Clinical Feature And Genetic Diagnosis Of Chediak-Higashi Syndrome

Background: Chediak-Higashi syndrome is a rare autosomal recessive disease, it is generally classified in the primary immunodeficiency due to the function defects of phagocyte. The pathogenic gene of CHS is LYST gene which is located in autosomal chromosome 1q42.1-42.2. Because of LYST is associated closely with the volume and function of lysosome, the mutations of LYST gene would result in dysfunction of lysosome-ralated organelle. These organelles are distributed in almost all the system of body, including skin, eyes, blood system, immune system and nervous system et al. The clinical features of CHS include hypopigmentation, nystagmus, immunodeficiency, bleeding tendency and regression of nervous system progressively, and when the patients get into the stage of so-called"accelerated phase", they would manifest hemophagocytic lymphohistiocytosis characteristically.Objective:1. To explore the clinical and laboratory features of CHS involved in this study.2. To perform genetic diagnosis of CHS and instruct the clinical therapeutic strategy.3. To confirm the carriers and give reasonable genetic counseling to them.Methods:1. To analyze the clinical and laboratory data of 5 cases of CHS children.2. To analyze the LYST gene obtained from the 5 cases of CHS peripheral blood by DNA-PCR, RT-PCR and direct sequencing.3. To analyze corresponding site of the parents and other relatives according to the gene mutation of patients, confirm the carriers.Results:1. Clinical feature and laboratory examination 5 cases of CHS children, 4 female and 1 male, were all presented appearance of hypopigmentation just after birth and some of them had nystagmus. Their onset were from birth but been diagnosed at average age of 4 years and 4months. 4 cases admitted chief complaint of"fever"when they came to here. The fever lasted from 1 week to 1 month. The patients suffered upper or lower respiratory tract infections in the several years from birth to diagnosis except case 4, once a month or 2 months on the average. They had no family history except case 2.The platelet of patients was detected to decrease by peripheral blood cell counts and there were no characteristic changes in serum immunoglobulin level and lymphocyte sort test. Cases 1 to 3 were found to reach"accelerated phase"by measuring their serum ferritin, alanine transaminase and serum triglyceride and fibrinogen level. Cases 1, 2 and 5 had the evidence of EBV infection. Case 1 was dead.2. Bone marrow detection and hair pigment distribution testThere were many giant acidophilic inclusion bodies in bone marrow nucleated cells with 4 patients and hemophagocytic phenomena in 2 cases of them. To observe the hair by light microscopy, we found the melanin of all patients decreased and presented small spotty distribution compared to control.3. CD107a mobilization testCase 4 and case 5 had performed the CD107a mobilization test. The CD107a mobilization of NK cells and CTL were decreased extraordinarily compared to the control.4. Genetic analysis of LYST4 patients had LYST gene mutations. They had heterozygous mutations all, and there were 8 mutations altogether including 5 nonsense mutations (Q980X, K2205X, R1718X, R145X, R2596X), 2 deletion mutations (c.5411-5414 del TTTC, c.5392-5393 del AA) and 1 missense mutation (R1563H). Except the missense mutation the rest of 7 mutations are novel mutations. Parents of the 4 cases of children were all carriers and the elder sisters of 2 cases of children were carriers too. Conclusion:1. CHS patients in this group began onset after birth and manifested characteristic hypopigmentation with or without nystagmus. The average diagnosis age was 4 years and 4months, cases 1 to 3 had reached the"accelerated phase".2. The CD107a mobilization detection can screen CHS.3. Bone marrow test and observation of the hair by light microscopy could be the evidence for primary diagnosis and differential diagnosis.4. Genetic analysis of LYST is the effective method to confirmed diagnosis of CHS and carrier analysis can provide a good basis for genetic counseling or prenatal diagnosis for patient's relatives.