WHIM Syndrome Diagnosis in a Parent and Child

Warts, hypogammaglobulinemia, immunodeficiency/infections, and myelokathexis (WHIM) syndrome is a rare autosomal dominant primary immunodeficiency (PID) caused by defects in the C-X-C motif chemokine receptor 4 (CXCR4) gene. Here we present the presentation, evaluation, and management of a father and son diagnosed with WHIM syndrome. Case 1 was a 39-year-old male with WHIM syndrome diagnosed 6 years prior via bone marrow biopsy with FoundationOne genetic testing positive for CXCR4 mutation (T322fs*26 and C1012dup with protein sequence change pser338Phefs*6). History was significant for frequent warts, rashes, and recurrent pneumonia since his early 20s, occurring 5-6 times a year. CT chest from the previous year showed tree-in-bud opacities in the right middle and posterior left lower lobes with mediastinal lymphadenopathy. He was treated with pegfilgrastim for the 6 months prior to representation. Initial workup showed reduced CD4, CD8, CD19, and pneumococcal antibody titers. Tetanus antibody titers, CBC, CMP, and total immunoglobulins were normal. Response to pneumococcal polysaccharide vaccine (PPSV23) revealed mild improvement in protective pneumococcal titers at 8 weeks. Mavorixafor was started and pegfilgrastim discontinued with no sinopulmonary infections or hospitalizations since initiation. However, skin rashes worsened, and he developed an axillary abscess requiring trimethoprim-sulfamethoxazole and cephalexin therapy. Case 2 was an 8-year-old male presenting for evaluation of WHIM syndrome given his father’s (Case 1) diagnosis. History was significant for warts and recurrent acute otitis media, requiring 2 bilateral myringotomy and tubes procedures. Initial workup showed absent absolute neutrophil count (ANC) with reduced white blood cells (WBCs), absolute lymphocyte count (ALC), CD4, CD8, IgG, and pneumococcal antibody tiers. Tetanus antibody titers and CMP were normal. Invitae IEI panel showed CXCR4 c.952dup (p.Thr318Asnfs*26) heterozygous variant, RNU4ATAC n.48G>A (RNA change) heterozygous variant, and AP3D1 c.3400A>C (p.Ile1134Leu) heterozygous variant of uncertain significance. Response to PPSV23 revealed adequate response in protective pneumococcal titers at 8 weeks. He was started on filgrastim. Eight weeks following initiation, WBCs, ALC and ANC normalized. Patient has had no infections, hospitalizations, or need for antibiotics since initiation. PIDs with milder phenotypes are often not considered in adult patients until severe manifestations occur, as seen in Case 1. Diagnosis of PIDs should prompt early immune evaluation with consideration of genetic testing in family members.