Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center University of Freiburg Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Department of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
J Clin Immunol. 2022 Nov;42(8):1748-1765. doi: 10.1007/s10875-022-01312-7. Epub 2022 Aug 10.
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.
疣、低丙种球蛋白血症、感染和骨髓嗜中性粒细胞减少伴骨髓细胞外基质嵌入（WHIM）综合征（WS）是一种由 C-X-C 趋化因子受体 4（CXCR4）基因突变引起的联合免疫缺陷。我们对一个由 66 例患者组成的独特国际队列进行了特征描述，其中包括 57 例（86%）以前未报告的病例，具有不同的临床表型。在我们的队列中，17 个不同的 CXCR4 基因突变中有 11 个是新的致病性突变，影响了 15 个人（23%）。所有的变体都影响相同的 CXCR4 区域，并损害 CXCR4 的内化，导致过度活跃的信号。我们队列中的中位诊断年龄（5.5 岁）表明 WHIM 综合征通常可在儿童期出现，尽管有些患者直到成年后才被诊断出来。我们队列中感染（88%/1.6 年）、中性粒细胞减少（98%/3.8 年）、淋巴细胞减少（88%/5.0 年）和疣（40%/12.1 年）的发病年龄和发病频率均有报道。然而，我们报告的 WHIM 综合征的自身免疫并发症的发生率和种类都比以前报道的要高（21.2%）。有家族史的 WHIM 综合征患者的诊断时间更早（22%，平均年龄 1.3 岁，无家族史的 WHIM 综合征患者的平均年龄为 5 岁）。有家族史的 WHIM 综合征患者也更早接受治疗，住院次数更少，终末器官损伤也更少。这一观察结果证实了以前的报告，即早期治疗 WHIM 综合征可以改善预后。只有 1 例患者死亡；死亡归因于造血干细胞移植的并发症。WHIM 综合征在儿科患者中的表现具有可变的表达性，这导致了他们的诊断和治疗延迟。即使没有疣，也应该对表现出严重中性粒细胞减少和/或淋巴细胞减少的早发性细菌性感染进行 WHIM 综合征的基因检测。
