1/16. 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) |
2/16. 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) |
3/16. Inverted duplications are recurrent rearrangements always associated with a distal deletion: description of a new case involving 2q.We studied the case of a subject with an inverted duplication of 40 cM of 2q33-q37 concurrent with a 10 cM deletion of the distal 2q, the latter not being detectable by cytogenetics. Microsatellite analysis demonstrated the absence of maternal alleles in the deleted region and a double dosage for one of the maternal alleles in the duplication region. We hypothesised that this type of rearrangement occurs at meiosis I, while the two homologues are synapsed for most of their length. The presence of inverted duplicons in the same chromosome arm would favour the partial refolding of one homologue into itself so leading to the intrachromatid synapsis and recombination of the inverted repeats. The arising recombinant chromosome is deleted for the region beyond the most distal repeat and with the chromatids joined together at the level of the region located between the two duplicons. At meiosis II, the two linked chromatids can join the opposite poles provided that a breakage between the two centromeres occurs leading to a duplicated/deleted chromosome and a simply deleted chromosome. This model can be extended to all the so-called inverted duplication cases and to part of the terminal deletions. In fact the finding that, in our invdup(2q), the entire 40 cM duplication region involves only one of the two maternal alleles, indeed indicates that the abnormal crossover occurs between sister chromatids. The phenotype associated with our 2q rearrangement led us to narrow the critical region for the Albright-like syndrome to 10 cM in the subterminal 2q region.- - - - - - - - - - ranking = 1keywords = breakage (Clic here for more details about this article) |
4/16. Combined immunodeficiency, chromosomal instability, and postnatal growth deficiency in a Japanese girl.We report on an 11-year-old Japanese girl with combined immunodeficiency and chromosomal instability. She had postnatal growth deficiency and microcephaly, preaxial polydactyly of the left hand, and susceptibility to infections. Immunological studies showed marked lymphocytopenia (around 500/ll), reduced lymphocyte response to various mitogens, and reduced or absent serum IgA, IgG, and IgM. Cell biological studies of her primary skin fibroblasts demonstrated spontaneous chromosome aberrations and radiation hypersensitivity. The combination of immunodeficiency, chromosomal instability, and radiation hypersensitivity as seen in the girl is present in both ataxia-telangiectasia and nijmegen breakage syndrome. ataxia-telangiectasia was excluded because of differences in clinical features and laboratory data. Likewise, nijmegen breakage syndrome is unlikely to be the case because the characteristic face, hyperpigmented spots, and mental retardation present in the syndrome were missing in the girl. sequence analysis of a nijmegen breakage syndrome responsible gene, NBS1, revealed no mutations. A normal NBS1 product was also demonstrated by immunoblot analysis using an anti-NBS1 antibody. We propose that the disorder in the girl represents a new combination of combined immunodeficiency and chromosomal instability.- - - - - - - - - - ranking = 21.041345675815keywords = breakage syndrome, breakage (Clic here for more details about this article) |
5/16. Atypical progeroid syndrome: an unknown helicase gene defect?We describe a boy with chromosomal breakage syndrome, who died of hepatocellular carcinoma at the age of 17 years. Other findings included growth retardation, bilateral cataracts, premature graying of hair and elevated levels of urinary hyaluronic acid. Intellectual functions were normal. Although some manifestations were suggestive of werner syndrome, the diagnosis could not be confirmed by molecular investigations. Therefore, this patient probably represents a provisionally unique syndrome, perhaps due to a mutation in a related (helicase) gene.- - - - - - - - - - ranking = 7.0137818919384keywords = breakage syndrome, breakage (Clic here for more details about this article) |
6/16. medulloblastoma with adverse reaction to radiation therapy in nijmegen breakage syndrome.A 3-year-old child with microcephaly, facial dysmorphism, growth retardation, and developmental delay was diagnosed with medulloblastoma. craniospinal irradiation resulted in severe radiation-induced dermatitis and gastroesophagitis, unresponsive to further medical therapy. Colony survival assay on the patient's transformed lymphocytes revealed a high degree of radiosensitivity ex vivo. The presence of radiation sensitivity, both clinically and ex vivo, in association with microcephaly and growth retardation, prompted a diagnostic workup for nijmegen breakage syndrome. The patient was confirmed to have a compound heterozygote genotype for the common founder mutation of NBS1 675del5 in exon 6, and 1142delC in exon 10. Because irradiation is an important component of therapy for brain tumors, caution should be exercised in cancer patients with associated microcephaly and growth retardation, as they may turn out to have the rare diagnosis of nijmegen breakage syndrome.- - - - - - - - - - ranking = 137.68858827967keywords = nijmegen breakage syndrome, breakage syndrome, nijmegen breakage, nijmegen, breakage (Clic here for more details about this article) |
7/16. T-cell prolymphocytic leukemia with autoimmune manifestations in nijmegen breakage syndrome.nijmegen breakage syndrome (NBS) is characterized by growth retardation, microcephaly, mental retardation, immunodeficiency, and predisposition to malignancies, especially B-cell lymphomas. In contrast, leukemia is rare. A 23-year-old NBS patient presented with anemia, thrombocytopenia, and hyperlymphocytosis. The diagnosis of T-cell prolymphocytic leukemia (T-PLL) was confirmed by cytological and immunological assays (TdT(-), CD2( ), CD5( ), CD3m, and CD7( )). Biological assays also showed a hemolytic anemia and a clotting factor V decrease. The patient was first treated by methylprednisone for 3 weeks. During this period the lymphocyte count decreased. The simultaneous normalization of the hemolysis and of factor V suggested that both could be related to T-PLL. Since T-PLL is refractory to conventional therapies with a poor prognosis, an intensive chemotherapy such as 2'-deoxycoformycin with anti-CDw52 monoclonal antibodies is usually favored. In the present case, however, because of the specific context (i.e., NBS-induced immunodepression, severe hemolytic anemia, and acquired factor v deficiency), he received pentostatin weekly during 1 month and in maintenance during 6 months. At last follow-up (7 months) he showed a persistent control of the lymphocytosis with no side effect.- - - - - - - - - - ranking = 35.068909459692keywords = breakage syndrome, breakage (Clic here for more details about this article) |
8/16. Progressive vitiligo, mental retardation, facial dysmorphism, and urethral duplication without chromosomal breakage or immunodeficiency.A boy, born to first cousin parents of Algerian origin, first presented at the age of 9 years with growth failure, mental retardation, and dysmorphic facies. Progressive vitiligo developed from the age of 12 and distal duplication of the urethra was later recognised. The basis of this syndrome remains to be determined; autoimmune disease, chromosomal breakage syndromes, and other neurocutaneous syndromes have been excluded.- - - - - - - - - - ranking = 11.013781891938keywords = breakage syndrome, breakage (Clic here for more details about this article) |
9/16. rhabdomyosarcoma in nijmegen breakage syndrome: strong association with perianal primary site.nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder resulting from mutations in the NBS1 gene, which encodes for the dna double strand break repair protein nibrin. NBS is clinically characterized by microcephaly, dysmorphic features, immunodeficiency, and increased susceptibility to malignancy, mainly of lymphoid origin. Here, we describe a 7-year-old girl with NBS who is homozygous for the NBS1 698del4 mutation. She had been diagnosed with perianal rhabdomyosarcoma (RMS) and experienced severe toxicity from chemotherapy. RMS arising perianally is extremely uncommon but has been previously described in two cases with NBS. The strong association of perianal RMS with NBS should, therefore, be considered when confronted with a perianal RMS, as this carries important clinical implications in terms of potential need for therapy modification and follow up investigations. In addition, it suggests a role for the NBS1 gene and the nibrin dependent pathway in the pathogenesis of RMS, especially those arising perianally.- - - - - - - - - - ranking = 35.068909459692keywords = breakage syndrome, breakage (Clic here for more details about this article) |
10/16. A patient with mutations in dna Ligase IV: clinical features and overlap with nijmegen breakage syndrome.The clinical phenotype of Ligase IV syndrome (LIG4 syndrome), an extremely rare autosomal recessive condition caused by mutations in the LIG4 gene, closely resembles that of nijmegen breakage syndrome (NBS), and is characterized by microcephaly, characteristic facial features, growth retardation, developmental delay, and immunodeficiency. We report a 4(1/2)-year-old boy who presented with acute T-cell leukemia. The facial gestalt was strongly reminiscent of NBS. The patient died shortly after the onset of treatment for his T-cell leukemia. Subsequent chromosome breakage studies showed a high rate of breakage in a fibroblast culture. Radiosensitivity was assessed by a colony survival assay; the results showed radiosensitivity greater than is typically seen in NBS. mutation screening of the NBS1 gene was negative. Sequencing of the LIG4 gene revealed a homozygous truncating mutation 2440 C>T (R814X). Although this mutation has been previously noted in LIG4 syndrome, this patient is the first reported homozygote for the mutation. In this study, we review the clinical features of this rare syndrome and provide suggestions for differential diagnosis.- - - - - - - - - - ranking = 37.068909459692keywords = breakage syndrome, breakage (Clic here for more details about this article) |
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