Kaiser Ali

Clinical and genetic analysis of unclassifiable inherited bone marrow failure syndromes.

OBJECTIVE. Unclassified inherited bone marrow failure syndromes are a heterogeneous group of genetic disorders that represent either new syndromes or atypical clinical courses of known inherited bone marrow failure syndromes. The relative prevalence of the unclassified inherited bone marrow failure syndromes and their characteristics and the clinical and economic challenges that they create have never been studied. METHODS. We analyzed cases of inherited bone marrow failure syndrome in the Canadian Inherited Marrow Failure Registry that were deemed unclassifiable at study entry. RESULTS. From October 2001 to March 2006, 39 of the 162 patients enrolled in the Canadian Inherited Marrow Failure Registry were registered as having unclassified inherited bone marrow failure syndromes. These patients presented at a significantly older age (median: 9 months) than the patients with classified inherited bone marrow failure syndrome (median: 1 month) and had substantial variation in the clinical presentations. The hematologic phenotype, however, was similar to the classified inherited bone marrow failure syndromes and included single- or multiple-lineage cytopenia, severe aplastic anemia, myelodysplasia, and malignancy. Grouping patients according to the affected blood cell lineage(s) and to the presence of associated physical malformations was not always sufficient to characterize a condition, because affected members from several families fit into different phenotypic groups. Compared with the classified inherited bone marrow failure syndromes, the patients with unclassified inherited bone marrow failure syndromes had 3.2 more specific diagnostic tests at 4.5 times higher cost per evaluated patient to attempt to categorize their syndrome. At last follow-up, only 20% of the unclassified inherited bone marrow failure syndromes were ultimately diagnosed with a specific syndrome on the basis of the development of new clinical findings or positive genetic tests. CONCLUSIONS. Unclassified inherited bone marrow failure syndromes are relatively common among the inherited bone marrow failure syndromes and present a major diagnostic and therapeutic dilemma.

Pain, Distress, and Adult-Child Interaction During Venipuncture in Pediatric Oncology: An Examination of Three Types of Venous Access

This study examined pain and distress from needles in children undergoing blood sampling as a function of adult-child interaction and type of venous access (i.e., central external venous lines, internalized ports, or peripheral access via venipuncture). Participants were 55 pediatric oncology patients, aged 3-18 years, who were undergoing routine blood work. Pain ratings were obtained using the Faces Pain Scale-Revised (FPS-R) and conversation during the procedure was audio taped for coding using the Child-Adult Medical Procedure Interaction Scale-Revised (CAMPIS-R). Childrens ratings of pain using the FPS-R were similar in the port (M=2.57/10, standard deviation [SD]=3.46) and peripheral (M=2.56/10, SD=3.24) groups, despite the fact that most children with internal ports were given a topical anesthetic. Similarly, there were no differences between port and peripheral groups in rates of child coping or distress, or parent and nurse observations of child pain. As would be expected, external line access was not associated with pain or distress, even among very young children, suggesting that they appropriately understood the pain rating scale. Results of the transcribed CAMPIS-R data indicate that the influences in adult-child interaction are bidirectional. Support was found for the well-established positive relationship between child distress and adult reassurance and empathy. Implications for intervention and selection of central venous access devices are discussed.

Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations

Introduction Inherited bone marrow failure syndromes (IBMFSs) often have substantial phenotypic overlap, thus genotyping is often critical for establishing a diagnosis. Objectives and methods To determine the genetic characteristics and mutation profiles of IBMFSs, a comprehensive population-based study that prospectively enrols all typical and atypical cases without bias is required. The Canadian Inherited Marrow Failure Study is such a study, and was used to extract clinical and genetic information for patients enrolled up to May 2010. Results Among the 259 primary patients with IBMFS enrolled in the study, the most prevalent categories were Diamond–Blackfan anaemia (44 patients), Fanconi anaemia (39) and Shwachman–Diamond syndrome (35). The estimated incidence of the primary IBMFSs was 64.5 per 106 births, with Fanconi anaemia having the highest incidence (11.4 cases per 106 births). A large number of patients (70) had haematological and non-haematological features that did not fulfil the diagnostic criteria of any specific IBMFS category. Disease-causing mutations were identified in 53.5% of the 142 patients tested, and in 16 different genes. Ten novel mutations in SBDS, RPL5, FANCA, FANCG, MPL and G6PT were identified. The most common mutations were nonsense (31 alleles) and splice site (28). Genetic heterogeneity of most IBMFSs was evident; however, the most commonly mutated gene was SBDS, followed by FANCA and RPS19. Conclusion From this the largest published comprehensive cohort of IBMFSs, it can be concluded that recent advances have led to successful genotyping of about half of the patients. Establishing a genetic diagnosis is still challenging and there is a critical need to develop novel diagnostic tools.

Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype–phenotype correlation

Hashmi SK, Allen C, Klaassen R, Fernandez CV, Yanofsky R, Shereck E, Champagne J, Silva M, Lipton JH, Brossard J, Samson Y, Abish S, Steele M, Ali K, Dower N, Athale U, Jardine L, Hand JP, Beyene J, Dror Y. Comparative analysis of Shwachman‐Diamond syndrome to other inherited bone marrow failure syndromes and genotype–phenotype correlation.

Expression of N-myristoyltransferase in human brain tumors.

N-myristoylation is a process of covalent irreversible protein modification that promotes association of proteins with membranes. Based on our previous findings of elevated N-myristoyltransferase (NMT) activity in colonic epithelial neoplasms that appears at an early stage in colonic carcinogenesis, together with elevated NMT expression in human colorectal and gallbladder carcinomas, we investigated NMT activity and protein expression of NMT1 and NMT2 in human brain tumors and documented elevated NMT activity and higher protein expressions. For the first time, we have demonstrated that NMT has the potential to be used as a marker of human brain tumors. However, further studies with larger number of patients are required to establish its role as a complementary diagnostic tool. This finding has significant implications for further understanding of biological mechanisms involved in tumorigenesis, as well as for diagnosis and therapy of human brain tumors.

Chronic immune thrombocytopenic purpura in children: a survey of the canadian experience.

Background Immune thrombocytopenic purpura (ITP) in children is a common pediatric bleeding disorder with heterogeneous manifestations and a natural history that is not fully understood. To better understand the natural history of chronic ITP and detect response trends and outcomes of therapy, we conducted a 10-year retrospective survey of children from age 1 to 18 years with a diagnosis of chronic ITP. Results Data on 198 patients from 8 Canadian Pediatric Hematology/Oncology centers were analyzed. The majority of patients were female (58%), and were previously diagnosed with acute (primary) ITP (85%). The age at diagnosis of chronic ITP ranged from 1.1 to 17.2 years with a mean of 8.2±4.4 years. Ninety percent of patients received some form of treatment. Untreated patients had a higher mean platelet count at diagnosis of chronic ITP (P=0.009) despite similarities in mean age at first presentation and mean duration of follow-up. Thirty-four (17%) patients underwent splenectomy. Splenectomized patients tended to be significantly older, had a lower mean platelet count at diagnosis of chronic ITP, and had a longer duration of follow-up. Conclusions The results from this study are consistent with published reports.

A new approach to concordance in mid-infrared spectromicroscopy mapping of malignant tumors

Mid-infrared spectromicroscopy studies on biological tissue sections require accurate identification of tumor-bearing areas in histology-stained and infrared-unstained tissue sections. Concordance was achieved as follows: paired stained and unstained thin (5 microm) human brain tumor cryosections mounted on slides were scanned with a Nikon Coolscan 4000 film scanner at 4000 dpi, edited with Adobe Photoshop CS2 software, and both digital images saved. A digital tractile grid, developed in our laboratory, was overlaid onto both images. Boundaries of tumor-containing areas in stained sections were identified by light microscopy, and a digital boundary map constructed. The map was transferred onto the unstained spectromicroscopy tissue image, and finally layered onto the gridded, equisized, spectromicroscope-generated overview image prior to Fourier transform infrared spectromicroscopy. Accurate identification of tumor-bearing areas, normal brain tissue and transitional zones allowed for meaningful interpretation of respective spectral patterns in detecting subtle differences within biochemical profiles. This is the first reported method of a standardized technique for ensuring concordance in mapping of malignant tumors by mid-infrared spectromicroscopy. This technique is applicable to all biological thin tissue sections, and serves to enhance accuracy of concordance between globar- and synchrotron-light generated infrared data with that obtained by conventional light microscopy.