WHIM syndrome, an autosomal dominant disorder: Clinical, hematological, and molecular studies

Abstract

The acronym WHIM refers to Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. The latter refers to the retention of white cells in the marrow, which becomes hypercellular. We have found approximately 20 examples of WHIM syndrome in the literature under various designations; the first examples are Zuelzer [1964] and Krill et al. [1964]. Chronic noncyclic neutropenia and hypercellular bone marrow represent defective release of marrow cells into the peripheral stream (myelokathexis). The hypermature neutrophils are bizarre in form. Condensed nuclei connected by long, stringy filaments and vacuolated cytoplasm suggest apoptosis. Fever or other stress increases the release of neutrophils. Hypogammaglobulinemia is marked and associated with recurrent upper respiratory infections (sinusitis, tonsillitis, otitis media, pneumonia). Patients have numerous warts, some venereal, with resultant cervical and vulval premalignant dysplasia. We report on a kindred of 6 affected individuals in 3 generations with autosomal dominant WHIM syndrome. The sex ratio among reported patients and in our kindred is 17 female to 8 male. Because there had been no male-to-male transmssion, search of the entire X-chromosome including the pseudoautosomal area was carried out and no linkage was found. Recently, the propositus has had an unaffected daughter, confirming our finding that the gene is not X-linked. A genome-wide search is being carried out.

MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1

“…44 G-CSF regulation of CXCR4 has gained much attention as a critical pathway for HSPC release in response to G-CSF. While the role of CXCR4 in the mobilization of myeloid cells, particularly with a contribution of CXCR2, is well-documented, 7,8,10,[13][14][15][16]45 its role in the mobilization of HSPC is not well documented. Previous studies showed that G-CSF administration in man induces a gradual increase in the expression of CXCR4 on bone marrow progenitors (CD34 + or CD38 + cells) over 5 days of treatment.…”

“…[9][10][11][12] Patients with WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) are neutropenic because of reduced neutrophil mobilization attributable, in most cases, to "gain-of-function" mutations of CXCR4. 13,14 Selective deletion of CXCR4 in myeloid cells causes a redistribution of neutrophils from the bone marrow to the blood resulting in neutrophilia. 10 AMD3100, a synthetic inhibitor of SDF1 binding to CXCR4, promotes neutrophil mobilization when injected into mice and humans.…”

Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2

“…Complete deletion of Gfi1 results in runting and inner ear defects in the mouse model 8 , but humans with amino acid substitutions show no evidence of these or other developmental problems. The combined neutropenia and immunodeficiency resembles the WHIM syndrome of myelokathexis 9 , but the undifferentiated appearance of the neutrophils differs from the hypermature appearance of neutrophils in WHIM syndrome.…”

Safety and efficacy of treatment using interleukin-2 in a patient with idiopathic CD4+ lymphopenia andMycobacterium avium-intracellulare

“…Several studies have evaluated IL-2 treatment of CD4 + lymphopenia because of HIV. Generally, these IL-2 treatments in HIV lymphopenia studies have revealed significant increases in CD4 + counts and possible clinical improvement in immunological function [16][17][18][19]. From these large studies the sideeffect profile of IL-2 in HIV CD4…”

“…The patient's lack of warts on physical examination, Ig profile, bone marrow biopsy findings and normal neutrophil counts were inconsistent with the warts, hypogammaglobulinaemia, infection and myelokathexis syndrome [16]. A very small number of case reports have described variant partial adenosine deaminase (ADA) deficiency that presents first in adults [17,18].…”