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Letters to the Editor
Biallelic CXCR2 loss-of-function mutations define a distinct congenital neutropenia entity
Neutrophil homeostasis results from a balance between neutrophil production, release from the bone marrow and clearance from the circulation, where chemokines and their receptors play central roles.1,2 Studies on mice demonstrated that CXCR4 and CXCR2 receptors antagonistically regulate bone marrow neu- trophil release.2 While CXCR4 and its chemokine CXCL12, which is constitutively expressed in the bone marrow, provide key signals for neutrophil retention, CXCR2 activation by the CXCL8 subfamily of chemokines promotes their release from the bone mar- row.1,2 Those events were shown in patients carrying het- erozygous CXCR4 gain-of-function mutations causing the rare autosomal dominant WHIM syndrome, charac- terized by human papillomavirus-induced warts, hypogammaglobulinemia, recurrent bacterial infections
and myelokathexis reflecting an accumulation of senes- cent neutrophils in the bone marrow.3 Profound neu- tropenia associated with myelokathexis was previously reported in two siblings carrying a homozygous truncat- ing CXCR2 loss-of-function mutation, supporting the importance of CXCR2 signaling in neutrophil mobiliza- tion.4 Myelokathexis and recurrent severe infections5 in that single pedigree led to it being included in the large series of WHIM syndrome and WHIM syndrome-like cases,6 and it remains the only published example of CXCR2 deficiency.
Herein, we report biallelic CXCR2 mutations, including one complete gene deletion, in four patients with chronic neutropenia, harboring a wild-type (WT) CXCR4 gene.
Patients were diagnosed during childhood with pro- found neutropenia in the context of recurrent gingivitis and oral ulcerations (Table 1). Bone marrow smears showed no major granulocytic maturation defect. Myelokathexis was present in only patient 1 (P1) and affected 35% of myeloid cells. Values of the other hema-
Table 1. Clinical profile of the four patients with biallelic CXCR2 loss-of-function mutations.
Characteristic
Clinical profile
Age at diagnosis (years) Oral lesions
Severe infectionsa (age)
Prophylactic treatment G-CSF therapy (dose, period)
Age at last follow-up (years)
Hematologic values at diagnosis
Neutrophils (x109/L) Monocytes (x109/L) Lymphocytes (x109/L) Hemoglobin level (g/dL) Platelets (x109/L)
Hematologic values during follow-up
Blood counts (n) Neutrophils (x109/L) Monocytes (x109/L) Lymphocytes (x109/L) Hemoglobin (g/dL) Platelets (x109/L)
Differential bone-marrow count
Myeloblasts
Promyelocytes & myelocytes Metamyelocytes & mature neutrophils Myelokathexis
Immunoglobulin levels (g/L) IgG
IgM IgA
Lymphocyte subsets
Subset determinations (n)
CD3+CD4+ T cells (x109/L) CD3+CD8+ T cells (x109/L)
CD19+ B cells (x109/L) CD3–CD16+CD56+ NK cells (x109/L)
P1 (8364)
Patient (Registry ID) P3
2.9 Yes No
No Yes (2 mg/kg, 2
36
0.56
0.31 2.0 12.4 359
18
0.57 (0.28-1.8) 0.29 (0.02-0.51) 1.66 (1-2.7) 12.6 (11.5 -13.3) 357 (257-439)
4% 15% 43% 35%
15.1 (14.2-20.5) 0.91 (0.81-1.12) 2.98 (1.73-3.06)
5
0.544 (0.333-0.700) 0.288 (0.170-0.429) 0.157 (0.121-0.177) 0.088 (0.078-0.129)
P2 (6487)
1.9
Yes
1 cellulitis (13 months) Cotrimoxazole No
22.5
0.6
0.46 6.3 12.2 371
24
0.45 (0.1-0.85) 0.43 (0.16-0.68) 2.03 (1-6.3) 11.5 (9.9-13.2) 277 (215-572)
0% 5% 29% 0%
16.7 (14.3-17.3) 1.77 (1.51-2.0) 3.75 (3.14-3.96)
10
0.677 (0.611-0.853) 0.501 (0.432-0.629) 0.295 (0.240-0.365) 0.171 (0.134-0.209
(6902)
1.8
Yes
1 pneumonitis (22 months) Cotrimoxazole Yes
(5 mg/kg, 1 month) 10
0.18
0.52 6.2 11.8 368
23
0.54 (0.1-10.8b) 0.53 (0.19-1.3) 4.0 (0.97-10.8) 12.2 (10.4-13.1) 324 (167-544)
1% 13% 38% 0%
10.9 (10.2-11.8) 2.41 (2.12-2.53) 1.75 (1.69-2.56)
3
0.920 (0.766-1.075) 0.611 (0.498-0.725) 0.468 (0.344-0.591)
0.153 (0.134-0.172)
P4 (8497)
1.2 Yes No
No No
6.5
0.6
0.46 4.6 10 225
7
0.35 (0.3-1) 0.52 (0.39-0.7) 4.58 (1.9-4.8) 10.7 (9.6-12.7) 523 (225-670)
2% 2% 37% 0%
14.8 1.63 3.35
1c 1.456 1.295 0.769 0.778
Reference range
1.5-8.0 0.1-1.0 1.5-6.5 11.5-15.5 150-400
1.5-8.0 0.1-1.0 1.5-6.5 11.5-15.5 150-400
0.3-4% 12-25% 33-48%
5.98-11.1 0.56-1.59 0.49-1.53
0.53-1.3 0.33-0.92 0.11-0.57 0.07-0.48
years)
Results are expressed as medians (range),unless stated otherwise.Bold type indicates lower values and bold italics indicate higher values compared to the reference range. aIntravenous antibiotic-treated infections. bAt the time of a fever of unknown origin (likely viral), the absolute neutrophil count increased spontaneously. cEvaluated at age of 4 years. G-CSF: granulocyte colony-stimulating factor; NK natural killer.
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