Predictive diagnosis and genetic screening: manipulation of fate?
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Attitude↗
Biomedical subjects
W Henn
Publications and source records attributed to W Henn.
Mosaicism in Turner's syndrome.
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Cognition↗
Clonal chromosome aberrations in three of five sporadic angiomyolipomas of the kidney.
Clonal chromosomal changes were detected in three of five sporadic angiomyolipomas of the kidney irrespective of a solitary or multifocal appearance of this benign tumor type. No specific chromosomal changes have been identified. Including the cytogenetic data of the four renal angiomyolipomas reported in the literature, trisomy 7 as the single clonal chromosomal abnormality was detected in two angiomyolipomas. Because trisomy 7 has been reported in both neoplastic and nonneoplastic kidney cells, it may be assumed that trisomy 7 is already physiologically resident in renal cells but undergoes positive selection in this tumor type.
Adult↗
Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia.
Cleidocranial dysplasia (CCD) is an autosomal-dominant condition characterized by hypoplasia/aplasia of clavicles, patent fontanelles, supernumerary teeth, short stature, and other changes in skeletal patterning and growth. In some families, the phenotype segregates with deletions resulting in heterozygous loss of CBFA1, a member of the runt family of transcription factors. In other families, insertion, deletion, and missense mutations lead to translational stop codons in the DNA binding domain or in the C-terminal transactivating region. In-frame expansion of a polyalanine stretch segregates in an affected family with brachydactyly and minor clinical findings of CCD. We conclude that CBFA1 mutations cause CCD and that heterozygous loss of function is sufficient to produce the disorder.
Alleles↗
[Meningioma. Classification and grading].
Meningiomas account for the most frequent primary intracranial neoplasms in adults. In 1993, the so-called atypical meningioma has additionally been introduced in the revised edition of the WHO Classification of Tumors of the Central Nervous System and should characterize meningiomas with an increased propensity to recur. Since the given qualitative histological criteria apply both to the "atypical" and anaplastic meningioma, mere histological grading appears somewhat critical. Therefore, additional parameters were tested for their contribution to meningioma grading: First of all, we succeeded in defining 3 meningioma "grades" by calculating corresponding 95% confidence intervals for the morphometrically assessed Ki-67 indices of 160 meningiomas in total, the validity of which was proved by comparison with the "recurrence"-free intervals. Histologically, atypical meningiomas were distinguished by a "syncytial", poorly structured growth pattern and macronucleoli. Only occasionally, nuclear pleomorphism, necroses and mitotic figures were found. Cytogenetics revealed, in 50% of the "atypical" and anaplastic meningiomas, partial loss of the short arm of one chromosome 1 (1p-). Histochemically, we could demonstrate, that the tissue non-specific type of alkaline phosphatase (ALPL), which is coded on chromosome 1p, is a convenient recurrence- and progression-associated marker enzyme for meningiomas with 1p-loss (loss of enzyme activity in 30/39 of intermediate and 8/8 anaplastic meningiomas). We favor to address the WHO "atypical" meningioma as meningioma of the intermediate type, since the attribute "atypical" in the context of histological diagnoses is highly susceptible to misinterpretations.
Adult↗
Progressive hydrocephalus in two members of a family with autosomal dominant Noonan phenotype.
We present a family with an autosomal dominant phenotype characterized by pulmonary valve stenosis, craniofacial dysplasia with marked hypertelorism and, as a variable feature, progressive hydrocephalus. This phenotype is manifested in four patients from three subsequent generations of a family, with expression ranging from mild pulmonary stenosis combined with slight but characteristic facial dysmorphism to severe cyanotic pulmonary valve stenosis with multiple malformations lethal in early childhood. We consider this to be an unusual variant of Noonan syndrome.
Adult↗
Loss of alkaline phosphatase activity in meningiomas: a rapid histochemical technique indicating progression-associated deletion of a putative tumor suppressor gene on the distal part of the short arm of chromosome 1.
Apart from defined histomorphologic features, increased Ki-67 indices and various numeric and structural chromosome aberrations, meningiomas of the intermediate (WHO grade II, atypical meningioma) and anaplastic type (WHO grade III) are cytogenetically distinguished from common-type meningiomas (WHO grade I) by frequent loss of the distal part of the short arm of one chromosome 1 (1p-), which formerly proved to be an independent predictor of shorter recurrence-free intervals. Histochemically, loss of alkaline phosphatase activity (ALPL, liver/bone/kidney type, EC 3.1.3.1) was another frequent, specific finding in meningiomas with signs of dedifferentiation. In a prospective study including 66 meningiomas, all common-type meningiomas except one case (18/19) were reactive for ALPL, whereas 75% (30/39) of intermediate type and all anaplastic meningiomas (8/8) showed loss of enzyme activity in large areas of the tumor. Exclusively, the ALPL negative phenotype was associated with 1p loss (15/19). Our data suggest that ALPL, which is coded as a single copy gene on chromosome 1p36.1-p34, is a useful marker enzyme for the loss of a putative regulatory (tumor suppressor) gene on chromosome 1p, or that ALPL itself represents a new tumor suppressor gene homozygously inactivated in meningiomas.
Alkaline Phosphatase↗
Chromosomal findings and p53-mutation analysis in chromophilic renal-cell carcinomas.
The chromosomal pattern of 31 specimens of chromophilic renal-cell cancer (RCC), selected according to the criteria mentioned in the classification of Thoenes and Störkel, is presented. A high male preponderance was found (8.7:1). Cytogenetic analysis revealed a typical pattern of numeric alterations specific for this sub-type in the majority of cases (i.e., --Y,+7, +12, +16, +17, and/or +20), which is different from the chromosomal patterns found in other sub-types of RCC. Gain of chromosome 20, as well as loss of the extra copy of chromosome 17 or loss of 17p, was found to be related to the higher-grade chromophilic carcinomas. None of the 14 cases examined by SSCP analysis revealed mutations of the p53 gene, indicating that other genes at 17(p) might be important in the progression of this sub-type of RCC.
Adult↗
Early proliferation enhancement by monosomy 10 and intratumor heterogeneity in malignant human gliomas as revealed by smear preparations from biopsies.
We performed simultaneous fluorescence in situ hybridization (FISH) with centromere-specific DNA probes for chromosomes 7 and 10 and Ki-67 proliferation labelling on smear preparations of 17 differentiated and anaplastic human astrocytomas and glioblastomas. In 15 of the 17 cases studied, Ki-67-positive clones differed from Ki-67-negative clones mainly by the loss of one copy of chromosome 10, either combined with or independent of trisomy 7. The findings suggest that monosomy 10 is an earlier event than generally supposed in the development of human gliomas and that it is directly related to cellular hyper-proliferation.
Astrocytoma↗
Correlation between cytogenetic and clinical findings in 215 human meningiomas.
The management of meningiomas remains a major challenge to the neurosurgeon because patients having this common benign tumor can be cured effectively by surgical resection. But there are a number of meningiomas that have an aggressive course and tend to recur. Predicting the recurrence of meningiomas has often been mentioned in the context of histology or surgical techniques and some approaches considered. However, the recurrence rate remains between 10% and 20%, even after total removal. To improve the care of patients with problematic meningiomas, 215 different human meningiomas were collected between 1976 and 1993 and cytogenetically analyzed using standard techniques. 140 patients could be observed for 1 to 17 years after complete tumor removal, whereby 21 tumors (15%) displayed one or more recurrences during that long-term observation period. The tumors were classified according to different clonal abnormalities: we observed recurrence in 10 (9.1%) of 111 (79.2%) tumors having a normal karyotype or typical monosomy of chromosome 22, whereas 9 (69.7%) of 13 tumors with pronounced hypodiploidy and 3 (35%) of 8 tumors with a hyperdiploid karyotype recurred. A loss of the short arm of chromosome 1 was identified in 6 meningiomas with a recurrence rate of 60%. Our observations show that the correlation between meningiomas and recurrence is highly significant (p = 0.002) and that these tumors require special treatment in addition to surgical skill.
Adult↗
A novel site of DNA amplification on chromosome 1p32-33 in a rhabdomyosarcoma revealed by comparative genomic hybridization.
Cytogenetic analysis of a human embryonal rhabdomyosarcoma revealed a near-diploid karyotype with structural chromosome aberrations not involving the typical rearrangements of rhabdomyosarcomas, plus a large number of double minutes. Comparative genomic hybridization revealed a previously undescribed site of DNA amplification on the short arm of chromosome 1 (band 1p32-33).
Child↗
Constitutive expression of c-fos and c-jun, overexpression of ets-2, and reduced expression of metastasis suppressor gene nm23-H1 in rheumatoid arthritis.
OBJECTIVES: To identify genes that are involved in the development and progression of rheumatoid arthritis (RA). METHODS: We used a multiple gene analysis system and a set of available genes participating in processes such as proliferation, differentiation, tumour progression, and metastasis, to identify their RA related expression. Synovial tissues from 22 patients with RA were evaluated in comparison with those from six patients with osteoarthritis and two patients with non-inflamed joints as controls, using northern blot and reverse transcriptase polymerase chain reaction experiments. RESULTS: Our data confirm the role of c-fos and c-jun as constitutive signal transmitters in solid RA tissues, thus demonstrating the potential of the approach. Activation of both genes persisted through multiple passages of the cells in tissue cultures derived from the synovial lining of RA tissues. There was an increased expression of ets-2 in 30% of RA samples and an up to 30-fold decreased expression of the potential metastasis suppressor gene nm23-H1 in 90% of RA tissues, compared with control tissues. CONCLUSIONS: The data presented show for the first time a significant decrease of nm23-H1 expression in RA, which is possibly involved in local invasiveness, and a strong activation of the ets-2 nuclear oncogene in about one third of RA tissues, which may also be part of a pathway leading to advanced disease stages. The constitutive expression of c-fos and c-jun in RA tissue most probably results from a continuing inflammatory stimulus. These findings with cell cultures suggest an intrinsic activation mechanism of these early response genes in RA.
Arthritis, Rheumatoid↗
Proliferation enhancement by spontaneous multiplication of chromosome 7 in rheumatic synovial cells in vitro.
Mosaic trisomy of chromosome 7 is known to occur in a variety of non-neoplastic hyperproliferative disorders. In long-term cell cultures established from rheumatic synovium with mosaic trisomy 7, we observed a continuous increase in the proportion of cells with trisomy 7 to over 50% by the 10th in vitro passage. Simultaneous in situ hybridization with a repetitive chromosome-7-specific DNA probe and fluorescent Ki-67 labelling showed a strong correlation between trisomy 7 and an elevated proliferation index in cultured rheumatic synovial cells. Moreover, we observed a fraction of rapidly proliferating cells with up to eight copies of chromosome 7 as the sole cytogenetic change. Frequent somatic pairing of centromeres of two chromosomes 7 in interphase nuclei suggests either atypical non-disjunction with a persisting centromere or selective endoreduplication of chromosome 7.
Arthritis, Rheumatoid↗
Triple approach for diagnosis and grading of meningiomas: histology, morphometry of Ki-67/Feulgen stainings, and cytogenetics.
With regard to meningioma grading and the recently introduced "atypical" meningioma, we evaluated 160 cases retrospectively by conventional histology and image analysis. For that, the cell nuclei were stained with a Ki-67 (MIB1)/Feulgen-method on paraffin sections, thus enabling the assessment of both the Ki-67 proliferation index and nuclear morphometric features, such as tumour cell arrangement, nuclear pleomorphism, and cellularity. It could be demonstrated that the Ki-67 proliferation index is the most important criterion for distinguishing anaplastic meningiomas (WHO "grade" III) (mean Ki-67 index: 11%) from those of common type (WHO "grade" I) (mean Ki-67 index: 0.7%). The parameter for the "relative volume weighted mean nuclear volume" is another valuable morphometric feature. The "atypical" meningioma (WHO "grade" II) which should represent an intermediate category between common type and anaplastic meningiomas is characterized by a mean Ki-67 proliferation index of 2.1%. Common type meningiomas which comprise almost 50% of the cases of this series have a relapse rate of 9%. "Atypical" and anaplastic meningiomas recurred in 29% and 50%, respectively. Since the term "atypical" meningioma is confusing in the context of tumour grading, the term "intermediate type meningioma" is proposed. Furthermore, the results of cytogenetic analyses of 142 cases of this series were evaluated and compared with the meningioma grades. Thereby, 25 cases disclosed, independent of the typical loss of one chromosome 22, cytogenetic features assumed to be progression-associated, e.g., the gain or loss of different chromosomes and the deletion of the short arm of one chromosome 1 (hyperdiploidy, increased hypodiploidy, 1p-), when correlated to the histological and morphometric findings or the high relapse rate. For meningioma diagnosis and grading, a practical guideline is proposed based upon histology, morphometry (Ki-67), and cytogenetics.
Biomarkers, Tumor↗
Monosomy 1p is correlated with enhanced in vivo glucose metabolism in meningiomas.
The 2-[18F]fluoro-2-deoxy-D-glucose (FDG) uptake of 25 human meningiomas was preoperatively evaluated in vivo by positron-emission tomography (PET). After surgery, meningioma biopsies were analyzed cytogenetically. Five meningiomas showed partial monosomy for chromosome 1p additional to other typical chromosome aberrations. This aberrant karyotype was correlated with increased FDG uptake. Three of five meningiomas with monosomy 1p were classified as grade II according to WHO, while only one of 20 tumors without monosomy 1p was classified as grade II. Thus, monosomy 1p and elevated FDG uptake in PET are to be regarded as cytogenetic and metabolic parameters for the aggressiveness of meningiomas.
Adult↗
Polysyndactyly and asymptomatic hypothalamic hamartoma in mother and son: a variant of Pallister-Hall syndrome.
We report on a 53-year-old woman and her 20-year-old son who both presented with polysndactyly, without other external malformations or mental retardation. MRI imaging revealed, as an incidental finding, asymptomatic hypothalamic hamartomas in both patients. The siblings of both mother and son are unaffected. This family may represent an autosomal dominant variant of Pallister-Hall syndrome.
Abnormalities, Multiple↗
Detection of numerical chromosome aberrations in brain tumours by fluorescence in situ hybridization on smear preparations of small tumour biopsies.
We present a technique for the preparation and interphase cytogenetic analysis of native tumour cell nuclei from smear preparations of small biopsies of human brain tumours. The presence of tumour-specific numerical chromosome aberrations can be determined by fluorescence in situ hybridization (FISH) analysis using chromosome-specific repetitive DNA probes. The FISH analysis of smear preparations provides cytogenetic information about brain tumour samples, within 2 days, avoiding time-consuming and artefact-prone tumour cell culture.
Biopsy↗
[18FDG-PET in intracranial meningiomas versus grading, proliferation index, cellular density and cytogenetic analysis].
62 intracranial meningiomas in 60 patients were studied with 18FDG-PET prior to neurosurgery in order to evaluate the relationship between 18FDG uptake and biological aggressiveness of the tumors. Histopathological grading, cellular density, Ki-67 proliferation index and evidence of chromosomal aberrations were used to assess tumor aggressiveness. Significantly elevated 18FDG uptake was found in grade 2- and 3- compared to grade 1-meningiomas, in tumors of high cellularity compared with those of low cellularity, and in meningiomas with an elevated Ki-67 proliferation index (above 2%). The two meningiomas with the most pronounced chromosomal aberrations revealed the highest 18FDG uptake of all cytogenetically studied meningiomas. We conclude that 18FDG-PET is useful for estimating the biological aggressiveness of intracranial meningiomas.
Adult↗