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Familial hemophagocytic lymphohistiocytosis with the MUNC13-4 mutation: a case report
Hiroshi Mizumoto1, Daisuke Hata, Ken Yamamoto
1Department of Pediatrics, Kitano Hospital, The Tazuke Kofukai Medical Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.
Insights
Familial hemophagocytic lymphohistiocytosis (FHL) in an infant was linked to MUNC13-4 mutations. Prompt treatment with corticosteroids and stem cell transplant led to remission, highlighting the importance of genetic analysis for FHL management.
Area of Science:
- Pediatric Hematology
- Immunology
- Genetics
Background:
- Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, life-threatening hyperinflammatory condition.
- MUNC13-4 mutations are a known genetic cause of FHL, impacting immune cell function.
Observation:
- A 44-day-old male infant presented with symptoms including fever, poor feeding, lymphocytosis, thrombocytopenia, and elevated inflammatory markers.
- Diagnosis of FHL was confirmed by hyperferritinemia, anemia, hypertriglyceridemia, and bone marrow hemophagocytosis.
- The patient experienced central nervous system complications despite initial response to corticosteroids.
Findings:
- Genetic analysis revealed compound heterozygous MUNC13-4 mutations (W721X and a premature stop codon), leading to complete loss of MUNC13-4 protein.
- The infant successfully underwent unrelated cord blood stem cell transplantation, achieving remission for over two years.
- Mild mental retardation was noted as a long-term sequela.
Implications:
- This case underscores the broad clinical spectrum of FHL and the critical role of MUNC13-4 mutations.
- Further research into FHL phenotype-genotype associations is crucial for optimizing treatment strategies.
- Early genetic diagnosis and timely intervention, including stem cell transplantation, are vital for improving outcomes in FHL.
Abstract:
A 44-day-old male infant with familial hemophagocytic lymphohistiocytosis (FHL) associated with the MUNC13-4 mutation is reported. He presented with fever and poor feeding, lymphocytosis with thrombocytopenia and CSF pleocytosis without virological explanation. On the basis of progressive hyperferritinemia (1323 ng/ml), anemia (hemoglobin: 5.2 g/dl), hypertriglyceridemia (547 mg/dl) and increased LDH (1063 IU/l) with hemophagocytosis in the bone marrow, hemophagocytic lymphohistiocytosis was diagnosed. He showed a good response to corticosteroid therapy and the disease was stable for more than 5 months. Thereafter, he suffered from central nervous system complications, and successfully underwent unrelated cord blood stem cell transplantation. A remission was observed for more than 2 years, with mild mental retardation. Genetic analysis revealed that he had a compound heterozygous mutation of MUNC13-4; namely a novel 2163G>A mutation resulting in W721X, and 754-1G>C resulting in a premature stop codon in this gene. Western blot analysis showed the complete loss of the MUNC13-4 protein, whereas other molecules associated with the SNARE systems were detected at normal levels. Conclusion. FHL may have a broad clinical spectrum, and further analysis on its phenotype-genotype association is required to establish an appropriate treatment strategy, including immunochemotherapy and stem cell transplantation in the future.
