Table 2.
Clinical and serological characteristics of patients with distinct phenotypes of RAG deficiency.
| CODE | Phenotype | Mutation | Sex | Age at clinical diagnosis | Clinical autoimmunity | Location of granulomas | Other clinical manifestations/infection | On IvIg | Other immune modulation | HCT | Current status Age (cause of death) |
Clinical autoantibodies (+) | Reference | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| L/AS-1 | Leaky/atypical SCID | RAG1 | a.2095(exon2)C>T b.2690(exon2)G>A | F | 1y 4m | AIHA; AN | _ | Severe pneumonia; CMV infection; pneumocystis jirovecii disease | yes | high-dose steroid and plasmapheresis | n.a. | Alive; 1y 7m | Coombs | Present case |
| L/AS-2 | Leaky/atypical SCID | RAG1 | a. R669W b. M435V |
M | 5 y | AIHA; ITP; AN | _ | pneumonia; sinus infection; oral candidiasis; vitiligo; psoriasis; Guillain-Barré sy | yes | _ | yes; 6y 6m | Alive; 14y 11m | Coombs; anti-platelet ab; anti-neutrophil ab; anti-TPO ab IBD serology+ | (11) |
| L/AS-3 | Leaky/atypical SCID | RAG1 | a./b. p.R108* | F | 3 m | AIHA | _ | CMV(+); dermatitis | yes; pre-HCT | _ | yes; 6.7m | Alive; 2y 7m | Coombs | (11) |
| L/AS-4 | leaky/atypical SCID | RAG1 | a./b. K86fs*33 | M | 11 m | AIHA | _ | pneumonia; chronic CMV infection; Miller Fisher Syndrome (polyradiculoneuritis with cranial nerve involvement) | yes; pre-HCT | high-dose steroid; rituximab; plasmapheresis | yes;1y 6m | Alive; 3y 4m | Coombs; anti-platelet ab | (11) |
| L/AS-5 | Leaky/atypical SCID | RAG1 | a. H65R b. A857V |
F | 2 y | AIHA | _ | adenovirus; CMV(+) | yes | _ | n.a. | Alive; 3y 1m | Coombs | (11) |
| L/AS-6 | Leaky/atypical SCID | RAG1 | a./b. R841W | M | 9m | AIHA | _ | _ | _ | _ | yes; 10m | Died; 1y 9m |
Coombs | (5) |
| L/AS-7 | Leaky/atypical SCID | RAG1 | a./b. R474H | F | 11y | AIHA; ITP | _ | amyloidosis | _ | _ | n.a. | Alive; 5y | Coombs | (5) |
| L/AS-8 | Leaky/atypical SCID | RAG1 | a.1420C(exon2)>T het b.2949(exon2)delA het | F | 3y 6m | AIHA | _ | recurrent viral and bacterial infections; and nephrotic syndrome | yes; pre-HCT | busulfan; fludarabine and anti-thymocyte globulin | yes; 8 y | Alive | Coombs; Lupus anticoagulant + ANCA; +anti-MPO; Thyroglobulin and thyroid peroxidase Ab; Anti-IFNα Ab | (12) |
| L/AS-9 | Leaky/atypical SCID | RAG1 | a.1420C(exon2)>Thet b.2949(exon2)delA het | F | 2y | AIHA; AN | _ | eczematous rash | yes; pre-HCT | busulfan; fludarabine and anti-thymocyte globulin | HSCT; 2y 5m | Alive | Coombs (IgG and complement); Anti-neutrophil Ab; Anti-IFNα Ab | (12) |
| L/AS-10 | Leaky/atypical SCID | RAG1 | a. W522C b. M435V/M1006 V |
M | 2y | AIHA; ITP | skin | _ | yes; pre-HCT | rituximab | yes;3y | Alive | Coombs; platelet | (5) |
| L/AS-11 | Leaky/atypical SCID | RAG1 | a. R396C b. M435V |
M | 1y 6m | AIHA | _ | vasculitis | yes; pre-HCT | steroids; IVIG; cyclophosphamide; alemtuzumab; and/or rituximab | yes;1y 9m | Died; 2y 8m |
Coombs; IFN-α | (5) |
| L/AS-12 | Leaky/atypical SCID | RAG1 | a. R561H b. R778Q |
M | 17y | AIHA | _ | _ | _ | _ | _ | Alive; 17y |
Coombs | (5) |
| L/AS-13 | Leaky/atypical SCID | RAG1 | a. N855S b. K992E | M | 2y 9m | AIHA | _ | hepatitis | _ | _ | yes; 3y | Alive; 3y | Coombs | (5) |
| L/AS-14 | Leaky/atypical SCID | RAG1 | a. R142* b. T477S | F | 2y 10m | AIHA; ITP; AN | _ | _ | _ | _ | yes; 3y 3m | Died; 3y 4m |
Coombs; platelet | (5) |
| L/AS-15 | Leaky/atypical SCID | RAG1 | a. R15L b. H735Q | F | n.a. | AIHA; ITP | _ | − | _ | _ | yes; 1y 4m | Alive; 3y 9m | Coombs; thyroid (TPO) | (5) |
| L/AS-16 | Leaky/atypical SCID | RAG1 | n.a. | M | 14y | AN; ITP; AIHA | _ | vitiligo; IBD | _ | _ | yes; 14y | Died; 14y | Coombs | (5) |
| CID-1 | CID-G/AI | RAG1 | a. R474C b. K983Nfs*9 |
F | 2y | AIHA; AN | _ | otitis media; RSV bronchiolitis; severe varicella with periorbital cellulits/keratitis | yes; pre-HCT | _ | yes; 2 and 4 y | Alive; 3m | Coombs;anti-neutrophil antibody+ | (11, 12, 13, 22) |
| CID-2 | CID-G/AI | RAG1 | a./b.S117fs | M | 8y | AIHA | skin | pneumonias; liver abscess; Mycobacterial osteomyelitis; herpes-zoster; diarrhea from rotavirus viral encephalitis after yellow fever vaccine; varicella | yes; pre-HCT | _ | yes;8 y | Alive; 8y | Coombs | (10) |
| CID-3 | CID-G/AI | RAG1 | a. K86fs*33 b. H65R |
F | 3y | ITP; AIHA | lung | recurrent sinopulmonary infections (Penicillium; Corynebacterium propinquum; and Pseudomonas aeruginosa); viral infections (shingles); and vitiligo) | yes; pre-HCT | corticosteroids and infliximab | yes; 18y | Alive; 20y |
Coombs; thyroid (TPO) | (13) |
| CID-4 | CID-G/AI | RAG1 | a./b. S480G | M | 6y | AIHA; AN | _ | Enteropathy;Glomerulonephritis; atherosclerosis;generalized urticaria | yes; pre-HCT | rituximab | yes; 9y 6m | Died; 10y |
Coombs; neutrophil | (14) |
| CID-5 | CID-G/AI | RAG1 | a./b.[His65Arg] | M | 7y | AIHA; ITP | skin | Severe varicella infection; generalized scabies; recurrent bronchitis | yes; pre-HCT | rituximab | yes; 7y 6m | Alive | Coombs | (14) |
| CID-6 | CID-G/AI | RAG1 | a./b.2095C>T | M | 6y | AIHA | skin, lung, liver, bone, pancreas, testes | otitis media; pallor and splenomegaly | yes; pre-HCT | high-dose steroid; rituximab; plasmapheresis | n.a. | Died | Coombs; ANA; dsDNA | (15) |
| CID-7 | CID-G/AI | RAG1 | a. R474C b. R975W |
F | 9y | AIHA; ITP | skin | _ | yes; pre-HCT | rituximab | yes; 20y | Died; 21y |
Coombs; platelet | (5) |
| CID-8 | CID-G/AI | RAG1 | a. W522C b. H994R |
M | 3y | AIHA | _ | vasculitis | yes; pre-HCT | steroids; cyclophosphamide; alemtuzumab; and/or rituximab | yes;5y | Died; 6y |
Coombs | (5) |
| CID-9 | CID-G/AI | RAG1 | a./b. R764C | F | 16y | AIHA; ITP | skin, bone | splenomegaly; hypergamma; globulinemia; pancytopenia | _ | _ | n.a. | Alive | Coombs | (16) |
| CID-10 | CID-G/AI | RAG1 | a. R841Q b. F974L |
F | 6m | AIHA; ITP; AN | _ | vasculitis; myopathy; central demyelinating neuropathy | yes | glucocorticoids; intravenous immunoglobulin; enoxaparin; and rituximab | died | Died; 2y |
Coombs; platelet | (17) |
| CID-11 | CID-G/AI | RAG1 | a./b. H65R | F | 15y 7m | AIHA; AN | _ | alopecia areata; thyroiditis | yes; pre-HCT | _ | yes; 17y |
Alive; 18y |
Coombs; IFN-α; thyroid (TPO/TG) | (5) |
| CID-5 | CID-G/AI | RAG1 | a./b. R507G | M | 5y | AIHA; AN | _ | hepato-splenomegaly | yes; pre-HCT | high-dose steroid; rituximab; plasmapheresis | yes; 5y 3m | Alive; 8y | Coombs; neutrophil | (18) |
| CID-13 | CID-G/AI | RAG1 | a./b. K86VfsX33 | M | 4y | AIHA; ITP; AN | _ | _ | yes; pre-HCT | _ | yes; 4y |
Alive; 7y 8m |
Coombs | (5) |
| CID-14 | CID-G/AI | RAG1 | a./b. N855S | M | 11y | AIHA | _ | enteropathy | none | _ | n.a. | Died; 11y |
Coombs; enterocyte/goblet cell | (5) |
| CID-15 | CID-G/AI | RAG1 | a./b. G816R | M | 7y 6m | AIHA | _ | sclerosing cholangitis | _ | _ | n.a. | Alive; 9y 6m |
Coombs | (5) |
| CID-16 | CID-G/AI | RAG1 | a.1187G>A (Arg396His) b.1566G>T (Trp522Cys) | F | 5y | AIHA | skin | herpes simplex virus (HSV) gingivostomatitis; bacterial pneumonia; and cutaneous abscess | yes; pre-HCT | high-dose steroid; rituximab; plasmapheresis | yes | Alive | Coombs | (19) |
| CID-17 | CID-G/AI | RAG1 | a.M435V (1303AG) b.R699W (2095C¡T) | M | 10m | AIHA; ITP; AN | _ | vitiligo; psoriasis;tetanus; diphtheria and Guillain-Barré syndrome | yes; pre-HCT | high-dose steroids; infliximab; and cyclophosph amide | yes; 6y | Alive | Coombs | (20) |
| CID-18 | CID-G/AI | RAG1 | a.M435V (1303AG) b.R699W (2095C¡T) | M | 8y | AIHA; AN | skin | varicella infection; pneumonia; tuberculosis infections; parasitic infections | yes; pre-HCT | high-dose steroids; infliximab; and cyclophosph amide | yes; 8y | Died; 8y | Coombs; pANCA; ANA | (23) |
| SCID-1 | SCID | RAG1 | a. N766l b.K86VfsX33 | M | 13y | AIHA; AN | _ | thyroiditis; hepatitis; urticaria | _ | _ | yes; 5m | Alive; 19y |
Coombs | (5) |
| SCID-2 | SCID | RAG1 | a./b. K86VfsX33 | F | 1m | AIHA | _ | _ | yes; pre-HCT | _ | yes;1y 3m | Alive 10y5m | Coombs | (5) |
| SCID-3 | SCID | RAG1 | del AA368–369 | M | 11m | AIHA; thrombocytopenia | _ | hepatosplenomegaly; CMV infection | yes; pre-HCT | ganciclovir; foscarnet; and CMV hyperImmunoglobulin | yes;1y 4m | Alive | Coombs | (21) |
| SCID-4 | SCID | RAG1 | g.8366-8367insT, c.3198-3199insT, p.L1025FfsX39 g.6472C>T, c.1304C>T, p.R394 W | F | 45d | AIHA; | _ | hepatosplenomegaly; erythroderma; lymphadenopathy | _ | _ | _ | _ | Coombs | (22) |
| OS-1 | OS | RAG1 | g.8366-8367insT, c.3198-3199insT, p.L1025FfsX39 | F | 82d | AIHA; ITP; | _ | _ | _ | _ | _ | _ | Coombs | (22) |
| OS-2 | Omenn syndrome | RAG1 | g.8366-8367insT, c.3198-3199insT, p.L1025FfsX39 g.7481G>A, c.2313G>A, p.C730Y | M | 60d | AIHA; | _ | hepatosplenomegaly; erythroderma; lymphadenopathy | _ | _ | _ | _ | Coombs | (22) |
| OS-3 | Omenn syndrome | RAG1 | g.7862C>T, c.2694C>T, p.A857 V | F | 120d | AIHA; | _ | hepatosplenomegaly; erythroderma; lymphadenopathy | _ | _ | _ | _ | Coombs | (22) |
AIHA (autoimmune hemolytic anemia), ITP (immune thrombocytopenia), AN (autoimmune neutropenia), CMV (cytomegalovirus), RSV (respiratory syncytial virus), TPO (thyroperoxidase antibody), HCT (Hematopoietic cell transplantation).