Introduction
Methods
Patients and Clinical Data
Characters | Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 | Patient 6 | Patient 7 |
---|---|---|---|---|---|---|---|
Gender | M | M | M | M | M | M | M |
Age of onset | 3 m | 12 m | 0.7 m | 4 m | 5 m | 0.5 m | 24 m |
Age of diagnosis | 11 m | 84 m | 4 m | 22 m | 108 m | 2 m | 60 m |
Age of last follow-up | 13 m | 138 m | 12 m | 31 m | 130 m | 15 m | 105 m |
Clinical presentation | BCG disease, axillary lymph node enlargement, recurrent pneumonia, diarrhea, soft tissue infection, osteomyelitis, sepsis, impaired liver function | Recurrent aphthous ulcer, soft tissue infection, cervical lymphadenitis, pneumonia | Recurrent pneumonia, rashes, impaired liver function | BCG disease, Recurrent fever, axillary lymph node enlargement, recurrent pneumonia, perianal abscess | BCG disease, lymph node enlargement, upper respiratory infection, otitis media | Recurrent fever, recurrent pneumonia, pulmonary abscess, perianal abscess, recurrent diarrhea, sepsis, skin and soft tissue infection | Recurrent fever, lymph node enlargement, pneumonia, oral ulcer |
Pathogenic microorganism | BALF: GM + ; Pus: Burkholderia gladioli (reads, 69); Blood: Mycobacterium neoaurum (reads, 78); Stool: Clostridium difficile | Negative | Negative | Sputum: Ureaplasma urealyticum; BALF: Corynebacterium striatum (reads, 200) | Negative | Skin pus: Klebsiella pneumoniae | Negative |
Treatment | Meropenem, vancomycin, voriconazole, SMZ, etc.; IVIG | Azithromycin, cefoperazone/sulbactam, rifampin, clarithromycin, SMZ, voriconazole; IFN-γ | Cefoperazone/sulbactam, moxalactam, imipenem, vancomycin, fluconazole, itraconazole and SMZ; IVIG | Isoniazide, rifampicin with ethambutol,linezolid, cefoperazone/sulbactam, azithromycin, itraconazole, SMZ | Isoniazide, rifampicin, ethambutol, pyrazinamide | Ceftriaxone, meropenem, cefoperazone/ sulbactam, fluconazole, vancomycin, cefaclor, SMZ, isoniazide, rifampicin, itraconazole; IVIG | Isoniazide, rifampicin, ethambutol, pyrazinamide, linezolid, itraconazole; IFN-γ |
Outcome | HSCT | Anti-infection | HSCT | Anti-infection | Anti-infection | HSCT | Anti-infection |
SI | 67.3 | 35.4 | 21.2 | 1.9 | 40.7 | 17.1 | 61.2 |
GP91 protein | X91 + | X91 + | X91 + | X91 + | X91 + | X91 + | X91 + |
CYBB Gene Mutation | c.162G > C | c.1462–2 A > T | c.170C > A | c.1223G > A | c.1243C > T | c.1244C > A | c.925G > A |
Amino acid change | p.R54S | partial del exon 12 p.Ala488_Glu497del | p.A57E | p.G408E | p.P415S | p.P415H | p.E309K |
SIFT score | 0.001 | 0 | 0.001 | 0 | 0 | 0.002 | |
Polyphen2 score | 0.904 | 0.999 | 1 | 1 | 1 | 0.998 | |
MutationTaster score | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
MAF in Gnomad | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Routine Immune Function Evaluation
Evaluation of Neutrophil Function
Expression of the gp91phox Protein
Gene Analysis
Statistical Analysis
Results
X-linked CGD Distribution
Clinical Manifestations of X91+ CGD
Overview
Infection Characteristics
Noninfectious Complications
Treatment and Follow-up
Comparison Between X91+ and Other X-linked CGD Types
X91 + | X91 − | X91 0 | P value | ||
---|---|---|---|---|---|
Patients, n | 7 | 6 | 51 | ||
Gender, male | 7 | 6 | 51 | ||
Age of onset, median (min, max) | 4 m (0.5–24) | 2 m (0.4–84) | 1 m (0.1–36) | 0.1092 | |
Age of diagnosis, median (min, max) | 22 m (2–108) | 10 m (2–156) | 9 m (1–96) | 0.4029 | |
Age of last follow-up, median (min, max) | 31 m (12–138) | 50 m (11–176) | 28 m (2–164) | 0.4899 | |
Frequency of severe infections*, (mean ± SD) | 2.07 ± 2.05 | 2.86 ± 2.68 | 2.78 ± 1.81 | 0.4457 | |
Sites of infections | |||||
Lung | 85.7% (6/7) | 100% (6/6) | 100% (51/51) | ||
Lymph node | 71.4% (5/7) | 50% (3/6) | 56.9% (29/51) | ||
Skin and soft tissue | 42.9% (3/7) | 33.3% (2/6) | 49% (25/51) | ||
Gastrointestinal tract | 14.3% (1/7) | 50% (3/6) | 21.6% (11/51) | ||
Perianal | 28.6% (2/7) | 50% (3/6) | 41.2% (21/51) | ||
Blood stream | 28.6% (2/7) | 33.3% (2/6) | 49% (25/51) | ||
Abdominal | 14.3% (1/7) | 33.3% (2/6) | 5.9% (3/51) | ||
Bone | 14.3% (1/7) | 16.7% (1/6) | 15.7% (8/51) | ||
Central nerve system | 0% (0/7) | 16.7% (1/6) | 5.9% (3/51) | ||
Pathogen of infection | |||||
Bacteria | 42.9% (3/7) | 83.3% (5/6) | 66.7% (34/51) | ||
Fungus | 14.3% (1/7) | 0% (0/6) | 58.8% (30/51) | ||
Mycobacterium tuberculosis | 71.4% (5/7) | 33.3% (2/6) | 68.6% (35/51) | ||
BCG infection | 42.9% (3/7) | 33.3% (2/6) | 54.9% (28/51) | ||
Mycoplasma | 14.3% (1/7) | 16.7% (1/6) | 13.7% (7/51) | ||
Non-infectious complications | |||||
ulcer colitis | 0% (0/7) | 16.7% (1/6) | 5.9% (3/51) | ||
oral ulcers | 28.6% (2/7) | 33.3% (2/6) | 11.8% (6/51) | ||
Treatment | |||||
SMZ | 71.4% (5/7) | 100% (6/6) | 100% (51/51) | ||
Antituberculosis | 71.4% (5/7) | 33.3% (2/6) | 54.9% (28/51) | ||
Antifungal | 85.7% (6/7) | 100% (6/6) | 100% (51/51) | ||
IFN-gama | 28.6% (2/7) | 16.7% (1/6) | 9.8% (5/51) | ||
Outcome | |||||
Lost | 0% (0/7) | 16.7% (1/6) | 5.9% (3/51) | ||
With HSCT | 42.9% (3/7) | 20% (1/5) | 70.8% (34/48) | ||
Without HSCT | 57.1% (4/7) | 80% (4/5) | 29.2% (14/48) | ||
Alive without HSCT | 100% (4/4) | 100% (4/4) | 85.7% (12/14) |
X91+ CGD Gene Mutations and Literature Review
Pt. ID | Nucleotide mutation | Amino acid mutation | MAF in Gnomad | MutationTaster score | SI | NBT | O2- production | GP91phox expression and detection method | cell type | cellular function test | Onset age | Diagnostic age | Age of death | Symptoms | Ref |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | c.162G > C | p.Arg54Ser | 0 | 1 | NA | weakly | 0 | Normal (WB) | Neu | NBT slide test | NA | 84 m | NA | Recurrent infection | 1, 4, 32* |
2 | c.170C > A | p.Ala57Glu | 0 | 1 | NA | NA | 0 | Normal (WB) | Neu | chemiluminescence | NA | 84 m | NA | Recurrent infection | 1, 10, 11* |
3 | c.890_904del15 | p.Ile297_Val301del X | 0 | NA | NA | 0.22 nmol/30 min/2 × 10 5 cells, 20% of normal | Normal (WB) | B cells | cytochrome c reduction | NA | NA | NA | NA | 1, 12* | |
4 | c.[907C > A;911C > G] | p.[His303Asn; Pro304Arg] | 0 | 1 | NA | 0% | 0 | Normal (spectroscopy and WB) | Neu | NBT slide test, cytochrome c reduction and chemiluminescence | 9 m | 96 m | NA | Lymphadenitis: Calmette–Guérin bacillus, hepatic abscess: Staphylococcus aureus | 10, 13*, 14* |
5 | c.907C > T | p.His303Tyr | 0 | 1 | NA | NA | 0 | Normal (WB) | Neu | cytochrome c reduction assay, DHR analysis and bactericidal activity | 54y | 61y | NA | Skin involvement, liver abscess, pneumonia, osteomyelitis | 1, 26* |
6 | c.1013A > G | p.His338Arg | 0 | 1 | NA | 45% | Residual | Normal (flow cytometry) | PMN | NBT slide test, cytochrome c reduction assay | 3 m | 10 m | 10 m | Pneumonia: Burkholderia cepacia, diarrhea | 1, 27* |
7 | c.1022C > A | p.Thr341Lys | 0 | 1 | NA | 0 | 0 | Normal (absorption spectroscopy and WB) | Neu | NBT slide test, cytochrome c reduction assay, chemiluminescence | 36 m | NA | NA | Pneumonia, lymph nodes infection | 1, 15* |
8 | c.1085C > G | p.Thr362Arg | 0 | 1 | NA | NA | NA | Normal (flow cytometry) | Neu | NBT slide test and DHR analysis | NA | NA | NA | Staphylococcus sciuri, Burkholderia spp.,tuberculosis | 1, 28* |
9 | c.1105 T > C | p.Cys369Arg | 0 | 1 | NA | 4% | 0 | Normal (absorption spectroscopy and WB) | Neu | NBT slide test, cytochrome c reduction assay, chemiluminescence | 36 m | NA | NA | Pneumonia: Aspergillus fumigatus | 1, 4, 15* |
10 | c.1222G > C | p.Gly408Arg | 0 | 1 | NA | 4% | NA | Normal (WB) | Neu | NBT slide test | 0.2 m | 12 m | NA | Pneumonia, hepatic abscess, skin abscess, skin involvement | 1, 16* |
11 | c.1222G > A | p.Gly408Arg | 0 | 1 | NA | 0 | 0 | Normal (absorption spectroscopy and WB) | Neu | NBT slide test, cytochrome c reduction assay, chemiluminescence | 8 m | NA | NA | Pneumonia, lymph nodes infection, liquor: Mycobacterium bovis | 1,15* |
12 | c.1222G > A | p.Gly408Arg | 0 | 1 | NA | 0 | 0 | Normal (WB and differential spectrophotometry) | Neu | NBT slide test and cytochrome c reduction assay | NA | 72 m | NA | Pneumonia, sepsis, skin involvement, perianal abscess, colitis, diarrhea, recurrent adenopathies | 1, 29* |
13 | c.1223G > A | p.Gly408Glu | 0 | 1 | 1 | NA | NA | Normal (flow cytometry) | Neu | DHR analysis | NA | NA | NA | NA | 2* |
14 | c.1226C > A | p.Ala409Glu | 0 | 1 | NA | NA | 0 | Normal (flow cytometry) | Neu | DHR analysis | NA | 72 m | NA | BCG complications, tuberculosis, subcutaneous abscesses, bronchitis, pneumonia, sinusitis, diarrhea | 1, 30* |
15 | c.1235G > A | p.Gly412Glu | 0 | 1 | NA | 0 | 0 | Normal (WB) | Neu | NBT slide test and cytochrome c reduction assay | NA | 6y | NA | Prolonged fever, pulmonary abcess, Cervical adenopathy, BCGititis, abscess of the anal margin, acute appendicitis, diarrhea | 1, 8* |
16 | c.1244C > A | p.Pro415His | 0 | 1 | NA | NA | 0 | Normal (WB) | Neu | NBT slide test | NA | NA | NA | NA | 1, 4, 17, 18* |
17 | c.1244C > T | p.Pro415Leu | 0 | 1 | NA | 0 | 0 | Normal (WB), 63% of normal (differential spectrophotometry) | Neu | NBT slide test and cytochrome c reduction assay | NA | 18 m | NA | Pulmonary abscess, sepsis, hyperthermia,adenopathy (S. aureus), skin inbvolvement | 1, 29* |
18 | c.1462-2A > G | partial del exon 12 p.Ala488_Glu497del | 0 | 1 | NA | NA | 3.3 (nmol/5 × 106 cells/20 min), 6% of nnormal | Normal (WB and spectrometry) | Neu | cytochrome c reduction assay | 69y | 69y | NA | DIC, gastational bleeding, renal failure, persistant fever, pseudomonas cepacia infection | 1, 9* |
19 | c.1462-2A > G | partial del exon 12 p.Ala488_Glu497del | 0 | 1 | NA | NA | NA | NA | Neu | cytochrome c reduction assay | NA | NA | 5y | Pneumonia | 1, 9* |
20 | c.1463C > A | p.Ala488Asp | 0 | 1 | 0.4 | 0 | 0 | Normal (WB) | Neu | NBT slide test, DHR analysis and bactericidal activity | 2y | 2y | NA | Persistant lymphadenitis | 1, 31* |
21 | c.1498G > T | p.Asp500Tyr | 0 | 1 | NA | 0 | NA | Normal | Neu | NBT slide test | NA | NA | NA | NA | 1, 19* |
22 | c.1498G > T | p.Asp500Tyr | 0 | 1 | NA | 0 | NA | NA | Neu | NBT slide test | NA | NA | NA | NA | 1, 19* |
23 | c.1498G > T | p.Asp500Tyr | 0 | 1 | NA | 0 | 7–9% of normal | Normal (WB) | PMN | NBT slide test, DCFH assay and chemiluminescence | NA | 6 m | NA | NA | 1, 20* |
24 | c.1498G > T | p.Asp500Tyr | 0 | 1 | 6 | NA | NA | Normal (flow cytometry) | Neu | DHR analysis | NA | NA | NA | NA | 2* |
25 | c.1499A > G | p.Asp500Gly | 0 | 1 | NA | NA | 1% of control, 0.13 ± 0.06μmolO2-/min | Normal (WB and spectrometry) | Neu | cytochrome c reduction assay | 6 m | 36 m | NA | Pneumonia, hepatic abscess, gastational bleeding | 1, 21* |
26 | c.1499A > G | p.Asp500Gly | 0 | 1 | 8.8 | NA | NA | Normal (flow cytometry) | Neu | DHR analysis | NA | NA | NA | NA | 2* |
27 | c.1500 T > G | p.Asp500Glu | 0 | 1 | NA | 0 | 0 | Normal (WB) | Neu | NBT slide test, DHR analysis and bactericidal activity | NA | 2y | NA | Recurrent pyrexia and chronic diarrhea, multiple lymph nodes,peri-anal infections | 1, 31* |
28 | c.1500 T > G | p.Asp500Glu | 0 | 1 | NA | 0 | 0 | Normal (WB) | Neu | NBT slide test, DHR analysis and bactericidal activity | 12 m | 12 m | NA | Diarrhea, peri-anal infections,lung abscess | 1, 31* |
29 | c.1508C > A | p.Thr503Lys | 0 | 1 | NA | NA | NA | Normal (flow cytometry) | Neu | NBT slide test and DHR analysis | NA | NA | Alive | S. marcescens infection | 1, 28* |
30 | c.1514 T > G | p.Leu505Arg | 0 | 1 | NA | 6% | 0 | Normal (WB) | Neu | cytochrome c reduction assay | NA | 24 m | NA | Sepsis, hepatosplenomegaly | 1, 22* |
31 | c.1521_1525delAAAGA insCATCTGGG | p.(Gln507_Thr509del, insHisIleTrpAla) | 0 | NA | 8% | 1% | Normal (WB and flow cytometry) | PMN | NBT reduction assay, cytochrome c reduction assays and chemiluminescence | 1 m | 36 m | ALive | Pneumonia, perianal abscesses, liver abscesses | 23* | |
32 | c.1609 T > C | p.Cys537Arg | 0 | 1 | NA | NA | 0 | Normal (WB) | Neu | DHR analysis, cytochrome c reduction assay and chemiluminescence | NA | NA | NA | NA | 1, 17, 24* |
33 | c.1609 T > C | p.Cys537Arg | 0 | 1 | 27 | NA | NA | Normal (flow cytometry) | Neu | DHR analysis | NA | NA | NA | NA | 2* |
34 | c.1637 T > C | p.Leu546Pro | 0 | 1 | NA | NA | 2.1–7.2% | Normal (flow cytometry) | Neu | DHR analysis | NA | NA | NA | NA | 1, 25* |
35 | c.1702G > A | p.Glu568Lys | 0 | 1 | NA | 0 | 0 | Normal (absorption spectroscopy and WB) | Neu | NBT slide test, cytochrome c reduction assay, chemiluminescence | 8 m | NA | NA | Sepsis: Salmonella, Staphylococcus, | 1, 15* |