Chediak-Higashi Syndrome: Report on Five Saudi Arab Children and Review of the Literature
1993; King Faisal Specialist Hospital and Research Centre; Volume: 13; Issue: 4 Linguagem: Inglês
10.5144/0256-4947.1993.321
ISSN0975-4466
AutoresAbdallah A. Al-Nasser, Harb A. Harfi, Rajeh Sabbah, Salim M. Malik,
Tópico(s)Otitis Media and Relapsing Polychondritis
ResumoOriginal ArticlesChediak-Higashi Syndrome: Report on Five Saudi Arab Children and Review of the Literature Abdallah A. Al-Nasser, MD, FAAP Harb A. Harfi, MD, FAAA&I, FACA&I Rajeh S. Sabbah, and MD Salim M. MalikMBBS Abdallah A. Al-Nasser From the Department of Oncology, Division of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh. Search for more papers by this author , Harb A. Harfi Address reprint requests and correspondence to Dr. Harfi: Head, Section of Allergy and Clinical Immunology, Department of Pediatrics and Medicine (MBC-58), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. From the Department of Pediatrics, and the Division of Allergy and Immunology, King Faisal Specialist Hospital and Research Centre, Riyadh. Search for more papers by this author , Rajeh S. Sabbah From the Department of Oncology, Division of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh. Search for more papers by this author , and Salim M. Malik From the Department of Pediatrics, and the Division of Allergy and Immunology, King Faisal Specialist Hospital and Research Centre, Riyadh. Search for more papers by this author Published Online:1 Jul 1993https://doi.org/10.5144/0256-4947.1993.321SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractFive cases of the Chediak-Higashi Syndrome (CHS) among Saudi Arab children were diagnosed between June 1978 and December 1990. All patients were males, ages 18 months to ten years, born to first degree consanguineous parents. All showed the typical somatic and laboratory characteristics of this syndrome with characteristic hyperpigmented irides in four patients. Three patients were in the accelerated phase, two of whom responded to a combination chemotherapy (vincristine and prednisone) and one improved after splenectomy. All patients died before they passed the first decade of their lives. This report is the first detailed description of CHS among Arab children in the Arabian peninsula.IntroductionThe Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease characterized by partial oculocutaneous albinism, frequent infections, and the presence of abnormal, large, cytoplasmic granules in all nucleated cells [1]. Eighty-five percent of the patients develop an accelerated phase characterized by fever, hepatosplenomegaly, lymphadenopathy, leukopenia, bleeding tendency, neurological changes, and a diffuse mononuclear cell infiltrate [2]. CHS in man was first described by Bequez-Cesar in 1943 [3], Steinbrink in 1948 [4], Chediak in 1952 [5], and Higashi in 1954 [6]. Sato coined the term CHS in 1955 [7]. A similar disease was described in cats [8], cattle [9], beige mice [10], mink [11], killer whales [12], blue foxes [13], and silver foxes [14]. Geographically, CHS has been reported to occur over a wide area, including the Far East and Middle East, Europe, and North and South America and has also been reported among American blacks [15,16]. However, it is felt by some to be uncommon in Asia [15,17]. One CHS case has been reported so far from Saudi Arabia (case 4) [18]. We report on the clinical presentations and laboratory findings of five patients who were diagnosed at King Faisal Specialist Hospital and Research Centre (KFSH&RC) between 1978 and 1990.Case 1: A.B., an 18-month-old male, was referred to our hospital in June 1978 with a history of recurrent fever, pallor and cervical lymphadenopathy. The parents were first degree cousins. The mother had lost four children, two being stillbirths and two male siblings who died at 18 and 24 months of age with identical clinical histories. Two maternal cousins died early in life with features similar to the patient (Figure 1). The patient appeared ill and lethargic. His hair was partially gray. The irides were deeply pigmented and the retina showed areas of pigmentation and areas of depigmentation. The skin was hyperpigmented with areas of partial depigmentation around the nose, mouth, left side of the face, buttocks, and knees (Figures 2 and 3). He had markedly enlarged cervical, axillary, and inguinal lymph nodes. His liver was 8 cm and the spleen was 6 cm below the costal margin. Laboratory investigations are summarized in Table 2. Peripheral blood smear and bone marrow aspirate showed no lymphocytes and neutrophils with large cytoplasmic inclusion bodies. Myeloid precursors, myelocytes, basophils, and eosinophils contained similar granules. His cerebrospinal fluid (CSF) cells were 26 WBC/mm3, with normal protein and glucose. IgG 1260 mg/dl (normal 344-1180), IgA 92 mg/dl (normal 2-90) and IgM 134 (normal 19-104). Computerized axial tomography (CAT) scan of the head showed moderate cerebral atrophy. The patient was started on a combination of vincristine, prednisone, and ascorbic acid. He had remarkable improvement, both clinically and hematologically. The large lymph nodes, liver, and spleen regressed in size within two weeks of initiation of the chemotherapy. The remainder of his clinical course was characterized by recurrent fever. Unfortunately, the patient developed intracranial hemorrhage and died before BMT was performed. The platelet count at the time of death was 12 x 109/L.Table 2. Laboratory and radiological findings in five cases of Chediak-Higashi Syndrome (CHS).Table 2. Laboratory and radiological findings in five cases of Chediak-Higashi Syndrome (CHS).Figure 1. The family pedigree of patients 1 and 2.Download FigureFigures 2 and 3. Somatic manifestations of patient 1.Download FigureCase 2: M.B., brother of case 1, was four years of age. He was referred to our hospital in July 1978 with fever for one month, anemia, and poor appetite. He appeared ill with a temperature of 40°C. His hair was silvery gray and his irides were hyperpigmented. His skin showed several areas of depigmentation with freckles, especially around the mouth. The patient had splenomegaly 10 cm below the costal margin. Peripheral blood smear and bone marrow aspirate showed lymphocytes and neutrophils with large cytoplasmic granules. IgG was 1820 mg/dl with a normal range of 440-1292 mg/dl, IgA at 256 mg/dl with a normal range of 39-123 mg/dl and IgM at 142 with a normal range of 19-167 mg/dl. The cerebrospinal fluid showed WBC 28/mm3 with glucose of 74 mg/dl (normal 40-80 mg/dl) and protein 108 mg/dl (normal 30-50 mg/dl). CT scan of the head showed generalized cortical atrophy. X-ray of the maxillary sinuses showed bilateral maxillary sinusitis. Chest radiograph showed left lower lobe pneumonia.A combination of vincristine, prednisone, and ascorbic acid were given. Within 36 hours, the patient became afebrile with regression of his spleen size and normalization of the hematological picture. The patient developed hepatitis and died about one month after discharge from our hospital.Case 3: N.S., a 16-month-old male, was referred to our hospital with a history of recurrent fever, hepatosplenomegaly, anemia, and leukopenia since the first year of life. The parents were first degree cousins. There was no similar condition in the family. He was pale and appeared acutely and chronically ill. He was febrile with a temperature of 39°C He had partial oculocutaneous albinism and silvery gray hair (Tables 1 and 2). The peripheral blood smear and bone marrow aspirate showed giant cytoplasmic granules in the polymorphonuclear leukocytes, lymphocytes, and monocytes. PMN chemotactic activity and phagocytosis were reduced, but both improved after treatment with ascorbic acid. Platelet function studies showed normal aggregation, but release reaction of the platelets was considerably reduced. IgG level was 546 mg/dl (normal 440-1292). IgA and IgM levels were low at less than 20 mg/dl with normal ranges of 39-123 and 19-167, respectively. The cerebrospinal fluid showed occasional abnormal lymphocytes with normal sugar and protein. CT scan of the head showed marked cerebral atrophy.Table 1. Clinical findings in five cases of Chediak-Higashi Syndrome (CHS).Table 1. Clinical findings in five cases of Chediak-Higashi Syndrome (CHS).The patient received parenteral antibiotics for two weeks and became afebrile. One week after antibiotics were discontinued, fever recurred and the patient became tachypneic with pulmonary infiltrates on chest x-ray. The liver and spleen started to enlarge after they had become impalpable. His WBC dropped to 0.5 x 109/L with thrombocytopenia and anemia. It was felt that he was in the early stage of the accelerated phase of his CHS; therefore, he received ascorbic acid and prednisone for five weeks and vincristine for six weeks. The patient’s WBC increased from 0.5 x 109/L to more than 5 x 109/L. He died outside the hospital a few months after he was discharged.Case 4: M.N. is a ten-year-old male reported earlier [18], who was referred to our hospital with high grade fever and hepatosplenomegaly in October 1987. On admission, CBC showed Hb 93 g/L, WBC 1.9 x 109/L with 8% PMN, 85% lymphocytes, 7% monocytes and platelets 9 x 109/L. The peripheral blood smear and the bone marrow aspirate showed abnormal cytoplasmic granules inside the WBC. Cerebrospinal fluid showed WBC 25/mm3, sugar 48 mg/dl (normal 40-80), protein 155 mg/dl (normal 30-50). Leukocyte chemotaxis (using modified Boyden chamber) and phagocytic activity as measured by chemoluminescence were markedly depressed. Serum IgG was 781 mg/dl (normal 697-1589), IgA 118 (normal 96-280), and IgM 54 (normal 50-178). The head CT scan was normal.The patient was given a ten day course of a combination of antibiotics and ascorbic acid 500 mg/day, but remained febrile. He was given a six week course of chemotherapy with vincristine and prednisone. There were no signs of either clinical or hematological improvement. Because of lack of response to chemotherapy and supportive measures, splenectomy was performed after immunization with pneumococcal vaccine. Within 24 hours post splenectomy, the WBC increased to 9 x 109/L, Hb to 104 g/L and platelets to 154 x 109/L. He became afebrile and no transfusion was required. His peripheral edema disappeared within a week and his liver regressed to normal size after six weeks. Repeat immunologic studies one and four weeks post splenectomy showed normalization of the immunological parameters. He died outside the hospital six months later with suspected intracranial hemorrhage.Case 5: Y.S. is a six-year-old male referred to our hospital in December 1990 with a history of fever and cervical lymphadenopathy for the preceding four months. He also had photophobia, skin photosensitivity, abdominal distention and abnormal color of hair since birth. Five months before referral, he had an attack of severe pneumonia and was treated with a prolonged course of parenteral antibiotics. His parents were second degree cousins. They lost two male siblings in early childhood with similar features. Physical examination showed partial oculocutaneous albinism, densely hyperpigmented irides, silvery gray hair, and photodermatitis. The remainder of the clinical and laboratory findings are summarized in Tables 1 and 2. Peripheral blood smear and bone marrow aspirate showed leukocytes and leukocyte precursors with large cytoplasmic granules. IgM was low at 0.2 g/L (normal 0.4-1.7 g/L) with normal IgG, IgA, and IgE. The cerebrospinal fluid showed WBC 20/mm3, mostly lymphocytes with normal sugar and protein. Head CT scan showed no abnormalities. The patient was started on ascorbic acid, daily prednisone, and weekly vincristine. His spleen showed significant reduction in size.DISCUSSIONTables 1 and 2 summarize the clinical, laboratory, and radiological findings in five cases of CHS. This is one of the diseases that stands at the interface between immunodeficiency and pediatric cancer. Unfortunately, the molecular basis of the defect in CHS is not known, but it probably involves a common coding or a common regulatory gene defect in view of the wide spectrum of cells affected. CHS is an autosomal recessive disease with a high percentage (48%) of marriages, known to be consanguineous, which produce affected children [15]. Since CHS is a progressive, serious, and eventually fatal disease, a method for prenatal diagnosis would be desirable. There are reported attempts toward this goal [8,19], although so far there is no human prenatal diagnostic test. The neurological manifestations of CHS were first described by Meyers et al [20] and have been extensively reviewed [15]. Despite the variety of neurological manifestations of CHS, brain atrophy as documented by head CT scans in our patients has not been considered a consistent one in previously reported cases. A few cases had clinical findings consistent with a form of spinocerebellar degeneration [21]. One case was unique in that there was evidence of spinocerebellar degeneration without any oculocutaneous manifestations of CHS [22]. Mental retardation has also been associated with CHS, but appeared to be independent of other neurological involvement. Only one of our patients was mentally retarded. Mental retardation is probably unrelated to CHS; its occurrence may be due to the high incidence of consanguineous marriages [15]. However, the possibility of the mental deterioration being secondary to CNS infiltration by atypical immature cells causing neurological damage cannot be excluded.Patients with CHS have a tendency to develop a lymphoma-like accelerated phase. Yamak et al [23] described an infant with CHS in whom malignant lymphoma developed during infancy. Tan et al [24] described Hodgkin disease in an eight-year-and-nine-month-old female with CHS. The fact that our patients responded well, both clinically and hematologically, to a combination of chemotherapy is suggestive of the premalignant nature of the accelerated phase of the syndrome. Also, the patients’ symptoms recur after initial response to chemotherapy, a behavior reminiscent of malignant diseases.The pathophysiology of the accelerated phase of CHS is unknown and the assignment of this phase of the syndrome as being either a neoplastic or a reactive process is controversial [15]. Previous reports have implied that CHS patients develop malignant lymphoma [15,23,24] or lymphoma-like [25,26] diseases in their terminal stages. The mononuclear infiltrates in the CHS children have been described as peculiar or atypical lymphoma [27]. Several reports suggest that the accelerated phase is a reaction to a viral infection. Virus-like particles have been demonstrated in peripheral blood cells by electron-microscopy [28]. Some of these particles in the leukocytes have a morphological appearance similar to that of atypical lymphocytes in infectious mononucleosis [27-29]. In a report by Risdall et al [30], evidence for association with viral infection was present in 15 out of 19 patients. They suggested that the viral infection itself precipitated an immune paresis. Only one of our patients had high antibody titer to EBV.Neutrophils in CHS have defective functions. Abnormalities include poor mobilization of neutrophils from the marrow [31], defective chemotactic response of neutrophils and monocytes [32,33] and decreased bactericidal activity [34]. In vivo skin window studies also demonstrated defective neutrophil migration [32]. CHS patients also have impaired NK activity and absent antibody-dependent, cell mediated cytotoxicity [35,36]. Virelizier et al [37,38] reported on one patient with CHS with reversal of NK defect after bone marrow transplantation. Kazmierowski et al [39] reported on the reversal of increased susceptibility to infection by bone marrow transplantation in mice with the syndrome.In vitro studies have shown that ascorbic acid has a corrective effect on the microtubule defect, Con-A capping, and the defective cell membrane fluidity [40]. Boxer et al [41,42] and Weening et al [43] reported correction of the microtubule defect, partial restoration of chemotaxis and significant reduction in the frequency of infections in CHS after therapy with ascorbic acid. On the other hand, Gallin et al [44] could demonstrate neither correction of the cellular defects nor reduction in the number of infections. Abnormal cyclic nucleotide levels were suggested as the reason for impaired microtubule function in CHS. However, other studies such as the one by Gallin et al [44] do not support this cytoskeletal model.Our patients, in addition to showing the typical features of CHS as mentioned above, have demonstrated the following features: cerebral atrophy, which has been reported in the literature rather infrequently, probably because no head computerized axial tomographies were done on most cases reported earlier; all our patients except case 4 showed densely hyperpigmented rather than hypopigmented irides; consanguinity was the rule among all the families of our patients. The fact that all five patients were males suggests that the mode of inheritance in our patients is an autosomal sex-linked recessive, rather than autosomal recessive as reported in the literature.Case 4 [18] is probably the first reported case of CHS in the English literature treated by splenectomy which led to the reversal of the immunological abnormalities of CHS. 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Barroga for her excellent secretarial assistance in preparing the manuscript.InformationCopyright © 1993, Annals of Saudi MedicinePDF download
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