Pattern of inheritance of idiopathic hypercalciuria in two families

Idiopathic hypercalciuria is a leading cause of frequency-dysuria syndrome in childhood. Different modes of inheritance have been suggested in this disease. This article presents the occurrence of idiopathic hypercalciuria in all children of two families. In the first family, a 5.5 year old girl with a history of renal stones and dysuria due to hypercalciuria, had two involved brothers and one sister. In the second family, hypercalciuria and medullary nephrocalcinosis were detected in two siblings who were admitted for polyuria and dysuria. Idiopathic type of hypercalciuria was diagnosed in these two families by normal laboratory exams and exclusion of other causes of normocalcemic hypercalciuria. According to the involvement of all offsprings (both sexes) in these two families, it is suggested that idiopathic hypercalciuria is an autosomal dominant disease with complete penetration. © 2006 Tehran University of Medical Sciences. All rights reserved

PATTERN OF INHERITANCE OF IDIOPATHIC HYPERCALCIURIA IN TWO FAMILIES

Idiopathic hypercalciuria is a leading cause of frequency-dysuria syndrome in childhood. Different modes of inheritance have been suggested in this disease. This article presents the occurrence of idiopathic hypercalciuria in all children of two families. In the first family, a 5.5 year old girl with a history of renal stones and dysuria due to hypercalciuria, had two involved brothers and one sister. In the second family, hypercalciuria and medullary nephrocalcinosis were detected in two siblings who were admitted for polyuria and dysuria. Idiopathic type of hypercalciuria was diagnosed in these two families by normal laboratory exams and exclusion of other causes of normocalcemic hypercalciuria. According to the involvement of all offsprings (both sexes) in these two families, it is suggested that idiopathic hypercalciuria is an autosomal dominant disease with complete penetration

Metastatic Colo-Rectal Cancer, 2005-2008: Treatment results

"nIntroduction: Colo-rectal cancer has 10% prevalence, among all of the cancer proportionally and also it is the third common cancer in the both sexes. Two recently introduced active drugs in the treatment of advanced colorectal cancer (ACC) are irinotecan and oxaliplatin. The combinations of oxaliplatin (OXA) or irinotecan (IRI) with 5FU-LV have been accepted as standard treatment for metastatic colorectal cancer. "nPatients and Methods: fifty four patients with colo-rectal cancer who came to the Oncology Clinic of Kermanshah University were assessed over a period of 4 years (2005-2008). All cases in stage III were treated by FOLFOX, unlike the patients in Stage IV treated with FOLFOX during 8 cycles fallowed by FOLFIRI in the same cycles (Sequential method). "nResults: the age average was less (49.1 years versus 55 years) than in other studies (6). A parallel analyzation of solid data, overall survival (OS), progression free survival (PFS) were 18 and 17.3 months, respectively. "nConclusion: FOLFOX and FOLFIRI were administrated in 8 cycles each concomitantly (Sequential form) which provided considerable response with manageable complications. The result of the treatment in the study was correlated with other trials utilizing more modern procedures of medication like ‘Target therapies’ (OS; 18.4m for CT versus 19-20m for target therapies)

PREVALENCE OF Y CHROMOSOME MICRODELETIONS IN IRANIAN INFERTILE MEN

This study was designed to determine the frequency of Y chromosome AZF (Azoospermia Factor ) subregions, microdeletions in patients with idiopathic nonobstructive azoospermia and severe oligozoospermia. Subjects included 40 men who had been referred to infertility clinics for assisted reproduction, 37 were azoospermic and 3 had severe oligospermia. Medical history and physical exam revealed no evidence of infection, obstruction of seminal tract, endocrine failure or chromosomal anomalies. Hormonal study was performed for all patients. Twenty six men had biopsies of the testes including 11 patients with hypospermatogenesis, 9 patients with maturation arrest, 4 patients with sertoli cell only syndrome and 2 patients with tubular sclerosis. In 14 men who did not have a testicular biopsy multiple, epididymal and testicular sperm aspirations under anesthesia failed and testicular sperm extraction was subsequently performed for ICSI. DNA was isolated from blood samples. Polymerase chain reaction (PCR) amplification of 11 loci spanning the AZFa, AZFb and AZFc subregions of the Y chromosome using sY81, sY83, sY127, sY130, sY131, sY147, sY149, sY157, sY158, sY254 and sY276 was performed. Microdeletions of the Y chromosome were found in two of the patients (5%), who had azoospermia. Deletions were restricted to DAZ (deleted in azoospermia ) locus in AZFc subregion. One of the patients had a history of cryptorchidism and the second had undergone a left side varicocelectomy. Testicular pathology showed sertoli cell only syndrome in both of them. Our experience adds to the current logic that men with azoospermia or severe oligospermia should be evaluated for Yq11 microdeletions before deciding to operate varicoceles or else scheduling them for assisted reproductive techniques

Early Detection of Renal Scarring in Children With Suspected Pyelonephritis: Comparison of Diuretic MAG3 Scintigraphy (F0) and DMSAScan

Background:Screening for patients at risk of renal scarring is a challenge in children with acute pyelonephritis(APN).Diuretic Tc-99m mercaptoacetyltriglycine (MAG3) scintigraphy with zero time injection of furosemide (MAG3-F0) was observed to display focal parenchymal disorders.The advantages of MAG3 include: lower radiation dose and short duration of the test.The aim of this study was to compare the role of Tc-MAG3(F0)dynamic study and Tc-99m dimercaptosuccinic acid (DMSA) scan in early detection of renal scarring of children with suspected pyelonephritis in comparison to after-6-month Tc-DMSAscan as gold standard. Methods:28 patients (56 renal units) with their first urinary tract infection (UTI) episode were evaluated prospectively for renal scarring with radioisotope scan. The patients were divided into 2 groups: Group Aconsisted of patients who underwent MAG3 scintigraphy in acute phase of pyelonephritis and Group B consisted of patients who underwent DMSA scan in this phase for renal cortical assessment.Follow up DMSA scan was performed for all patients in both groups 4-6 months after UTI episode.Results: The accuracy of MAG3-F0 scintigraphy and DMSA scan in detecting parenchymal changes in acute pyelonephritic phase were 89.3% and 96.4%,respectively.Positive predictive value(PPV)of both MAG3-F0 and DMSA was 100%.Whereas,negative predictive values (NPV) of MAG3-F0 and DMSA scan were 62.5% and 75%,respectively.Conclusion:Conclusively, if the MAG3 parenchymal image is abnormal, then there is renal damage but if this image is normal, a focal defect has not been excluded. Thus an abnormal MAG3-F0 precludes the need for a Tc-DMSAscan for detection of persistent renal damage in acute phase of pyelonephritis

Short-term and long-term outcome of hemolytic uremic syndrome in Iranian children

Background: Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure during infancy. Many symptoms and clinical features have been proposed as prognostic factors for HUS in the short and long term, while the results of different studies have often been controversial. The aim of this study was to evaluate short-term and long-term outcomes of HUS in Iranian children. Methods: Medical records of all 92 children suffering from HUS admitted to the pediatrics nephrology ward at Ali-Asghar Children Hospital in Tehran, Iran, from 1990 to 2004, were retrospectively reviewed. Results: Out of 92 children, mortality was observed in 18 patients (19.6) during the acute phase of the disease. Significant correlation between mortality and seizures, coma and hypertension in the acute phase was found (p0.05). In the long-term, the presence of hypertension in the acute phase of the disease (p=0.023; relative risk RR = 3.89; 95% confidence interval 95% CI, 1.01-13.76), hypertension at discharge time (p<0.001; RR=10; 95% CI, 2.44-40.91) and need for dialysis (p=0.021; RR=1.38; 95% CI, 1.13-1.70) were shown to be significant risk factors for future hypertension in HUS patients. Conclusion: Central nervous system involvement is associated with mortality in the acute phase of HUS, whereas the severity of disease in the admission phase is related to occurrence of hypertension in future. © Società Italiana di Nefrologia

Patients with SF3B1 Mutation Have Good Prognosis Even in the Presence of Other Poor Prognostic MDS Features and Have Better Outcomes During Treatment with Low Intensity Chemotherapy

Abstract Abstract 3831 The discovery of mutations in components of the RNA splicing machinery has underlined the importance of this pathogenetic mechanism in MDS biology. We and others reported that mutations in SF3B1 are frequent in refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T). We recently reported good survival outcomes in a large cohort of SF3B1 mutant patients similar to the findings of Papaemmanuil et al, NEJM< 2011. Here, we aimed to evaluate the correlation between SF3B1 mutations in association with other poor prognostic clinical and pathologic factors in MDS. We focused on a large cohort of patients with several myeloid malignancies (n=340). Patients were grouped in MDS (n=176), MDS/MPN (n=88) and secondary AML (sAML) from a previous MDS (n=76). Diseases were classified according to the 2008 WHO classification. Survival outcomes (overall survival [OS], progression free survival [PFS] and event free survival [EFS]) were defined according to MDS IWG criteria. We studied a total of 340 patients with myeloid malignancies. median age, 69 years old (range 19–92), sex (Male, n=222; females, n=118). We performed direct sequencing for SF3B1 (exon 13–16) on a large cohort of MDS, MDS/MPN and sAML patients and found 11.8% SF3B1 mutants. The outcomes of SF3B1 mutant vs WT patients were compared based on the presence of poor clinicopathologic factors associated with MDS like RBC transfusion dependence, presence of SNP-A lesions, presence of acquired somatic uniparental disomy (AS-UPD), Age ≥ 60 years, presence of reticulin fibrosis in the bone marrow. We also assessed the effects of therapies in the prognostic effect of SF3B1 mutations. We previously reported that the presence of new SNP-A lesions in myeloid malignancies including MDS and AML are associated with poor prognostic outcomes. However, the good prognostic effects of SF3B1 mutation is still apparent even in the patients with new SNP-A abnormalities (OS: 40 vs 16 mos, p=.003; PFS: 40 vs 10 mos, p=.003, 40 vs 10 mos, p=.0007. However, when analysis is limited to acquired somatic uniparental disomy defects which we recently reported as the worst lesion among SNP-A abnormalities, the good prognostic effect of SF3B1 is lost (OS: 19 vs 9 mos, p=.29, PFS: 18 vs 7 mos, p=.20, EFS: 19 vs 8 mos, p=.17). Age is an important predictor of outcomes in MDS with higher age associated with worse outcomes. SF3B1 remained predictive of good outcomes in patients ≥ 60 years of age (OS: 40 vs 16, p=.002; PFS: 40 vs 11 mos, p=.003; EFS: 40 vs 10 mos, p=.0005). Persistent RBC transfusions are also associated with inferior survival in MDS, yet SF3B1 mutant patients continued to have good outcomes (OS 34 vs 13, p=.002; PFS: 27 vs 8 mos, p=.004; EFS: 14 vs 9 mos, p=.001). Reticulin fibrosis in the bone marrow is a characteristic feature of myeloproliferative neoplasms but their presence in MDS is associated with unfavorable results, SF3B1 mutant retain their good outcomes even in the presence of reticulin fibrosis in the BM (OS: 40 vs 15 mos, p=.09; PFS: 47 vs 12 mos, p=.04; EFS: 75 vs 13 mos, p=.008). Patients screened for SF3B1 were also further stratified according to treatments received. No patients with SF3B1 mutations underwent allogeneic hematopoietic stem cell transplantation and high intensity chemotherapy specifically induction chemotherapy or high dose cytarabine. However based on treatment with LIC, SF3B1 mutant patients have better survival outcomes compared to WT patients (OS: 61 vs 17 mos, p=.004; PFS: not reached [NR] vs 7 mos; p=.009; EFS: 61 vs 10 mos, p=.001). These observed survival outcomes remain significant when patients were stratified according to disease subtypes. MDS and MDS/MPN patients treated with LIC have better outcomes if they have SF3B1 mutation (OS: 61 vs 23 mos, p=.005; PFS: NR vs 16 mos, p=.01; EFS: 61 vs 16 mos, p=.001). A high number of TET2/DNMT3A mutations are found in SF3B1 mutants. TET2/DNMT3A mutations have been previously association with improved response to hypomethylating agents which is one of the possible reasons why SF3B1 mutants treated with LIC did better than their WT counterpart. In conclusion, SF3B1 retains its favorable prognostic effect even in the face of poor prognostic factors such as RBC transfusion dependence, presence of SNP-A lesions, Age ≥ 60 years, presence of reticulin fibrosis in the bone marrow except in the presence of AS-UPD. SF3B1 mutants treated with LIC also have better outcomes. Disclosures: No relevant conflicts of interest to declare

A case of mistaken identity: When lupus masquerades as primary myelofibrosis

Introduction: Autoimmune myelofibrosis is an uncommon hematologic disease characterized by anemia, bone marrow myelofibrosis, and an autoimmune feature. Myelofibrosis is often associated with other conditions, including infections, nutritional/endocrine dysfunction, toxin/drug exposure, and connective tissue diseases, including scleroderma and systemic lupus erythematosus. Absence of clonal markers ( JAK2 ) and heterogeneity of the symptoms often complicate the diagnosis. Case presentation: Here, we present two cases of systemic lupus erythematosus–induced autoimmune myelofibrosis. The first case is of a 36-year-old African American female with diagnosis of systemic lupus erythematosus at the age of 12 years. The second patient is a 44-year-old African American male with family history of systemic lupus erythematosus who developed anemia and constitutional symptoms later on. Both patients showed hypercellularity and fibrotic changes of the bone marrow. Moreover, mutational analysis showed that both patients were wild type for JAK2 (V617F and exon 12) and MPL (exon 10). Conclusions: These two cases illustrate that anemic patients with fibrotic changes in the bone marrow without other clinicopathologic features associated with primary myelofibrosis in the presence of clinical manifestations and history of an autoimmune disease should suggest an autoimmune myelofibrosis. These cases demonstrate that a good clinical history combined with molecular technologies and pathomorphologic criteria are helpful in distinguishing between primary myelofibrosis and a nonclonal myelofibrosis from an associated condition

A case of mistaken identity: When lupus masquerades as primary myelofibrosis

Introduction: Autoimmune myelofibrosis is an uncommon hematologic disease characterized by anemia, bone marrow myelofibrosis, and an autoimmune feature. Myelofibrosis is often associated with other conditions, including infections, nutritional/endocrine dysfunction, toxin/drug exposure, and connective tissue diseases, including scleroderma and systemic lupus erythematosus. Absence of clonal markers ( JAK2 ) and heterogeneity of the symptoms often complicate the diagnosis. Case presentation: Here, we present two cases of systemic lupus erythematosus–induced autoimmune myelofibrosis. The first case is of a 36-year-old African American female with diagnosis of systemic lupus erythematosus at the age of 12 years. The second patient is a 44-year-old African American male with family history of systemic lupus erythematosus who developed anemia and constitutional symptoms later on. Both patients showed hypercellularity and fibrotic changes of the bone marrow. Moreover, mutational analysis showed that both patients were wild type for JAK2 (V617F and exon 12) and MPL (exon 10). Conclusions: These two cases illustrate that anemic patients with fibrotic changes in the bone marrow without other clinicopathologic features associated with primary myelofibrosis in the presence of clinical manifestations and history of an autoimmune disease should suggest an autoimmune myelofibrosis. These cases demonstrate that a good clinical history combined with molecular technologies and pathomorphologic criteria are helpful in distinguishing between primary myelofibrosis and a nonclonal myelofibrosis from an associated condition

Spliceosome Gene Mutations Are Frequently Found In JAK2 Negative Myelofibrosis and Associated With Worse Clinical Outcomes

Abstract Myelofibrosis (MF), a Philadelphia chromosome negative myeloproliferative neoplasm (MPN) requires clonal markers for accurate diagnosis according to the 2008 World Health Organization classification scheme. However, molecular mutations in Janus Kinase 2 (JAK2) are found in only 50% of MF patients (pts). Various somatic mutations identified in other myeloid cancers have also been found in MF with pre-existing JAK2 V617F mutations. We previously reported in 57 pts diagnosed with Triple Negative MF (TN-MF: JAK2 exon12/14 and wild type (WT) MPL) the absence of mutations in genes commonly identified in other myeloid malignancies, specifically TET2, DNMT3A, CBL, IDH1/2, SH3B2 (LNK), N/KRAS and EZH2. Only somatic mutations in ASXL1 were identified in a small cohort of TN-MF (16%). Mutations in components of the RNA splicing machinery have been recently identified in varying frequencies in different myeloid malignancies. We performed RNA-sequencing on 2 samples (JAK2 mutant (MUT) and 1 JAK2 WT) and found that 2 spliceosome genes (U2AF1 and SF3B1) had higher mRNA expression levels in the JAK2 WT (MFC=0.76 and 0.82, respectively) compared to JAK2 MUT patient. We hypothesized that somatic mutations in RNA splicing factor genes occur in TN-MF pts and may be helpful in the biological characterization of this group of pts. Therefore, we isolated DNA from bone marrow (BM) or peripheral blood mononuclear cells from a cohort of MF pts (N=132; JAK2 MUT:75 and JAK2 WT:57) and performed Sanger sequencing for SF3B1 (exons 13-16), U2AF1 (exons 2, 6 and 7), and SRSF2 (exons 1 and 2). Baseline characteristics of pts and clinical data including hematologic parameters, BM results, and presence of splenomegaly by palpation were collected. Pts were stratified based on the Dynamic International Prognostic Scoring System-Plus risk as high=40, Int-2=51, Int-1=11 and low-risk=5 pts. The mean duration of follow-up was 16.5 months in JAK2 MUT and 12.8 months in JAK2 WT. Spliceosome mutations were found in 35/132 (27%) (SRSF2=17%, U2AF1=8% and SF3B1=2%) of pts. Interestingly, the frequency of spliceosome mutations in JAK2 WT was higher (31%; SRSF2=26%, U2AF1= 5%, SF3B1=0) compared to JAK2 MUT (18%; SRSF2=10%, U2AF1=6%, SF3B1=2%) pts. Of note, the 2 pts with SF3B1 mutations (K700E) had ring sideroblast in the BM (occasional and 50%). A large number of WT JAK2 patients (50%) had concomitant SRSF2 and ASXL1 mutations. Both SRSF2 and ASXL1 have been associated with poor prognosis in MF. Indeed, in our JAK2 WT cohort, pts who harbored SRSF2 mutations had a higher mean percentage of BM blasts compared to the ones that were SRSF2 WT (5.6% vs 1.8%; P=.006). Moreover, JAK2 WT pts carrying spliceosome mutations had more severe anemia as shown by lower hemoglobin (8.98 g/dL vs 10.5) and higher leukocyte counts (27.5 x109/L vs 20.5) compared to WT cases. Furthermore, we noticed that they also had higher frequency of RBC (Red Blood Cells) transfusions compared to WT (60% vs 40%) cases. Spleen examination by palpation below the left sub-costal margin showed that JAK2 WT cases carrying spliceosome mutations had larger splenomegaly compared to WT cases [10.1 cm (range 4-26), vs 8.7cm (range 2-20); P=0.05]. In conclusion, molecular alterations in the spliceosome machinery are frequently found in MF pts who are WT for JAK2/MPL and are associated with higher BM blast percentage, more severe anemia, higher leukocyte counts, transfusion dependence and more prominent splenomegaly. The observation of appreciable frequency of spliceosome mutations in JAK2 WT MF pts opens the possibility of using spliceosome inhibitors in the management of this disease group. Disclosures: No relevant conflicts of interest to declare