TNFRSF6 (Fas Antigen) Mutations in Patients with Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease).

Sinus histiocytosis with massive lymphadenopathy (SHML or Rosai-Dorfman disease) is a rare histiocytic proliferation of unknown etiology. There is a known association between SHML and immune disorders. Recently, histologic changes of SHML have been found in lymph nodes of patients with autoimmune lymphoproliferative syndrome (ALPS), a disorder most commonly associated with mutations in the TNFRSF6 gene that encodes the Fas antigen. We retrospectively analyzed tissue from 22 patients with SHML for TNFRSF6 gene mutations using isolated genomic DNA from paraffin-embedded tissue followed by screening of PCR products for the promoter regions and all exons (1–9) of the gene for possible mutation by high performance liquid chromatography. Mutations were confirmed by direct sequencing. We identified six patients (27%) with SHML and mutations of the TNFRSF6 gene as listed below, including three cases (14%) with potentially significant mutations (*) involving promotor and splice donor regions, and frameshift mutations. The samples with mutations had a 4:2 male:female ratio with a mean/median age of 39/43 years (range 7–68 years) compared to a 9:7 male:female ratio, mean/median age of 42/43 years (range 12–76 years) for the non-mutated samples. No differences in site of disease were identified in the mutated versus non-mutated groups. None of the samples had morphologic features to suggest ALPS. These results suggest that at least a subset of cases of SHML are associated with disruption of the Fas apoptotic pathway. Additional study of other components of the apoptotic pathway may be warranted in this disease.

Cases with TNFRSF6 mutations.