The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS).

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently defined combined primary immunodeficiency disease (PID) characterized by recurrent respiratory tract infections, lymphoproliferation, autoimmunity and lymphoma. Gain-of-function mutations in PIK3CD and loss-of-function of PIK3R1 genes lead to APDS1 and APDS2, respectively. METHODS: Demographic, clinical, immunological and genetic data were collected from medical records of 15 pediatric patients, who were genetically identified using the whole-exome sequencing method. RESULTS: Fifteen patients (6 APDS1 and 9 APDS2) were enrolled in this study. Recurrent respiratory tract infections followed by lymphoproliferation and autoimmunity were the most common manifestations (86.7%, 53.3% and 26.7%, respectively). Five patients (33.3%) had a Hyper-IgM-syndrome-like immunoglobulin profile. In the APDS1 group, splice site and missense mutations were found in half of the patients and the C-lobe domain of PIK3CD was the most affected region (50%). In the APDS2 group, splice site mutation was the most frequent mutation (77.8%) and the inter-SH2 domain was the most affected region of PIK3R1 (66.7%). Mortality rate was significantly higher in APDS2 group (P = .02) mainly due to chronic lung infections. CONCLUSION: Respiratory tract infections and humoral immunodeficiency are commonly the most important complication in pediatric APDS patients, and they can be fatal by ultimately causing catastrophic damage to the structure of lungs. Hence, physicians should be aware of its significance and further work-up of patients with recurrent respiratory tract infections especially in patients with lymphoproliferation. Moreover, delineation of genotype-phenotype associations with disease severity could be helpful in the timely application of appropriate management and patients' survival.

Identifying Novel Mutations in Iranian Patients with LPS-responsive Beige-like Anchor Protein (LRBA) Deficiency.

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.

Hereditary Spherocytosis Unmasked by Human Parvovirus B19 Induced Aplastic Crisis in a Family.

Human parvovirus (HPV) B19 induced aplastic crisis in a family leading to the diagnosis of hereditary spherocytosis (HS) is a very rare condition being barely reported in the literature. We herein report a 4-year-old girl, her brother, and their mother who all presented with progressive pallor and jaundice after a febrile illness. The HPV B19 was diagnosed using polymerase chain reaction (PCR) and positive serology for specific anti-HPV B19 IgM. They were further diagnosed with having HS. The clinical importance of this report is that in the case of an abrupt onset of unexplained severe anemia and jaundice, one should consider underlying hemolytic anemias mostly hereditary spherocytosis complicated by HPV B19 aplastic crisis. Herein, we report the occurrence of this condition, simultaneously in three members of a family. The distinguished feature of this report is that all affected family members developed some degrees of transient pancytopenia, not only anemia, all simultaneously in the course of their disease.

Efficacy and safety of deferasirox in ß-thalassemia major patients in Iran: a prospective study from a single referral center in Iran.

INTRODUCTION: Herein, the results of a prospective study evaluating the efficacy and safety of treatment with deferasirox are studied in iron-overloaded patients with ß-thalassemia major during an 18-month trial. METHODS: Thirty patients who were previously chelated with deferoxamine with/without deferiprone, and fulfilled the inclusion criteria were recruited. Patients received an initial dose of 10-30 mg/kg/day. Liver and cardiac MRI T2* were evaluated before and after the trial. In addition, serum ferritin level was assessed every 3 months. Primary endpoint was regarded as significant improvement in the severity of liver and cardiac iron overload in severe and moderate cases, in addition to improvement or maintenance of the grade of severity in patients with mild iron overload or normal iron accumulation. Therapy was considered effective if primary endpoint was met in >50%. RESULTS: Liver MRI values improved significantly (P = .002), achieving a 73.33% success rate. A successful outcome regarding myocardial iron overload was observed in 80%. Finally, an overall of 66.66% of patients met the success criteria. Secondary endpoint, regarded as safety and tolerability was reached by 93.33%. The most common adverse events were skin rash and gastrointestinal disturbance. A dose between 30 and 40 mg/kg/day, tailored to each patient was considered the optimal dose. CONCLUSION: Deferasirox proved as an efficient and safe chelating agent in our patients, specifically in mild to moderate iron overloaded patients.

Primary hemophagocytic lymphohistiocytosis in Iran: report from a single referral center.

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.

Torque teno virus and hepatitis C virus co-infection in Iranian pediatric thalassemia patients.

OBJECTIVE: Torque teno virus (TTV) infects patients at risk for parenteral exposure and chronic blood transfusion, such as those with ß-thalassemic. This study aimed to assess the prevalence of TTV infection and co-infection of TTV and hepatitis C virus (HCV) in pediatric thalassemia patients receiving chronic blood transfusion. MATERIAL AND METHODS: The study included 90 pediatric thalassemia patients receiving chronic blood transfusion that presented to the Mofid Children's Hospital, Tehran, Iran. The control group included 90 healthy volunteer children. Serum TTV DNA detection via semi-nested PCR and HCV Ab were performed in all the participants. Demographic characteristics and clinical data were collected from each participant for statistical analysis. RESULTS: In all, 64.4% of the patients had TTV infection, versus 24.4% of the controls (P < 0.01). The thalassemia patients had a greater probability of having TTV and HCV infections than the controls, with a common OR of 5.60 (95% CI: 2.94-10.69) and 2.15 (95% CI: 1.83-2.50), respectively. In total, 17.2% (10/58) of the patients that were TTV positive were also HCV positive, whereas 6.3% (2/32) of the TTV-negative patients were anti-HCV antibody (Ab) positive (P = 0.14). CONCLUSION: The prevalence of TTV and HCV infection was higher in the Iranian thalassemia patients on chronic transfusion therapy than in the controls. The high prevalence of TTV in pediatric thalassemia patients on chromic transfusion therapy may indicate the superiority of the parenteral route compared to other routs of TTV transmission.

A 10-year single center survey of pediatric patients with histiocytic disorders in Iran.

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.

Development of secondary T-cell acute lymphoblastic leukemia in a child with hemophagocytic lymphohistiocytosis.

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.

Humoral immunity against hepatitis B, tetanus, and diphtheria following chemotherapy for hematologic malignancies: a report and review of literature.

Malignancy and its treatment are major causes of secondary immunodeficiency in childhood. The authors investigated the effects of chemotherapy on humoral immunity against hepatitis B, tetanus, and diphtheria in children with hematologic malignancies. The authors recruited 54 patients with hematologic malignancies after the completion of chemotherapy (group A), 25 patients with newly diagnosed hematologic malignancies before initiation of chemotherapy (group B), and 74 healthy controls (group C). All participants had been vaccinated against hepatitis B, tetanus, and diphtheria according to the Iranian national vaccination scheme. Patients in group A achieved protective levels of diphtheria and hepatitis B antibodies significantly less frequently than the other 2 groups and protective levels of tetanus antibody significantly less frequently than group C (P <.05). After controlling for age, the association observed for tetanus lost its significance, but chemotherapy was a significant and independent predictor of failure to achieve protective levels of antibodies against diphtheria (odds ratio [OR] = 7.7, P < .001) and hepatitis B (OR = 3.13, P = .008). These results indicate that chemotherapy has independent adverse effects on vaccine-induced antibody protection against diphtheria and hepatitis B.

Severe hypochromic microcytic anemia in a patient with congenital atransferrinemia.

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.

Nail involvement in langerhans cell histiocytosis.

Nail involvement, which is distinctly uncommon in Langerhans cell histiocytosis (LCH), is characterized by various features like longitudinal grooving, purpuric striae, hyperkeratosis, subungual pustules, deformity, loss of nail plate, paronychia, onycholysis, and pitting. Here the authors report the case of a child who presented with isolated nail unit changes due to Langerhans cell histiocytosis before the evolution of systemic features. The authors suggest that LCH should be considered in differential diagnoses of nail changes that are resistant to therapy.

Rhabdoid tumor of the kidney presenting with hemiplegia: report of a case.

Rhabdoid tumor of the kidney (RTK) is a rare and highly malignant neoplasm of infancy, with a strong tendency for early metastasis to distant regions. RTK is unique in its significant association with primary or metastatic brain tumors. The authors report the first case of RTK presenting initially with hemiplegia. The patient was found thereafter to have RTK concurrent with pulmonary metastases, a brain tumor, and a cerebral ischemic lesion. Intensive chemotherapy consisting of carboplatin and etoposide alternating with cyclophosphamide was unsuccessful and the patient died 5 months later because of severe respiratory distress resulting from widespread pulmonary metastases.

Tumor lysis syndrome in children with non-Hodgkin lymphoma.

This study was designed to evaluate the incidence of tumor lysis syndrome (TLS) among children with non-Hodgkin lymphoma and to define whether renal involvement can be associated with higher incidence of TLS after chemotherapy. Medical charts of 59 patients were reviewed. TLS was diagnosed using laboratory and clinical criteria. Renal involvement was diagnosed based on ultrasound and CT scan findings. Laboratory TLS occurred in 7 patients (11.85%) and clinical TLS was observed in 7 patients (11.85%) as well. In 5 out of 14 TLS patients, hemodialysis was required to correct electrolyte abnormalities and TLS related death was reported overall in 3 patients. Sex, age, pretreatment LDH, and initial WBC count were not associated with higher incidence of TLS after chemotherapy, but a significant correlation was found between pretreatment renal involvement at imaging studies and development of TLS after chemotherapy (p = .027). The results indicate that despite all preventive measures, tumor lysis syndrome still occurs in children with non-Hodgkin lymphoma following chemotherapy. Patients who have evidence of renal involvement at imaging studies are more likely to develop TLS after chemotherapy.

Generalized myelolipoma.

Myelolipoma is a benign tumor originating from hematopoietic and adipose tissue. This tumor usually develops in the adrenal gland, but rare presentations of extraadrenal myelolipoma are also reported, which usually arise from the presacral region. Herein, we present a 6-year-old girl with myelolipoma with generalized involvement of her abdomen, pelvis, chest, and retroorbital region.

Inherited Thrombocytopenia with a Different Type of Gene Mutation: A Brief Literature Review and Two Case Studies.

Hereditary thrombocytopenias are rare bleeding disorders, which cause a deficiency of platelets in early infancy. This group of disorders is sometimes associated with abnormal phenotypes, like absence of radius. Diagnosis of this type of thrombocytopenia is usually difficult; other causes of thrombocytopenia, such as immune disorders and infections, must be ruled out. The symptoms of hereditary thrombocytopenia also vary from seldom and mild to severe bleeding and occasionally may first occur in late childhood. In this group of patients, we must differentiate heritable disorders from the acquired types of thrombocytopenia, like immune thrombocytopenic purpura. It is also important to watch for pitfalls to avoid unnecessary and potentially hazardous treatment. Herein, we briefly review the recent literature on hereditary thrombocytopenia and then present the cases of two referred patients. The first case had suffered from persistent thrombocytopenia since early infancy and was diagnosed with congenital amegakaryocytic thrombocytopenia, while the other patient presented with Wiskott - Aldrich syndrome.

Secondary ALL after Successful Treatment of Ewing's Sarcoma: A Case Report.

Treatment with intensification of chemotherapy using alkylating agents and Topoisomerase II inhibitors and radiotherapy has improved the outcome of patients with solid tumors such as Ewing's sarcoma. However, there are several reports of secondary malignancy following treatment of these tumors. In this article, we describe a 12 years old girl with ALL who had Ewing's sarcoma when she was 8 years old and underwent successful treatment but after two and half years at 12 years old, she came back with pallor and muscular pain.

Primary Ewing's Sarcoma of the temporal bone in an infant.

Introduction : Ewing's sarcoma is the second most common primary malignant tumor of bone found in children after Osteosarcoma. It accounts for 4-9% of primary malignant bone tumors and it affects bones of the skull or face in only 1-4% of cases. Hence it rarely affects the head and neck. Subject and Method : In this case report, we describe a case of primary Ewing's sarcoma occurring in the temporal bone. The tumor was surgically excised, and the patient underwent chemotherapy for ten months. Results : Neither recurrence nor distant metastasis was noted in these 10 months after surgery but about 18 months after surgery our patient was expired. Conclusion : Although the prognosis of Ewing's sarcoma is generally poor because of early metastasis to the lungs and to other bones, a review of the article suggested that Ewing's sarcoma occurring in the skull can often be successfully managed by intensive therapy with radical excision and chemotherapy. This result was supported by the case reported here.

Multifocal kaposiform hemangioendothelioma of soft tissue with bilateral pulmonary involvement in an adolescent.

Kaposiform hemangioendothelioma (KHE) is a rare, locally aggressive vascular tumor of intermediate malignancy with resemblance to Kaposi sarcoma. It occurs predominantly in pediatric age groups as a cutaneous lesion with focal infiltration into the adjacent soft tissue and bone. Although visceral involvement is very uncommon, several cases with bone, retroperitoneal, or mediastinal involvement have been described. KHE has been reported to occasionally occur in unusual sites such as the thymus, tonsils, larynx, paranasal sinuses, deltoid muscle, spleen, uterine cervix, thoracic spine, and even the breast. Multifocal KHE is an extremely rare entity with few reports available in the literature, none of which describes pulmonary involvement. Herein, we report a unique case of multifocal KHE in a 13-year-old boy presenting with a huge soft tissue mass in the upper extremity complicated by bilateral pulmonary nodules that developed into large, necrotic tumor masses.

Primary intrarenal neuroblastoma with hypertension and disseminated intravascular coagulation.

The primary intrarenal neuroblastoma (IRNB) is a rare condition. Intrarenal neuroblastoma typically results from direct renal invasion from an adrenal neuroblastoma, but true intrarenal neuroblastoma originates either sequestered adrenal rests during the fetal life or intrarenal sympathetic ganglia. Clinical, radiological, and pathological correlation is very essential for diagnosis and appropriate management of this type of unusual cases. The distinction of this rare tumor from Wilms' tumor is an important challenge since both tumors have major differences in prognostic and therapeutic response. We present a 3-year-old boy of primary intrarenal neuroblastoma with extensive abdominal and mediastinal mass, persistent hypertension, and disseminated intravascular coagulation (DIC).