The reference OMIM entry for this protein is 603552

Hemophagocytic lymphohistiocytosis, familial, 4; fhl4
Hplh4
Hlh4

A number sign (#) is used with this entry because familial hemophagocytic lymphohistiocytosis-4 (FHL4) is caused by homozygous 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 in the families with FHL4 reported by Muller et al. (2014) was consistent with autosomal recessive inheritance.

MAPPING

In a large consanguineous family of Kurdish descent with FHL, Zur Stadt et al. (2005) performed homozygosity 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, wheras 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 homozygosity 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 homozygosity 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 exper ... More on the omim web site

Subscribe to this protein entry history

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 603552 was added.