Atypical Griscelli Syndrome Presenting with Immune Dysregulation, Systemic Granulomatosis and Normal Pigment Secondary to A Structural Variant in RAB27A

Abstract

Griscelli Syndrome Type 2 (GS2) is a rare autosomal recessive disease characterized by organ granulomas, central nervous system inflammation, hemophagocytic lymphohistiocytosis (HLH) and partial albinism. Patients have immune dysregulation secondary to dysfunctions in natural killer (NK) cell and T cell cytotoxicity as a result of poor vesicular transport [1-2]. Typically, patients also have abnormal skin and hair pigmentation from accumulation of melanosome clumps in hair shafts and melanocytes. Homozygous or compound heterozygous pathogenic variants in RAB27A are associated with GS2. However, patients with atypical GS2 harbor a structural rearrangement in RAB27A not detected by typical genetic sequencing [3]. We present two cases of atypical GS2 (below and in supplement) characterized by systemic granulomatosis, neuroinflammation and normal skin and hair pigment, secondary to a structural variant (SV) in RAB27A and a second pathogenic sequence variant on the other allele of the gene.