Griscelli Syndrome Type 2 in Mexican Patients with a Recurrent RAB27A Variant: Phenotypic Variability and Diagnostic Challenges

Background: Griscelli syndrome type 2 is a rare autosomal recessive disorder caused by pathogenic variants in the RAB27A gene, characterized by partial albinism, immunodeficiency, and a high risk of hemophagocytic lymphohistiocytosis (HLH). Case descriptions: We report two unrelated Mexican patients with GS2 harboring the same homozygous RAB27A frameshift variant (c.335del; p.Asn112Thrfs*3) and describe their clinical and immunological features. Both patients presented with silvery-gray hair and subsequently developed HLH, although with variable onset and clinical course. One patient initially manifested with isolated central nervous system involvement, lacking systemic or laboratory abnormalities, which led to diagnostic uncertainty and delayed treatment. The second patient presented early in life with classical systemic features of HLH. Despite treatment with standard HLH-directed therapy, both patients experienced disease reactivation and ultimately died before undergoing hematopoietic stem cell transplantation. The homozygous pathogenic RAB27A variant (c.335del; p.Asn112Thrfs*3) was identified by polymerase chain reaction followed by Sanger sequencing in the two index cases; both sets of parents were heterozygous carriers. Comparison with previously reported cases carrying the same variant highlights notable phenotypic variability despite a shared genotype. The recurrence of this variant exclusively in individuals of Hispanic origin raises the possibility of a founder effect. Conclusions: These findings underscore the importance of early recognition of pigmentary abnormalities, the integration of clinical and molecular diagnostics approaches, and the consideration of HLH in patients presenting with atypical neurological manifestations. Early diagnosis is critical to enable prompt therapeutic intervention and improve clinical outcomes.