Hemophagocytic Lymphohistiocytosis, Familial, 5

A number sign (#) is used with this entry because familial hemophagocytic lymphohistiocytosis-5 (FHL5) is caused by homozygous or compound heterozygous mutation in the syntaxin-binding protein-2 gene (STXBP2; 601717) on chromosome 19p13.

For a phenotypic description and a discussion of genetic heterogeneity of familial hemophagocytic lymphohistiocytosis, see 267700.

Mapping

Zur Stadt et al. (2009) performed genomewide linkage analysis and homozygosity mapping in 1 Saudi Arabian and 14 unrelated Turkish probands, all from consanguineous backgrounds, who had familial hemophagocytic lymphohistiocytosis but did not have mutations in the 3 known FHL genes. A maximum heterogeneity lod (hlod) score of 5.9 was obtained on chromosome 19p; fine mapping yielded a hlod of 8.3 at rs634968, and detailed genotype analysis revealed an overlapping region of homozygosity in 7 of the 15 cases, a 1,040-kb interval containing 36 genes. Whole-genome analysis of another consanguineous FHL family from Saudi Arabia with 2 affected and 3 unaffected sibs revealed 3 homozygous regions with lod scores greater than 2.0, 1 of which overlapped with the previously identified interval on chromosome 19p.

In 8 patients from 6 consanguineous families with FHL in which known causes had been excluded by genetic analysis, Cote et al. (2009) performed genomewide SNP analysis and found a common region of homozygosity on chromosome 19p13.2-p13.3; of 40 genes within the interval, the STXBP2 gene appeared to be the most plausible candidate.

Molecular Genetics

In 8 unrelated probands with familial hemophagocytic lymphohistiocytosis mapping to chromosome 19p, from 2 Saudi Arabian and 6 Turkish consanguineous families, zur Stadt et al. (2009) identified homozygous mutations in the STXBP2 gene in all 8 patients (see, e.g., 601717.0001-601717.0003). Sequence analysis in other patients from nonconsanguineous FHL families revealed homozygosity or compound heterozygosity for additional mutations in the STXBP2 gene in 4 patients from Germany and the Czech Republic (see, e.g., 601717.0004-601717.0006), 2 of whom had previously been reported (Beutel et al., 2009; Sparber-Sauer et al., 2009). Corresponding heterozygous mutations were found in all available unaffected parents, and none of the mutations were detected in 210 chromosomes from ethnically matched controls. The 7 patients who were homozygous for missense mutations or a 3-bp deletion had early-onset disease, diagnosed before 1 year of age, whereas the remaining 5 patients, who were homozygous for a splice site mutation or compound heterozygous for the splice site mutation and another mutation, had disease that developed after 1 year of age. Zur Stadt et al. (2009) identified STX11 (605014), mutations in which causes FHL4 (603552), as an interaction partner of STXBP2, and demonstrated that this interaction is eliminated by the missense mutations identified in the FHL5 patients, leading to decreased stability of both proteins. Analysis of CD107 degranulation in 3 early-onset and 2 late-onset patients demonstrated marked reduction or absence of natural killer and cytotoxic T-cell activity.

In affected members of 6 consanguineous families with FHL mapping to chromosome 19p13.2-p13.3, Cote et al. (2009) sequenced the STXBP2 gene and identified homozygosity for the P477L mutation (601717.0001) in 3 Saudi Arabian families and for the IVS14 splice site mutation (601717.0003) in 3 families of Turkish, Palestinian Arab, and Iranian origin, respectively. In all patients with the P477L mutation, FHL was early in onset and rapidly led to death in 3 of 5 patients, whereas FHL manifestations occurred several years later in patients with the splice site mutation, and 1 individual homozygous for the splice site mutation was asymptomatic at 32 months of age. Cote et al. (2009) confirmed STX11 as the main partner of STXBP2 in lymphocytes, with STXBP2 being required for its expression.

Cetica et al. (2010) analyzed the STXBP2 gene in 28 FHL families in which mutations in known FHL genes had been excluded by sequence analysis, and identified homozygosity for 4 different missense mutations in the STXBP2 gene in 4 (14%) of the 28 families, originating from Italy, England, Kuwait, and Pakistan, respectively (see, e.g., 601717.0001 and 601717.0007). Cetica et al. (2010) noted that the presenting features of these FHL5 patients appeared largely comparable to those of other FHL subgroups, in particular FHL2 (603553) and FHL3 (608898).