Familial hemophagocytic lymphohistiocytosis (FHL) is an immune dysregulation disorder in which most patients develop hemophagocytic lymphohistiocytosis (HLH) within the first year of life. Recently, an increasing number of patients with hypomorphic variants in FHL-related genes presenting with atypical features in late childhood or adulthood have been reported.
A previously healthy 12-year-old girl presented with painful erythema at age 10. Laboratory tests revealed pancytopenia, and she was referred to our department. Although the erythema resolved spontaneously, splenomegaly was noted. Bone marrow examination showed hypocellularity without dysplasia or malignancy. Flow cytometry demonstrated TCRαβ+ double-negative T cells (DNTs) accounting for 2.5% of lymphocytes (3.3% of T cells). Cytokine analysis revealed markedly elevated IL-18 (5,804 pg/mL) and CXCL9 (8,688 pg/mL), while IL-6 was <3 pg/mL, and soluble TNF receptor II was 5,390 pg/mL. Based on these findings, an immune dysregulation disorder such as autoimmune lymphoproliferative syndrome (ALPS) was suspected. Genetic testing revealed compound heterozygous variants in UNC13D (c.2588G>A and c.1596+1G>C). Functional analysis showed mildly reduced Munc13-4 expression in platelets and impaired degranulation function in natural killer cells and cytotoxic T lymphocytes.
Previous reports have described late-onset FHL and CLIPPERS syndrome in patients with missense variants in UNC13D or PRF1, most of which suggested these are hypomorphic variants. Variants in FHL-related genes can produce a broad clinical spectrum ranging from early-onset FHL to late-onset or atypical inflammatory phenotypes, depending on the degree of residual cytotoxic function.
We report a case of atypical cytopenia associated with hypomorphic UNC13D variants. Currently, pancytopenia is the only clinical manifestation, and the patient is receiving prophylactic trimethoprim–sulfamethoxazole. However, considering the risk of neurological sequelae with central nervous system involvement, hematopoietic stem cell transplantation is being considered.
