Immune gene polymorphisms associated with poor response to platelet transfusion and recombinant factor VII administration in Glanzmann thrombasthenia.

INTRODUCTION: Poor response to platelet and recombinant factor VII administration is a major problem in patients with Glanzmann Thrombasthenia (GT). The risk factors associated with poor response to treatment in these patients are unknown. Some genetic variations of cytokines may contribute to therapy resistance. AIMS: We evaluated, for the first time, whether genetic polymorphisms on cytokine genes are related to poor treatment response in GT patients. METHODS: We enrolled 30 patients with GT (15 resistant and 15 non-resistant) and 100 healthy controls. Gene polymorphisms of IL-10 and TNF-α were analysed using TaqMan Realtime PCR, and IL-1, IL-1R1 and IL-1RN were investigated with the RFLP method. In-silico analyses were performed to predict the potential impact of these polymorphisms. RESULTS: In the resistant group, all patients had a variant of the IL-10 gene at the -1082 position (rs1800896), with a GG genotype that was significantly more frequent than the non-resistant group. Analysis between healthy controls and GT patients revealed a probable correlation between rs3783550, rs3783553, rs3917356 and rs2234463 and GT. The In-silico study indicated that TNF-α rs1800629 and IL-10 rs1800896 polymorphisms result in different allelic expressions which may contribute to poor response to therapy. CONCLUSIONS: These findings suggest that polymorphisms in the IL-10 and IL-1 receptor antagonist genes may play a role in poor therapy response in GT patients. In addition, some polymorphisms in IL-1α, IL1-ß, IL-1R1 and IL-R antagonists might be involved in the GT progression.

Prevalence of hemorrhagic ovarian cysts in patients with rare inherited bleeding disorders.

BACKGROUND: In comparison with the general population, women with bleeding disorders are more prone to develop obstetrical and gynecological problems. However, no comprehensive evaluation has investigated the prevalence of hemorrhagic ovarian cysts (HOCs) in rare bleeding disorders (RBDs). In this study, we sought to determine the prevalence of HOCs in a large cohort of Iranian patients with RBDs. METHODS: A total of 210 symptomatic patients suspected of HOCs with RBD were included. The median age of the study population was 24 years. Patients were diagnosed with fibrinogen disorders (n = 7, 3%), factor (F) II (n = 4, 2%), FV (n = 28, 13%), FVII (n = 4, 2%), FX (n = 6, 3%), FXIII (n = 122, 58%), combined FV and FVIII (n = 8, 4%), Glanzmann's thrombasthenia (n = 10, 5%), and von Willebrand disease (VWD) type 3 (n = 21, 10%). RESULTS: Following further clinical and ultrasound examinations of these 210 patients, 68 (32.4%) were confirmed with a diagnosis of HOCs. Of which, FXIII deficiency with 46 cases (67.6%), followed by VWD type 3 (6 cases, 8.8%) showed the highest number. Other coagulation defects associated with HOCs were including fibrinogen deficiency (n = 2, 3%), FII (n = 2, 3%), FV (n = 4, 6%), FVII (n = 2, 3%), FX (n = 1, 1.5%), combined FV and FVIII (n = 2, 3%), and Glanzmann's thrombasthenia (n = 3, 4.5%). CONCLUSION: This study found a high prevalence of HOCs in patients with RBDs, indicating the importance of early diagnosis and optimal management of obstetric and gynecological complications in these patients.

Assessment of Tribo-charging and Continuous Feeding Performance of Direct Compression Grades of Isomalt and Mannitol Powders.

Tribo-charging is often a root cause of mass flow deviations and powder adhesion during continuous feeding. Thus, it may critically impact product quality. In this study, we characterized the volumetric (split- and pre-blend) feeding behavior and process-induced charge of two direct compression grades of polyols, galenIQ™ 721 (G721) for isomalt and PEARLITOL® 200SD (P200SD) for mannitol, under different processing conditions. The feeding mass flow range and variability, hopper end fill level, and powder adhesion were profiled. The feeding-induced tribo-charging was measured using a Faraday cup. Both materials were comprehensively characterized for relevant powder properties, and their tribo-charging was investigated for its dependence on particle size and relative humidity. During split-feeding experiments, G721 showed a comparable feeding performance to P200SD with lower tribo-charging and adhesion to the screw outlet of the feeder. Depending on the processing condition, the charge density of G721 ranged from -0.01 up to -0.39 nC/g, and for P200SD from -3.19 up to -5.99 nC/g. Rather than differences in the particle size distribution of the two materials, their distinct surface and structural characteristics were found as the main factors affecting their tribo-charging. The good feeding performance of both polyol grades was also maintained during pre-blend feeding, where reduced tribo-charging and adhesion propensity was observed for P200SD (decreasing from -5.27 to -0.17 nC/g under the same feeding settings). Here, it is proposed that the mitigation of tribo-charging occurs due to a particle size-driven mechanism.

Genotyping of blood groups in alloimmunized patients with ß-thalassemia major by T-ARMS-PCR and multiplex-aso-pcr.

INTRODUCTION: Beta-thalassemia major is a severe hemolytic anemia requiring life-long blood transfusion. Planned random donor blood transfusion is associated with alloimmunization against incompatible antigens. Determination of the minor blood group systems phenotype or genotype, and administration of the compatible blood components can significantly reduce the rate of alloimmunization. The present study aimed to determine the prevalence of alloimmunization, and genotype/phenotype characteristics of the minor blood groups systems in patients with ß-thalassemia major. MATERIAL AND METHODS: This study was conducted on 1147 ß-thalassemia major patients. Initially, antibody screening and antibody identification were performed. Then, phenotyping and genotyping for the Rh, Kell, Kidd, and Duffy blood groups were done in alloimmunized patients using monoclonal antibodies and Multiplex-Allele Specific Oligonucleotide-Polymerase Chain Reaction (Multiplex-ASO-PCR) and Tetra-primer amplification refractory mutation system-PCR (T-ARMS-PCR), respectively. Any phenotype/genotype discrepancy was assessed by direct sequencing. RESULTS: Ninety-seven (8.5 %) out of 1147 patients had alloantibodies against the minor blood group antigens (44 males, 45.4 %, and 53 female, 54.6 %). The most common alloantibodies were against the RH (n: 47, 48.5 %), and the Kell (n: 23, 23.7 %) blood groups systems. Twenty-three (2.1 %) genotype/phenotype discrepancies out of 1067 tests, including 9 in the Rh (9.3 %), 8 in Duffy (34.8 %), and 6 in Kidd (26.1 %) blood groups were detected. No discrepancy was found in the Kell blood group system. Direct sequencing revealed that the results of molecular methods were correct. CONCLUSION: Multiplex-ASO-PCR and T-ARMS-PCR molecular methods are fast, reliable and cost-benefit molecular methods for the minor blood group genotyping in multi-transfused ß-thalassemia major patients.

Premarital Screening Program for Congenital Factor XIII Deficiency in Iran.

BACKGROUND: Factor XIII deficiency is one of the most severe congenital bleeding disorders with high rate of life-threatening bleeding including central nervous system bleeding, umbilical cord bleeding, and recurrent miscarriages. Due to the highest global incidence of the disorder in Iran, this study aimed to design a premarital screening program in Iran. METHODS: This descriptive study was performed on 30 couples with a positive family history of factor XIII deficiency. Underling F13A gene mutation was determined in the family members, and all the selected couples underwent molecular testing mutations by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), tetra primer-amplification refractory mutation system-PCR (T-ARMS-PCR), and sequencing. RESULTS: The probability of affected childbirth existed for ten couples. Three couples decided not to marry, while seven got married and three of them decided to have a baby. The genotypes of the fetuses were determined and revealed that none of them was a homozygote for the F13A gene mutation. CONCLUSIONS: Because of the importance of factor XIII deficiency diagnosis, it can be helpful to control the incidence of factor XIII deficiency by implementing preventive programs such as premarital screening.

A retrospective study on clinical manifestations of neonates with FXIII-A deficiency.

We assessed clinical presentations and the rate of central nervous system (CNS) bleeding in neonates with FXIIID who exhibited bleeding diathesis in the early days of their lives. A total of 27 neonates presented bleeding or abnormal clinical symptoms, diagnosed with FXIII deficiency were evaluated. Factor XIII concentrate was initiated as the first-line of treatment, and prophylactic therapy was given to all patients. Umbilical cord bleeding, delayed detachment of umbilical stunt, seizure, hematoma, and ecchymosis were concurrent complications in 27 (100%), 5 (18.5%), 5 (18.5%), 3 (11.1%), and 1 (3.7%) of the patients, respectively. History of having CNS bleeding was detected in 13 (48.1%) patients. There was no significant association between CNS bleeding and gender, familial history of FXIIID, or other clinical presentations. Also, there was no significant difference in the mean age of the patients who had CNS bleeding (3.4 ±â€¯0.9 days) and without CNS bleeding (2.9 ±â€¯0.7 days). However, a near significant threshold difference between the patients with and without CNS bleeding was found regarding the mean number of suspicious FXIIID death in their family (1.8 ±â€¯0.5 and 0.7 ±â€¯0.1, respectively, P = 0.05). Therefore, a suggested diagnostic algorithm based on prenatal diagnosis could be useful for timely detection of FXIII deficiency in neonates.

A Unique Factor XIII Mutation in Southeastern Iran with an Unexpectedly High Prevalence: Khash Factor XIII.

Congenital factor XIII (FXIII) deficiency is an extremely rare hemorrhagic disorder characterized by a deficiency of FXIII and associated with a high rate of morbidity and mortality. The disorder is more frequent in Iran, especially in Khash, a city in the southeast of the country. As identified in the current report, the prevalence of FXIII deficiency in this city is 1 homozygote per approximately 500 population (which is ∼4,000 times higher than the worldwide prevalence) with 3.5% heterozygotes. The disorder is accompanied by a high rate of mortality in rural areas of Khash, given an averaged observed rate of approximately three deaths per each family with FXIII deficiency, mostly due to late-diagnosis and/or misdiagnosis, and fetal consequences of both umbilical cord and central nervous system bleeding. Almost all patients with FXIII deficiency in the southeast Iran have a unique mutation in F13A gene (Trp187Arg), which leads to a severe FXIII deficiency. This mutation is used for pre-marriage and prenatal diagnosis, as well as for carrier detection and diagnostic confirmation. Fibrogammin P has been used worldwide for about one decade, along with different therapeutic regimens for prophylaxis treatment, major and minor surgeries, and successful delivery. Due to the rapid increase in the number of patients identified to have congenital FXIII deficiency, and the high rate of related morbidity and mortality, a comprehensive regional preventive program is necessary to prevent further expansion of this condition and decrease the burden on the health care system. The area of Khash city provides novel insights into severe FXIII deficiency due to its high prevalence in this region. This report also provides a review of FXIII deficiency, its diagnosis, prevalence, molecular basis, clinical manifestations, management, and treatment, with a particular focus on Iran, representing a hotspot for this disorder.

Correlation of bleeding score with frequency and severity of bleeding symptoms in FXIII deficiency assessing by the ISTH Bleeding Assessment Tool.

OBJECTIVES: The ISTH bleeding assessment tool (ISTH-BAT) is developed for standardization of bleeding symptoms in bleeding disorders. The aim of this study is to apply this bleeding score for FXIII deficient patients and its relation to the frequency and severity of symptoms. METHODS: In this cross-sectional study, 63 patients with severe FXIII deficiency were evaluated for the assessment of bleeding score according to the standard ISTH-BAT questionnaire. All patients were registered at two major thrombosis and hemostasis centers in Iran affiliated to Zahedan University of medical sciences (50 patients) and Shiraz University of medical sciences (13 patients). RESULTS: Significant correlations between the bleeding score and number of symptoms (r = 0.668, P < 0.001) and with a number of severe symptoms (r = 0.938, P < 0.001) were detected. There was no significant relationship between the mean bleeding score and CNS bleeding (P = 0.390). CONCLUSION: The ISTH-BAT score is an acceptable bleeding assessment tool for standardization and evaluation of patients with FXIII deficiency.

Coincidence of celiac disease with nongastrointestinal tumors in children.

The association of celiac disease (CD) with cancers of gastrointestinal origin has been noted. However, coincidence of CD with nongastrointestinal neoplasms is an unusual event. Here we present five children with concurrent CD and nongastrointestinal neoplasms. All of the patients had positive serologic results for anti-tTG antibodies. Histological investigation of intestinal mucosa showed inflammation (Marsh score = 2) in all the patients. Two of these patients represented with germ cell malignancies. One patient had Wilms' tumor. To our knowledge, these are the first reports of coincidence of these two cancers with CD in children. From the remaining two patients, one was diagnosed with acute lymphoblastic leukemia, and the other with astrocytoma. The diagnosis of malignancy preceded CD diagnosis in all the patients (mean ages of cancer and CD diagnosis of 1.8 and 5.4 years old, respectively). Whether malignancy can promote immune deregulation and predispose to CD is uncertain. On the other hand, undiagnosed celiac may be a risk factor for cancer. Our results suggest a potential association of CD with malignancy nature of CD, however, occurrence of CD may be influenced by various intrinsic and extrinsic factors. There are few reports noting CD as a paraneoplastic condition. Further investigations are necessitated to stablish such relationship.

IKZF1 gene polymorphisms increased the risk of childhood acute lymphoblastic leukemia in an Iranian population.

Genome-wide association studies (GWAS) have proved the association of IKZF1 polymorphisms with childhood acute lymphoblastic leukemia (ALL). In the present study, we aimed to inspect the impact of IKZF1 gene polymorphisms and childhood ALL in a sample of Iranian population who live in south east of Iran. This case-control study was done on 110 children diagnosed with ALL and 120 healthy children. The IKZF1 (rs4132601 T > G, rs11978267 A > G, rs11980379 T > C, and rs10272724 T > C) polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The results showed that rs4132601 T > G polymorphism increased the risk of ALL in the codominant (OR = 2.96, 95 % CI = 1.58-5.54, p = 0.0008, TG vs TT; and OR = 2.75, 95 % CI = 1.31-5.76, p = 0.0094, GG vs TT) and dominant (OR = 2.89, 95 % CI = 1.61-5.19, p = 0.0004, TG + GG vs TT) inheritance models. On the other hand, the rs4132601 G allele increased the risk of ALL (OR = 1.86, 95 % CI = 1.28-2.96; p = 0.0011) in comparison with the T allele. We have also showed that rs11980379 T > C variant increased the risk of ALL in codominant (OR = 2.43, 95 % CI = 1.28-4.60, p = 0.0076, TC vs TT; and OR = 2.35, 95 % CI = 1.14-4.85, p = 0.0291, CC vs TT) and dominant (OR = 2.40, 95 % CI = 1.32-4.36, p = 0.0038, TC + CC vs TT) inheritance models. The rs11980379 C allele increased the risk of ALL (OR = 1.59, 95 % CI = 1.10-2.31, p = 0.0151) compared with T allele. Our study also revealed that the rs10272724 T > C polymorphism increased the risk of ALL in codominant (OR = 2.18, 95 % CI = 1.19-3.99, p = 0.0115, TC vs TT; and OR = 2.67, 95 % CI = 1.24-5.77, p = 0.0131, CC vs TT) and dominant (OR = 2.31, 95 % CI = 1.30-4.08, p = 0.0049, TC + CC vs TT) inheritance models. On the one hand, the rs11980379 C allele increased the risk of ALL (OR = 1.70, 95 % CI = 1.17-2.46, p = 0.0062) compared with T allele, while the rs11978267 A/G polymorphism was not associated with ALL risk. In conclusion, our findings confirm the impact of IKZF1 polymorphisms on childhood ALL risk in a sample of Iranian population. Further studies with larger sample sizes and different ethnicities are needed to confirm our findings.

Morbidity and mortality in a large number of Iranian patients with severe congenital factor XIII deficiency.

With 473 patients, Iran has about one third of the world's patients with severe congenital factor XIII (FXIII) deficiency. A considerable number of patients with FXIII deficiency (FXIIID) are affected by life-threatening bleeding episodes, such as central nervous system (CNS) bleeding or recurrent miscarriage and umbilical cord bleeding (UCB), that cause a high rate of morbidity and mortality in Iranian patients with FXIIID. Among 317 Iranian patients with FXIIID, 145 cases experienced 166 CNS bleeds (CNSBs) that recurred in 21 cases. CNSB caused different types of neurological complications in 69 patients. A total of 62 miscarriages were observed in 24 women of childbearing age, and 21 deaths were observed due to umbilical cord bleeding or mucosal bleeding. In fact, 49 deaths (15.4 %) were observed in these patients, which highlight the importance of early diagnosis and intensive health care among patients with FXIIID.

Molecular Characterization of ß-Thalassemia Intermedia in Southeast Iran.

Inheritance of mild mutations within the ß-globin gene and coinheritance of α-thalassemia (α-thal) are known as two important genetic modifiers in ß-thalassemia (ß-thal) intermedia (ß-TI). We aimed to evaluate the spectrum of ß- and α-thal mutations in ß-TI patients in Southeast Iran. Common ß- and α-globin gene mutations were detected by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and multiplex gap-PCR, respectively. There were 26 male (57.8%) and 19 female (42.2%) patients. HBB: c.92 + 5T > C [IVS-I-5 (G > C)] and HBB: c.-138C + 1G > A [IVS-II-I (G > A)] represented the prevalent alleles with respective frequencies of 60.0 and 10.0%. Other ß-globin mutations included HBB: c.-138C > T [-88 (C > T)], HBB: c.27_28insG [frameshift codons (FSC) 8/9 (+G)], HBB: c.46delT [codon 15 (-T)], HBB: c.93-22_95del (IVS-I, 25 del), and the 619 bp deletion (NG_000007.3: g.71609_72227del619). The predominant genotypic combinations were ß(0)/ß(0) (68.9%), ß(0)/ß(+ )(8.9%) and ß(+)/ß(+ )(2.2%). Coinheritance of α-thal was observed in 33.0% of the patients, with the -α(3.7) (rightward) (NG_000006.1: g.34164_37967del3804) as the most common deletion (86.0%). One patient was diagnosed with the -α(4.2) (leftward) (AF221717) and one with the - -(MED) (g.24664_41064del16401) deletions, while no patients carried the -(α)(20.5) (g.15164_37864del22701), α(-5 nt) (HBA2: c.95 + 2_95_6delTGAGG) or codon 19 (-G) (HBA2: c.56delG) mutations. The alleviating molecular mechanism was not explainable by ß(+ )or concurrent α-thal in more than half of our ß-TI patients. This encourages conducting more studies to identify other contributing factors, especially Hb F-inducing genetic modifiers.

Factor XIII deficiency in Iran: a comprehensive review of the literature.

Factor XIII deficiency (FXIIID) is a rare bleeding disorder with an estimated prevalence of 1 in 2-million population worldwide. In Iran, a Middle Eastern country with a high rate of consanguineous marriages, there are approximately 473 patients afflicted with FXIIID. An approximately 12-fold higher prevalence of FXIIID is estimated in Iran in comparison with overall worldwide frequency. In this study, we have undertaken a comprehensive review on different aspects of FXIIID in the Iranian population. The distribution of this disease in different regions of Iran reveals that Sistan and Baluchestan Province has not only the highest number of patients with FXIIID in Iran but the highest global incidence of this condition. Among Iranian patients, umbilical cord bleeding, hematoma, and prolonged wound bleeding are the most frequent clinical manifestations. There are several disease causing mutations in Iranian patients with FXIIID, with Trp187Arg being the most common mutation in FXIIID in Iran. Traditionally, the management of FXIIID in Iran was only based on administration of fresh frozen plasma or cryoprecipitate, until 2009 when FXIII concentrate became available for patient management. Various studies have evaluated the efficacy and safety of prophylactic regimens in different situations with valuable findings. Although the focus of this study is on Iran, it offers considerable insight into FXIIID, which can be applied more extensively to improve the management and quality of life in all affected patients.

Congenital factor V deficiency: comparison of the severity of clinical presentations among patients with rare bleeding disorders.

BACKGROUND: Factor V deficiency (FVD) is a rare bleeding disorder (RBD) mostly present in regions with a high rate of consanguinity. FVD after FXIII deficiency is the next more prevalent RBD in Sistan and Baluchistan (S&B) in southeastern Iran. The aim of this study was to evaluate the clinical manifestations and severity of bleeding diathesis in patients with FVD. METHODS: This descriptive study was conducted on 23 patients with FVD in S&B province. FVD was diagnosed by clinical findings and routine laboratory tests. Bleeding diatheses were classified into three grades (I-III) depending on the severity of symptoms. The severity of bleeding episodes in our patients was compared with other RBDs. RESULT: Based on residual plasma FV activity, 6 (26%), 16 (69.5%) and 1 (4.5%) patients had mild, moderate and severe factor deficiency, respectively. 24% of the patients had grade III life-threatening bleeding episodes which in comparison with FVII deficiency (17.4%) and FI deficiency (21%) had a higher incidence, and in comparison with FX deficiency (41.7%) and FXIII deficiency (63.1) had a lower incidence. Grade II and grade I bleeding diathesis were observed in 56.2 and 16.7% of the patients, respectively. CONCLUSION: FVD is the second most common type of RBD in S&B province and grade II bleeding episodes were the major bleeding presentation and observed in more than half of the patients.

Association of functional polymorphism at the miR-502-binding site in the 3' untranslated region of the SETD8 gene with risk of childhood acute lymphoblastic leukemia, a preliminary report.

MicroRNAs (miRNAs), a class of non-coding RNAs, bind to the 3' untranslated regions (UTRs) of mRNAs, where they interfere with translation of genes and are implicated in the pathogenesis of diverse diseases. In the present study, we evaluate the impact of rs16917496 polymorphism within the miR-502 miRNA seed region at the 3'UTR of SEDT8 on childhood acute lymphoblastic leukemia (ALL). This case-control study was done on 75 ALL and 115 healthy children. Genotyping of rs16917496 C/T polymorphism was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that CT as well as CT + TT decreased the risk of ALL in comparison with CC genotype (odds ratio (OR) = 0.29, 95 % confidence intervals (95 % CI) = 0.11-0.78, P = 0.014 and OR = 0.31, 95 % CI = 0.12-0.82, P = 0.016, respectively). Our results demonstrated that SETD8 rs16917496 C/T polymorphism was associated with decreased risk of developing pediatric ALL in Zahedan, southeast Iran. Larger studies with different ethnicities are desired to validate our findings.

A functional polymorphism in the miR-146a gene is associated with the risk of childhood acute lymphoblastic leukemia: a preliminary report.

Growing evidence showed that microRNAs (miRs) are involved in normal hematopoiesis and the pathogenesis of several hematological malignancies. Genetic variations or mutations occurring in the miR gene region may affect the property of miRs through altering miR expression and/or maturation. The aim of the present study was to evaluate the possible relationship between two miRs polymorphisms, hsa-miR-146a (rs2910164 G>C) and hsa-miR-499 (rs3746444 T>C), and the susceptibility to childhood acute lymphoblastic leukemia (ALL) in a sample of Iranian population. This case-control study was performed on 75 children diagnosed with ALL and 115 age- and sex-matched children with no history of cancer of any type (as the control group). Tetra-primer amplification refractory mutation system-polymerase chain reaction was applied for genotyping the variants. We found that the rs2910164 G>C variant of hsa-miR-146a significantly increased the risk of ALL (CC vs. GG, OR = 4.24, 95% CI = 1.52-11.87, P = 0.006; GC vs. GG, OR = 3.55, 95% CI = 1.41-8.93, P = 0.007; C vs. T, OR = 1.73, 95% CI = 1.13-2.67, P = 0.012). With respect to hsa-miR-499 rs3746444 T/C, no significant difference in allele and genotype frequencies of the rs3746444 variant between ALL patients and controls was observed. Our results for the first time demonstrated that the miR-146a rs2910164, but not miR-499 rs3746444 variant, was associated with increased risk for developing pediatrics ALL in an Iranian population.

Intracranial hemorrhage pattern in the patients with factor XIII deficiency.

Intracranial hemorrhage (ICH) is one of the most severe and life-threatening manifestations occurring in the patients with factor XIII (F XIII) deficiency. The aim of this study was to describe the ICH pattern in the patients suffering from F XIII deficiency. In this case series, we investigated 38 patients with severe F XIII deficiency in south of Iran from January to May 2012. ICH pattern, neurologic complications, efficacy of treatment, and incidence of recurrence were reported. The site of ICH was intraparenchymal in 35 patients (92.1 %), subdural in 2 patients (5.2 %), and epidural hemorrhage in 1 patient (2.6 %). Besides, neurologic complications occurred in 21 patients (55.2 %), including locomotor disability in 8, psychological impairment in 7, mental disorders in 5, speech impairment in 4, and visual impairment in 2. Prophylaxis was started with a dose of 10 IU/kg Fibrogammin every 4-6 weeks for all the patients, except for one. All the patients on prophylaxis showed good response without any episodes of recurrence, except for one. The most frequent site of ICH in our patients was intraparenchymal. It seems that long-term prophylactic treatment with a dose of 10 IU/kg Fibrogammin could be effective in the prevention of CNS bleeding in the patients with F XIII deficiency. Moreover, all the patients with severe F XIII deficiency even without severe bleeding symptoms are recommended to undergo prophylactic treatment.

A prospective study of tubular dysfunction in pediatric patients with Beta thalassemia major receiving deferasirox.

BACKGROUND: Beta thalassemia major is a lifelong transfusion-dependent disorder. Transfusion-dependent thalassemia patients are prone to develop renal dysfunction due to iron overload, chronic anemia, and/or chelation therapy. METHODS: In this prospective study, thalassemia patients who fitted inclusion and exclusion criteria received Deferasirox 20 mg/kg/day. A complete biochemistry analysis of serum and 24-hour-urine specimens was performed before and after treatment. Estimated glomerular filtration rate (eGFR), Fractional excretion of sodium (FENA), potassium (FEK), uric acid (FEUA), and the maximum ratio of tubular reabsorption of phosphorus to eGFR (TmP/GFR) at baseline and after treatment was calculated and compared. RESULTS: A total of 30 patients with mean age of 4.9 ± 3.2 years were recruited. The mean serum creatinine increased significantly after 6 months of treatment (0.54 ± 0.08 vs. 0.67 ± 0.16, P < .001) while eGFR was decreased (104.36 ± 19.62 vs. 86.00 ± 16.92, P < .001). Mean potassium level in serum was increased after treatment, while serum calcium, magnesium, and uric acid levels decreased significantly (P > .05). A significant increase was confirmed for mean urinary ß2-microglobulin (ß2-MG), protein, uric acid, calcium, and magnesium (P > .05). CONCLUSION: Our findings highlighted tubular nephropathy induced by Deferasirox in patients with beta thalassemia, and confirmed the necessity for diligent monitoring of renal function in thalassemia patients receiving Deferasirox.

A de novo TINF2, R282C Mutation in a Case of Dyskeratosis Congenital Founded by Next-Generation Sequencing.

Background: Dyskeratosis congenita (DC), an inherited and rare disease prevalent in males, is clinically manifested by reticulate hyperpigmentation, nail dystrophy, and leukoplakia. DC is associated with the increased risk of malignancy and other potentially lethal complications such as bone marrow failure, as well as lung and liver diseases. Mutations in 19 genes were found to be correlated with DC. Herein, we report a 12-year-old boy carrying a de novo mutation in TINF2 gene. Methods: Whole exome sequencing (WES) was performed on DNA sample of the proband, and the variant was investigated in the family by Sanger sequencing. Population and bioinformatics analysis were performed. Results: The NM_ 001099274.3(TINF2): c.844C>T (p.Arg282Cys) mutation was found by WES. Conclusion: There was no history of the disease in the family, and the variant was classified as a de novo mutation.