WHIM Syndrome Cured by Chromothripsis

Chromothripsis, the catastrophic disruption and random reassembly of a chromosome or chromosome region, has been estimated to occur in 2% to 3% of cancers. Rather than producing disease, we present a case in which chromothripsis resulted in disease cure. A 59-year-old woman was troubled with the manifestations of WHIM syndrome until she experienced spontaneous resolution of symptoms in her 30s. WHIMS, an autosomal dominant immunodeficiency disorder caused by gain of function mutations in the chemokine receptor CXCR4 gene, is characterized by warts, hypogammaglobulinemia, recurrent infections and myelokathexis (impaired egress of mature neutrophils from bone marrow [BM] causing neutropenia). The patient, who now had leukocytosis, had the PCR-RFLP detected mutant CXCR4R334X allele of her affected daughters in her skin fibroblasts, but not in her blood. BM evaluation revealed an acrocentric chromosome 2. FISH demonstrated a centromeric inversion, deletion of NMYC, and ALK in the long arm. Oligo-SNP microarray revealed 7 deletions of chromosome 2 resulting in hemizygous loss of 163 genes including CXCR4 at 2q22.1. Next generation sequencing showed the abnormal chromosome 2 was composed of 18 segments arranged in random order and orientation. Competitive mouse BM transplantation experiments demonstrated that Cxcr4 haploinsufficiency is sufficient to confer a strong long-term engraftment advantage of donor BM over BM from wild-type or WHIMS mice, suggesting a mechanism for the patient’s cure after a hematopoietic stem cell (HSC) underwent chromothripsis. These findings suggest partial inactivation of CXCR4 may be a strategy to promote HSC engraftment in transplantation.