Background: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive immune disorder that is caused by mutations in 6 different genes related to the formation and function of secretory lysosomes within cytotoxic T lymphocytes and natural killer (NK) cells. Thus, defect in these genes is associated with the accumulation of antigens due to defective cytotoxic function. FHL type 3 (FHL3) accounts for nearly 30-40% of FHL, and its underlying reason is mutation in UNC13D gene which encodes Munc13-4 protein. Methods: For the first time, we aimed to systematically review clinical features, immunologic data, and genetic findings of patients with FHL3. We conducted electronic searches for English-language articles in PubMed, Web of Science, EMBASE, and Scopus databases to collect comprehensive records related to patients with UNC13D mutations. Results: A total of 279 abstracts were initially reviewed for inclusion. Among them, 57 articles corresponding to 322 individual FHL3 patients fulfilled our selection criteria. Finally, 73 and 249 patients were considered as severe and mild feature groups, respectively. Our results confirmed that fever, hepatosplenomegaly, and hemophagocytosis are common clinical features in the disease. Moreover, reduced fibrinogen and NK cell activity, as well as increased ferritin and triglycerides, are important markers for early diagnosis of the FHL3 disease. Investigation of genotype showed that the most prevalent type and zygosity of UNC13D are splice-site errors and compound heterozygous, respectively. Conclusion: FHL3 patients have a wide range of clinical manifestations, which makes it difficult to diagnose. Therefore, it seems that the sequencing of the entire UNC13D gene (coding and non-coding regions) is the most appropriate way to accurate diagnosis of FHL3 patients. | 187 AMIRIFAR et Al.

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Objectives: To investigate the prognosis factors of survival in patients with colorectal cancer in presence of competing risks, using generalized Weibull distribution, and to compare the results of Weibull model as well as semi parametric models. Methods:A total of 1462 patients with colorectal cancer, registered in cancer registry center of research institute of gastroenterology and liver disease (from 2004 to 2015), Taleghani hospital, Tehran, Iran entered this study. Death and the causes of death were confirmed via telephone contact to patients' families. The demographic and clinical features included age at diagnosis, sex, family history of CRC, body mass index (BMI), tumor size and tumor site extracted from hospital documents. Generalized Weibull distribution, Cox regression analysis and Fine-Gary model were used to assess the prognosis of CRC survival. The analysis was carried out using R software version 3.0.2. P value less than 0.05 were considered significant. Results:Overall, 1060 CRC patients with completed data were included in the analysis. 58% were men and the mean ± SD of age at diagnosis was 53.67 ± 0.46 years. The mean ± SD of survival time was 56.96 ± 1.46 with median = 45.5 months. 380 patients (35.5%) died from CRC and 49 patients (4.6%) died from other causes of death, such as myocardial infarction, stomach cancer, liver cancer etc. Generalized Weibull model with competing risk analysis and other models indicated age and BMI as the prognosis. Conclusions:This study indicated age and BMI as the prognosis, using a generalized Weibull model with competing risk analysis. Also according to the survival curve estimation, generalized Weibull model with competing risk has a better fit to the data, compared to Weibull model.

Background: Ataxia-telangiectasia (A-T) is a rare genetic disorder characterized by a distinct range of clinical manifestations, including progressive ataxia, immunodeficiency, and radiosensitivity. Methods: Clinical data, laboratory results, and genetic data were collected from forty-three A-T patients. Whole exome sequencing and Sanger sequencing were done for the patients clinically diagnosed as suffering from A-T. Based on the phenotype severity of the disease, patients were divided into severe and mild sub-groups. Results: The median (IQR) age of diagnosis in this cohort was 5 (3-7) years and various types of clinical manifestations, including fever (p= 0.005), lower respiratory tract infection (p= 0.033), diarrhea (p= 0.014), and hepatosplenomegaly (p= 0.032) were significantly higher amongst patients diagnosed with the severe phenotype. Our results showed a strong correlation between phenotype severity and mutation type. The chance of having severe phenotype in patients who have severe mutations, including frameshift and nonsense, was 7.3 times higher compared to patients who were categorized in the mild genotype group (odds ratio= 7.3, p= 0.006). Thirty-four types of mutations including 9 novel mutations, were observed in our study. Conclusion: Molecular analysis provides the opportunity for accurate diagnosis and timely management in A-T patients with chronic progressive disease, especially infections and the risk of malignancies. This study characterizes for the first time, the broad spectrum of mutations and phenotypes in Iranian A-T patients which are required for carrier detection and reducing the burden of disease in future using the patients’ families and for the public health care system. Keywords: Ataxia-telangiectasia (A-T), ATM, Whole-exome sequencing, Class switching recombination (CSR), phenotype severity.