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

Hemophagocytic lymphohistiocytosis (HLH) is a severe life-threatening hematological disorder characterized by the dysregulation of the immune system and a hyperinflammatory response. Prompt treatment is crucial to prevent fatality. Although primarily affecting infants, HLH can also occur in children and adults. It is classified as primary and secondary, with primary HLH being genetic and predominantly affecting children. Secondary HLH is triggered by infections, malignancy, metabolic disorders, and rheumatological conditions. Diagnosis is based on the HLH-2004 criteria, considering clinical and laboratory parameters. Early diagnosis and treatment improve prognosis. Treatment follows the HLH-94 and HLH-2004 protocol and consists of eight weeks of induction therapy with cyclosporine, corticosteroids, and etoposide. This case describes a 26-year-old female diagnosed with HLH and successfully treated according to the protocol. The patient exhibited improvement and was discharged, demonstrating the importance of early diagnosis and appropriate management in adult HLH cases.

Allogeneic hematopoietic stem cell transplant for familial hemophagocytic lymphohistiocytosis: a case report and literature review.

Objectives: This study aims to discuss the clinical manifestations and treatment of Familial hemophagocytic lymphohistiocytosis (FHL) caused by a mutation in the UNC13D gene. Methods: A 6-year-old female child presented with unexplained febricity, splenomegaly, pancytopenia, hemophagocytic lymphohistiocytosis in bone marrow, decreased NK cell activity, soluble CD25 levels > 44000ng/ml. Genetic sequencing revealed a mutation in the UNC13D gene. Additionally, the patient experienced intermittent fever with seizures characterized by involuntary twitching of the left upper limb. Head magnetic resonance imaging (MRI) showed white matter lesions. Results: According to the HLH-2004 diagnostic criteria revised by the International Society of Histiocytosis the patient was diagnosed with FHL. Despite receiving HLH-2004 treatment, the disease relapsed. However, after a salvage allogeneic Hematopoietic Stem Cell Transplant (HSCT), febricity, abnormal blood cells, and neurological symptoms significantly improved. Conclusions: Prompt performance of allogeneic HSCT is crucial upon diagnosis of FHL, especially when neurological involvement is present.

Novel and atypical splicing mutation in a compound heterozygous UNC13D defect presenting in Familial Hemophagocytic Lymphohistiocytosis triggered by EBV infection.

Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL3) is a genetic disorder caused by mutations in UNC13D gene, coding the granule priming factor Munc13-4 that intervenes in NK and T cell cytotoxic function. Here we report the case of a 17-month-old girl with prolonged symptomatic EBV infectious mononucleosis and clinical symptoms of hemophagocytic syndrome. In vitro functional analysis pointed to a degranulation defect. The genetic analysis of UNC13D gene identified initially a heterozygous mutation (c.753+1G>T) in the donor splice-site that resulted in exon 9 skipping (maternal allele). Mutations in other genes were considered, but additional analysis of UNC13D cDNA revealed in the paternal allele a heterozygous transition from G to A (c.2448-13G>A) at the 3' acceptor splice-site in intron 25, generating a new acceptor splice-site that leads to a frameshift and a premature STOP codon. Allele specific amplification of the cDNA confirmed the absence of a functional mRNA from the paternal allele. This case illustrates an atypical compound heterozygous UNC13D mutation affecting the RNA splicing that generates a typical FHL3 phenotype.

Spinal cord involvement in a child with familial hemophagocytic lymphohistiocytosis.

The involvement of the central nervous system (CNS) in familial hemophagocytic lymphohistiocytosis (FHL) has known to be limited to the brain, brain stem, and cerebellum. Herein, we report an 11-year-old boy who presented with neurological symptoms and was diagnosed as FHL by molecular diagnosis. The hemophagocytic lesions in the CNS were shown to extend to the thoracal level of spinal cord which completely disappeared after the completion of hemophagocytic lymphohistiocytosis-2004 protocol.