Clinicopathologic Features and the Spectrum of Myelokathexis in Warts, Hypogammaglobulinemia, Infections, Myelokathexis Syndrome

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.

Keywords: CXCR4; Hypogammaglobulinemia; WHIM syndrome; Warts; immunodeficiency; myelokathexis; neutropenia.