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Background: Lymphoproliferative disorders include a heterogeneous list of conditions that commonly involve dysregulation of lymphocyte proliferation resulting in lymphadenopathy and bone marrow infiltration. These disorders have various presentations, most notably autoimmune manifestations, organomegaly, lymphadenopathy, dysgammaglobulinemia, and increased risk of chronic infections. Case Presentation: A young boy presented with symptoms overlapping different lymphoproliferative disorders, including episodes of chronic respiratory tract infections, dysgammaglobulinemia, lymphadenopathy-associated with splenomegaly as well as skin rashes. Genetic studies revealed multiple heterozygous variants, including a novel mutation in the NFκB1 gene. Conclusion: This novel mutation can reveal new aspects in the pathogenesis of lymphoproliferative disorders and propose new treatments for them.

Cernunnos deficiency is a rare radiosensitive form of severe combined immunodeficiency (SCID). Herein, we report a patient with recurrent infections, birdlike face, microcephaly, Failure to thrive (FTT), and hypogammaglobinemia accompanied by considerable and rare features of sensorineural hearing loss and hypothyroidism with a mutation in splicing site of the third intron of non-homologous end joining 1 (NHEJ1) gene. The mutation was associated with T-B-NK + in flowcytometry. Distinct clinical manifestation along with a rarely reported genetic site mutation was noticeable in the reported case. The clinicians should be sensitive enough to suspect SCID in any patient with recurrent infections, microcephaly, FTT, and hypogammaglobinemia. Also, it is highlightable that every case of SCID with microcephaly should prompt us to the SCIDs with genetic mutations sensitive to radiation and further investigations are mandatory in highly suspicious patients.

Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430GA, c.962TC [p.Leu321Pro], c.281CA [p.Ser94*]), GALNS (c.319GA [p.Ala107Thr], c.860CT [p.Ser287Leu], c.1042AG [p.Thr348Ala]), and IDUA (c.1AC [p.Met1Leu], c.1598CG [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants.

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD., Alborz University of Medical Sciences, This work was supported by the vice chancellor for research, Alborz University of Medical Sciences.

LPS-responsive beige-like anchor protein (LRBA) deficiency is a monogenic primary immunodeficiency characterized by a heterogeneous spectrum of clinical manifestations associated with immune dysregulation. In this study, we reported clinical, immunologic, and genetic evaluation of two Iranian patients from unrelated families, both suffering from recurrent respiratory tract infections, failure to thrive, interstitial lung disease, autoimmune cytopenia, and hypogammaglobulinemia. Pulmonary abscess in one patient and persistent enteropathy in another were also observed. Further investigations revealed causative mutations in the exon (c.2166_2766del) and intron (c.4730–3 T > G) of the LRBA gene. These results may provide further elucidation of the clinical phenotypes and responsible genetic factors of LRBA deficiency.

The hyper-immunoglobulin M (HIGM) syndrome comprises a group of rare inherited immunodeficiency disorders characterized by normal or elevated levels of serum IgM with low or absent levels of serum IgG, IgA, and IgE. Patients with this syndrome usually present with a history of recurrent infections or opportunistic infections. Here, we report two male cousins from homozygote twin mothers. The first cousin presented with no signs or symptoms other than neutropenia, which was accidentally found in a routine blood test. Immunological workup in this patient showed undetectable IgG and IgA levels and normal IgM levels. The second cousin had a history of recurrent infections, and at the time of admission, he was diagnosed with Pneumocystis jirovecii infection. The immunologic workup of this patient showed undetectable IgG, decreased IgA, and increased IgM level. Due to their interesting family relationship, genetic analysis was performed, which detected a novel mutation in exon 2 (c.266 del G) of the CD40 ligand gene (CD40LG).

Usage of cancer chemotherapeutics drugs can be associated with adverse drug reactions. When IgE-mediated drug reactions are formed following administration of a chemotherapeutics drug that is a drug of choice, drug desensitization protocols can be helpful. HSR can be allergic or nonallergic, but the clinical manifestations are similar. RDD is effective when used appropriately, however it is often over utilized instead of performing a drug challenge. RDD is both an acceptable approach and a high-risk treatment modality in patients, in whom the offending agent is the first choice in chemotherapy. The safety of this modality has been acceptable in large studies. The side effects are often less frequent and less severe by repeating the protocol. We present 4 cases of successful desensitization in cancer patients, who have developed IgE- mediated reactions to their major chemotherapy drug.

DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) is a potentially life-threatening syndrome, which reflects a serious hypersensitivity reaction to drugs, presenting by generalized skin rash, fever, eosinophilia, atypical lymphocytosis, and internal organ involvement. Herein a 21-month old male infant with DRESS and Encephalopathy syndrome is presented who complicated after phenobarbital usage that persisted due to phenytoin cream usage. The case received phenobarbital after a seizure disorder presented as "status epilepticus". He developed drug eruption, fever, hepatosplenomegaly, increased liver enzymes, encephalopathy and progressive loss of consciousness with extensive hyperintense white matter lesions in brain MRI. After discontinuation of phenobarbital and phenytoin, all symptoms were resolved, while brain MRI became normal after two months. To our best knowledge, this is the first reported case that developed leukoencephalopathy along with DRESS syndrome.

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by fever, hepatosplenomegaly, and cytopenia, and widespread accumulation of lymphocytes and histiocytes, sometimes with hemophagocytosis, primarily involving the spleen, lymph nodes, bone marrow, and liver. HLH can either occur sporadically (secondary HLH) or as part of a familial syndrome (primary HLH), including familial HLH and the distinct immunodeficiency syndromes. Herein the authors report 6 Iranian patients with primary HLH and their outcome from a single tertiary-care center.

Studies of renal involvement in thalassemia syndromes have been varied and few. The most important cause of mortality and morbidity in these patients is organ failure due to iron deposition. We report here a cross-sectional study carried out between February 2005 and February 2006 on all beta-thalassemia major patients being treated in Mofid Children's hospital, Tehran. The aim of the study was to detect renal dysfunction in these patients. The patient cohort consisted of 103 patients with various disease severities. Fresh first morning urine samples were collected and analyzed for sodium (Na), potassium (K), calcium (Ca), creatinine (Cr), phosphate, uric acid (UA), N-acetyl beta-D-glucosaminidase (NAG) and amino acids. We also carried out a complete blood count evaluation and assayed fasting blood sugar and serum ferritin, sodium, potassium, creatinine, uric acid and amino acids in all patients. The mean age of our patient cohort was 12.5+/-5.53 years and 53.4% were female. Abnormal levels of urinary NAG were detected in 35.9% of patients (confidence interval 26-45%). Abnormal levels of fractional excretion (FE)-Na, FE-K and FE-UA and abnormal urine protein Pr/Cr and urine Ca/Cr ratios were present in 29.1, 7.8, 52.4, 0.3 and 22.3% of the patients, respectively. There was a significant relationship between urinary NAG and the age of the patient (R=0.35), duration of deferoxamine therapy (R= 0.31), duration of receiving blood transfusions (R=0.34) and level of fasting blood sugar (R=0.2). We concluded that renal disorders are not rare in patients with beta-thalassemia major and that they may increase in terms of frequency with age, increased duration of transfusion and deferoxamine usage and high levels of blood sugar.

This study evaluated the incidence of sensory neural hearing loss (SNHL) in beta-thalassemia major patients treated with deferoxamine in Mofid Children's Hospital. Based on the patients' file review, this descriptive and cross-sectional study was performed in all thalassemia patients older than 5 years old who were treated with regular blood transfusion and deferoxamine pump injection during the year 2006. The first visit with the otolaryngologist was performed in all patients to demarcate the presence of cerumen, otitis, and congenital abnormalities of ears. Then pure tone audiometery in frequency ranges of 250-8000 Hz was performed. Data statistical analysis was done by Mann-Whitney, chi square, and Fisher tests. There were 67 patients over 5 years old in our study. Five patients (7.4%), including 2 boys and 3 girls, in the age range of 7-24 years (mean:17.8 +/- 6.6 years) had SNHL. Their hearing loss was bilateral and in the frequency range of 2000-4000 Hz, with a mean of 3200 +/- 836.66 Hz. There were no significant differences between SNHL and non-SNHL patients in age, sex, serum ferritin level, age of the first transfusion, starting age of deferoxamine infusion, or duration and dosage of deferoxamine therapy. It seems that SNHL is not directly related to the serum ferritin level or deferoxamine dosage and other factors, including genetic or constitutional characteristics, may be also related. On the other hand, this complication may occur with doses lower than 50 mg/kg/day of deferoxamine, so no dosage can be considered safe for this drug. Despite the results of this study, hearing evaluation of beta-thalassemia major patients by audiometry is recommended because of the importance of this complication and the consequent disabilities.

Here, we report on a ten-year-old girl with chronic draining nonhealing ulcer in her neck and unilateral cervical chronic lymphadenopathy. Her ulcer had poor clinical response to broad spectrum antibiotics and anti-tuberculosis treatment. She had undergone several wound biopsies with no conclusive results. She was otherwise healthy with no known underlying disease. Final wound excisional biopsy with specific immunohistochemistry (IHC) staining confirmed her diagnosis. Histopathology report and IHC were compatible, indicating an anaplastic large cell lymphoma.

Avascular necrosis of the femoral head is usually seen in children aged 1.5 to 10 years, reaching a peak incidence between the ages of 4 and 9. Avascular necrosis of the femoral head is a known complication of corticosteroid therapy in acute lymphoblastic leukemia. There are few reports in the literature regarding the natural history of this condition, and there is no consensus on its management. This study examined the natural history of avascular necrosis of the femoral head in children with leukemia. From 1993 to 2006, a total of 865 children with acute lymphoblastic leukemia were admitted to the hematology-oncology ward of a children’s hospital. The diagnosis of acute lymphoblastic leukemia was established by bone marrow aspiration. Based on clinical and radiographic findings, avascular necrosis of the femoral head was found in 7 patients; these patients underwent follow-up for 4 to 9 years. Avascular necrosis of the femoral head was clinically symptomatic in all of the children, and they had advanced radiographic collapse of the femoral head. However, the head of the femur was not at risk in any patient based on clinical and radiographic findings. Patients received supportive treatment such as abduction brace and physiotherapy. After 4 to 9 years of follow-up, clinical and radiographic results were satisfactory. Provided that the head of the femur is not at risk, avascular necrosis of the femoral head in children with acute lymphoblastic leukemia may be successfully managed with nonoperative care.

Purpose This study aimed to evaluate iron levels in cardiac and hepatic tissues using magnetic resonance imaging (MRI) T2⁎. Methods Cardiac and hepatic MRI was performed for 93 patients with β-thalassemia major. Results Cardiac T2⁎ was in the range of 2.9–56.6 ms. Myocardial siderosis was detected in 44% of patients; 25 patients had moderate and severe siderosis with serum ferritin level (SFL) of 576–10,284 ng/ml. There was a significant correlation between SFL and cardiac T2⁎ ( p Conclusions The effective role of MRI as a noninvasive producible method in measurement of iron concentration in tissues is not accessible with conventional techniques.

Childhood histiocytosis is a rare and diverse group of proliferative disorders, characterized by accumulation and infiltration of antigen-presenting cells or antigen-processing cells, which can affect any tissue or organ. This study was performed in order to investigate the clinical characteristics of Iranian children with different types of histiocytic disorders. Thirty-five patients, with a median age of 3.5 years, who were referred and diagnosed with histiocytic disorders in a referral Children's Hospital in Iran from 1997-2006, were investigated in this study. According to the World Health Organization classification, 27 patients were in class 1, followed by 6 patients in class 2, and 1 patient in class 3. Moreover, 1 patient was diagnosed with sinus histiocytosis with massive lymphadenopathy. Bone lesions were the most common manifestation, which were detected in 15 cases, followed by skin lesions (11 cases) and fever (10 cases). Nonspecific findings like hepatomegaly and splenomegaly were found in 15 cases. Different types of treatment protocols were used according to the diverse groups of histiocytic disorders and different stages of disease, including surgical excision, radiotherapy, chemotherapy, and stem cell transplantation. Twelve patients did not respond well to the treatment and subsequently died due to complications of their disease. Although histiocytosis is considered a rare condition, it can be problematic for pediatric hematologists because of the unknown etiologies and pathogenesis, variable classifications and subtypes, diagnostic difficulties, poor therapeutic responses with high mortality, and some complications after different therapeutic protocols.

Background Although a marked proportion of thalassemic patients acquire Torque teno virus (TTV) through blood transfusion, its clinical importance is unclear. This study was designed to investigate the clinical importance of TTV infection in thalassemic patients with and without hepatitis C virus (HCV) co-infection in Iran. Methods In this case-control study, 107 thalassemic patients on chronic transfusion and 107 healthy individuals were selected. According to HCV and TTV infection status (detected by semi-nested PCR), patients were categorized into 4 groups: TTV and HCV negative, TTV positive, HCV positive, and TTV and HCV positive. Blood ferritin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels in these 4 groups were assessed. Results Approximately half of the thalassemic patients (50.5%) and 27.1% of controls had TTV infection. Thalassemic patients had a greater chance of TTV infection compared to the control group with a sex-adjusted OR of 4.13 (95% CI=2.28-8.13). The increased levels of ALT, AST, and ferritin in the TTV and HCV-infected group were not significantly different from those in the TTV and HCV negative group. Co-infection with TTV and HCV did not significantly increase ALT, AST, and ferritin levels compared to infection with TTV alone. Conclusion Although common in thalassemic patients, TTV infection appears to have a negligible role in increasing the severity of liver disease, even when co-infection with HCV occurs.

Histological typing, especially the evidence of anaplasia and stage of the tumor are two major prognostic indicators in Wilms tumor, but some genetic factors have recently been noted. Mutations in TP53, which is a tumor suppressor gene, have been demonstrated to be associated with poor prognosis in some malignancies. There are also few studies which have confirmed the correlation between p53 protein overexpression and advanced course in Wilms tumor. This study was conducted to determine the correlation p53 immunoexpression and prognosis and outcome of Wilms tumor.The overexpression of p53 in 44 specimens of children (26 boys and 18 girls) with Wilms tumor (median age, 36 months; range, 4 to 96 months) was assessed in Mofid Children's Hospital, Tehran, Iran. The overexpression of p53 was determined by immunohistochemistry with antihuman p53 antibody.A positive immunostaining for p53 was detected in 24 of the 44 cases (54.7%). The grade of the tumor and anaplasia were associated with p53 positivity, but there was no association of p53 with the tumor stage. In comparison to p53 negatives, week-moderate and high p53-expressing tumors had significantly decreased the overall survival (hazard ratio, 3.75 and 8.61; P = .05 and P = .01, respectively).Overexpression of p53 protein in Wilms tumor is an indicator of poor pro gnosis, because it is correlated with unfavorable histology tumors and a shorter survival period.

Congenital atransferrinemia or hypotransferrinemia is a very rare autosomal recessive disorder, characterized by a deficiency of transferrin, resulting in hypochromic, microcytic anemia and hemosiderosis. The authors describe a 10-year-old Iranian girl with hypochromic microcytic anemia. The age presentation of anemia was 3 months. Further evaluations indicate severe hypochromic microcytic anemia with decreased serum levels of iron, TIBC, and increased serum level of ferritin in this patient. The serum level of transferrin was decreased. The diagnosis of atransferrinemia was confirmed. Although atransferrinemia is a rare condition, it should be considered in the cases with hypochromic microcytic anemia, decreased serum levels of iron, TIBC, and increased serum level of ferritin.

For many years, subcutaneous therapeutic port system was known as a major route to access central veins. However, significant complications have been reported through recent years. One of the most important complications of subcutaneous port implantation is skin necrosis. In order to decrease this complication, we would like to introduce subpectoral fascia port implantation through this study.Five hundred and twenty four patients with a variety of neoplastic diseases underwent port implantation, from March 2003 to March 2008 (60 months). All suitable size catheters were put in the superior vena cava through the internal jugular vein under general anesthesia. The ports were placed in the subcutaneous pocket (SCP group) in 342 patients and in the subpectoral fascia pocket (SPFP group) in 182 patients. Data were analyzed using Chi-square test and survival analysis for time (Kaplan-Meier).A total of 538 devices were placed for 524 patients in two groups (14 patients received a second device after removal of the first one, due to failure of the first implantation). Mean follow-up period was 508 days (8 - 2025 days).Common complications observed in the SPFP group were as follows: wound infection (7 cases, 3.8%), catheter obstruction (7 cases, 3.8%), catheter displacement (6 cases, 3.2%), port related infection (5 cases, 2.7%), and pocket hematoma (2 cases, 1.1%).Common complications observed in the SCP group were as follows: catheter displacement (12 cases, 3.5%), skin necrosis (11 cases, 3.21%), port exposure (9 cases, 2.6%), port related infection (8 cases, 2.3%), catheter obstruction (8 cases, 2.3%), and port rotation (3 cases, 0.9%).The results showed that port implantation in the subpectoral fascia pocket had a lower rate of skin complications than the subcutaneous pocket implantation. According to this study, this procedure was not complicated by skin necrosis over the port, port exposure or port rotation.

Hemophagocytic lymphohistiocytosis (HLH) is a severe life-threatening disorder, characterized by hyperactivation of macrophages. A 12-year-old female was referred to our center; the diagnosis of HLH was made for the patient and immunosuppressive regimen was started. After a 2-year follow-up, the patient developed secondary T-cell acute lymphoblastic leukemia (T-ALL), confirmed by flow cytometric studies. Treatment was started based on T-ALL protocol, but the patient died because of relapse and sepsis. This case highlights the issue of secondary malignancy following HLH and demonstrates the need for continued follow-up in such patients.