Introducing a new histologic scoring system for iron deposition in liver of thalassemic patients, compared with atomic absorption spectrometry.

Iron deposition in liver is a major finding in thalassemic patients and because of direct iron toxicity to liver it is associated with several consequences for example liver fibrosis. Liver biopsies from 63 patients were evaluated, 40 (63.5%) were male and 20 (36.5%) were female. The mean age of the patients was 8.01 ± 3.7 and the age range was from 1.8 to 15 years. Histologic grading and staging was performed for each case according to modified HAI (Hepatitis Activity Index) system. Iron scoring was performed according to Sindram & Marx and MTK1-3 scoring systems. The mean (SD) dry weight (dw) of liver specimens was 1.34 (0.11) mg (range 0.20 to 3.80 mg). The mean (SD) of hepatic iron concentration was 230.9 (121.2)µmol/g dry weight. The relationship between the variables HIC, HII (hepatic iron index) and all histological gradings of iron (S&M and MTK1-3) was very strong. The relationship between the HIC and staging by HAI method was good. Significant differences were identified between the mean HIC in scores 1&2 of all histological iron scorings (S&M and MTK1-3), but no significant differences identified between mean HIC in other adjacent scores in all histological iron scorings (S&M and MTK1, 2 and 3). New scoring system introduced by us in this study which considered size and density of iron granules as well as zone of iron deposition was very much the same as simple Sindram and Marx classification.

Spectrum of bone marrow failures of myeloid series: new report of neutropenic patients from a referral pediatric center in Iran.

Neutropenia is a reduction of the absolute neutrophil count (ANC), which could be seen in different conditions, while its association with a number of primary immunodeficiency diseases has been reported. This study was performed in all neutropenic patients who were admitted in a referral pediatric hospital during a 6-year period (2006-2011). One hundred and forty patients with ANC of below 1500/mm(3) were investigated in this study. The most common causes of neutropenia were severe congenital neutropenia (41%), aplastic anemia (19%), cyclic neutropenia (11%), hyperimmunoglobulin M syndrome (9%), and fanconi anemia (7%). The patients experienced their first manifestation at a median age of 1 year, while the median diagnostic age was 21 months. Parental consanguinity was present in about half of the cases. The most common clinical manifestations of the patients were sinusitis (62 cases), periodontitis (51 cases), acute diarrhea (39 cases), pneumonia (38 cases), abscess (36 cases), skin rashes (35 cases), and otitis media (31 cases). Twenty two patients (16%) died during the study period. Considering the differential diagnosis of neutropenia, making the diagnosis and appropriate treatments are the keys in management of patients with neutropenia to avoid further complications.

Prevalence of ETV6/RUNX1 Fusion Gene in Pediatric Patients with Acute Lymphoblastic Leukemia in Iran.

OBJECTIVE: ETV6/RUNX1 (also known as TEL/AML1) is the most frequent gene fusion in childhood acute lymphoblastic leukemia (ALL). Sixty-three patients were enrolled in this study to explore the distribution of this gene in Iranian population. METHODS: This study used 63 peripheral blood and bone marrow (PB/BM) samples from children with ALL. Immunophenotyping of PB and BM samples were performed using flow cytometry to illustrate the lineage. Moreover, reverse transcriptase polymerase chain reaction (RT-PCR) technique was used to amplify transcripts of leukemia-specific chromosome fusion gene ETV6/RUNX1 and to monitor the expression levels of the ETV6/RUNX1 in patients according to Van Dongen et al protocol. FINDINGS: On the basis of French-American-British (FAB) classification, 47 individuals had ALL-L1. The incidence of ETV6/RUNX1 fusion gene in this study was 34.9%. The laboratory and clinical features of twenty two ETV6/RUNX1 positive ALL cases were similar to those of other studies. The most positive cases of ETV6/RUNX1 fusion gene had the early pre B ALL and pre B ALL immunophenotypes. CONCLUSION: The ETV6/RUNX1 fusion gene is a common genetic anomaly in Iranian childhood ALL patients and the prevalence of the ETV6/RUNX1 fusion gene is similar to that of ALL patients in other countries. However early pre B cells were the most common type in studied patients.

Bone mineral density in adult patients with major thalassaemia: our experience and a brief review of the literature.

INTRODUCTION: Metabolic bone disease represents a major cause of morbidity in patients with thalassaemia major. The aim of our study was to assess the prevalence and underlying contributory factors of osteopenia/osteoporosis in a randomly selected population of adult patients with thalassaemia major. PATIENTS AND METHODS: The study population was selected using the random sampling method from the patients' database of our thalassaemia clinic. Only transfusion-dependent beta-thalassaemia patients aged over 17 and with no history of treatment with bisphosphonates were included. BMD of lumbar spine and right femoral neck were measured by means of the calibrated dual energy X-ray absorption method. Independent factors likely to be associated with low bone mass were determined and included in the analysis to ascertain possible associations. RESULTS: Our study included 40 patients (19 female and 21 male; mean age: 23.0 ± 4.1). The mean Z score of the right femoral neck was -1.2 (95% CI: -0.9 to -1.5) and for lumbar spine was -2.1 (95% CI: -1.7 to -2.5). The prevalences of osteopenia and osteoporosis involving the right femoral neck were 37.5%, and 12.5%, respectively. The respective prevalence rates for lumbar spine were 47.5% and 37.5%. Our study showed patient's weight, age, duration of the disease and history of hypogonadism or concurrent hypothyroidism are significant contributory factors or predictors of bone mineral loss. CONCLUSIONS: Regarding the high prevalence of osteopenia/osteoporosis in patients with thalassaemia major, all patients should be screened periodically for bone disease. The uncertainty and disagreements as to the possible role of different factors indicate the necessity for further studies in order to recognise the pathophysiologic fundamentals of this serious complication of thalassaemia major.

Monitoring of serum vancomycin concentrations in pediatric patients with normal renal function.

Vancomycin is a a glycopeptide antibiotic with bacetiocidal effects on gram positive bacteria by interfering with cell wall synthesis. The necessity for monitoring of serum vancomycin concentrations (SVCs) has been recently noticed at many institutions because of concerns for its nephrotoxicity. We aimed to describe the SVCs monitoring in pediatric patients, in an effort to determine subtherapeutic or toxic levels. The medical records were reviewed for all patients older than 60 days of age admitted to the general or subspecialty services who received intravenous vancomycin at Children's Medical Hospital in Tehran, Iran between July 2003 and December 2005. Because pharmacokinetic parameters for children with cancer may be different, this group was evaluated separately. During the study, 167 infants and children without cancer and 42 patients with cancer; aged between 3 months to 17.5 years were treated with vancomycin for various infections. In children without cancer, peak SVCs were in an adequate therapeutic range for 93% of patients (8-55 microg/ml). For children with cancer, peak SVCs was lower than 10 microg/ml (10%), and trough values were lower than 5 microg/ml (21%). In conclusion, according to the results of this research, due to different pharmacokinetics of vancomycin in cancerous patients, the monitoring of vancomycin plasma concentrations is necessary for the best therapeutic antibacterial activities with a fewer occurrence of serious adverse effects.

Pulmonary metastatic calcification in a leukemic patient: a case report.

Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children and accounts for 80% to 85% of cases. Hypercalcemia-associated pulmonary calcification has been observed in ALL, but overall it is a rare condition. Hereby, we wanted to report a case of pulmonary metastatic calcification in a 4-year-old girl with diagnosis of ALL in our center, who died 1 year after diagnosis of leukemia. Pulmonary infiltrates were seen 2 months after diagnosis of leukemia, which was proved to be the flecks of calcium in alveolar spaces after open-lung biopsy performed 4 months after diagnosis of ALL, but elevated serum calcium was detected late in the course of the disease (7 mo after lung biopsy), this late occurrence of hypercalcemia is not reported yet.

Augmentation of left atrial contractile function: a herald of iron overload in patients with beta thalassemia major.

Early detection of myocardial iron overload is crucial for optimal management of patients with beta thalassemia major, which could lead to intensification of iron chelating therapy. In this study, we evaluate the conventional echocardiography and tissue Doppler imaging measurements in patients with beta thalassemia major and further introduce the assessment of atrial ejection force as a feasible price-saving approach for early detection of myocardial iron overload. During a 1-year period, 42 cases of beta thalassemia major aged <21 years and with preserved systolic function were evaluated with magnetic resonance T2* imaging (MRI T2*), conventional echocardiography, and tissue Doppler imaging techniques. Patients were classified into two groups according to their myocardial MRI T2* values, with and without critical iron loading. All patients with echocardiographic evidence of moderate and severe stages of diastolic dysfunction showed critical iron loading in their MRI T2*. After excluding those patients with severe and moderate ventricular diastolic filling abnormality, the atrial ejection force index (P = 0.002) and a number of volume indexes of the left atrium showed a significant difference between the two groups. None of the tissue Doppler imaging measurements showed a statistically significant difference between the two groups. The atrial ejection force index of 7.41, with a sensitivity of 93% and a specificity of 74%, was suggested to detect critical cardiac iron loading. These results imply that combining the atrial ejection force index with the transmitral-derived echocardiographic assessment is a feasible way to detect early stages of myocardial iron overload in patients with beta thalassemia major.

Coincidence of Niemann-Pick Disease and beta-Thalassemia; a Case Report.

BACKGROUND: Niemann-Pick disease and ß-thalassemia are distinct conditions with specific clinical and morphological manifestations. ß-thalassemia is the most common inherited blood disorder in Iran whereas Niemann-Pick disease, a lysosomal storage disorder, is rarely found in this country. CASE PRESENTATION: This 5-month old girl, a known case of ß-thalassemia major was hospitalized for failure to thrive and hepathosplenomegaly. Because of unusual splenomegaly and liver enzymes disturbance that was not compatible with the first diagnosis, further evaluation revealed cherry red spot and high lipid profile suggestive of lysosomal storage disease. Foamy cells in the bone marrow and low activity of the specific enzyme led to the diagnosis of Niemann-Pick disease. CONCLUSION: This unique case illustrates the importance of looking for a second pathological condition in a patient whose clinical profile does not support the first diagnosis in its entirety.

Angiocentric nasal T-cell lymphoma in a patient withidiopathic CD4+ lymphocytopenia.

Idiopathic CD4+ Lymphocytopenia is a rare combined immunodeficiency disease, characterized by low CD4+ T-cell count and increased susceptibility to opportunistic infections, autoimmunity and malignancies after exclusion of secondary forms of CD4 lymphocytopenia. Here we present a 13-year old boy who was referred to our center because of destructive ulceration of soft and hard palates with extension to nose and maxillary sinus starting at 6 months of age. He had a history of recurrent otitis media, chronic diarrhea, arthritis and herpetic lesions of eyes and mouth since the age of 5 years. Laboratory studies revealed very low number of CD4+ T-cells (<100 cells/mm(3)). Secondary causes of CD4 lymphocytopenia, including HIV infection, were ruled out. Immunohistological studies of destructive lesions in oral and nasal cavity revealed angiocentric T-cell lymphoma. Unfortunately, the patient died in spite of treatment with a combination of irradiation and chemotherapy. This patient is the first reported case of lethal midline granuloma with origin T-cell lymphoma in idiopathic CD4+ lymphocytopenia.

Molecular basis of thalassemia intermedia in Iran.

Thalassemia intermedia shows considerable heterogenity in phenotype and molecular basis. The aim of this study was to evaluate the prevalence and effect of different beta-globin mutations, alpha-globin defects and (G)gamma XmnI polymorphisms in Iranian patients. Forty-five Iranian patients with clinical criteria of thalassemia intermedia were studied. The molecular background of the diseases was investigated. The mean age of onset varied from 1.5 to 30 years. Only 22.2% of cases received occasional blood transfusions. The hemoglobin (Hb) level in more than half of the cases was stable (10-12 g/dL) with no need for blood transfusions. In most cases (88.9%) the Hb F level was more than 50%. Sixty-eight point nine percent of patients were homozygous for beta(0)-thalassemia (beta-thal) mutations. The positive XmnI polymorphism with the capability of enhancing Hb F production was seen in 60% of the studied chromosomes. Co-inheritance of alpha-globin gene defects was seen in 22.2% of cases. Only 8.9% of patients had beta(+) or beta(++) mutations. We concluded that the main molecular basis of the thalassemia intermedia phenotype in Iranian cases is co-inheritance of a positive XmnI polymorphism with beta-globin mutations, which can enhance the capability of Hb F production. Co-inheritance of alpha-globin defects and mild beta-globin mutations are second and third causes of thalassemia intermedia phenotypes respectively. These factors must be considered in genetic counseling, prediction of disease prognosis and treatment and prenatal diagnosis.

Multicenter study of the molecular basis of thalassemia intermedia in different ethnic populations.

We studied 325 thalassemia intermedia patients from Iran, India, Pakistan, Thailand, Mauritius and Cyprus to examine factors which influence the phenotype. The beta-thalassemia (thal) mutations were determined for 219 beta-thal/beta-thal and 106 beta-thal/Hb E [beta26(B8)Glu-->Lys, GAG-->AAG] thalassemia intermedia patients. Thirty-one different mutations were identified, and their combination gave rise to more than 44 different genotypes, of which 14 (31.8%) had the beta(0)/beta(0), 21 (47.7%) the beta(0)/beta(+) and nine (20.5%) the beta(+)/beta(+) types. Thus, the beta(+)-thal mutations were present in 68.2% of patients. alpha-Thalassemia mutations were present in frequencies higher than in the general population of all ethnic groups studied, as 45% of the patients carried alpha-thal mutations. Correlation of alpha-thal mutations with beta-globin mutations showed that the alpha-thal mutations were mainly co-inherited with the beta(+)-thal mutations. The XmnI (G)gamma polymorphic site at -158 (C-->T) was positive (T) in nine (8.8%) of 102 patients of the beta(+)/beta(+) genotype, and the percentage of both XmnI (G)gamma polymorphism [+/-] (T/C) and [+/+] (T/T) genotypes increased to 42.9 and 87.3, respectively, in the beta(0)/beta(+) and beta(0)/beta(0) patients. This polymorphism was found in the majority of beta(+)-thal/Hb E compound heterozygote patients (88.6%), and beta(0)-thal/Hb E patients (84.8%), suggesting that it could be linked to the Hb E chromosome. Therefore, the XmnI (G)gamma polymorphism at -158 (C-->T) was associated with beta(0)-thal mutations as well as the Hb E chromosome. The present study demonstrates that in cases of thalassemia intermedia with beta(+) mutations, the common ameliorating factor is the presence of alpha-thal mutations, while in cases with beta(0) mutations, the common ameliorating factor is the presence of the XmnI (G)gamma polymorphism at -158 (C-->T).

The clinical, immunohematological, and molecular study of Iranian patients with severe congenital neutropenia.

Severe congenital neutropenia (SCN) is a rareE primary immunodeficiency disorder characterized by early onset recurrent infections in association with persistent severe agranulocytosis. To identify the clinical, immunohematological, and molecular characteristics of patients with SCN, 18 Iranian patients with the mean age of 8.8 +/- 5.8 years were investigated in this study. All of these patients experienced severe neutropenia; the mean of absolute neutrophil count was 281.4 +/- 137.7 cells/mm3. Bone marrow findings were typified by a myeloid maturation arrest at the promyelocyte-myelocyte stage in these patients. Molecular analysis revealed different mutations in the ELA-2 gene of one patient and in the HAX-1 gene of another three patients. The most common presenting complaints in these patients were superficial abscesses, oral ulcers, cutaneous infections, omphalitis, and pneumonia. During the course of illness, all patients developed mucocutaneous manifestations, and 16 cases had respiratory infections. The most commonly manifestations were abscesses, oral ulcers, pneumonia, periodontitis, otitis media, cutaneous infections, mucocutaneous candidiasis, and acute diarrhea. Three patients died because of a severe infection. Although SCN is a rare disorder, early onset of severe and recurrent infections should always raise a suspicion, which deserves further evaluation for detecting such disorder.

Bilateral basal ganglia involvement in a patient with Griscelli syndrome.

We report a 6-year-old Iranian boy with silvery-gray hair, eyelashes and the eyebrows who was admitted because of seizures and subsequent stupor. He had previous history of acute hemiparesis at 1 year of age and hepatitis-like syndrome 3 months ago. Microscopic examination of the patient's hair shaft revealed different sized clumps of melanin seen in the center of the shafts. Bone marrow aspiration revealed erythroid hyperplasia and erythrophagocytic cells. Bilateral frontal cortical and subcortical high signal lesions, dirty white matter, high signal areas in the upper pons and in both caudates and lentiform nuclei in T2 WI were the brain MRI findings of the patient. He died in the accelerated phase of Griscelli Syndrome (GS) type 2. To our knowledge we report the first case of GS from Iran.

Congenital neutropenia and primary immunodeficiency disorders: a survey of 26 Iranian patients.

Inherited neutropenia is characterized by a decrease in the absolute number of circulating neutrophils and an increased susceptibility to infections. The current study was performed to determine the clinical and laboratory findings of Iranian patients with inherited neutropenias. Records of 26 patients (14 male, 12 female) with inherited neutropenia were reviewed in this study. The patients had been referred to Children's Medical Center, a referral center for immunodeficiency disorders in Iran, during a 22-year period (1981-2003). Primary immunodeficiency disorders of these patients were as follows: cyclic neutropenia (8 patients), Shwachman-Diamond syndrome (7 patients), Kostmann syndrome (6 patients), and Chediak-Higashi syndrome (5 patients). The mean absolute neutrophil count of patients was 398.2 +/- 259.3 cells/mm (range 74-1,152/mm) at the first visit. Twenty-one patients showed severe, four moderate, and one mild neutropenia. Sixteen of these patients had leukopenia, seven anemia, two thrombocytopenia, and one monocytosis. The most common presenting complaints in these patients were oral ulcer, otitis, pneumonia, diarrhea, cutaneous abscess, and oral candidiasis. The patients first manifested symptoms of infection suggesting neutropenia at a median age of 7.5 months (range 1 month to 10 years). During follow-up, respiratory infections developed in 24 cases, oral manifestations in 20 patients. The most common infections, in descending order of frequency, were otitis media, abscesses, pneumonia, oral ulcers, acute diarrhea, cutaneous infections, oral candidiasis, and periodontitis. Less frequent infections were sinusitis, cystitis, conjunctivitis, meningitis, and osteomyelitis. Nonspecific symptoms (hepatomegaly and splenomegaly) were also detected in 10 patients and 1 patient, respectively. Three patients died of recurrent infections. The infectious manifestations both at presentation and during follow-up in inherited neutropenia were similar. Although inherited neutropenias are rare, recurrent infections always deserves further evaluation for detecting such disorders.

Clinical and laboratory findings in Iranian children with cyclic neutropenia.

Cyclic neutropenia is a rare immunodeficiency syndrome, characterized by regular periodic oscillations in the circulating neutrophil count from normal to neutropenic levels through 3 weeks period, and lasting for 3-6 days. In order to determine the clinical features of cyclic neutropenia, this study was performed. Seven patients with cyclic neutropenia (3 males and 4 females), who experienced neutropenic periods every 3 weeks (5 with severe and 2 with moderate neutropenia), were investigated in this study. They had been referred to Iranian Primary Immunodeficiency Registry during 23 years (1980-2003). The range of patients' ages was from 7 to 13 years (median 11 years). The median age at the onset of the disease was 12 months (1 month- 2 years) and the median age of diagnosis was 2 (1.5-5) years, with a median diagnosis delay of 1 year (2 months- 5 years). Neutropenia was associated with leukopenia (3 patients), anemia (3 patients), and thrombocytopenia (1 patient). Patients were asymptomatic in healthy phase, but during the episode of neutropenia suffered from aphthous ulcers, abscesses and overwhelming infections. The most commonly occurred manifestations were: otitis media (6 cases), oral ulcers (5 cases), abscesses (4 cases), pneumonia (3 cases), diarrhea (3 cases), oral candidiasis (3 cases), cutaneous infections (2 cases), and periodontitis (2 cases). One of these patients subsequently died because of recurrent infections. Unusual, persistent or severe infections should be the initiating factors to search for an immune deficiency syndrome such as cyclic neutropenia, because a delay in diagnosis may result in chronic infection, irretrievable end-organ damage or even death of the patient.

Report of six cases of chediak-higashi syndrome with regard to clinical and laboratory findings.

Chediak - Higashi Syndrome (CHS) is a rare, primary Immunodeficiency disorder with an autosomal recessive (AR) inheritance and characterized by recurrent infection, partial occulocutaneous albinism and an accelerated phase.In this report we describe clinical and laboratory findings from 6 CHS patients. Clinical and laboratory information of six patients who were referred to our center during the last 20 years (from 1983 - 2003) were reviewed.Onset age of disease was between 3 months to 10 years. All patients had history of consanguineous parents and two patients were siblings. All patients had oculocutaneous albinism, nystagmus, recurrent infections which included upper and lower respiratory tract (U and LRT) infections, stomatitis, thrush, and skin abscesses and hepatitis. In laboratory findings, all patients had neutropenia and normal immunoglobulins and normal CD3, CD4, CD8 and CD19 lymphocyte by flowcytometry and three of the four patients had chemotatic defect. Five patients certainly had giant granule in bone marrow neutrophil and in one patient it was equiovocal. Three patients had an accelerated phase, and for one patient bone marrow transplantation was done that was tolerated well and had been well after 7 years.We emphasize the need for early diagnosis on basis of characteristic facies and diagnostic laboratory examinations and early bone marrow transplantation (BMT) in patients.