STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America

Mutations in STX11 are responsible for Familial Hemophagocytic Lymphohistiocytosis (FHLH) type 4, a rare primary immunodeficiency which has previously been observed only in patients of Kurdish, Turkish, and Lebanese ethnic background.

We conclude that mutations in STX11 are responsible for HLH in approximately 1% of North American patients and can cause variable defects in syntaxin 11 expression and function with resultant impact on clinical phenotype.

We reviewed our experience with STX11 mutations among North American patients and studied the impact of patient mutations upon syntaxin 11 expression and NK cell function.

Between 2007 and 2008, 243 patients with HLH (lacking disease-causing mutations in PRF1 and UNC13D) were referred for STX11 mutational analysis. We observed 1 novel homozygous nonsense mutation, 73 G > T (E25X), occurring in Hispanic siblings, and 2 novel biallelic heterozygous missense mutations, 106G > C (E36Q) and 616G > A (E206K), occurring in 1 Caucasian patient. The N-terminal nonsense mutation resulted in absence of detectable syntaxin 11 and abrogation of in vitro NK cell degranulation and function, while the biallelic heterozygous missense mutations resulted in detectable mutated syntaxin 11 and preservation of in vitro NK cell degranulation and cytotoxicity. The two sibling patients with the nonsense mutations presented with HLH during infancy, whereas the patient with biallelic heterozygous missense mutations presented at 5 years of age.