Clinicopathologic Features and the Spectrum of Myelokathexis in Warts, Hypogammaglobulinemia, Infections, Myelokathexis Syndrome
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency disorder predominantly caused by germline CXCR4 variants. Bone marrow (BM) evaluation showing myelokathexis helps to establish the diagnosis of WHIM syndrome, but unfamiliarity with pertinent diagnostic features and variability in morphologic and clinical findings may result in disease underrecognition. We aimed to characterize the clinical, BM, and peripheral blood (PB) features of 30 patients with germline CXCR4 variants, including genotype–phenotype analysis and correlation between morphologic features and functional CXCR4 receptor internalization defect. We also aimed to examine PB features of a mouse model of WHIM syndrome ( Cxcr4 +/1013 ) and examine WHIM syndrome and WHIM mouse PB morphologic changes after CXCR4 antagonist therapy. Carboxy-terminal nonsense/frameshift CXCR4 variants were associated with myelokathectic neutrophil morphology in 32% to 80% (median, 66%) and 4% to 14% (median, 9%) of total neutrophils in the BM and PB, respectively. In contrast, myelokathectic neutrophils were infrequent in 5 missense CXCR4 variants (3 CXCR4 D84H and 2 CXCR4 S341Y ). Compared with neutropenic controls, carboxy-terminal CXCR4 nonsense/frameshift variants were associated with >10% BM or >5% PB myelokathectic neutrophils (100% specific; 100% [BM] or 93% [PB] sensitive), as well as more frequent neutrophil apoptosis (BM, P = .0093; PB, P < .0001), dysmorphic/vacuolated eosinophils (BM, P = .012; PB, P < .0001), neutrophil vacuolization (BM, P < .0001), and nonparatrabecular neutrophil clusters in the BM ( P = .0059). BM myeloid hyperplasia occurred in 54% of carboxy-terminal CXCR4 nonsense/frameshift variants and in no controls. BM myelokathectic neutrophil percentage correlated with the functional CXCR4 internalization defect ( P ≤ .0042). Like humans, WHIM mice ( Cxcr4 +/1013 ) demonstrated circulating myelokathectic-like neutrophils with nuclear hypersegmentation. CXCR4 antagonist therapy in patients with WHIM syndrome (n = 5) and mice increased both morphologically normal and myelokathectic neutrophils in PB. We demonstrated notable genotype–phenotype heterogeneity between CXCR4 variants and myelokathexis, which correlates with functional CXCR4 internalization defect. The morphologic features of WHIM syndrome may be subtle, resulting in misdiagnosis. We described key morphologic features that are useful to facilitate diagnosis.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it