Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations.
BACKGROUND
Griscelli syndrome type 2 (GS2) is an autosomal-recessive immunodeficiency caused by mutations in RAB27A, clinically characterized by partial albinism and haemophagocytic lymphohistocytosis (HLH). We evaluated the frequency of RAB27A mutations in 21 unrelated patients with haemophagocytic syndromes without mutations in familial HLH (FHL) causing genes or an established diagnosis of GS2. In addition, we report three patients with known GS2. Moreover, neurological involvement and RAB27A mutations in previously published patients with genetically verified GS2 are reviewed.


METHODS
Mutation analysis of RAB27A was performed by direct DNA sequencing. NK cell activity was evaluated and microscopy of the hair was performed to confirm the diagnosis.


RESULTS
RAB27A mutations were found in 1 of the 21 families. This Swedish family had three affected children with heterozygous compound mutations consisting of a novel splice error mutation, [c.239G>C], and a nonsense mutation, [c.550C>T], p.R184X. The three additional children all carried homozygous RAB27A mutations, one of which is a novel splice error mutation, [c.240-2A>C]. Of note, five of the six patients displayed neurological symptoms, while three out of six patients displayed NK cell activity within normal reference values, albeit low. A literature review revealed that 67% of GS2 patients have been reported with neurological manifestations.


CONCLUSIONS
Identification of RAB27A mutations can facilitate prompt diagnosis and treatment, and aid genetic counselling and prenatal diagnosis. Since five of six patients studied herein initially were diagnosed as having FHL, we conclude that the diagnosis of GS2 may be overlooked, particularly in fair-haired patients with haemophagocytic syndromes.
Meeths
Marie
M
Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. marie.meeths@ki.se
Bryceson
Yenan T
YT
Rudd
Eva
E
Zheng
Chengyun
C
Wood
Stephanie M
SM
Ramme
Kim
K
Beutel
Karin
K
Hasle
Henrik
H
Heilmann
Carsten
C
Hultenby
Kjell
K
Ljunggren
Hans-Gustaf
HG
Fadeel
Bengt
B
Nordenskjöld
Magnus
M
Henter
Jan-Inge
JI
D000015:Abnormalities, Multiple / Q000235:genetics; D000293:Adolescent; D000417:Albinism / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006197:Hair / Q000648:ultrastructure; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis* / Q000235:genetics*; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics*; D008297:Male; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D010375:Pedigree; D020691:rab GTP-Binding Proteins / Q000235:genetics*; D000075745:rab27 GTP-Binding Proteins
D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins