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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3505-3507 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.2225
Chediak-Higashi Syndrome Masquerading As Acute Leukemia: The Significance of Lymphocyte InclusionsDepartments of Hematopathology and Pediatric Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India A 3-year-old female patient was referred to our hospital with the clinical suspicion of leukemia due to a history of fever and enlarged cervical lymph nodes. She had an ear discharge earlier. She was the fourth child of a second-degree consanguineous marriage. Other siblings were healthy. Immunization and developmental milestones were healthy. On examination, the child had silvery gray hair (Fig 1), generalized hypopigmented mottling of the skin seen more on the extremities, oral thrush, angular stomatitis, and enlarged cervical lymph nodes measuring 1 cm to 2 cm. The abdomen was soft with a mild degree of hepatosplenomegaly and lungs showed bilateral crepitations. Ophthalmic examination showed hyperpigmented iris and a pale disc. Ultrasound examination of the abdomen showed hepatosplenomegaly. The CNS and the cardiovascular system were within normal limits. Complete blood count showed a hemoglobin level of 8.0 G/dL, total WBC count of 5,000 µL, with a differential count of 10% neutrophils and 90% lymphocytes. The platelet count was 100,000/µL. Peripheral smear showed neutropenia with an absolute neutrophil count of 500 cells/µL. The majority of the lymphocytes showed a large, single, round to oval, purple-colored granule within their cytoplasm in Wright stained smears (Fig 2; originial magnification x 1,000). The neutrophils showed multiple, scattered, irregular, slate gray to blue colored granules in their cytoplasm (Fig 2). Bone marrow aspiration smears were hypercellular with megaloblastic erythropoesis. The myeloid precursors showed giant intracytoplasmic round to oval inclusions, some of them as big as erythrocytes and were myeloperoxidase positive (Fig 3; original magnification x 1,000). Megakaryocytes were normal in number and morphology. No evidence of lymphoma or lymphohistiocytic infiltration was noted. Fine needle aspiration of the cervical lymph node showed reactive hyperplasia with scattered lymphocytes having abnormal granules.
Chediak-Higashi syndrome (CHS) is a rare syndrome with autosomal recessive inheritance characterized by partial oculocutaneous albinism, frequent pyogenic infections, presence of abnormal granules in the granulocytes of blood and bone marrow, and an accelerated lymphohistiocytic phase.1 The abnormal granules are less commonly found in lymphocytes, monocytes, and plasma cells, and rarely in erythroid cells.2 CHS was described by Beguez-Cesar in 1943,3 Steinbrick in 1948,4 Chediak in 1952,5 and Higashi in 1954.6 CHS is an autosomal recessive immunodeficiency disorder caused by mutations in a single gene characterized in 1996 as the lysomal trafficking regulator gene (LYST) or the CHS 1 gene localized to 1q42-43. The CHS gene encodes a protein called the lysosomal trafficking regulator responsible for synthesis and maintenance of storage and secretory granules in various types of cells.6,7 Apart from blood leukocytes, abnormal granules are also found in melanocytes, fibroblasts, endothelial cells, neurons, and Schwann cells, which are formed through a combined process of fusion, cytoplasmic injury, and phagocytosis.1,6,7 The disease is usually detected around the age of 5 years, and the patients are affected by frequent and severe pyogenic infections of the skin, lung, and respiratory tract, secondary to abnormal neutrophil function. Approximately 80% of patients undergo an accelerated phase, which is characterized by a lymphohistiocytic lymphoma like infiltration of multiple organs, associated with anemia, bleeding disorders, hepatosplenomegaly, fever, jaundice, and neurologic changes leading to death. The few patients who live to adulthood develop progressive neurologic dysfunction.6 The presence of abnormal granules in leukocytes is pathognomonic of this disease. They are most frequently seen in neutrophils and less commonly in lymphocytes. The neutrophilic granules are giant lysosomes and are peroxidase positive.8 The abnormal neutrophils show reduced mobilization, defective chemotactic response, decreased bactericidal activity, and microtubular abnormality. The abnormal granules in the lymphocytes are usually single and are acid phosphatase and nonspecific esterase positive.6 Functionally, there is a profound defect in cytotoxic and natural killer (NK) cell functions. Other T-cell functions are unimpaired in CHS.6,9 Grossi et al5 performed cytochemical and ultrastructural analyses as well as functional assays to determine whether CHS abnormality was expressed in the different lymphocyte subsets. It was shown that B cells expressed the CHS defect following activation and differentiation. CHS abnormality could be detected in NK cells, and T cells lacking the NK lineage appear to be morphologically and functionally normal.9 CHS patients have thrombocytopenia in late stages and platelets are functionally defective with reduced dense bodies and decreased platelet aggregation.10 The diagnostic hallmark of CHS is the occurrence of giant granules in the granulocytes and their precursors,6 and can be easily diagnosed by examining the peripheral blood smear. In our case the patient had neutropenia with an absolute neutrophil count of only 500 cells/µL, and the abnormal granules were first noted in the blood lymphocytes and prompted us to search for the characteristic granules in neutrophils. As many patients in chronic and accelerated phase of CHS have neutropenia,11 abnormality in the neutrophils may be overlooked, and the significance of identifying the abnormal granules in lymphocytes cannot be overemphasized. Most patients with CHS develop a lymphoma-like disease with generalized lymphohistiocytic infiltrates, which is often fatal and they require bone marrow transplantation without which the mean survival is only approximately 3 years. Authors' Disclosures of Potential Conflicts of Interest The authors have indicated no potential conflicts of interest.
REFERENCES 1. Barak Y, Nir E: Chediak Higashi syndrome. Am J Pediatr Hematol Oncol 9:42-45, 1987 2. Skubitz KM: Qualitative disorders of leucocytes, in Lee GR, Foerster J, Lukens J, et al (eds): Wintrobe's Clinical Hematology. Baltimore, MD, Williams & Wilkins, 1999, pp 1892-1894 3. Beguez-Cesar A: Neutropenia cronica maligna familiar con granulaciones atipicas de los leucositos. Sociedad Cubana de Pediatr Boletin 15:900-922, 1943 4. Steinbrink W: Uber eine neue granulationsanomalie der leukocyten. Dtsch Arciv Klin Med 193:577-581, 1948 5. Chediak MM: Nouvelle anomalie leucocytaire de caractere costitutionelle et familiar. Rev Hematol 7:362-367, 1952 6. Higashi O: Congenital gigantism of peroxidase granules. Tohoku J Exp Med 59:315, 1954 7. Barrat FJ, Auloge L, Pastural E, et al: Genetic and physical mapping of the Chediak Higashi syndrome on chromosome. Am J Hum Genet 59:625-632, 1996[Medline] 8. Rozenszajn LA, David ED, Sela SB: Large granules and lysosomal fusion in human Chediak Higashi white blood cells. Acta Hematol 57:279-289, 1977 9. Grossi CE, Crist WM, Abo T, et al: Expression of Chediak Higashi lysosomal abnormality in human peripheral blood lymphocyte populations. Blood 65:831-844, 1985 10. Apitz-Castro R, Cruz MR, Ledezma E, et al: The storage pool deficiency in platelets from humans with the Chediak Higashi syndrome; study of six patients. Br J Haematol 59:471-483, 1985[Medline] 11. Blume RS, Wolffe SM: The Chediak Higashi syndrome: Study in four patients with a review of literature. Medicine 51:247-280, 1972[Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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