D1.349 - Early Diagnosis of WHIM Syndrome in Infancy: A Case with a De Novo CXCR4 Mutation

WHIM syndrome (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) is a rare autosomal dominant combined primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. The classical tetrad typically manifests in late childhood or adolescence, leading to delayed diagnosis in infants who present primarily with severe neutropenia. Early recognition is essential to prevent recurrent infections and long-term complications.

We report the clinical, immunological, bone marrow, and genetic findings of a 6-month-old female infant presenting with persistent severe neutropenia. Laboratory evaluation included complete blood count, immunoglobulin levels, lymphocyte subset analysis by flow cytometry, and bone marrow aspiration. Clinical exome sequencing was performed to identify potential genetic causes.

The patient demonstrated persistent severe neutropenia (absolute neutrophil count 40–150/mm³), lymphopenia (900–1180/mm³), and hypogammaglobulinemia (IgG 189–270 mg/dL). Flow cytometry revealed decreased CD19⁺ B cells (3.9%). Bone marrow examination showed findings consistent with myelokathexis, without evidence of malignancy. Clinical exome sequencing identified a heterozygous pathogenic nonsense variant in CXCR4 (NM_003467.3: c.1000C>T; p.Arg334*), confirmed as de novo by parental testing. Based on these findings, a diagnosis of WHIM syndrome was established.

WHIM syndrome may present in infancy without the full classical tetrad and may initially manifest solely as persistent severe neutropenia. In infants with unexplained neutropenia and bone marrow findings suggestive of myelokathexis, early genetic evaluation is crucial to prevent diagnostic delay. Early diagnosis allows appropriate infection monitoring and timely consideration of emerging targeted therapies.