The Spectrum of Clinical, Immunological, and Molecular Findings in Familial Hemophagocytic Lymphohistiocytosis: Experience From India

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune dysregulation characterized by hyperactivation of the immune system, excessive cytokine secretion and severe systemic inflammation. HLH is classified as familial (FHL) when associated with mutations in PRF1, UNC13D, STX11, and STXBP2 genes. There is limited information available about the clinical and mutational spectrum of FHL patients in Indian population. This study is a retrospective analysis of 101 molecularly characterized FHL patients over the last 10 years from 20 different referral centers in India. FHL2 and FHL3 together accounted for 84% of cases of FHL in our cohort. Patients belonging to different FHL subtypes were indistinguishable based on clinical and biochemical parameters. However, flow cytometry-based assays viz. perforin expression and degranulation assay were found to be specific and sensitive in diagnosis and classification of FHL patients. Molecular characterization of respective genes revealed 76 different disease-causing mutations including 39 (51%) novel mutations in PRF1, UNC13D, STX11, and STXBP2 genes. Overall, survival was poor (28%) irrespective of the age of onset or the type of mutation in our cohort. Altogether, this article sheds light on the current scenario of FHL in India. Our data reveal a wide genetic heterogeneity of FHL in the Indian population and confirms the poor prognosis of FHL. This study also emphasizes that though mutational analysis is important for diagnostic confirmation of FHL, flow cytometry based assays help significantly in rapid diagnosis and functional validation of novel variants identified.

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

“…Of note, severe forms of HLH have been recently described during SARS‐COV2 infection, both in adults and children 14 . Worldwide incidence of primary HLH differs from several authors as there are differences among ethnic groups but it has been estimated at 1:50,000–1:100.000 live births 15 ; furthermore, considering that HLH is a complex disease that mirrors other pathologies, underdiagnosis of this entity affects the real incidence data 16 . Contrary to adult patients, primary forms of HLH typically affect children during their first years of life, although some cases have been reported during adulthood 11 .…”

“…14 Worldwide incidence of primary HLH differs from several authors as there are differences among ethnic groups but it has been estimated at 1:50,000-1:100.000 live births 15 ; furthermore, considering that HLH is a complex disease that mirrors other pathologies, underdiagnosis of this entity affects the real incidence data. 16 Contrary to adult patients, primary forms of HLH typically affect children during their first years of life, although some cases have been reported during adulthood. 11 Moreover, pediatric patients are more susceptible to suffer from HLH due to infections, especially EBV, while in adults, it is usually prompted by neoplasia.…”

Overcoming Diagnostic Challenges: A Rare Presentation of Primary Hemophagocytic Lymphohistiocytosis (HLH) in a Young Female and the Importance of Timely Recognition

“…The incidence of HLH is approximately 1.2 in 1,000,000 individuals per year worldwide [ 1 ]. HLH can be classified as primary or familial, associated with autosomal recessive inheritance and mutations in genes such as PRF1 or UNC13D , which account for 40%-60% of familial HLH cases [ 2 , 3 ]. Secondary or acquired HLH is typically triggered by infections, malignancy, metabolic disorders, and autoimmune/rheumatological conditions.…”

Familial hemophagocytic phohistiocytosis induced by PRF1 mutation with neurologic manifestations as the initial clinical presentations: A case report

“…[1] It is induced by the mutations of various genes, including PRF1, UNC13D, and STX11 genes. [2] Such mutations could lead to the cellular toxicity induced by natural killer cells and granules of T cells, the uncontrolled activity of immune cells, over-release of inflammatory cytokines, and finally, immune-mediated multiple organ injuries, [3] among which injuries to the hematological system, liver, and spleen are the most prominent ones. Central nervous system (CNS) involvement can also occur [4] ; however, it is very rare as the initial presentation.…”