Griscelli syndrome type 2 (GS2), caused by biallelic variants in RAB27A, is classically associated with hypopigmentation and life-threatening hemophagocytic lymphohistiocytosis (HLH). However, a subset of patients exhibits normal pigmentation, a presentation termed GS2 sine albinism. We identified two unrelated Japanese patients with this presentation caused by compound heterozygous RAB27A variants, representing the first functionally characterized cases in Japanese patients. We performed functional analysis of the identified RAB27A variants, including two that have not been previously reported, to help elucidate the molecular basis of preserved pigmentation in GS2.
Patient 1 is a previously healthy 3-year-old girl with no history of hypopigmentation, who developed systemic and central nervous system (CNS)-HLH. Targeted next-generation sequencing identified three RAB27A missense variants: p.Val143Ala (c.428T>C), p.Gly94Ser (c.280G>A), and the novel p.Trp73Arg (c.217T>C). Flow cytometric CD107a degranulation assays revealed markedly reduced natural killer (NK) and CD8+ T cell degranulation. The patient received HLH-2004 induction therapy, achieving initial remission. Following a CNS relapse, she underwent re-induction with dexamethasone, ruxolitinib, and four weekly intrathecal injections and subsequently received unrelated umbilical cord blood transplantation with reduced-intensity conditioning. She remains relapse-free without graft-versus-host disease or neurologic sequelae 1 year post-transplant. Patient 2 is a previously healthy 11-year-old girl with no history of hypopigmentation, who developed systemic and CNS-HLH during the recurring episodes of HLH-like hyperinflammatory state. Targeted sequencing identified compound-heterozygous RAB27A variants: a novel missense p.Ser115Arg (c.345C>G) and a paternal frameshift p.Ser106PhefsTer18 (c.315_316del). CD107a degranulation assays revealed severely impaired NK and CD8+ T cell degranulation. The patient received HLH-2004 induction therapy and subsequently underwent myeloablative conditioning, followed by unrelated umbilical cord blood transplantation. However, HLH remained refractory, and the patient died on post-transplant day 18. Analysis using mouse-derived cell line expressing the variants revealed that Trp73Arg showed loss-of-function to both melanophilin (MLPH) and MUNC13-4 binding, whereas Ser115Arg and Val143Ala retained MLPH binding but exhibited reduced interaction with MUNC13-4. This explains preserved pigmentation despite defective immunity, and both cases were diagnosed with GS2 sine albinism.
Compound-heterozygous RAB27A variants can impair cytotoxic granule release while preserving melanosome transport, resulting in GS2 with sine albinism and a high risk of HLH. An integrated approach that combines genetic testing with standardized functional assays is important, even in patients with sine albinism.
