Chediak-Higashi syndrome : case report in afro-descendant individual

This is a Chediak-Higashi Syndrome (CHS) case report in afro-descendant individual, male, 3 months old, born from consanguineous union. On admission he had fever for a month, unresolved pneumonia, and hepatosplenomegaly. He evolved to bacterial sepsis, septic shock, and death. CHS presents quantitative and morphological and hematological changes. Abnormal leukocyte inclusions are the pathognomonic finding of the disease; its recognition and differentiation from other leukocyte inclusions is essential for diagnosis and institution of therapy. Early diagnosis of CHS increases the life expectancy of the individual and provides appropriate therapeutic approach for patients affected by the disease.

On the fifth day of hospitalization (DOH), the CBC showed abnormal leukocytes granules in patient's peripheral blood smear, stained by Wrigth method (Figure 2).In this case report, inclusions were described as intracytoplasmic giant granules in all neutrophil-lineages, suggesting CHS investigation.

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On the 34 th day of hospitalization, he showed fever peek, facial swelling, diarrhea, abdominal distension, and e tachypnea.On the 36 th day of hospitalization, he was transferred to Intensive Care Unit (ICU), where new antimicrobial therapeutic was implemented, including broad-spectrum drugs (meropenem) and measures of supportive therapy.
Two blood cultures and one catheter tip culture were performed during hospitalization.The result of first blood culture was positive, and Staphylococcus epidermidis was isolated, which presents high potential to produce biofilm, especially in immunocompromised patients.After establishing the treatment, new blood and catheter tip cultures were performed, and both results were negative.
On the 41 st day of hospitalization, he presented another fever peek, abdominal distension, and diarrhea.And, despite the imposition of necessary support measures, there were worsening of general condition with severe tachypnea and hypotension, which culminated in cardiac arrest and death in the 45 th day of hospitalization.The cause of death was reported as sepsis caused by CHS complication.

DiSCuSSion
It is a rare disease, with 200 cases described in the literature (15) , and it is especially rare in black people (5) .During our search in the U.S. National Library of Medicine (PUBMED) baseline, in March 2014, we found seven cases of CHS diagnosis in black children.CHS diagnosis may be difficult, since characteristic clinical and laboratorial findings are not well defined, or are not properly reported by laboratorians or well interpreted by the prescribing physician.
Chediak-Higashi syndrome: case report in afro-descendant individual In general, patients with CHS seek health service due to recurrent infections in early, and the disease is diagnosed when they are about 5 years old (1,5) .This period depends on disease presentation and severity.In this case, the clinical presentation was early identified, with pulmonary infection, not responsive to first-line antibiotics, and persistent fever.Increased susceptibility to infections comes from phagocyte primary dysfunction, which keeps its ability to phagocytosis of pathogens; but digestion is not effective due to lysosomal deficiency (7,8,10,11,24) .Patients suffering from this disease have an average life expectancy of 10 years, if hematological symptoms of the disease are not treated (1,5) .In case reported, the patient progressed quickly and unsatisfactorily, with recurrent infections caused by resistant microorganisms likely enough, due to his stay in the nosocomial environment.Although cultures kept negative results, patient presented persistently increased levels of CRP, indicative finding of inflammatory or infectious process, consistent with the case, considering the related immunodeficiency, that does not change the systemic inflammatory response against the pathogen, but it strongly affects phagocytic activity (4,10,11,13) .

Neutrophils absolu counting
Hematological dysfunction in CHS causes important changes in CBC, such as qualitative/morphological and quantitative abnormalities (5,12,18,24) .Neutropenia persisstende is observed by increasing apoptosis, throughout hospitalization, evolving to febrile neutropenia.On the fifth day of hospitalization, it was observed giant azurophilic lysosomal granules in the neutrophils and other leukocytes cytoplasm (2,4,10,11) .
Establishing a diagnosis, goes through a suitable description of inclusions in CBC report, so that there is an accurate investigation and diagnostic differentiation from other hypotheses, such as Hermansky-Pudlak Syndrome (HPS), and Griscelli syndrome, which exhibit symptoms similar to CHS, differing only in regards to granular leukocytes (9,14) .CHS lysosomal granules may be easily differentiated from typical toxic granulation of severe infectious processes (Figure 3), which represent benign response, helping neutrophil phagocytosis, and they are markers of infection severity (13) .These granules are present during the process, and cease in stimulus absence.CHS lysosomal granules are not restricted to neutrophils (Figure 2B), they may be present in lymphocytes (Figure 2A) and monocytes (Figure 2C), in addition, they are larger and rougher, and are present in all stages of disease, with or without symptomatology (12,13,16) .Other inclusions that may get confused with CHS are Alder Reilly inclusions, which are more common in individuals with Tay-Sachs disease and mucopolysaccharidosis, which present azurophils variable in size and shape from spherical to ellipsoid, that may hide nucleus cell (16,22) .May-Hegglin Anomaly is another condition that presents leukocytes inclusions, in which the spindle granules are similar to Döhle bodies, which are typically peripheral, bright blue basophils, and irregular contour (16) .

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Platelets in CHS are also altered and have less ability to aggregate due to adenosine diphosphate and serotonin deficiency, resulting from Delta-storage pool deficiency, that influences the quantity and content of dense-granules in megakaryocytes and platelets, and may result in thrombocytopenia (7,23) , exacerbated in septic processes, consistent to patient outcome.
CHS course with periods of acceleration and chronicity of the disease.The accelerated phase is a complication with obscure and usually fatal prognosis, which must be avoided (1,3,11,18) .
Changes in hepatic markers may be directly related to the disease, or as the result of frequent infections.At this phase, activated T CD8 lymphocytes and macrophages infiltrate viscera in several organs, especially the highly perfused ones, leading to increase in transaminase and decrease in liver activity, also contributing to decrease in prothrombin activity (1,3,17) .
The treatment considered curative for CHS is bone marrow transplantation (BNT) (6,12,19,20) , which should occur in the stable of disease, although some authors assert that BNT is healing only for the hematological symptoms of disease (6,21) , showing no interference in other symptoms, such as neurological and cutaneous.CHS early and correctly diagnosis is especially important, due to complications during clinical course of disease, and its need for appropriate therapy.It is noteworthy that since CHS is a rare disorder, it may affect patients of different ages and ethnicities, including afro-descendant, as the case reported, and impose different degrees of immunodeficiency (3) .
The accurate description of the CHS abnormal giant azurophilic granules, that are peroxidase-positive, is decisive for diagnosis.This fact requires clinical analyst to improve knowledge and skills necessary to differentiate leukocytes abnormalities, since cytomorphological diagnosis is essential in the disease differential diagnosis process.This report is of particular relevance since it presents CHS occurrence in an afro-descendant individual.As the occurrence is rare in this race, cytomorphologic differentiation with correct statement of characteristic leukocyte inclusions, and laboratory findings associated with the disease, may contribute decisively, together with clinical findings, to differential diagnosis and subsequent better clinical management.rESuMo Trata-se de relato de caso de síndrome de Chediak-Higashi (SCH) em indivíduo afrodescendente, sexo masculino, 3 meses de idade, filho de união consanguínea.Apresentava na admissão febre há um mês, pneumonia não resolvida e hepatoesplenomegalia. Evoluiu para sepse bacteriana, choque séptico e óbito.A SCH apresenta alterações hematológicas, morfológicas e quantitativas.As inclusões leucocitárias anormais constituem achado patognomônico da doença e seu reconhecimento e sua distinção de outras inclusões leucocitárias é fundamental para diagnóstico e instituição da terapêutica.O diagnóstico precoce da SCH aumenta a expectativa de vida do indivíduo e proporciona abordagem terapêutica adequada aos pacientes acometidos pela doença.

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figurE 1 -Severe neutropenia in patient with CHS in the presence of infection CHS: Chediak-Higashi syndrome.