Abstract
Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutation in the MYO5A (GS1, Elejalde), RAB27A (GS2) or MLPH (GS3) genes. Typical features of all three subtypes of this disease include pigmentary dilution of the hair and skin and silvery-gray hair. Whereas the GS3 phenotype is restricted to the pigmentation dysfunction, GS1 patients also show primary neurological impairment and GS2 patients have severe immunological deficiencies that lead to recurrent infections and hemophagocytic syndrome. We report here the diagnosis of GS2 in 3-year-old twin siblings, with silvery-gray hair, immunodeficiency, hepatosplenomegaly and secondary severe neurological symptoms that culminated in multiple organ failure and death. Light microscopy examination of the hair showed large, irregular clumps of pigments characteristic of GS. A homozygous nonsense mutation, C-T transition (c.550C>T), in the coding region of the RAB27A gene, which leads to a premature stop codon and prediction of a truncated protein (R184X), was found. In patient mononuclear cells, RAB27A mRNA levels were the same as in cells from the parents, but no protein was detected. In addition to the case report, we also present an updated summary on the exon/intron organization of the human RAB27A gene, a literature review of GS2 cases, and a complete list of the human mutations currently reported in this gene. Finally, we propose a flow chart to guide the early diagnosis of the GS subtypes and Chédiak-Higashi syndrome.
Highlights
Griscelli syndrome (GS) is a fatal autosomal recessive disorder, first described by Griscelli et al [1] as partial albinism associated with immunodeficiency
A total of 101 cases with the clinical and laboratory features of GS2 have been reported in the literature [see OMIM (Online Mendelian Inheritance in Man) 607624 and 603868, and for a list of references on GS2 case reports, which have not identified the mutation and are not cited in OMIM, see our WEB resource at FMRP.USP cited ]
The exon numbering of RAB27A is currently done in accordance to the nomenclature proposed by Tolmachova et al [22], when two 5’UTR exons had been detected; a much higher complexity has been revealed by a large number of expressed sequences matching this locus, generating discrepancies in the literature
Summary
Griscelli syndrome (GS) is a fatal autosomal recessive disorder, first described by Griscelli et al [1] as partial albinism associated with immunodeficiency. It is a rare and not widely known disease, and its clinical features such as silvery-gray hair and immunological dysfunction resemble Chédiak-Higashi syndrome (CHS), an erythrophagocytic lymphohistiocytosis [2]. Electron microscopic examination of a skin biopsy from CHS patients reveals giant melanosomes in both melanocytes and keratinocytes [2]. GS patients show melanocytes with a massive accumulation of mature melanosomes with adjacent keratinocytes containing only sparse melanosomes [3]
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