Table 1.
Clinical presentation of monoallelic loss of nuclear factor kappa-light-chain-enhancer of activated B cells 1 (NF-κB1) function. A comparison of phenotypes of affected individuals shows various occurrences and degrees of infections, autoimmunity and autoinflammatory syndromes, and varying manifestations of Epstein–Barr virus (EBV). Genetic information, diagnosis and clinical symptoms were extracted from the respective studies. Individuals are listed according to study reference, respective patient code, and type of mutation. Information about treatment and surgery is shown, if indicated in the respective publications. Asymptomatic mutation carriers are not listed.
| Reference | Patient | G | Mutation | AoO | Diagn. | Symptoms |
IgG (g/L) | IgA | IgM | Treatment | Surgery | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Infection | Autoimmunity/Autoinflammation | Other | |||||||||||
| (5) | FamNL1_16 | ♀ | c.730+4A>Gp.D191_K244delinsE | 29 years | Common variable immunodeficiency (CVID) | Respiratory tract infections, pansinusitis, atrophic gastritis, pneumonia | COPD | Pyoderma gangrenosum, squamous cell carcinoma, pulmonary insufficiency | 2.76 | 0.30 | 0.16 | IVIG, etanercept | n/a |
| FamNL1_18 | ♀ | c.730+4A>Gp.D191_K244delinsE | 65 years | CVID | Sinopulmonary infections, Campylobacter enteritis | Splenomegaly, lymphadenopathy | Ischemic heart disease, lung adenocarcinoma, thrombocytopenia | 2.49 | 0.13 | 0.53 | n/a | n/a | |
| FamNL1_19 | ♀ | n/a | 46 years | – | Bronchitis, pneumonias (H. influenzae) | COPD | Coronary insufficiency, impaired pulmonary function | 3.0 | 0.4 | 0.4 | IVIG | n/a | |
| FamNL1_21 | ♂ | c.730+4A>Gp.D191_K244 delinsE | 31 years | CVID | pneumonias, recurrent sinusitis, bronchiectasis | COPD | Lung fibrosis, respiratory insufficiency | 6.0 | 1.26 | 0.4 | IVIG | Appendectomy | |
| FamNL1_23 | ♀ | n/a | n/a | – | Recurrent lower airway infections | COPD | Defective vaccination response | HGG | n/a | n/a | IVIG | n/a | |
| FamNL1_24 | ♀ | n/a | n/a | Recurrent lower airway infections | COPD with pulmonary insufficiency | Defective vaccination response, mannose-binding lectin deficiency | HGG | n/a | n/a | IVIG | n/a | ||
| FamNL1_25 | ♀ | c.730+4A>Gp.D191_K244 delinsE | 52 years | CVID | Pulmonary infection | COPD | Respiratory insufficiency, pulmonary hypertension | 4.6 | 1.0 | 0.4 | IVIG | n/a | |
| FamNL1_34 | ♂ | c.730+4A>Gp.D191_K244 delinsE | 44 years | CVID | Recurrent respiratory infections | Hypothyroidism | Alopecia areata, pyoderma gangrenosum | 8.0 | 0.83 | 0.25 | IVIG | Surgery for VSD | |
| FamNL1_36 [P.2 (6), P.4 (13)] | ♀ | c.730+4A>Gp.D191_K244 delinsE | 30 years | CVID | Pneumonia, recurrent sinusitis, otitis media, Salmonella enteritis | – | – | 1.81 | 0.06 | 0.48 | IVIG | n/a | |
| FamNL1_40 | ♀ | c.730+4A>Gp.D191_K244 delinsE | 34 years | CVID | Recurrent upper airway infection, sporadic lower respiratory tract infections | COPD | – | 5.1 | <0.5 | 0.65 | IVIG | n/a | |
| FamNL1_42 | ♀ | c.730+4A>Gp.D191_K244 delinsE | n/a | HGG | Recurrent paronychia, superficial skin infections | – | – | n/a | n/a | n/a | n/a | n/a | |
| FamNL1_48 | ♀ | c.730+4A>Gp.D191_K244 delinsE | 15 years | HGG | Folliculitis, furunculosis | Thyroiditis | Aortic stenosis | 3.72 | 0.59 | 0.74 | Levothyroxine | n/a | |
| FamNL1_49 | ♀ | c.730+4A>Gp.D191_K244 delinsE | 9 months | CVID | Giardiasis, recurrent respiratory tract infections, trichophyton skin infections | Thyroiditis | – | 9.1a | 1.41 | 0.11 | IVIG | n/a | |
| FamNL1_57 | ♀ | c.730+4A>G p.D191_K244 delinsE | 39 years | CVID | Lymphocytic interstitial pneumonitis, recurrent sinopulmonary infections | – | Nodular regenerative hyperplasia, ongoing diarrhea, reticunodular and lymphocytic infiltrates, liver eosinophilic and lymphocytic infiltrates | 1.3 | <0.04 | 0.3 | IVIG, IV-antibiotics, ursodeoxycholic acid | n/a | |
| FamNL1_62 | ♀ | c.730+4A>Gp.D191_K244 delinsE | 30 years | CVID | Recurrent sinus infections | – | – | 4.7 | 0.4 | 0.3 | IVIG | n/a | |
| Fam089_I1 | ♂ | c.835+2T>Gp.K244_D279delinsN | 64 years | CVID | Severe pneumonia with pleural empyema | – | Multiple liver hemangiomas | 1.42 | 0.08 | 0.4 | IVIG | n/a | |
| Fam089_II2 [P.5 (13)] | ♀ | c.835+2T>Gp.K244_D279delinsN | 16 years | CVID | Recurrent pulmonary infections, pneumonia | Hemolytic anemia, hepatomegaly, lymphadenopathy | Idiopathic thrombocytopenic purpura, infection-induced neutropenia, intermittent diarrhea, recurrent arthralgias | 6.29 | <0.3 | <0.3 | IVIG, rhG-CSF | n/a | |
| Fam089_III2 | ♀ | c.835+2T>Gp.K244_D279delinsN | 14 months | HGG | – | – | Transient hypogammaglobulinemia | 1.94 | <0.07 | 0.29 | n/a | n/a | |
| FamNZ_I2 | ♀ | c.465dupAp.A156Sfs*12 | n/a | – | – | – | Alopecia, thrombocytopenia | 9.9 | 0.58 | 0.8 | n/a | n/a | |
| FamNZ_II1 | ♂ | c.465dupAp.A156Sfs*12 | 2 years | CVID | – | Hemolytic anemia | Thrombocytopenia, neutropenia | 5.17 | 0.07 | 0.53 | IVIG | Splenectomy | |
| FamNZ_II2 | ♀ | c.465dupAp.A156Sfs*12 | 20 years | CVID | Bronchiectasis, recurrent infections | – | Alopecia, marginal zone non-Hodgkin lymphoma, nodular regenerative hyperplasia | n/a | n/a | n/a | Rituximab, chlorambucil, IVIG | n/a | |
| (6) | Patient 1 | ♂ | c.1517delC p.A506Vfs*17 | 7 years | CVID | Recurrent respiratory infections, pneumonia, sinusitis | Thyroiditis, enteropathy | Gastric adenoma | 1.6 | 0.14 | 0.14 | IVIG, budesonide | n/a |
| (7) | Index patient | ♀ | c.494delGp.G165Afs*32 | 2 years | CID with EBV-LPD | Recurrent respiratory infections, recurrent EBV infection with EBV-LPD | Hepatosplenomegaly, esophagitis, cervical/anxillary/supraclavicular lymphadenopathy | Bacterial parapharyngeal abscess, chronic abscess-forming inflammation, neutropenia, leukopenia, thrombocytopenia | 2.32 | <0.05 | 0.012 | IVIG, antibiotics, corticosteroids, rituximab | Tonsillectomy, adenectomy |
| Father | ♂ | c.494delGp.G165Afs*32 | n/a | – | Non-respiratory tract infections | – | – | 4.09 | 0.23 | 0.41 | – | n/a | |
| (8) | Patient 1 | ♀ | c.139delAp.I47Yfs*2 | n/a | CVID | Recurrent pneumonias, upper respiratory tract infection, fever, chronic otitis, mastoiditis, sinusitis, vulvovaginitis; recurrent viral (chronic EBV, recurrent herpes zoster, HPV38, HSV, RSV), bacterial (Gardnerella and group A Streptococcus, C. braakii), Candida (C. lusitaniae) infections | Hemolytic anemia, idiopathic thrombocytopenia, pancytopenia, autoantibodies, organ infiltration (liver, lung, spleen, kidney) with hepatosplenomegaly, pancolitis, generalized mucositis, recurrent aphthae and painful ulcers of mouth, esophagus, and genitalia | Recurrent idiopathic diarrhea, abdominal pain, bloody stools, ascites, intermittent proteinuria, latent hypothyreosis, multiple ovarian cysts, lack of calcium and vitamin D, recurrent headaches with vertigo, numbness and paresis of left arm and hand | 4.85 | <0.06 | 0.24 | Steroids, mycophenolate, IVIG, mofetil, antibiotics, antiviral medication, calcium, vitamin D | Cholecystectomy, colectomy, mastoidectomy, ulcer excision, myringotomy, tympanostomy |
| Patient 2 | ♀ | c.469C>T p.R157* | n/a | CVID | Recurrent pneumonias (S. pneumoniae), upper respiratory tract infection, H. influenzae, Salmonella infections | Hemolytic anemia, idiopathic thrombocytopenia, leukopenia, splenomegaly | Recurrent diarrhea | 10.9 | <0.05 | 3.62 | IVIG, steroids | n/a | |
| (9) | F1.II-4 | ♀ | c.200A>G p.H67R | n/a | Behçet-like; AB def | Upper respiratory tract infection | Recurrent monoarthritis, complex aphthae (mouth, genitalia), small vessel vasculitis | Periodic abdominal pain, chronic idiopathic diarrhea | HGG | n/a | n/a | IVIG | n/a |
| F1.III-2 | ♀ | c.200A>G p.H67R | n/a | Behçet-like; AB def | – | – | Benign kidney tumor | HGG | n/a | n/a | n/a | n/a | |
| F1.III-3 | ♂ | c.200A>G p.H67R | n/a | Behçet-like; AB def | Upper respiratory tract infection | Complex aphthae (esophagus) | Rudimentary left kidney, febrile attacks | HGG | n/a | n/a | IVIG | n/a | |
| F1.III-6 | ♀ | c.200A>G p.H67R | n/a | Behçet-like; AB def | Upper respiratory tract infection | Complex aphthae (mouth) | – | HGG | n/a | n/a | IVIG | n/a | |
| F1.III-7 | ♀ | c.200A>G p.H67R | n/a | Behçet-like | Upper respiratory tract infection | Recurrent monoarthritis, hyperinflammatory response to tooth excision, complex aphthae (mouth, genitalia) | Febrile attacks, periodic abdominal pain, keratitis | n/a | n/a | n/a | n/a | n/a | |
| F1.III-8 | ♀ | c.200A>G p.H67R | n/a | Behçet-like; AB def | Upper respiratory tract infection | Recurrent monoarthritis, microscopic colitis, complex aphthae (mouth) | Febrile attacks, periodic abdominal pain | HGG | n/a | n/a | IVIG | n/a | |
| F1.IV-2 | ♀ | c.200A>G p.H67R | n/a | Behçet-like; AB def | Upper respiratory tract infection | Complex aphthae (mouth, genitalia) | Febrile attacks, periodic abdominal pain | HGG | n/a | n/a | n/a | n/a | |
| F2.II-3 | ♀ | c.1659C>Gp.I553M | n/a | CVID | Respiratory tract infection, autoimmune hypothyroiditis | Spondyloarthropathy oligoarthritis | Chronic idiopathic diarrhea, asthma | HGG | n/a | n/a | IVIG | n/a | |
| F2.III-2 | ♂ | c.1659C>Gp.I553M | n/a | CVID | Respiratory tract infection | Celiac disease, asthma | – | n/a | n/a | n/a | n/a | n/a | |
| F3.II-1 | ♂ | c.469C>Tp.R157* | n/a | FNC | Respiratory tract infection | Postoperative necrotizing cellulitis | – | n/a | n/a | n/a | n/a | Yes (unknown) | |
| F3.II-5 | ♂ | c.469C>Tp.R157* | n/a | FNC | – | Postoperative necrotizing cellulitis | – | n/a | n/a | n/a | n/a | Yes (unknown) | |
| (10) | Patient 1 | ♂ | c.1301-1G>A(intronic) | 42 years | CVID | Pneumonias, chronic sinusitis, conjunctivitis, otitis, shingles | Lymphoid hyperplasia, aphthous ulcers, hypersplenism | Lung granulomas, enteropathy, neutropenia | Tx | <0.07 | <0.11 | n/a | Splenectomy |
| Patient 2 | ♀ | c.1301-1G>A (intronic) | 19 years | CVID | Pneumonias, chronic sinusitis, conjunctivitis, otitis, shingles, C. difficile colitis | – | Morphea | <0.51 | <0.05 | <0.05 | n/a | n/a | |
| Patient 3 | ♂ | c.259-4A>G (intronic) | 21 years | CVID | Pneumonias, empyema, chronic sinusitis | Bronchiectasis, hypothyroidism, vitiligo | – | Tx | <0.01 | <0.05 | n/a | Lobectomy | |
| Patient 4 | ♀ | c.957T>A p.Y319* | 19 years | CVID | MAl, pneumonia, lung abscesses, PML | Autoimmune hemolytic anemia, immune thrombocytopenia | Aplastic bone marrow | Tx | <0.07 | <0.l7 | n/a | Splenectomy | |
| Patient 5 | ♀ | c.1375delT p.F459Lfs*26 | 7 years | CVID | Pneumonias, otitis, giardiasis, C. difficile colitis, HSV infection, cellulitis, MAI | Bronchiectasis | Enteropathy, osteopenia, poor growth | Tx | <0.02 | <0.02 | n/a | n/a | |
| (11) | Patient 26 | ♀ | n/a | n/a | CVID | n/a | n/a | n/a | n/a | n/a | n/a | n/a | n/a |
| Patient 27 [P.6 (13)] | ♂ | c.469C>T p.R157* | n/a | CVID | n/a | n/a | n/a | n/a | n/a | n/a | n/a | n/a | |
| Patient 28 | ♀ | n/a | n/a | CVID | n/a | n/a | n/a | n/a | n/a | n/a | n/a | n/a | |
| (12) | P9.1 | c.904dupT p.S302Ffs*7 | n/a | AB def | H. influenzae, pulmonary fibrosis | Autoimmune hemolytic anemia | – | n/a | n/a | n/a | Prednisol., rituximab | n/a | |
| P9.2 | c.904dupT p.S302Ffs*7 | n/a | AB def | Autoimmune hemolytic anemia, immune thrombocytopenia, autoimmune neutropenia | – | n/a | n/a | n/a | Prednisol., Ig | n/a | |||
| (13) | Patient 1 | ♂ | c.1517delC p.A506Vfs*17 | 13 years | CVID | Recurrent pulmonary infections | Autoimmune thyroiditis, autoimmune enteropathy | Gastric adenoma | 1.6 | 0.1 | 0.1 | n/a | n/a |
| Patient 2 | ♀ | c.1365delT p.V456* | 33 years | CVID | Pneumonias, necrotizing tonsillitis, periodontitis, infections (h. zoster, CMV viremia, intermittent low-grade EBV) | Autoimmune cytopenia, splenomegaly, lymphadenopathy, interstitial lung disease | Multiple liver hemangiomas | 6.7 | 0.3 | 0.3 | n/a | n/a | |
| Patient 3 | ♂ | c.1365delT p.V456* | 43 years | CVID | Recurrent sinusitis and otitis, pneumonia, Salmonella enteritis | Autoimmune cytopenia, arthritis, splenomegaly, vitiligo, lymphadenopathy, granulomatous lung disease | – | 0.08 | 0.05 | 0.05 | n/a | n/a | |
| Patient 6 [p.27 (11)] | ♂ | c.469C>T p.R157* | 47 years | CVID | Chronic sinusitis, recurrent otitis, pneumonia, JC virus encephalitis, norovirus, EBV reactivation | Skin abscesses, atopic dermatitis, autoimmune enteropathy, nodular regenerative hyperplasia, splenomegaly, lymphadenopathy, thrombocytopenia | – | 2.7 | <0.06 | 0.21 | n/a | n/a | |
| Patient 7 | ♀ | c.295C>T p.Q99* | 20 years | CVID | Recurrent bronchitis, sinusitis | Enteropathy, splenomegaly | Basal cell carcinoma, osteoporosis | n/a | n/a | n/a | n/a | n/a | |
G, gender; AoO, Age of onset (diagnosis); Diagn., diagnosis; COPD, chronic obstructive pulmonary disease; IVIG, intravenous immunoglobulin; HGG, hypogammaglobulinemia; VSD, ventricular septal defect; EBV-LPD, Epstein–Barr virus-associated lymphoproliferative disease; AB def, antibody deficiency; FNC, familial necrotizing cellulitis; prednisol., prednisolone; MAI, mycobacterium avium intracellulare; PML, progressive multifocal leukoencephalopathy; n/a, not applicable.
aAfter IVIG.