Kawai Toshinao, Malech Harry L
Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan.
Curr Opin Hematol. 2009 Jan;16(1):20-6. doi: 10.1097/MOH.0b013e32831ac557.
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is characterized by susceptibility to human papilloma virus infection-induced warts and carcinomas; neutropenia, B-cell lymphopenia and hypogammaglobulinema-related infections; and bone marrow myelokathexis (myeloid hyperplasia with apoptosis). The purpose of this report is to review new findings about WHIM.
Most WHIM patients have heterozygous C-terminus deletion mutations of the intracellular carboxy terminus of the chemokine receptor CXCR4. WHIM leukocytes have enhanced responses to CXCL12, the cognate ligand of CXCR4. Enhanced activity of CXCR4 delays release of mature neutrophils from bone marrow, resulting in neutropenia and apoptosis of mature neutrophils retained in the marrow. Finding two patients with WHIM who do not have detectable mutations of CXCR4 but whose cells are hyperresponsive to CXCL12 raises the possibility that there is more than one genetic basis for WHIM. One patient had low levels of G-protein receptor kinase 3, and the functional hyperactivity response to CXCL12 was corrected by forced gene transfer-mediated overexpression of G-protein receptor kinase 3, implicating defects in function of this protein as a potential alternate genetic cause of WHIM.
Subjects reviewed include clinical presentation, diagnosis, and treatment of WHIM and advances in understanding the genetic basis of WHIM.
疣、低丙种球蛋白血症、感染和髓系细胞滞留（WHIM）综合征的特征为易患人乳头瘤病毒感染所致的疣和癌；中性粒细胞减少、B细胞淋巴细胞减少及低丙种球蛋白血症相关感染；以及骨髓髓系细胞滞留（伴有凋亡的髓样增生）。本报告旨在综述关于WHIM的新发现。
大多数WHIM患者存在趋化因子受体CXCR4细胞内羧基末端的杂合性C末端缺失突变。WHIM白细胞对CXCR4的同源配体CXCL12反应增强。CXCR4活性增强会延迟成熟中性粒细胞从骨髓中释放，导致中性粒细胞减少以及滞留于骨髓中的成熟中性粒细胞凋亡。发现两名没有可检测到的CXCR4突变但其细胞对CXCL12反应亢进的WHIM患者，这增加了WHIM存在不止一种遗传基础的可能性。一名患者G蛋白偶联受体激酶3水平较低，通过强制基因转移介导的G蛋白偶联受体激酶3过表达纠正了对CXCL12的功能性亢进反应，这表明该蛋白功能缺陷可能是WHIM的另一种潜在遗传病因。
所综述的内容包括WHIM的临床表现、诊断、治疗以及在理解WHIM遗传基础方面的进展。
