WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure

Abstract

WHIM syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow; monocytopenia and lymphopenia, especially B lymphopenia, also commonly occur. WHIM syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and β-arrestin-dependent responses. Accordingly, CXCR4 antagonists have shown promise as mechanism-based treatments in phase 1 clinical trials. This review is based on analysis of all 105 published cases of WHIM syndrome and covers current concepts, recent advances, unresolved enigmas and controversies, and promising future research directions.

Keywords: CXCL12; CXCR2; CXCR4; Chemokine; human papillomavirus; myelokathexis; plerixafor.

Figure 1.

Defining hematologic features of myelokathexis, the pathognomonic syndromic feature of WHIM syndrome: neutropenia, myeloid hyperplasia with a shift to the right, and a high frequency of degenerating dysmorphic neutrophils in bone marrow. Eleven different CXCR4 mutations (see Figure 3) and one CXCR2 mutation (p.H323fs329X) have been reported in WHIM patients. The figure is a modification of Figure 1 in Reference . Gr., Greek. In some patients and in WHIM model mice, the neutrophils are not dysmorphic, but the other features are present.

Figure 2.

Genetic mechanisms of myelokathexis. The balance of CXCR2 release signals and CXCR4 retention signals determines the rate of neutrophil egress from bone marrow to blood and the distribution of neutrophils between the two compartments. Thus, both loss of function CXCR2 mutations and gain of function CXCR4 mutations cause myelokathexis. CXCR4 mutations account for >95% of genotyped cases of WHIM syndrome, whereas a CXCR2 mutation has been identified in two siblings.

Figure 3.

CXCR4 mutations in WHIM syndrome are located in the C-terminus of the receptor. The 7-transmembrane domain crystal structure of CXCR4 is shown on the left with stars demarcating locations of WHIM mutations. The sequence of the C-tail of the mutant receptors is shown on the right compared to the wild-type sequence. Neo-sequence imposed by frameshift mutations is underlined. The circled amino acid is a missense mutation. The figure is modified and updated from Figure 2 in Reference [43].

Figure 4.

Leukocyte distribution in immune organs is distorted in WHIM model mice [97]. A corresponding detailed assessment of leukocyte distribution is unavailable in WHIM patients. Eff/Mem, effector/memory. The figure is reproduced from [204].

Figure 5.

CXCR4 antagonist plerixafor has shown promise in Phase 1 trials in patients with WHIM syndrome. A, Structure of the bicyclam plerixafor. B, Plerixafor durably increases the absolute neutrophil count in WHIM patients. This figure is reproduced from Reference [49]. C, Plerixafor treatment of WHIM patients was associated with clinical improvement. Photographs show clinical manifestation from two patients before and approximately 6 months after twice daily treatment with plerixafor, including partial regression of a heavy wart burden on the hand, reduced myelokathexis in bone marrow and resolved chronic inflammatory lower leg lesions. The ‘before’ photograph of the leg in panel C is reproduced from Reference [87]; the after photograph of the leg shows discoloration at sites of previous inflammation, probably due to hemosiderin deposition that had not yet cleared. See details in Reference [87].

Figure 6.

Chromothriptic cure of WHIM patient WHIM-09. Chromothripsis, a Greek neologism that means chromosome shattering, affected one copy of chromosome 2 in a single hematopoietic stem cell from the patient. The WHIM copy of CXCR4 and 163 other genes on that chromosome were deleted and the remaining non-deleted shattered fragments were rejoined to form a derivative chromosome. The cell clonally expanded and selectively replaced the myeloid lineage with non-WHIM cells, resulting in clinical cure. The lymphoid lineage was unaffected by the event, so that the patient is a hematologic chimeric of WHIM lymphoid cells and chromothriptic non-WHIM myeloid cells. The patient is estimated to have lived >25 years since the chromothriptic event. This case report suggests that WHIM allele inactivation may be superior to WHIM allele correction as a gene therapy strategy. Consistent with this, Cxcr4 haploinsufficiency markedly enhanced hematopoietic reconstitution of donor HSCs and corrected leukopenia in unconditioned transplanted WHIM model mice. The figure is modified from Reference [58].