Dysplasia of Granulocytes in a Patient with HPV Disease, Recurrent Infections, and B Lymphopenia: A Novel Variant of WHIM Syndrome?

Abstract

WHIM syndrome is a condition in which affected persons have chronic peripheral neutropenia, lymphopenia, abnormal susceptibility to human papilloma virus infection, and myelokathexis. Myelokathexis refers to the retention of mature neutrophils in the bone marrow (BM), which accounts for degenerative changes and hypersegmentation. Most patients present heterozygous autosomal dominant mutations of the gene encoding CXCR4. Consequently, aberrant CXCL12/CXCR4 signaling impairs the receptor downregulation causing hyperactivation (gain-of-function) that affects BM homing for myelopoiesis and lymphopoiesis and the release of neutrophils in the bloodstream. We report the case of a 26-year-old female with severe foot and hand cutaneous warts since childhood, recalcitrant genital condylomatas, bacterial infections, and intraepithelial cervical neoplasia. Laboratory tests revealed severe B lymphopenia and HPV high and low risk types. HIV testing was negative. Not only CXCR4 but also GATA2, NEMO, and CD40L gene mutations were excluded. BM smears revealed, in the presence of a normal cellularity, hyperplasia of myeloid cells (MPO positive) and karyorrhexis, especially in neutrophils and eosinophils. Of note, neutrophils with altered lobation of nuclei connected by long thin chromatin filaments were observed. Our patient presented a clinical and histological picture reminiscent of WHIM in the presence of normal peripheral neutrophil counts and wild-type CXCR4 gene. Although the BM did not reveal a classical pattern of myelokathexis, the observation of consistent signs of neutrophil dysplasia has fuelled the hypothesis of a novel WHIM variant or a novel immunodeficiency. We speculate that abnormalities that affect CXCR4/CXCL12 pair, including GRK levels or activity, might be responsible for this WHIM-like disorder.

Case Report: Altered NK Cell Compartment and Reduced CXCR4 Chemotactic Response of B Lymphocytes in an Immunodeficient Patient With HPV-Related Disease

“…Our patient is a 32-year-old female who was described as a WHIM-like disorder at 26 years of age on the basis of dysplasia of granulocytes, recurrent infections, HPV-associated disease and B-cell lymphopenia (17). As previously reported, no family members showed HPV-susceptibility.…”

“…Since the original description of our patient (17,19), extended clinical monitoring as well as immunological and genetic investigations here presented have allowed further understanding of this novel IEI, underscoring the contribution of CXCR4/CXCL12 signaling pathway and of NK cells in host defense against HPV and providing new clues for targeted therapies. consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.…”

“…Over the years, WHIM-like disorders showing variations both in genotype and phenotype from the paradigmatic WHIM syndrome have been reported, also including disorders developing in the absence of CXCR4 mutations (13). Here we report B and NK cell anomalies in a female patient with HPV-related disease for whom we have previously proposed a diagnostic hypothesis of WHIM-like syndrome with wild-type CXCR4 (17). The expression of CXCR4 in peripheral lymphocyte subsets and their CXCR4/CXCL12dependent chemotaxis were investigated unveiling a previously unrecognized B lymphocyte defect discrepant with a WHIMrelated response.…”

“…Individuals with IEI may suffer of increased infectious susceptibility either to a specific pathogen or multiple pathogens (24). Here we provide original data on a patient previously proposed as a potential WHIM-like case with disseminated and persistent mucocutaneous HPV infection, recurrent upper respiratory tract infections, B-cell lymphopenia and dysplasia of granulocytes, while in a context of wild-type CXCR4 and normal peripheral neutrophil and monocyte counts (17,19). In line with previous observations made in typical WHIM patients, our patient showed B-cell lymphopenia as prominent immunologic alteration and poor maintenance of memory response to vaccines.…”

“…Serum immunoglobulin levels, including IgG subclasses and IgE, were within the normal range. Protective anti-pneumococcus IgG levels were detected after polysaccharide vaccine, although they tended to wane over time (17). Also, an adequate humoral and cellular response to COVID-19 vaccine was observed.…”