Mutation analysis and prenatal diagnosis of a family with Griscelli syndrome type 2: two novel mutations in the RAB27A g
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Correspondence Mutation analysis and prenatal diagnosis of a family with Griscelli syndrome type 2: two novel mutations in the RAB27A gene
World J Pediatr, Online First, May 2017 . www.wjpch.com
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Correspondence
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riscelli syndrome type 2 (GS2; OMIM#607624) is a rare autosomal recessive disorder characterized by hypomelanosis with immunologic abnormalities and haemophagocytic lymphohistocytosis.[1] Neurological manifestations were reported in 67% of GS2 patients.[2] It is caused by mutations in the RAB27A gene.[3] The RAB27A gene encodes Rab27a, a member of the small GTPase superfamily, involved in vesicular fusion and trafficking.[3] Mutations in the MYO5A, RAB27A, or MLPH genes cause GS1, GS2 or GS3, respectively. It has been demonstrated that the tripartite protein complex (Rab27a/ melanophilin/myosin Va) in melanocytes is needed for capturing mature melanosomes for transferring to keratinocytes.[4] In this study, we report a Thai boy who was admitted to King Chulalongkorn Memorial Hospital for the first time at two years of age because of recurrent fever. He was the first child born to non-consanguineous parents. Hepatosplenomegaly was first noted at the age of 9 months. On physical examination, he was found to have silvery-gray hair and eyebrows, pale conjunctivae and hepatosplenomegaly with the liver edge palpable 7 cm below the right costal margin (span: 12 cm) and the spleen palpable 5 cm below the left costal margin. Lab investigation showed large clumps of pigment in the hair shafts seen under the light microscope (Fig. A), pancytopenia (haemoglobin B: 9.4 g/dL; white blood cell count: 4450 mm3; platelet count: 20 000 mm3), normal to slightly high immunoglobulin levels [IgG: 637.4 mg/dL (380-950 mg/dL); IgM: 143.6 mg/dL (28-112 mg/dL); IgA: 108.7 mg/dL (18-110 mg/dL); total IgE: 79.7 IU/mL (0-60 IU/mL)]. Bone marrow aspiration revealed hypercellular marrow, increased normally matured megakaryocytes, and increased histiocytes. Flow cytometry showed total T cells (CD3) of 3386 cells/mm3 (72%; CD4 18% and CD8 42%), B cells (CD19) 15% and natural killer cells (CD16 & 56) 8%. Chest X-ray showed diffuse granular infiltration. At the age of three years, he developed ataxia and refused to walk. Magnetic resonance imaging of the brain showed almost symmetrical white matter lesions involving bilateral cerebellar hemispheres and parietooccipital regions. After informed consent, genomic DNA and total RNA was isolated from peripheral leukocytes. Direct
sequencing of polymerase chain reaction (PCR)amplified complementary DNA representing the entire coding regions of RAB27A was performed. It revealed that the patient was compound heterozygous for two novel mutations, c.109A>T (p.K37X) and c.318T>G (p.S106R) (Fig. B). Genomic DNA was amplified and sequenced, confirming the existence of both mutations. His conditions worsened and bone marrow transplantation using an unrelated donor was performed at the age of four years. He passed away a few weeks after the transplantation due to sepsis. Identification of the diseas
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