1/6. Four radiation hypersensitivity cases and their implications for clinical radiotherapy.BACKGROUND AND PURPOSE: Over a 20 year period, four out of 2000 paediatric radiotherapy patients, treated at St. Bartholomew's Hospital (three with lymphoma, one with angiosarcoma), have revealed extreme/fatal clinical hypersensitivity in normal tissues. patients AND methods: Cellular hypersensitivity was confirmed in vitro and attributed to the ataxia-telangiectasia (A-T) gene in cases I and II, a newly described defect in the dna ligase 4 gene in case III, and a novel and as yet incompletely defined, molecular defect in case IV who presented with xeroderma pigmentosum (XP). RESULTS: The severe clinical hypersensitivity preceded the cellular and molecular analysis, but did not manifest as a clinically exaggerated normal tissue reaction until 3 weeks after the start of a conventionally fractionated course of radiotherapy, by which time the latent damage had been inflicted. There were no clinical stigmata to alert the clinician to a predisposing syndrome in two patients (cases I and II). We point out that approximately 20% of A-T patients are classified as variants with delayed expression of clinical symptoms, and case II falls into this category. CONCLUSIONS: As lymphoma (incidence, one in 100000 children) constituted the majority of the diagnoses, questions arise as to: (1), the probability of other centres having experienced and being presented in the future with similar problems (particularly bearing in mind that other oncologically predisposing radiosensitivity syndromes have not been not represented in our experience); and (2), the appropriateness, efficiency and applicability of predictive assays. Unambiguous cellular radiosensitivity would have been apparent from clonal assays on fibroblast cultures from all four cases prior to treatment, but such assays take 4-6 weeks to produce results. While estimates of chromosome damage or clonal assays on pre-treatment blood derived cells would be faster, there is a health economics issue as to the general applicability of such 'screening' assays.- - - - - - - - - - ranking = 1keywords = probability (Clic here for more details about this article) |
2/6. risk in numbers--difficulties in the transformation of genetic knowledge from research to people--the case of hereditary cancer.Difficulties in communicating diagnostic information are exacerbated when the 'diagnosis' is a 'genetic risk' for cancer. The risk estimation demanded in this situation differs from other types of probability estimations. Observations of participants in 45 consultation sessions between physicians and potential patients were conducted at a clinic for hereditary cancer to explore the communication of genetic information. Thirty-three sessions were audiotaped, transcribed verbatim and analyzed, along with notes from the other sessions. A dominant theme was found to be numerical discussion of risk. Further analysis resulted in the description of problems for practitioners in the process of translating scientific knowledge into clinical management. Problems in providing information include unclear aims of the consultation sessions, mixing various types of background information and probabilities, recognizing how low the predictive values are, and difficulties in communicating the relationship between probability and conclusions. Problems in communicating information about the genetic risk for cancer are of at least two types: dilemmas arising from uncertainties implicit in the nature of the information itself and difficulties in communicating information in a manner that those concerned can interpret. These issues need clarification, so that information with far-reaching consequences can be made as clear and comprehensible as possible for those involved.- - - - - - - - - - ranking = 2keywords = probability (Clic here for more details about this article) |
3/6. Susceptibility to mycobacterial infections due to interferon-gamma and interleukin-12 pathway defects.A case of interferon-gamma (IFN-gamma)/interleukin-12 (IL-12) pathway defect is presented. Pathophysiology, clinical characteristics, diagnostic test, and case management are reviewed. Clinical Pearls and Pitfalls include: (1) A high probability of a defect in the IFN-gamma/IL-12 cascade exists in patients with disseminated or recurrent infection due to poorly pathogenic mycobacteria or systemic infections caused by non-typhi salmonella species that are persistent and recurrent despite antibiotic therapy. (2) Although less frequent, patients with impaired IFN-gamma/IL-12 mediated immunity are more susceptible to cytomegalovirus, human herpesvirus 8, herpes simplex virus, listeria monocytogenes, and histoplasma capsulatum.- - - - - - - - - - ranking = 1keywords = probability (Clic here for more details about this article) |
4/6. Whole-arm translocations between chromosome 1 and acrocentric G chromosomes are associated with a poor prognosis for spermatogenesis: two new cases and review of the literature.OBJECTIVE: To analyze unusual translocations involving a chromosome 1 whole arm and an acrocentric G chromosome p arm found in two men with azoospermia. DESIGN: Case report with review of the scientific literature. SETTING: cytogenetics department. PATIENT(S): Two men with azoospermia and normal hormonal levels. INTERVENTIONS(S): Peripheral blood lymphocytes were obtained for karyotype, and metaphases were studied by standard GBG, RBG, and CBG banding procedures. MAIN OUTCOME MEASURE(S): karyotype GBG, RBG, and CBG banding. RESULT(S): karyotype revealed balanced translocation involving a chromosome 1 whole arm and an acrocentric G chromosome p arm: 46,XY,t(1;21)(q11;p13) (patient 1) and 46,XY,t(1;22)(q11;p11) (patient 2). CONCLUSION(S): With regard to published cases of whole-arm translocation of human chromosome 1 with an acrocentric p arm and a maternal origin of these abnormalities, we argue for an impairment of meiosis resulting in a high probability of quadrivalent-XY-body interaction. Male factor infertility might be due to two poor prognostic factors, first the involvement of human chromosome 1 (and its heterochromatic region) and second the involvement of an acrocentric chromosome p-arm breakpoint. This probable interaction between the pachytene quadrivalent and XY body might explain azoospermia.- - - - - - - - - - ranking = 1keywords = probability (Clic here for more details about this article) |
5/6. Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy.Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus and elevated bile acid serum concentrations in late pregnancy. Splicing mutations have been described in the multidrug resistance p-glycoprotein 3 (MDR3, ABCB4) gene in up to 20% of ICP women. Pedigrees studied were not large enough for linkage analysis. Ninety-seven family members of a woman with proven ICP were asked about pruritus in earlier pregnancies, birth complications and symptomatic gallstone disease. The familial cholestasis type 1 (FIC1, ATP8B1) gene, bile salt export pump (BSEP, ABCB11) and MDR3 gene were analyzed in 55 relatives. We identified a dominant mode of inheritance with female restricted expression and a new intronic MDR3 mutation c.3486 5G>A resulting in a 54 bp (3465-3518) inframe deletion via cryptic splicing site activation. Linkage analysis of the ICP trait versus this intragenic MDR3 variant yielded a lod score of 2.48. A Bayesian analysis involving MDR3, BSEP, FIC1 and an unknown locus gave a posterior probability of >0.9966 in favor of MDR3 as causative ICP locus. During the episode of ICP the median gamma-glutamyl transpeptidase (gamma-GT) activity was 10 U/l (95% CI, 6.9 to 14.7 U/l) in the index woman. Four stillbirths were reported in seven heterozygous women (22 pregnancies) and none in five women (14 pregnancies) without MDR3 mutation. Symptomatic gallstone disease was more prevalent in heterozygous relatives (7/21) than in relatives without the mutation (1/34), (P = 0.00341). CONCLUSION: This study demonstrates that splicing mutations in the MDR3 gene can cause ICP with normal gamma-GT and may be associated with stillbirths and gallstone disease.- - - - - - - - - - ranking = 1keywords = probability (Clic here for more details about this article) |
6/6. Autistic symptoms among children and young adults with isodicentric chromosome 15.A standardized assessment of autistic symptomatology was completed for 29 children and young adults with a supernumerary isodicentric chromosome 15 (formerly known as inverted duplication 15). Although there was variability in severity, 20 individuals with an isodicentric chromosome 15 [idic(15)] had a high probability of being autistic. Eight of the 9 remaining children were under age 5 years and were more sociable than the rest of the cohort. Group characteristics such as gender and seizure presence could not explain the observed difference between older and younger individuals in our study. The natural history of isodicentric 15 syndrome remains to be shown through longitudinal work and may include an age-related risk for developing autism.- - - - - - - - - - ranking = 1keywords = probability (Clic here for more details about this article) |