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A number sign (#) is used with this entry because familial hemophagocytic lymphohistiocytosis-4 (FHL4) is caused by hom*ozygous mutation in the syntaxin-11 gene (STX11; 605014) on chromosome 6q24.
Description
Hemophagocytic lymphohistiocytosis is a hyperinflammatory disorder clinically diagnosed based on the fulfillment of 5 of 8 criteria, including fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent natural killer (NK) cell activity, hyperferritinemia, and high soluble IL2 receptor levels (IL2R; 147730). The disorder typically presents in infancy or early childhood. Persistent remission is rarely achieved with chemo- or immunotherapy; hematopoietic stem cell transplantation is the only cure (summary by Muller et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of familial hemophagocytic lymphohistiocytosis (FHL), see 267700.
Clinical Features
Muller et al. (2014) reported 3 unrelated children, each born of consanguineous Pakistani parents, with hemophagocytic lymphohistiocytosis. The patients were diagnosed at ages 2 months, 5 years, and 48 months, respectively. Clinical details for 1 of the patients was not available; she was lost to follow-up. The other 2 patients had fever, hepatosplenomegaly, and laboratory evidence of a hyperinflammatory state. Patient NK cells showed defective lysis and degranulation, which could be partially restored by IL2 (147680) stimulation.
Inheritance
The transmission pattern of FHL4 in the families reported by Muller et al. (2014) was consistent with autosomal recessive inheritance.
Clinical Management
Locatelli et al. (2020) investigated the efficacy and safety of emapalumab, a human anti-interferon-gamma (147570) antibody, administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving previously treated and untreated patients with primary hemophagocytic lymphohistiocytosis 18 years of age or younger. A total of 34 patients, 27 previously treated and 7 previously untreated, received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40%. In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis. The authors concluded that emapalumab is an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis.
Mapping
In a large consanguineous family of Kurdish descent with FHL, Zur Stadt et al. (2005) performed hom*ozygosity mapping and identified a novel FHL locus on chromosome 6q24, within a 10-cM region defined by markers D6S1569 and D6S960. They designated this locus FHL4.
Molecular Genetics
In the Kurdish family in which they mapped the FHL4 locus, Zur Stadt et al. (2005) identified a 5-bp deletion in the syntaxin-11 gene (605014.0001). The syntaxin-11 protein was absent in the mononuclear cell fraction of patients with the deletion. Two additional consanguineous Turkish/Kurdish FHL kindreds harbored the same mutation, whereas 1 family displayed a large 19.2-kb genomic deletion spanning the entire coding region (exon 2) of STX11 (605014.0002), and 2 families exhibited a nonsense mutation leading to a premature stop codon in the C-terminal end of the protein (Q268X; 605014.0003). As both STX11 and UNC13D (608897) are involved in vesicle trafficking and membrane fusion, the authors concluded that, besides mutations in perforin-1 (170280), defects in the endocytotic or the exocytotic pathway may be a common mechanism in FHL. In a mutation analysis in a group of 63 unrelated patients with FHL of different geographic origins, Zur Stadt et al. (2006) found 6 mutations in the STX11 gene, all in patients of Kurdish origin. Rudd et al. (2006) analyzed the STX11 gene in 34 patients with FHL from 28 unrelated families in whom PRF1 (170280) mutations had been excluded. They identified hom*ozygosity for the 5-bp deletion in 2 brothers previously reported by Zur Stadt et al. (2005) and in an unrelated brother and sister. They identified hom*ozygosity for the Q268X mutation in a Turkish girl previously reported by Zur Stadt et al. (2005) and in a unrelated Turkish boy. Three of the children experienced more than 1 year in remission without specific treatment, which the authors stated was very uncommon in this disease. Two of the children developed severe psychom*otor retardation, one developed acute myelodysplastic syndrome, and one developed acute myelogenous leukemia. Rudd et al. (2006) suggested that STX11 mutations may be associated with secondary malignancies. They noted that a total of 13 individuals from 8 Turkish families had been shown to carry STX11 mutations. In 3 unrelated Pakistani children with FHL4, each born of consanguineous parents, Muller et al. (2014) identified a hom*ozygous missense mutation in the STX11 gene (L58P; 605014.0004). Peripheral blood cells, including NK cells, from 1 of the patients showed significantly decreased STX11 protein levels compared to controls. In vitro functional expression studies in HEK293 cells showed that the mutant L58P protein was expressed, but did not bind to STXBP2 (601717). In contrast, the C-terminal Q268X mutant protein (605014.0003) did not show impaired binding to STXBP2. Muller et al. (2014) suggested that the impaired binding to STXBP2 may have led to degradation of the mutant L58P STX11 protein.
