Griscelli Syndrome Type 2: Comprehensive Analysis of 149 New and Previously Described Patients with RAB27A Deficiency

Abstract

Griscelli syndrome type 2 (GS2) is a rare, life-threatening immunodysregulatory disorder characterised by impaired cytotoxic activity leading to susceptibility to haemophagocytic lymphohistiocytosis (HLH) and hypopigmentation. We completed a literature review and analysis of clinical data of 149 patients with GS2 including 8 new patients.We identified three founder mutations which show diverse phenotypic profiles (RAB27A c.244 C > T, p.R82C, c.514_518delCAAGC, p.Q172NfsX2, c.550 C > T, p.R184X). The most common presentation was HLH (119/149, 80%), with high proportion of central nervous system involvement (68/149, 46%). Features of partial albinism were present in 105 of 149 cases (70%). Hypopigmentation can be absent in GS2 and should not exclude the diagnosis. Patients with biallelic protein truncating variants (PTV) were more likely to have systemic HLH (44/56, 79%) and partial albinism (45/56, 80%), in comparison to hypomorphic variants (9/41, 22%; 20/41, 49%). Patients with hypomorphic variants presented later (5.4 years cf. 0.4 years, p = < 0.0001) and were more likely to have isolated CNS HLH (2% cf. 42%, p = 0.001).Mortality was high in the cohort (50/149, 34%). Survival of cases post-HLH who underwent transplantation is superior to un-transplanted patients, suggesting adequate HLH control followed by early HSCT is highly beneficial. Mortality was reduced in HSCT recipients versus the un-transplanted group where follow-up data was available (14% compared to 58%).Asymptomatic cases identified through family history/genetic screening may benefit from pre-emptive HSCT, but access and development of robust functional testing are required. High mortality related to HLH remains concerning and emphasises the need for improved molecular characterisation and clinical prognostic factors to guide management decisions.

Fig. 1

RAB27A biallelic pathogenic variants. Founder mutations with phenotypic features depicted in bar charts. The first 2 exons of RAB27A are non-coding

Fig. 2

A: Frequency of occurrence of clinical features. Values represent percentages of total cases (n = 149). B: Frequency of occurrence of diagnoses. Values represent percentages of total cases (n = 149)

Fig. 3

Frequency of clinical features according to genotype groups. Compound variant types were excluded * denotes p-value < 0.05 from unpaired t-tests

Fig. 4

Onset of any symptoms in patients with PTVs and hypomorphic variants in Griscelli syndrome type 2

Fig. 5

(A) RAB27A pathogenic variants in patients who presented at 10 years and over. The first 2 exons are non-coding (B) Phenotypic characteristics of patients with Griscelli syndrome type 2 presenting at age 10 or older (n = 16)

Fig. 6

Comparison of outcomes in patients who received HSCT to those who did not