Li Jingwei, Delecourt-Billet Marine, Fenneteau Odile, Neff Jadee L, Roland Lilian, Schell Bérénice, Gourhand Vanessa, Espeli Marion, Balabanian Karl, Taplin Sarah, Defontis Myriam, Nguyen Chi Huu, Mordhorst Julia, Johnson Robert, Taveras Arthur, Geier Christoph B, Schuetz Catharina, Thiede Christian, Yilmaz Melis, Sakovich Inga, Sharapova Svetlana, Moschese Viviana, Mauriello Alessandro, Walter Jolan E, Cavieres Mirta, Akahane Daigo, Mousallem Talal, Li Julie, Newburger Peter E, Tarrant Teresa K, Kelley Merideth L, Bolyard Audrey Anna, Dale David C, Donadieu Jean, Zmajkovicova Katarina, Bledsoe Jacob R
Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Service d'Hématologie Biologique, Hôpital Robert-Debré, AP-HP, Paris, France.
Lab Invest. 2025 Apr 14;105(8):104174. doi: 10.1016/j.labinv.2025.104174.
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) 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 and 2 CXCR4). 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) 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.
疣、低丙种球蛋白血症、感染、髓细胞扣留（WHIM）综合征是一种罕见的原发性免疫缺陷疾病，主要由种系CXCR4变异引起。骨髓（BM）评估显示髓细胞扣留有助于确立WHIM综合征的诊断，但对相关诊断特征不熟悉以及形态学和临床发现的变异性可能导致疾病未被充分认识。我们旨在描述30例种系CXCR4变异患者的临床、BM和外周血（PB）特征，包括基因型-表型分析以及形态学特征与功能性CXCR4受体内化缺陷之间的相关性。我们还旨在研究WHIM综合征小鼠模型（Cxcr4）的PB特征，并检查CXCR4拮抗剂治疗后WHIM综合征和WHIM小鼠PB的形态学变化。羧基末端无义/移码CXCR4变异分别与BM和PB中32%至80%（中位数为66%）和4%至14%（中位数为9%）的总中性粒细胞中的髓细胞扣留性中性粒细胞形态相关。相比之下，5种错义CXCR4变异中髓细胞扣留性中性粒细胞较少见（3种CXCR4和2种CXCR4）。与中性粒细胞减少的对照组相比，羧基末端CXCR4无义/移码变异与>10%的BM或>5%的PB髓细胞扣留性中性粒细胞相关（特异性100%；BM为100%或PB为93%敏感），以及更频繁的中性粒细胞凋亡（BM，P = 0.0093；PB，P < 0.0001）、畸形/空泡化嗜酸性粒细胞（BM，P = 0.012；PB，P < 0.0001）、中性粒细胞空泡化（BM，P < 0.0001）以及BM中非小梁旁中性粒细胞簇（P = 0.0059）。54%的羧基末端CXCR4无义/移码变异出现BM髓系增生，而对照组未出现。BM中髓细胞扣留性中性粒细胞百分比与功能性CXCR4内化缺陷相关（P≤0.0042）。与人类一样，WHIM小鼠（Cxcr4）表现出循环中的髓细胞扣留样中性粒细胞，核分叶过多。对5例WHIM综合征患者和小鼠进行CXCR4拮抗剂治疗后，PB中形态正常和髓细胞扣留性中性粒细胞均增加。我们证明了CXCR4变异与髓细胞扣留之间存在显著的基因型-表型异质性，这与功能性CXCR4内化缺陷相关。WHIM综合征的形态学特征可能很细微，导致误诊。我们描述了有助于促进诊断的关键形态学特征。
