Kleine Deletion—große Auswirkung

Zusammenfassung Das velokardiofaziale Syndrom (VCFS) oder Shprintzen-II-Syndrom zeichnet sich v. a. durch Gaumenspalte (69%), Herzfehler (74%), charakteristische faziale Dysmorphien sowie Lernschwierigkeiten (70–90%) aus. Es weist Phänotypüberlappungen mit dem DiGeorge-Syndom (DGS) auf. 1992 wurde nachgewiesen, dass bei Patienten mit VCFS eine partielle Monosomie 22q11 vorliegt. Deletionsbereich und variable Deletionsgröße unterscheiden sich bei vielen VCFS-Patienten nicht von denen der DGS-Patienten. Für den HNO-Arzt ist wichtig, dass bei Auffälligkeiten in Form von Mittelohraffektionen und einer—ggf. auch submukösen—Gaumenspalte auch nach kardialen Erkrankungen gefragt werden sollte. Liegt eine Kombinationserkrankung vor, sollte zu einer humangenetischen Untersuchung des Kindes geraten werden, um dem Verdacht auf das Vorliegen eines velokardiofazialen Syndroms zu bestätigen oder auszuschließen. Nur so kann diese genetisch bedingte Erkrankung frühzeitig erkannt werden.     

Fluorescent in situ hybridizaton evaluation of p53 gene deletions at a tumor interface of lingual carcinoma

OBJECTIVE/HYPOTHESIS: To evaluate the ability of fluorescent in situ hybridization (FISH) to detect malignant cells missed by standard histological assessment at an interface between malignant and normal tissue in lingual squamous cell carcinoma (SCC) and to correlate findings of FISH assessment with patients' clinical stages. STUDY DESIGN: Retrospective assessment of archival tissue from 31 patients with lingual SCC treated at University of Wisconsin Hospital and Clinics in Madison. METHODS: An assay combining standard histological and FISH techniques was used to assess a tumor interface tissue section and allow identification of each tumor's ploidy characteristics and p53 gene deletions and the presence or absence of malignant cells within tissue viewed as "normal" on histological review. RESULTS: Forty-five percent of tumors (14 of 31) demonstrated ploidy changes and 84% (26 of 31) showed p53 deletions. Of these 26 tumors with p53 deletions, 14 were found to have "microfoci" with p53 deletions within tissue that appeared normal on histological examination. These microfoci were found in 75% of late-stage tumors and in only 35% of early-stage tumors. CONCLUSIONS: FISH allowed identification of malignant cells in tissue viewed as normal on standard histological assessment, and this finding occurred more frequently in late-stage tumors.     

Genotype and phenotype in patients with Prader-Willi syndrome in Taiwan

AIM: Several different genetic defects have been found to result in the characteristic phenotypic expression of Prader-Willi syndrome (PWS). METHODS: We performed a retrospective analysis of 67 cases of molecularly confirmed PWS diagnosed from January 1980 through July 2006 in five medical centres in Taiwan. Clinical manifestations were compared between patients with deletion and those with maternal uniparental disomy (UPD). RESULTS: Deletion was present in 56 (84%), UPD in 10 (15%), and a probable imprinting centre deletion or imprinting defect in 1 (1%). PWS with deletion was more likely than that with UPD to be characterized by hypogonadism (p < 0.001), small hands and feet (p < 0.001), and hypopigmentation (p < 0.002). Both maternal (p = 0.015) and paternal age (p = 0.021) were higher in the UPD group. No other clinical features differed significantly different between the two groups. CONCLUSION: In contrast to most Western populations with a higher incidence of UPD, this study of PWS in Taiwan shows a higher incidence of deletion. There may be subtle phenotypic differences between the UPD and deletion genotypes, but its not clear that these are important clinically.     

Study on hepatitis B virus pre-S/S gene mutations of renal tissues in children with hepatitis B virus-associated membranous nephropathy

This study aims to clarify the prevalence and significance of the emergence of hepatitis B virus (HBV) pre-S/S mutations in children with hepatitis B virus-associated membranous nephropathy (HBVMN). Direct sequencing of polymerase chain reaction products of renal tissue samples that were obtained via percutaneous renal biopsy from seven children revealed the presence of HBV DNA. Seven adr subtypes were analyzed. Deletions in the HBV pre-S region were observed once per seven patients. The deletions were noted in both the pre-S1 (27 bp) and pre-S2 (60 bp) regions. Various point mutations in the HBV pre-S region were detected in all seven patients and proved to be more frequent in the pre-S1 region than in the S2 region. Point mutations in the HBV S region were detected in six patients. Among these mutations, the mutation in the “a” determinant region was noted in five patients. No deletion, however, was observed in the HBV S region. These observations suggested that deletions and point mutations in the HBV pre-S1 and pre-S2 regions and point mutations in the HBV S region, especially the “a” determinant region, are common frequent findings. These results also suggested that HBV pre-S/S region mutations may be involved in the pathogenesis in children with HBVMN.     

Risk estimation in localized unresectable single copy MYCN neuroblastoma by the status of chromosomes 1p and 11q

In localized neuroblastoma, the identification of patients requiring intensive treatment is still difficult. We retrospectively analyzed data of 280 single copy MYCN stage 2 and 3 neuroblastoma patients with gross residual tumor after initial surgery. The 3-year-event free survival of the total group was 83+/-2%, and 3-year-overall survival was 92+/-2%. Patients < or=1.5 years had a better outcome than older children. Deletions/imbalances of chromosome 1p were found in 9/90 patients and were associated with a higher event rate but not with a higher death rate. Aberrations of chromosome 11q in 14/91 patients were correlated with a higher event and death rate. Multivariate analysis identified 1p aberrations as important for event free survival and 11q aberrations for overall survival.     

Direct repeats in mitochondrial DNA and mammalian lifespan

Mitochondria have long been suspected to be among the leading determinants of aging due to their functional importance and accelerated deterioration caused by accumulation of mutations in the mitochondrial DNA. Direct repeats are known to contribute to deletion formation in mtDNA and are a powerful source of reactive oxygen species (ROS)-independent mutagenesis. To evaluate the potential importance of homology-based deletion formation, we have analyzed the association between direct repeats in the mtDNA sequence and the lifespans of 65 mammalian species. Here, we report a significant negative correlation between the mutagenic potential of direct repeats and the mammalian lifespan, which is especially evident in closely related species.     

Bone marrow transplantation for therapy-related acute myeloid leukemia in congenital retinoblastoma associated with 13q deletion syndrome

Children with constitutional deletion of the long arm of chromosome 13 are at risk for retinoblastoma (RB) due to loss of the RB tumor suppressor gene. The prognosis is poor since the tumors are often bilateral, aggressive, and recurrent and the patients often harbor other congenital abnormalities. One further complication is that of therapy-related malignancies later in life. We report a case of allogeneic stem cell transplantation for therapy-related acute myeloid leukemia in an 8-year-old girl after multimodality treatment for refractory bilateral relapsing RB, with excellent outcome in both the ophthalmic and marrow disease.     

Evaluation of mechanical strengths of three types of mini-implants in artificial bones

We investigates the effect of the anchor area on the mechanical strengths of infrazygomatic mini-implants. Thirty mini-implants were divided into three types based on the material and shape: Type A (titanium alloy, 2.0 × 12 mm), Type B (stainless steel, 2.0 × 12 mm), and Type C (titanium alloy, 2.0 × 11 mm).The mini-implants were inserted at 90° and 45° into the artificial bone to a depth of 7 mm, without predrilling. The mechanical strengths [insertion torque (IT), resonance frequency (RF), and removal torque (RT)] and the anchor area were measured. We hypothesized that no correlation exists among the mechanical forces of each brand. In the 90° tests, the IT, RF, and RT of Type C (8.5 N cm, 10.2 kHz, and 6.1 N cm, respectively) were significantly higher than those of Type A (5.0 N cm, 7.7 kHz, and 4.7 N cm, respectively). In the 45° test, the RFs of Type C (9.2 kHz) was significantly higher than those of Type A (7.0 kHz) and Type B (6.7 kHz). The anchor area of the mini-implants was in the order of Type C (706 mm²) > Type B (648 mm²) > Type A (621 mm²). Type C exhibited no significant correlation in intragroup comparisons, and the hypothesis was accepted. In the 90° and 45° tests, Type C exhibited the largest anchor area and the highest mechanical strengths (IT, RF, and RT) among the three types of mini-implants. The anchor area plays a crucial role in the mechanical strength of mini-implants.     

Identification of Two Potential Suppressor Gene Regions on Chromosome Arm 14q That Are Commonly Lost in Advanced Colorectal Carcinomas

Background: Remarkably little is known about the molecular alterations contributing to the establishment of a distant metastasis from a primary colorectal carcinoma. Previous studies on primary colorectal carcinomas have suggested an association between loss of chromosome 14 sequences and cancer progression. Methods: In the present study, we analyzed 20 distant metastases and peripheral blood samples from 18 patients using 24 microsatellite markers spanning chromosome arm 14q. In addition, DNA from microdissected corresponding primary tumors (formalin-fixed and paraffinembedded) was analyzed at selected 14q loci. Results: Sixty-five percent (13/20) of the metastases, from 11/18 patients, showed loss of one or more markers at 14q, and the majority (94%) of the primary carcinomas showed identical 14q genotypes to those found in the metastasis. Two minimal common deleted regions were delineated in the metastases, one between markers D14S288-D14S52 at 14q13-21 and the other between D14S284-D14S81 at 14q24-31, pinpointing two previously unrecognized map positions for potential target genes. The genotype pattern of five tumors was consistent with monosomy or large chromosomal deletions spanning both potential suppressor regions. The reasons for monosomy in cancer remain unknown, but our data support the hypothesis that deletions of several tumor suppressor genes are more readily obtained by one chromosome loss than by several molecular events, and through this unison loss a growth advantage may be provided. Conclusion: Our data suggest that 14q loss is not a rate-limiting event in colorectal metastasis formation, but the high frequency of this alteration in primary tumors with metastatic ability, as well as in the metastases themselves, suggests it is part of the tumor clone with selective growth capacity.