From the Guidelines
Familial Hemophagocytic Lymphohistiocytosis (FHLH) type 2 is a rare genetic disorder caused by mutations in the PRF1 gene, leading to impaired perforin expression and function, resulting in uncontrolled immune activation and proliferation.
Key Characteristics of FHLH Type 2
- Caused by mutations in the PRF1 gene, which encodes perforin 1
- Impaired cytotoxic granule content and function 1
- Decreased or absent perforin expression, as detected by flow cytometry 1
- Presents with symptoms such as persistent high fever, enlarged liver and spleen, neurological abnormalities, skin rashes, and abnormal blood counts 1
Diagnosis and Treatment
- Genetic analyses, such as next-generation sequencing, and functional testing, including NK cell cytotoxicity and CD107a upregulation, are necessary for diagnosis 1
- Treatment involves immunosuppressive therapy with medications like etoposide, cyclosporine, and corticosteroids to control hyperinflammation 1
- Hematopoietic stem cell transplantation (HSCT) is currently the only curative option 1
Importance of Early Diagnosis and Treatment
- Early diagnosis and aggressive treatment are essential for improving survival rates in affected individuals 1
- Without treatment, FHLH type 2 is usually fatal within months of onset due to multi-organ failure 1
From the Research
Definition and Classification of FHLH
- Familial Hemophagocytic Lymphohistiocytosis (FHLH) is a rare, genetically determined condition characterized by unremitting CD8 T lymphocyte and macrophage activation, leading to death in the absence of therapy 2.
- FHLH is classified into different types based on genetic linkage analysis and chromosomal localization, with five specific genetic defects identified, accounting for approximately 90% of all patients 3.
FHLH Type 2
- FHLH type 2 is caused by mutations in the perforin (PRF1) gene 4, 3.
- Perforin is a protein critical for the cytotoxic and regulatory functions of T lymphocytes and natural killer (NK) cells 5.
- FHLH2 is the most frequently reported subtype, and it may present beyond the pediatric age and up to the fifth decade 4.
Clinical Features and Diagnosis
- The most common presenting features of FHLH are pyrexia of unknown origin, pronounced hepatosplenomegaly, and cytopenias 3.
- Neurological features tend to present later and are associated with poor prognosis 3.
- Absent or decreased lymphocyte cytotoxicity is the cellular hallmark of FHLH, and biochemical features such as hyperferritinaemia, hypertriglyceridaemia, and hypofibrinogenaemia are usually present 3.
- Bone marrow aspirate may demonstrate the characteristic haemophagocytes, but initially is non-diagnostic in two-thirds of patients 3.
Treatment and Prognosis
- The disease is fatal unless a haematopoietic stem cell transplant (HSCT) is performed 3.
- The introduction of HSCT has dramatically improved the prognosis of the disease, but the mortality of the disease is still significantly high, and a number of challenges remain to be addressed 3.
- Active disease at the time of the transplant is the major significant poor prognostic factor, and delayed diagnosis, after irreversible organ damage has occurred, especially neurological damage, disease reoccurrence, and pre-transplant mortality, remain a concern 3.