Myelodysplastic features in Griscelli syndrome.

To the Editor: Griscelli syndrome (GS) is a rare, autosomal recessive disease characterized by partial albinism and variable immunodeficiency. The only cure is allogeneic stem cell transplantation (SCT). The clinical findings are silvery hair, occasionally associated with diffuse cutaneous hypopigmentation, recurrent infections, and accelerated phases with lymphohistiocytic infiltration and hemophagocytosis of multiple organs leading to hepatosplenomegaly, lymphadenopathy, and fever. Essentially, these accelerated phases are identical to hemophagocytic lymphohistiocytosis (HLH). Most patients are diagnosed in their first years of life. Laboratory findings include pancytopenia, coagulopathy, and hypertriglyceridemia. Immunologic abnormalities include impaired natural killer (NK) cell and granulocyte activity and various lymphocyte function abnormalities. Mutations in the MYO5A and RAB27A genes, both located on chromosome 15q21, were described in association with GS. Recently, a patient with GS has been described who was given the additional diagnosis of myelodysplastic syndrome (MDS). We describe here two children with GS who had clear myelodysplastic features without fulfilling the criteria of MDS. Patient 1, a 17-month-old girl, was admitted with a history of a severe varicella and herpesvirus type 6 infection and disseminated cutaneous papulonecrotic tuberculids after bacille Calmette-Guérin (BCG) vaccination. Physical examination revealed silvery-gray hair and eyebrows, hepatosplenomegaly, and cutaneous papules. Laboratory investigations showed mild pancytopenia with monocytosis (12%). Bone marrow biopsy revealed markedly reduced cellularity. Myeloid cells had hypogranulated cytoplasm. Erythropoiesis showed no megaloblastic transformation; some erythroblasts showed nuclear lobulation. Micromegakaryocytes and small binucleated megakaryocytes were noted. There were 8% blast cells in the bone marrow. Moderate hemophagocytosis was present. Immunophenotyping of blood lymphocytes revealed no abnormalities, but NK cell function was decreased. Lymphocyte proliferative responses to phytohemagglutinin, concanavalin A, and tetanus toxoid were reduced. Serum immunoglobulin (Ig) levels were normal. Cytogenetic analysis showed a normal 46 XX chromosome pattern. Histologic examination of a skin biopsy specimen showed hyperpigmentation of the basal melanocytes with hypopigmentation in the adjacent keratinocytes. Hair shafts showed centralization of the pigment in the medullar part. DNA analysis revealed a one base pair deletion (149delG in exon 2) of the Rab27A gene. The patient suffered several “accelerated” or HLH-like episodes with fever and transfusiondependent anemia and thrombocytopenia. Because no HLA-identical donor could be found, a haploidentical peripheral SCT was carried out with cells of her mother. The conditioning regimen consisted of busulphan, cyclophosphamide, ATG, and thiotepa. She received a Tand B-cell–depleted graft with 2 × 10/kg CD34 cells. There was no evidence of engraftment. G-CSF therapy was started but without a response in the white cell count. Her clinical condition worsened due to an adenovirus type 2 infection, unresponsive to ribavirin therapy. Five weeks after the first SCT she underwent a second haploidentical SCT, this time with cells of her father. After transplantation her clinical condition deteriorated rapidly, with persistent diarrhea, ascites, and cardiac, renal, and hepatic failure. She died at day +4 due to adenovirus infection-induced multiple organ failure. Patient 2, a 13-month-old girl, was admitted with malaise, coughing, and fever unresponsive to antibiotic treatment. Physical examination revealed an irritable infant with silvery-gray hair, eyebrows, and eyelashes, lymphadenopathy, and hepatosplenomegaly. Laboratory investigations showed moderate pancytopenia and elevated liver function tests. Epstein-Barr virus (EBV) serology was positive for VCA (IgG) but negative for EA and PCR for viral DNA. Bone marrow aspirate showed decreased cellularity with mild erythrophagocytosis, decreased megakaryopoiesis with an occasional hypolobulated megakaryocyte, and nuclear irregularities in the erythroblasts. Blood lymphocytes had a normal phenotype and normal perforin expression. NK cell function was decreased. Lymphocyte proliferative responses were reduced. Serum Ig levels were slightly elevated. Microscopic examination of her hair revealed irregular, large agglomerations of melanin pigment, consistent with GS. DNA analysis revealed a larger deletion (154del154-343 in exon 3+4) of the Rab27A gene. GS was diagnosed, with a postulated EBV-associated hemophagocytosis. Liver function and the pancytopenia improved with prednisone therapy. After 3 weeks steroids were tapered off. The laboratory findings became normal. At this stage her parents refused SCT. In the next 6 months she developed two new episodes of EBV reinfection with fever, hepatosplenomegaly, lymphadenopathy, positive EBVPCR, and hemophagocytosis. After renewed prednisone pulse treatment, cyclosporin and low-dose steroid therapy were started. Twelve months after the diagnosis, her parents consented to allogeneic SCT, and this was carried out with marrow from her HLA-identical brother. The conditioning regimen consisted of busulphan, cyclophosphamide, and ATG. She engrafted after 17 days and no graft-versus-host disease occurred. Chimerism studies showed 100% donor signal. At 15 months follow-up, she was clinically well without graft-versus-host disease. GS is characterized by accelerated phases or HLH-like episodes, triggered by viral or bacterial infections. Similar