Germline Compound Heterozygous Variants Identified in the STXBP2 Gene Leading to a Familial Hemophagocytic Lymphohistiocytosis Type 5: A Case Report

Abstract

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, potentially fatal autosomal-recessive immunodeficiency, and STXBP2 mutations have been associated with FHL type 5 (FHL-5). Here, we report a case of a 2-year-old boy who presented with recurrent fever, hepatosplenomegaly, pancytopenia, hyperferritinemia, and hypofibrinogenemia since 4 months of age. His genetic analysis revealed a compound heterozygosity of the STXBP2 gene with a described pathogenic mutation, c.1247-1G>C (splicing acceptor site), harbored by his father and a likely pathogenic variant of uncertain significance (VUS), c.704G>A (p.Arg235Gln), harbored by his mother. He was diagnosed as compound heterozygous for FHL-5 and was treated with the HLH-2004 protocol. Since treatment, this patient has been in remission, and he is being evaluated for a hematopoietic stem cell transplantation (HSCT).

Keywords: STXBP2; familial hemophagocytic lymphohistiocytosis type 5; hepatosplenomegaly; hyperferritinemia; pancytopenia.

Figure 1

(A) Pathogenic variant and a variant of uncertain significance (VUS) for the STXBP2 gene from ClinVar. The pathogenic variant c.1247-1G>C found in the patient is in a splicing site and therefore is not illustrated in this figure (variation ID: 330555; dbSNP: rs140148806). The VUS found in the patient is indicated by a black arrow (c.704>A; p. Arg235gln). There are 10 pathogenic variants and 81 VUS described for STXBP2 in ClinVar, as shown in the figure. The color legend is indicated in the corner of the figure. (B) Protein alignment for the residue Arg235 (VUS) among five organisms: Homo sapiens, Rattus norvegicus, Mus musculus, Canis lupus familiaris, and Bos taurus. Conservation of the arginine (R) is highlighted in blue. Alignment position among the five species: 257; sequence position: 235.

Figure 2

Peripheral blood counts over time. Hb, hemoglobin; ANC, absolute neutrophil count; ALC, absolute lymphocyte count; Plt, platelet count.