Griscelli syndrome type 2: a novel mutation inRAB27Agene with different clinical features in 2 siblings: a diagnostic conundrum

Abstract

Griscelli syndrome type 2 (GS2) is a rare autosomal recessive disease caused by mutations in the RAB27A gene. It is characterized by cutaneous hypopigmentation, immunodeficiency, and hemophagocytic lymphohistiocytosis. We describe 2 brothers who had GS2 with clinically diverse manifestations. The elder brother presented with a purely neurological picture, whereas the younger one presented with fever, pancytopenia, hepatosplenomegaly, and erythema nodosum. Considering that cutaneous hypopigmentation was a common feature between the brothers, genetic analysis for Griscelli syndrome was performed. As the elder sibling had died, mutation analysis was only performed on the younger sibling, which revealed a novel homozygous mutation in the RAB27A gene on chromosome 15 showing a single-base substitution (c.136T>A p.F46I). Both parents were heterozygous for the same mutation. This confirmed the diagnosis of GS2 in the accelerated phase in both siblings. The atypical features of GS2 in these cases are a novel mutation, isolated neurological involvement in one sibling, association with erythema nodosum, and 2 distinct clinical presentations in siblings with the same genetic mutation.

Further evidence for genotype-phenotype disparity in Griscelli syndrome

“…Thus, the proband in our study, who has a phenotype suggestive of GS1 (silvery‐grey hair with primary neurological involvement), in fact has molecular data indicating a diagnosis of GS2 (silvery‐grey hair and predicted immunological abnormalities). These findings therefore go against the current paradigm of genotype–phenotype correlation for GS, although rarely other published cases have also shown some disparities . RAB27A is expressed at only low levels in the brain, but previous reports have suggested that neurological symptoms without immunodeficiency may be due to lymphocytic infiltration into the brain, which thus accelerates the onset of central nervous system abnormalities .…”

“…Lastly, GS3 (MIM609227) features hypomelanosis without additional neurological or immunological impairment, and is caused by mutations in MLPH . Of the three types, GS2 is the most common, although clinical heterogeneity makes genotype–phenotype correlation challenging …”

Cerebellar involvement of Griscelli syndrome type 2

“…The gene associated with GS2, the RAB27A gene, is not expressed in neuronal cells, so the neurological symptoms reported in GS2 cases are attributed to histolytic infiltration of the central nervous system. Mishra et al 7 described two brothers who had GS2 with clinically diverse manifestations; one of the siblings was diagnosed with GS2 and cerebral lymphohistiocytic infiltration. Similarly Arushi et al have also reported a cerebellar involvement of GS2 in a 3-year-old boy based on MRI findings 8.…”

Inhibition of Rab27a and Rab27b Has Opposite Effects on the Regulation of Hair Cycle and Hair Growth

“…These results were caused by the binding affinity of Slp4 effector to Rab27a or binding affinity of Slac2b effector to Rab27b [16]. In addition, there have been some cases in which the expressions of Rab27a and Rab27b were opposite, as in Griscelli syndrome type II disease [18,21]. In these previous studies, we can deduce that Rab27a and Rab27b might have functional differences in the cells that make up HFs, resulting in different results in hair cycle regulation and hair growth.…”

“…An example that demonstrates the different functions of these two proteins is Griscelli syndrome type II [17]. Griscelli syndrome type II is a disease caused by knockout of Rab27a, resulting in silvery gray hair and immunodeficiency owing to the disruption of transport of melanosomes and regulation of secretion in other immune cells, including neutrophils and cytolytic T lymphocytes [18][19][20]. However, Rab27b has been upregulated in human Griscelli syndrome type II melanocytes [21].…”