1/43. Normal expression of the fanconi anemia proteins FAA and FAC and sensitivity to mitomycin C in two patients with Seckel syndrome.Seckel syndrome is a rare autosomal recessive disorder. The classical presentation includes pre- and postnatal growth deficiency, mental retardation, and characteristic facial appearance. There have been several reports of associated hematological abnormalities and chromosomal breakage, findings suggestive of fanconi anemia (FA). We tested for these findings in two Arabic patients with this syndrome. We compared the growth profile of lymphoblastoid cells from our patients and their parents with the FA group A cell line HSC72 in the presence and absence of mitomycin C (MMC). By Western analysis, we also determined the expression of FAA and FAC, two FA disease gene products that together account for approximately 80% of FA. Unlike HSC72 cells, cells from the patients were resistant to MMC, and both FAA and FAC proteins were expressed at similar levels in all cell lines. There is an increasing recognition of clinical variability and perhaps genetic heterogeneity in Seckel syndrome. Our results demonstrate that cross-link sensitivity comparable to FA is not a uniform finding in patients with Seckel syndrome.- - - - - - - - - - ranking = 1keywords = breakage (Clic here for more details about this article) |
2/43. Embryonal rhabdomyosarcoma and chromosomal breakage in a newborn infant with possible Dubowitz syndrome.We report on a newborn girl with Dubowitz syndrome (DS) and embryonal rhabdomyosarcoma (ERMS), with multiple chromosomal breakage (MCB). The tumor was resected but recurred in a few months, resulting in the infant's death. Malignancy and chromosomal breakage have been reported previously in DS. However, ERMS has not been reported among the malignant tumors diagnosed in DS. To our knowledge, concurrence of DS, ERMS, and MCB has not been reported previously. This is the first observation of DS in the Arab ethnic group.- - - - - - - - - - ranking = 6keywords = breakage (Clic here for more details about this article) |
3/43. telomere-telomere (end to end) fusion of chromosomes 7 and 22 with an interstitial deletion of chromosome 7p11.2-->p15.1: phenotypic consequences and possible mechanisms.We report a rare case of a de novo end to end fusion of chromosomes 7 and 22 in conjunction with an interstitial deletion of chromosome 7p11.2p15.1 in a newborn with congenital anomalies. The proband presented for chromosome analysis with bilateral cataracts, dysmorphic facies and distal limb abnormalities. Chromosome analysis showed a 45,XY,der(22)psu dic(22;7)(p13;p22.3)del(7)(p11.2p15.1) karyotype. This short arm to short arm fusion of chromosomes 7 and 22 resulted in a pseudodicentric chromosome. The interstitial deletion in the short arm of chromosome 7 was likely a result of breakage and reunion related to instability of the dicentric chromosome. Loss of genetic material in this region of chromosome 7p has been implicated in the pathophysiology of craniosynostosis and cephalopolysyndactyly syndromes.- - - - - - - - - - ranking = 1keywords = breakage (Clic here for more details about this article) |
4/43. 657del5 mutation in the NBS1 gene is associated with nijmegen breakage syndrome in a Turkish family.We report on a consanguineous Turkish family whose first son died of anal atresia and whose second son presented with severe pre- and post-natal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosomal instability and rhabdomyosarcoma in the anal region. The proband was found to carry the homozygous 657del5 mutation in the NBS1 gene, which is responsible for nijmegen breakage syndrome (NBS) in most of the Slav populations. Our family, the first diagnosed with NBS in the Turkish population, represents one of the most severely affected examples of the syndrome, with profound pre- and post-natal growth retardation associated with structural abnormalities, and expands the clinical spectrum of this rare disorder.- - - - - - - - - - ranking = 24.973289694881keywords = breakage syndrome, breakage (Clic here for more details about this article) |
5/43. genetic heterogeneity for a Nijmegen breakage-like syndrome.nijmegen breakage syndrome (NBS) is a rare, autosomal-recessive chromosome instability disorder characterized by growth and developmental defects, immunodeficiency, high susceptibility to lymphoid malignancies, hypersensitivity to ionizing radiation and aberrant cell-cycle checkpoint control. The disease is caused by mutations in the NBS1 gene, which encodes nibrin, a component of the hMre11-Rad50-p95 complex involved in cellular response to DNA double-strand breaks. genetic heterogeneity has been suggested in at least two patients with the NBS phenotype, but no mutation in the NBS1 gene; recently, mutations in the gene encoding the enzyme ligase IV have been identified in patients with signs of NBS. We describe a boy with an NBS clinical phenotype but no mutation in either the NBS1 or the LIG4 genes. The analysis of his cellular phenotype reveals chromosome instability and radiosensitivity, but normal cell-cycle checkpoint control. In addition, a literature review was carried out to summarize and compare data of all NBS-like patients reported to date. This case confirms genetic heterogeneity for NBS. We believe that dissecting the clinical and cellular phenotypes of this and other NBS-like patients will provide useful information for the research of new genes involved in cellular response to dna damage and the assessment of cancer risk in NBS-like syndrome.- - - - - - - - - - ranking = 8.9946579389761keywords = breakage syndrome, breakage (Clic here for more details about this article) |
6/43. Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized nijmegen breakage syndrome.BACKGROUND: In large-scale pediatric chemo- and radiotherapy trials a proportion of patients as high as 10-15% is usually reported as having severe treatment related toxicity occasionally resulting in toxic death. Little is known on the underlying predisposition of the individual child. Several hereditary disorders including immunodeficiency (ID) syndromes or repair disorders, ataxia telangiectasia (AT), and nijmegen breakage syndrome (NBS) were associated with an elevated risk for severe treatment related toxicity. PROCEDURE: This report involves the case of a 7-year-old boy with medulloblastoma who suffered from remarkably severe side effects during and after postoperative radio- and chemotherapy. Several months following craniospinal radiation with a total dose of 36 Gy, late normal tissue side effects were observed within the treated volume. Eighteen months after initiation of treatment the patient died due to protracted cardiopulmonary failure. RESULTS: To quantify the intrinsic radiation sensitivity, lymphoblastoid cells were used to examine chromosomal aberrations by fluorescence in situ hybridization detecting between two to ninefold higher chromosomal breakage rates in comparison to cells of average cancer patients. skin fibroblasts showed in the clonogenic survival assays a twofold increased sensitivity. Western blotting demonstrated a typical lack of Nbs1. PCR-SSCP analysis followed by direct sequencing of positive samples revealed a homozygous truncating mutation of the NBS1 gene (657del5). CONCLUSIONS: This case highlights that severe treatment related complications in pediatric cancer patients may be the result of increased intrinsic radio- and chemosensitivity due to NBS, AT, and other ID syndromes. It is suggested to exclude such conditions in all patients with anthropometric parameters below the 3rd centile and other signs suggestive for repair disorders or ID syndromes.- - - - - - - - - - ranking = 25.973289694881keywords = breakage syndrome, breakage (Clic here for more details about this article) |
7/43. Inv dup del(4)(:p14 --> p16.3::p16.3 --> qter) with manifestations of partial duplication 4p and wolf-hirschhorn syndrome.An 8-year-old girl with a combination of clinical manifestations of partial duplication 4p and the wolf-hirschhorn syndrome was studied. Chromosomal G-banding and FISH analyses showed a 33.2-Mb segment of inverted duplication at 4p14-p16.3 and a 2.8-Mb segment of deletion at 4p16.3-pter (including the wolf-hirschhorn syndrome critical region). The chromosomes of the parents were normal. Her karyotype was thus 46,XX, inv dup del(4)(:p14 --> p16.3::p16.3 --> qter) de novo. The inverted duplication deletion was assumed to have arisen through chromatid breakage at 4p16.3, U-type reunion at the breakpoints to produce a dicentric intermediate, breakage of the dicentric to result in a monocentric, and telomere capture/healing of the broken end. Olfactory receptor gene clusters at 4p16.3 were ruled out as an intermediary of the duplication deletion process.- - - - - - - - - - ranking = 2keywords = breakage (Clic here for more details about this article) |
8/43. Hallermann-Streiff syndrome associated with small cerebellum, endocrinopathy and increased chromosomal breakage.Hallermann-Streiff syndrome (HSS) is a rare clinic entity of unknown aetiology. Further clinical and metabolic-genetic evaluations are indicated. A 2-mo-old female baby presented with ocular abnormalities and severe failure to thrive since birth. The clinical features were compatible with the diagnosis of HSS. Further imaging, metabolic and cytogenetic examinations were performed. Features characteristic of HSS were dyscephaly with mandibular and nasal cartilage hypoplasia, microphthalmia, bilateral cataracts with congenital glaucoma, natal teeth and proportionate dwarfism. Rare anomalies such as choanal atresia and small cerebellum, very low insulin-like growth factor i level, hypothyroidism, generalized organic aciduria were also noticed. An increased chromosomal breakage rate is suggestive of the existence of some dna repair defects in HSS patients. CONCLUSION: The associated anomalies in this patient may broaden the clinical spectrum of HSS. Underlying conditions of organic aciduria, growth factor deficiency and impaired dna repair are likely to contribute to the progeria-like facies, congenital cataracts and growth failure.- - - - - - - - - - ranking = 5keywords = breakage (Clic here for more details about this article) |
9/43. VACTERL with hydrocephalus: one end of the fanconi anemia spectrum of anomalies?Two cases of fanconi anemia presenting as hydrocephalus are discussed. Both infants had initially been considered to have features of VACTERL. Chromosomal breakage studies should be performed in all cases of VACTERL with hydrocephalus so that fanconi anemia may be excluded.- - - - - - - - - - ranking = 1keywords = breakage (Clic here for more details about this article) |
10/43. Retrospective diagnosis and subsequent prenatal diagnosis of nijmegen breakage syndrome.OBJECTIVE: We report on the retrospective diagnosis of nijmegen breakage syndrome (NBS) confirmed by molecular genetic analysis and consecutive prenatal diagnosis in the same family. METHOD: Thirteen years after the death of their daughter due to fatal recurrent infections, a couple presented in our genetic counselling unit asking for the recurrence risk of their daughter's disease. Retrospective analysis of the medical record suggested that the girl might have suffered from NBS. Therefore, molecular genetic analysis for NBS was performed in the parents. RESULTS: After the diagnosis, NBS could be indirectly proven by molecular genetic heterozygosity testing of the parents, and a reliable prenatal diagnosis for a new pregnancy could be offered. In a following pregnancy, a massive hydrocephalus was diagnosed by ultrasound investigation. amniocentesis was performed, and molecular analysis of the fetal DNA revealed homozygosity for the NBS1 mutation 657del5. CONCLUSION: The analysis of this family allows a further delineation of the prenatal NBS phenotype including hydrocephalus and dystopic kidneys that are helpful parameters to recognise NBS prenatally, also by ultrasound investigations in pregnancy. Additionally, we conclude that hydrocephalus might be more common in NBS patients than previously suggested.- - - - - - - - - - ranking = 24.973289694881keywords = breakage syndrome, breakage (Clic here for more details about this article) |
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