Genetic and clinical characteristics of pediatric patients with familial hemophagocytic lymphohistiocytosis

Abstract

Background: Our study was designed to investigate the frequencies and distributions of familial hemophagocytic lymphohistiocytosis (FHL) associated genes in Saudi patients.Methods: FHL associated gene screening was performed on 87 Saudi patients who were diagnosed with hemophagocytic lymphohistiocytosis (HLH) between 1995 and 2014. The clinical and biochemical profiles were also retrospectively captured and analyzed.Results: Homozygous mutations and mono-allelic variants were identified in 66 (75.9%) and 3 (3.5%) of the study participants, respectively. STXBP2 was the most frequently mutated gene (36% of patients) and mutations in STXBP2 and STX11 accounted for 58% of all FHL cases and demonstrated a specific geographical pattern. Patients in the FHL group presented at a significantly younger age than those belonging to the unknown-genetics group (median, 3.9 vs. 9.4 mo; P=0.005). The presenting clinical features were similar among the various genetic groups and the 5-year overall survival (OS) was 55.4% with a 5.6 year median follow-up. Patients with PRF1 mutations had a significantly poorer 5-year OS (21.4%, P=0.008) and patients undergoing hematopoietic stem cell transplant (72.4%) had a significantly better 5-year OS (66.5% vs. 0%, P=0.001). Conclusion:Our study revealed the predominance of the STXBP2 mutations in Saudi patients with FHL. A genetic diagnosis was possible in 80% of the cohort and our data showed improved survival in FHL patients who underwent hematopoietic stem cell transplant.

Successful use of emapalumab in refractory hemophagocytic lymphohistiocytosis in a child with Chédiak–Higashi syndrome: a case report

“…Establishing the genetic profile of HLH and the prevalent mutations in local populations is important to improve early diagnosis and treatment. STXBP2 and STX11 gene mutations were previously reported to be the two most predominant mutations in Saudi patients with HLH [ 15 ]. Our findings fit the spectrum of pathogenic variants reported for nonfamilial HLH in Saudi Arabia, where pathogenic variants of the LYST gene (some of which were novel mutations) were detected in 5.8% of all mutant patients [ 15 ].…”

Diagnostic challenges during the COVID‐19 pandemic: A child with tuberculosis‐induced haemophagocytic lymphohistiocytosis misdiagnosed as multi‐inflammatory syndrome in children

“…In our patient, mutations in PRF1, UNC13D and STX11 genes were investigated, which are the most common in the Turkish population. 3 Secondary HLH is triggered by underlying diseases such as infections, malignancies and inflammatory diseases. 4 HLH is often associated with viral infections, including EBV, CMV, parvovirus, HSV, VZV, HHV‐8, influenza and HIV.…”

“…Familial HLH is caused by mutations in the PRF1, UNC13D, STX11 and STXBP2 genes, which affect the lymphocyte‐perforin pathway. In our patient, mutations in PRF1, UNC13D and STX11 genes were investigated, which are the most common in the Turkish population 3 . Secondary HLH is triggered by underlying diseases such as infections, malignancies and inflammatory diseases 4 .…”

Pediatric inborn errors of immunity causing hemophagocytic lymphohistiocytosis: Case report and review of the literature

“…24 Patients carrying PRF1 mutations account for 20-50% of all FHL cases with the higher prevalence in North America, being UNC13D and STXBP2 mutations more prevalent in some regions around the globe. [25][26][27] PRF1 is a specialized pore-forming protein stored within intracellular secretory vesicles of CTL and NK cells. They facilitate the entry of granzymes into target cells to induce apoptosis of target cells at the immunologic synapse (IS), a process in which there is specific microtubule organizing complex remodeling.…”

“…Patients carrying PRF1 mutations account for 20–50% of all FHL cases with the higher prevalence in North America, being UNC13D and STXBP2 mutations more prevalent in some regions around the globe 25–27 . PRF1 is a specialized pore‐forming protein stored within intracellular secretory vesicles of CTL and NK cells.…”