Current challenges of genomic diagnostics in hemophagocytic syndromes in pediatrics: a case report

Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a disease of the autoimmune system that presents with an excessive inflammatory syndrome caused by activated T lymphocytes and histiocytosis. It occurs with autosomal or recessive inheritance linked to the X chromosome. Approximately 90% of children diagnosed are under 2-years-old and the incidence is approximately 0.12 per 100.000. It can be divided into five subtypes based on the causative genetic variant. The most involved pathogenic variants are in the genes for perforin 1 (PRF1) and homologue D of the UNC-13 protein (UNC13D). The main clinical features are persistent fever, hepatosplenomegaly, pancytopenia, and decreased natural killer (NK) cell activity.

Case Report: We present the case of an 11-year-old preadolescent with a history of recurrent infections and close contact with patients with Mycobacterium tuberculosis, who presents with a convulsive syndrome associated with intermittent fever, low weight and height for age, hepatomegaly, and mild cognitive disability. In the initial approach, infectious, immunological, hematological, metabolic and oncological diseases were ruled out.

Results: The clinical exome for primary immunodeficiencies showed a pathogenic variant p.A91V homozygous in the PRF1 gene of autosomal recessive inheritance, a result related to familial hemophagocytic lymphohistiocytosis type 2 (FHL2).

Discussion/Conclusions: Reduced production or activity level of perforin can lead to impaired immune defense systems and dysregulation of apoptotic mechanisms. The conformational change of the altered PRF1 reduces the cytotoxic activity of the protein and causes the disease. It produces a disproportionate expansion of CD8 T lymphocytes and excessive production of cytokines, including gamma interferon (IFN-γ), and persistent activation of macrophages, leading to tissue infiltration by macrophages and histiocytes and increased production of proinflammatory cytokines. Patients carrying defects in the PRF1 gene are vulnerable to infections, autoimmune diseases, and malignancies. With a defined and precise diagnosis, it is possible to guide health actions, follow-up guidelines, heritability risk assessment through an index case to find other possible carriers, carry out complete genetic counseling, implement and start targeted treatments that reduce the morbidity and mortality associated with this pathology. Currently there are several studies in different phases of research on molecules that can intervene in the natural history of the disease.