title: Clinical presentation of Griscelli syndrome type 2 and spectrum of RAB27A mutations.
abstract: 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.
authors: Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. marie.meeths@ki.se
authors: Marie
authors: M
authors: Meeths
authors: Yenan T
authors: YT
authors: Bryceson
authors: Eva
authors: E
authors: Rudd
authors: Chengyun
authors: C
authors: Zheng
authors: Stephanie M
authors: SM
authors: Wood
authors: Kim
authors: K
authors: Ramme
authors: Karin
authors: K
authors: Beutel
authors: Henrik
authors: H
authors: Hasle
authors: Carsten
authors: C
authors: Heilmann
authors: Kjell
authors: K
authors: Hultenby
authors: Hans-Gustaf
authors: HG
authors: Ljunggren
authors: Bengt
authors: B
authors: Fadeel
authors: Magnus
authors: M
authors: Nordenskjöld
authors: Jan-Inge
authors: JI
authors: Henter
mesh_terms: 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
chemical_list: D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins