Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients

Abstract

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.

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“…However, using neutropenia and lymphopenia as diagnostic tools also poses difficulties due to the normalization of ANC and ALC during recurrent infections and stress during childbirth. Despite being one of the WHIM tetrad, warts are noted later in life, with an average age of onset of 14 years in our international cohort, thus leading to a delay in consideration of WHIM syndrome as part of the differential diagnosis (Geier et al, 2022).…”

“…Although WHIM syndrome is an acronym for a tetrad of possible clinical manifestations, the majority of previously reported patients do not present with all four characteristics (Geier et al, 2022). In addition, WHIM syndrome is a rare primary immunodeficiency disorder and familiarity with the disorder is uncommon among clinicians.…”

“…Therefore, infants with WHIM syndrome may be concealed by their borderline-low TREC levels, which prompts some states to flag as abnormal while other states not. However, it is important to highlight that although severe lymphopenia may not be present at birth, it has been noted to be progressive in early childhood (Geier et al, 2022). These findings are especially of importance in the setting of an infant with neutropenia.…”

“…However, the clinical presentation of WHIM syndrome is highly heterogeneous with variable severity, even in individuals sharing the same CXCR4 variant as a result of incomplete penetrance. Although WHIM syndrome is an acronym for a tetrad of possible clinical manifestations, the majority of previously reported patients do not present with all four characteristics (Geier et al, 2022). In addition, WHIM syndrome is a rare primary immunodeficiency disorder and familiarity with the disorder is uncommon among clinicians.…”

“…However, bone marrow biopsy is an invasive procedure and myelokathexis is a phenomenon seen infrequently in routine pathology, making it easy to be overlooked or misdiagnosed (i.e., myelodysplastic syndrome). Neutropenia, another hallmark of WHIM syndrome, is not only the most common laboratory finding but also one of the first clinical features to be noted, after infections, in reported patient cohorts (Beaussant Cohen et al, 2012; Geier et al, 2022). However, using neutropenia and lymphopenia as diagnostic tools also poses difficulties due to the normalization of ANC and ALC during recurrent infections and stress during childbirth.…”