5 | 18.6 | 1.6-20.2 |
| CD4+CD45RA−CXCR5+, % | n.d. | n.d. | 3.4 | n.d. | 5 | n.d. | 7.3 | n.d. | n.d. | 7.6 | 8.5 | 3.2 | 2.9 | 1.8-8.9 |
| CD4+CD25+FOXP3+, % | n.d. | n.d. | 2 | n.d. | 2 | n.d. | 0.6 (L) | n.d. | n.d. | 1.6 | 0.9 (L) | 2.3 | 1.7 | 1.6-4.3 |
| CD20 B, ALC | 76 | 38 (L) | 35 (L) | 247 | 27 (L) | 121 | 92 | 118 | 41 (L) | 44 (L) | 217 | 154 | 351 (H) | 59-329 |
| CD20 B, % | 7.6 | 2.4 (L) | 3.1 | 17.7 | 1.8 (L) | 4.4 | 6.7 | 5.2 | 3.5 | 2.9 (L) | 10.8 | 5.7 | 7.4 | 3-19 |
| CD20+CD27−IgM+ % | n.d. | 78.8 | 84.5 | n.d. | 39.2 (L) | 84.2 | 91.2 | 84.8 | 98.7 (H) | 98.8 (H) | 89.3 | 53.3 (L) | 86.6 | 56.2-91.5 (% of B cells) |
| CD20+CD27+IgM+, % | n.d. | 12.0 | 12.5 | n.d. | 45.19 (H) | 4.3 (L) | 3.9 (L) | 5.7 | 0.5 (L) | 0.9 (L) | 6.9 | 29.9 | 7.9 | 4.8-38.5 (% of B cells) |
| CD20+CD27+IgM−, % | n.d. | 6.6 | 2 (L) | n.d. | 6.5 | 6.1 | 3.2 (L) | 6.2 | 0 (L) | 0.2 (L) | 2.7 (L) | 15.4 | 2.6 (L) | 4.3-19.9 (% of B cells) |
| CD19+CD24++CD38++, % | n.d. | 6.1 | 18.7 | n.d. | 0 (L) | 16.8 | 7.7 | 4.9 | 11.1 | 3.2 (L) | 10.6 | 4.2 (L) | 4.1 (L) | 4.7-18.7 (% of B cells) |
| CD19+CD24−CD38+, % | n.d. | 0.6 | 0.3 | n.d. | 0 (L) | 0.1 (L) | 0.1 (L) | 0.4 | 0 (L) | 0 (L) | 0.1 (L) | 1.5 | 0.7 | 0.3-3.6 (% of B cells) |
| NK, ALC | 106 (L) | 158 | 130 | 353 | 134 | 104 (L) | 85 (L) | 336 | 125 (L) | 95 (L) | 233 | 454 | 209 | 126-729 |
| NK, % | 10.61 | 10 | 11.5 | 25.2 | 8.9 | 3.8 (L) | 6.2 | 14.8 | 10.7 | 6.2 | 11.6 | 16.8 | 4.4 (L) | 6.2-34.6 |
| Immunoglobulins, mg/dL | ||||||||||||||
| IgG | n.d. | 516 (L) | 1001* | 672.7 (L) | 349 (L) | 1147 | n.d. | n.d. | 59.8 (L) | 984* | n.d. | n.d. | 740 | 700-1600 |
| IgA | n.d. | 36 (L) | 49 (L) | 90.5 | 28 (L) | 98 | n.d. | <10 (L) | 12 (L) | n.d. | n.d. | 112 | 70-400 | |
| IgM | n.d. | 15 (L) | 14 (L) | 54.3 | <7 (L) | <10 (L) | n.d. | n.d. | <10 (L) | 6 (L) | n.d. | n.d. | 98 | 40-230 |
| Autoantibodies | n.d. | n.d. | Anti-platelet Ab positive, Coombs negative | n.d. | n.d. | n.d. | n.d. | n.d. | n.d. | Coombs positive | n.d. | n.d. | ANA positive, anti-dsDNA negative, Coombs negative | |
| ANA positive | ||||||||||||||
| Vaccine response | n.d. | n.d. | Progressive loss of protective titers toward pneumococcal and HiB antigens | n.d. | Positive to 1/14 pneumococcal serotypes, nonprotective titers to tetanus toxoid, diphtheria toxoid, measles, mumps, rubella or varicella | Positive to 5/23 pnemococcal serotypes prevaccination and 8/23 postvaccination, tetanus protective | n.d. | n.d. | n.d. | Positive to 2/14 pnemococcal serotypes, protective to diphtheria and tetanus | n.d. | n.d. | n.d. | |
| Clinical history | Asymptomatic | 1 pneumonia (age 25 y), pernicious anemia | ITP, progressive hypogammaglobulinemia | Type 2 diabetes, hypothyroidism | T-ALL, recurrent diarrhea, hypogammaglobulinemia | Pneumonia (×2, starting in her 50s) | Asymptomatic | Asymptomatic | Recurrent URIs, hypogammaglobulinemia, fibromyalgia | ITP, AIHA, hypogammaglobulinemia s/p rituximab | Hashimoto’s | Asymptomatic | Burkitt lymphoma, lymphadenopathy, ITP, neutropenia |
The B-cell subsets are expressed as the percentage of CD19+ cells. H and L indicate values above/below the normal range, respectively, compared with adult controls in National Institutes of Health Clinical Center.
ALC, absolute lymphocyte count; ANA, antinuclear antibody; dsDNA, double-stranded DNA; F, female; g-mother, grandmother; HiB, Haemophilus influenzae type B; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; M, male; n.d., not determined; NK, natural killer (cells); pt, patient; URI, upper respiratory infection.
The patient was receiving IgG replacement therapy.