Clinical, radiological, and immunological findings in two patients with GS2. (A) Pedigrees and results of RAB27A sequencing. Patients 1 and 2 carried compound-heterozygous combinations of one previously reported allele and one novel allele. Novel variants are highlighted in red. (B) Transmission electron microscopy of a hair shaft from patient 1 showing normal, evenly distributed mature melanosomes along the hair-shaft cortex (left, ×4,000; right, ×30,000), consistent with normal pigmentation. (C) Axial T2 FLAIR brain MRI from both patients demonstrating white-matter lesions (yellow arrows) compatible with CNS-HLH. (D) Natural killer (NK) cell degranulation assay. NK cells were defined as CD3⁻CD56⁺ cells, and degranulation was quantified as the percentage of CD107a⁺ cells within this population. Degranulation was markedly reduced in patients 1 (4.0%) and 2 (3.5%) compared with healthy controls (30–38%). (E) CD8⁺ T cell degranulation assay under P815+OKT3 stimulation. CD8⁺ T cells were defined as CD3⁺CD8⁺ cells, and degranulation was quantified as the percentage of CD107a⁺ cells (CD57⁺ subset) after IL-2 treatment. Responses were severely impaired in patients 1 (0.7%) and 2 (1.4%) compared with controls (17–21%) after 2-h stimulation. Healthy control donors were not age-matched. Due to limitations in sample availability and clinical constraints, the assay was performed once per patient, and the flow cytometry plots shown correspond to the data obtained for each individual. These findings demonstrate profound defects in NK and cytotoxic T cell degranulation despite normal pigmentation, consistent with RAB27A-related GS2 sine albinism.