Transcobalamin (TC) deficiency--potential cause of bone marrow failure in childhood.

It is unusual for inborn errors of metabolism to be considered in the investigative work-up of pancytopenia. We report a family in which the proband presented with failure to thrive at 2 months of age and subsequent bone marrow failure. A previous sibling had died at 7 months of age with suspected leukaemia. Haematological findings in the proband were significant for pancytopenia, and bone marrow aspiration showed dysplastic changes in all cell lineages. Urinary organic acid analysis revealed elevated methylmalonic acid. The synthesis of transcobalamin II (transcobalamin, TC) by cultured fibroblasts was markedly reduced, confirming the diagnosis of TC deficiency. The proband and his younger asymptomatic sister (also found to have TC deficiency) were homozygous for R399X (c.1195C>T), a novel mutation resulting in the loss of the C- terminal 29 amino acids of TC, a highly conserved region. Response to parenteral vitamin B(12) in the proband was dramatic. At 6 years 3 months of age, physical examination is normal and developmental level is age appropriate. His sister is clinically asymptomatic and is also developing normally. Propionylcarnitine concentrations were not elevated in the newborn screening cards from the proband and sister, but that was for specimens retrieved from storage after 7 years and 5 years, respectively. Inherited and acquired cobalamin disorders should both be considered in the differential diagnosis of bone marrow failure syndromes in young children. Early detection of the metabolic causes of bone marrow failure can ensure prompt recovery in some cases involving the vitamin B(12) pathway.

A survey of children's acute, recurrent, and chronic pain: validation of the pain experience interview.

The ultimate objective of our epidemiological research is to complete a longitudinal population-based study to document the prevalence and impact of acute, recurrent, and chronic pain in children and adolescents. As the first phase of our epidemiological research, we developed a comprehensive screening instrument for identifying children with acute, recurrent, and chronic pain, the Pain Experience Interview. We designed this interview to provide information about the lifetime and point prevalence of various pains, and also to provide information about the intensity, affect, duration, and frequency of children's pain. The primary objective of this study was to validate the Pain Experience Interview using the discriminant validation procedure of group differences. The secondary objectives of our study were to obtain descriptive data on children's acute, recurrent, and chronic pain experiences and to conduct exploratory analyses on age- and gender-related differences in children's pain experiences. We interviewed 187 children from five different health groups (arthritis, cancer, enuresis, recurrent headaches, and healthy) to provide distinct subsets of children with respect to their acute, recurrent, and chronic pain experience, and from four different age groups (5-7, 8-10, 11-13, and 14-16 years) to provide distinct subgroups with respect to children's developmental level. To test the interview we determined a priori several study predictions about children's pain experiences. These included four predictions about the common response patterns that we would expect to observe for all children based on our understanding of acute pain caused by trauma/disease, and six predictions about the distinct response patterns that we would expect to observe based on the known differences among children in their experiences of headache, acute treatment-related pain, recurrent pain, and chronic pain. All study predictions were confirmed, demonstrating that the Pain Experience Interview is a valid screening instrument for differentiating children with different types of pain problems. The interview can provide estimates for the lifetime and point prevalence of various pains in children, and data on the intensity, affect, duration, and frequency of their pain experiences.

Malignant rhabdoid tumor of brain: an aggressive clinical entity.

OBJECTIVE: We report three patients with malignant rhabdoid tumor (MRT) of the brain, two children and an adult. There were three purposes to this report: to describe the clinical course in an adult with MRT; to describe the interesting histopathological metamorphosis of one of the tumors; and to report the outcome of the treatment regimens we used in order to help guide future treatment. Since these tumors are quite rare it is important to continue to try new regimens in the search for effective therapy rather than to repeat ineffective ones. METHOD: Report of three patients. RESULTS: The clinical course in all three patients was typical of these aggressive neoplasms in that chemotherapy and radiotherapy were ineffective in modifying the rapid deterioration leading to death. CONCLUSIONS: MRT can occur in adults. Autopsy in one patient showed that the tumor seemed to undergo an evolution in appearance when compared with the original pathology specimen from craniotomy. Administration of systemic therapy should be prompt and include intrathecal chemotherapy.

Management of children with acute lymphoblastic leukemia by the Dana-Farber Cancer Institute protocols. An update of the Ontario experience.

The primary purpose of this study was to determine the therapeutic efficacy of a protocol of treatment for acute lymphoblastic leukemia (ALL) in children. A prospective approach was adopted with an inception cohort of patients. Outcome measures were assessed on December 31, 1990. The study was conducted at two tertiary care centres (pediatric oncology programs) in Ontario, Canada. All children with ALL were eligible for study and consecutive recruitment took place between May 1984 and July 1987. They were classified at diagnosis into one of three categories for risk of relapse according to standardized criteria. Thirty-nine children were designated as having standard risk (SR), 31 as having high risk (HR), and 12 as having very high risk (VHR) disease. All patients are included in the analysis. Treatment was administered according to risk category-specific chemotherapy protocols, the details of which have been published. A distinguishing feature of these strategies is the intensive use of intramuscular L-asparaginase. Patients remained on these regimens for 2 years or until relapse or toxic death (events) ensued. Total and event-free survival data were determined by life-table analysis (Kaplan-Meier plots). With a minimum interval from diagnosis of 186 weeks and a median interval exceeding 5 years, the cumulative proportion of the entire cohort (C) surviving is 85% [95% confidence interval (CI), 77-93%]. For the respective risk groups, the corresponding proportions are SR 94% (95% CI, 87-100%), HR 74% (95% CI, 59-89%), and VHR 81% (95% CI, 59-100%).(ABSTRACT TRUNCATED AT 250 WORDS)

Molecular and genetic characterization of human cell lines resistant to L-asparaginase and albizziin.

Human cell lines resistant to L-asparaginase or albizziin were isolated by multistep selection of HT1080 fibrosarcoma and MIA PaCa-2 pancreatic carcinoma cells. Mutants were cross-resistant to both drugs, but more resistant to the drug used for selection. The drug-resistant cell lines expressed elevated levels of asparagine synthetase activity and protein, up to 17-fold over that of the parental cells. Enzyme overproduction was due to gene amplification in the albizziin-resistant cells, whereas increased expression without amplification was observed in L-asparaginase-resistant cells.

Molecular structure of the human asparagine synthetase gene.

The human gene for asparagine synthetase has been isolated and the molecular organization has been determined by mapping and DNA sequencing of intron-exon boundaries. The gene spans 35 kb and contains 13 exons. The structure of the human gene has a high degree of similarity to that of the hamster asparagine synthetase gene, with identical positions for all but one of the intron regions. The 5' upstream region of this gene, like other housekeeping genes, lacks conventional TATA and CAAT boxes. Comparisons of the 5' upstream sequences of the human and hamster genes show limited similarity; however, both have a very high G + C content which may play a role in expression through DNA methylation.

Acute megakaryoblastic leukaemia in children.

We report four children with acute megakaryoblastic leukaemia (AMKL) and compare their clinical course with 16 previously reported cases of AMKL in children. In adults, AMKL has been reported as a rapidly progressive disease characterized by pancytopenia associated with bone marrow fibrosis, absence of organomegaly, and unresponsiveness to therapy. Although some of the childhood cases present with these features, the clinical course can be quite variable, particularly in young children, with both organomegaly and leucocytosis occurring. Down syndrome, or other constitutional abnormalities of chromosome 21 were present in four of 20 reported cases. Two of the four cases reported herein were initially diagnosed cytologically as childhood acute lymphoblastic leukaemia (ALL). All four patients achieved a complete remission, and three remain in remission from 34 to 56 months from diagnosis. Greater recognition of AMKL in the future will help to clarify the disease characteristics, prognosis and optimal treatment of this unusual form of leukaemia.