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Introduction

    Chediak Higashi syndrome (CHS; MIM 214500) is an autosomal recessive disorder characterized by partial oculocutaneous albinism (OCA), a mild bleeding tendency, immunodeficiency, neurologic features and enlarged granules in leukocytes and other cells. It was first described by Beguez-Cesar in 1943 (1) and, posteriorly by Chediak (2) and Higashi (3). The incidence of CHS is very low and was estimated to less than 1 to 1,000,000 births (4). In its classic form, CHS presents in childhood with a history of recurrent infections and early development of the accelerated phase, characterized by lymphoproliferative infiltration of bone marrow and reticuloendotelial system. Nevertheless, in atypical cases, the accelerated phase has a later onset, the history of unusual or severe infections is absent and neurological impairment is more prominent (5, 6). This paper aims to report the case of a patient with atypical CHS.

Case report

    A 39-year-old male was admitted complaining of a daily and continuous unmeasured fever for 4 months, associated with asthenia, loss of appetite and prostration. He noticed a weight loss of about 10 kg in the last 3 months and a mass in the left side of his neck.

    He denied a past of surgeries, blood transfusions, hypertension, diabetes. His mother denied a history of recurrent infections and reported episodes of intense bleeding after minor injuries. He wasn’t using any continuous medication, nor alcohol or tobacco. One of his brothers died due to leukemia, and another brother was diagnosed with lymphoma. His parents were first cousins.

    The physical examination revealed impaired cognition, prostration, divergent strabismus on the left eye, nistagmus, cutaneous albinism, many enlarged cervical and supraclavicular lymph nodes at the left side. Blood pressure was 100/60 mmHg; heart rate, 80 bpm; respiratory rate, 13 rpm. No abnormalities were found on cardiovascular and respiratory systems. The abdominal palpation showed hepatosplenomegaly. Fundoscopy showed reduced retinal pigmentation.

    The complete blood count showed pancytopenia, with a hemoglobin of 8.6; hematocrit of 28.3%; MCV of 77.96; MCH of 23.97 and MCHC of 23.97; white blood cells count of 2,650 (platelets of 62,000). Peripheral blood smear showed microcytosis. Reticulocytes were 0.4%. Lactic dehydrogenase was 440 U/L; Ferritin was 2,545.00 ng/mL. C Reactive protein was positive (96 mg/L). PTTa was 33.7 seconds; AST, 34 u/mL; ALT 44 u/mL, alkaline phosphatase 258 u/L; Potassium, 4.1 mEq/L.

    Kala-azar Detect and Serologies for HIV (types 1 and 2) and HTLV were negative. Electrocardiogram and protein electrophoresis were normal.

    The abdominal ultrasound confirmed the presence of hepatomegaly and described the spleen with increased size, as well as heterogeneous texture and nodules. Computer Tomography identified the presence of retroperitoneal lymphadenopathy.

    Lymph node biopsy showed diffuse subversion of the nodal architecture by infiltrate of lymphocytes permeated by giant cells, exhibiting eosinophilic conspicuous nucleolus and retraction artifact on the periphery of these cells.

    The bone marrow aspirate was discretly hypocelular, with mild dysplasic alterations on eritrocyte serie. There weren’t atypical cells, or parasites.

    He was then diagnosed with accelerated phase of Chediak-Higashi syndrome. The patient was referred to another hospital in order to receive appropriate care.

Discussion

    CHS results from abnormalities in lysosomal transport caused by homozygous mutation in LYST/CHS gene. Much of pathophysiological clues of CHS were obtained from studies with mouse models, such as beige and Souris, which resemble the phenotype of CHS patients (7). In view of that, the identification of the gene associated with CHS followed the description of mutations in Lyst gene of beige mice (8, 9). Human LYST gene is localized in the 1q42.3 region and codes for a cytosolic protein with 3801 amino acids (10). Although little is known about its function, Yeast two-hybrid (Y2H) screening has shown that LYST protein can interact with other proteins that regulate vesicle docking and fusion in exocytosis (11).

    Diagnosis is based on clinical suspicion and the observation of the characteristic cytoplasmatic vesicles in white blood cells (WBC). In the patient reported, the diagnosis of CHS was made after the identification of OCA, a history of bleeding tendency and a clinical picture consistent with the accelerated phase, with pancytopenia, increased ferritin, lymphadenopathy and hepatosplenomegaly.

    Molecular genetic testing is also available for the CHS. Besides aiding in the diagnosis, the testing can have prognostic relevance, since the type of mutation correlates with the phenotype. Stop codon and frame shift mutations are associated to early onset, whereas adult presentations are more associated with missense mutations (6).

    As an autosomal recessive disease, CHS is usually inherited by heterozygous parents and consanguineous marriages, as in the case reported, are common. Nevertheless, cases of maternal or paternal isodisomy were also reported (4, 12). In this sense, parental molecular testing can be useful for genetic counseling purposes.

    Patients with CHS present variable degrees of OCA. This is associated with an impaired ability for the delivery of melanin from the melanocytes to adjacent epithelial cells (13). Pigmentation of hair is frequently irregular, with a silvery color. Skin tone depends on the ethnic background of affected individuals. The visual acuity can be improved with correction o refractive errors. Sunglasses are recommended for protection from UV light (5). Skin protection need depends on the degree of hypopigmentation (5).

    Bleeding tendency is usually mild, includes epistaxis, mucosal bleeding and easy bruising and often is not reported as a concern by the patients (5). It is associated with the reduction of vesicles in the interior or platelets. Nonsteroidal anti-inflammatory drugs must be avoided in order to prevent exacerbation of bleeding tendency (5).

    Immune deficiency is an important feature and a history of pyogenic infections is common (14). Functional immune studies have shown that patients with CHS have reduced bactericidal activity and NK cell or T cell lymphocyte cytotoxicity (5). Prophylactic treatment with antibiotics has been proposed to CHS patients, but there are objections about the benefits of this practice (14, 15). Other strategy under investigation is the pharmacologic upregulation of protein kinase C, which improves NK cell activity (16). It is important to note that the immune deficiency of CHS is not a contraindication for immunization (5). Patients with later onset CHS, such as the patient reported, usually don’t have significant immunodeficiency (6).

    Neurological abnormalities such as cognitive deficit, ataxia and parkinsonism are also described (14). These are more common in the early adulthood, in patients with atypical CHS or patients with classical CHS that were treated with HSCT. The neurological findings are thought to result from cumulative damage to central nervous system due to impaired LYST protein function and is not related to transplant-conditioning regimen or the accelerated phase (17). In fact, Y2H screens identified possible interactions between LYST protein and other proteins associated with neuronal function and neurodegeneration (11). Furthermore, a mouse model with missense mutation in WD40 domain of Lyst presented a phenotype similar to adult-onset CHS, without severe impairment in immune system and severe progressive Purkinje cell degeneration (18).

    The accelerated phase of CHS results from an uncontrolled activation of T-cells and macrophages culminating in the hemophagocytic lymphohistiocytosis (HLH). It is manifested by fever, hepatosplenomegaly, jaundice, lymphadenopathy, pancytopenia, hypertriglyceridemia, increased ferritin and soluble interleukin-2 and bleeding disorders (14). For children with typical CHS, the hematopoietic stem cell transplant (HSCT) can be used before the onset of HLH as a preventive measure. In patients with atypical CHS, annual screenings for clinical and laboratorial manifestations of HLH is proposed (7). The treatment consists of a combination of etoposide, dexamethasone and cyclosporine A (19). HSCT can be considered after clinical remission of HLH (5).

References

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2. Chediak MM. [New leukocyte anomaly of constitutional and familial character]. Rev Hematol. 1952;7(3):362-7.

3. Higashi O. Congenital gigantism of peroxidase granules; the first case ever reported of qualitative abnormity of peroxidase. Tohoku J Exp Med. 1954 Feb 25;59(3):315-32.

4. Dufourcq-Lagelouse R, Lambert N, Duval M, Viot G, Vilmer E, Fischer A, et al. Chediak-Higashi syndrome associated with maternal uniparental isodisomy of chromosome 1. Eur J Hum Genet. 1999 Sep;7(6):633-7.

5. Introne WJ, Westbroek W, Golas GA, Adams D. Chediak-Higashi Syndrome. 1993.

6. Karim MA, Suzuki K, Fukai K, Oh J, Nagle DL, Moore KJ, et al. Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. Am J Med Genet. 2002 Feb 15;108(1):16-22.

7. Jessen B, Maul-Pavicic A, Ufheil H, Vraetz T, Enders A, Lehmberg K, et al. Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome. Blood. 2011 Oct 27;118(17):4620-9.

8. Nagle DL, Karim MA, Woolf EA, Holmgren L, Bork P, Misumi DJ, et al. Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome. Nat Genet. 1996 Nov;14(3):307-11.

9. Barbosa MD, Nguyen QA, Tchernev VT, Ashley JA, Detter JC, Blaydes SM, et al. Identification of the homologous beige and Chediak-Higashi syndrome genes. Nature. 1996 Jul 18;382(6588):262-5.

10. Magrane M, Consortium U. UniProt Knowledgebase: a hub of integrated protein data. Database (Oxford). 2011;2011:bar009.

11. Tchernev VT, Mansfield TA, Giot L, Kumar AM, Nandabalan K, Li Y, et al. The Chediak-Higashi protein interacts with SNARE complex and signal transduction proteins. Mol Med. 2002 Jan;8(1):56-64.

12. Manoli I, Golas G, Westbroek W, Vilboux T, Markello TC, Introne W, et al. Chediak-Higashi syndrome with early developmental delay resulting from paternal heterodisomy of chromosome 1. Am J Med Genet A. 2010 Jun;152A(6):1474-83.

13. Westbroek W, Adams D, Huizing M, Koshoffer A, Dorward H, Tinloy B, et al. Cellular defects in Chediak-Higashi syndrome correlate with the molecular genotype and clinical phenotype. J Invest Dermatol. 2007 Nov;127(11):2674-7.

14. Ortuno FJ, Fuster JL, Jerez A. [Chediak-Higashi syndrome]. Med Clin (Barc). 2010 Oct 9;135(11):512-8.

15. Kaplan J, De Domenico I, Ward DM. Chediak-Higashi syndrome. Curr Opin Hematol. 2008 Jan;15(1):22-9.

16. Tanabe F, Kasai H, He L, Kin T, Fujikado T, Kumamoto T, et al. Improvement of deficient natural killer activity and delayed bactericidal activity by a thiol proteinase inhibitor, E-64-d, in leukocytes from Chediak-Higashi syndrome patients in vitro. Int Immunopharmacol. 2009 Mar;9(3):366-70.

17. Tardieu M, Lacroix C, Neven B, Bordigoni P, de Saint Basile G, Blanche S, et al. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome. Blood. 2005 Jul 1;106(1):40-2.

18. Rudelius M, Osanger A, Kohlmann S, Augustin M, Piontek G, Heinzmann U, et al. A missense mutation in the WD40 domain of murine Lyst is linked to severe progressive Purkinje cell degeneration. Acta Neuropathol. 2006 Sep;112(3):267-76.

19. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31.

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