Chromosome instability and X-ray hypersensitivity in a microcephalic and growth-retarded child.

We report on a microcephalic, growth-retarded newborn girl without major anomalies who has chromosome instability in lymphocytes and fibroblasts. Frequent involvement of bands 7p13, 7q34, 14q11, and 14q32 suggested the diagnosis of ataxia telangiectasia (AT) or a related disorder. Supportive evidence was radioresistant DNA synthesis in fibroblasts and radiation hypersensitivity of short-term lymphocyte cultures. Follow-up for nearly 4 years showed largely normal development, and no signs of telangiectasia, ataxia, or immunodeficiency. Serum AFP levels turned from elevated at age 5 months to normal at age 2 years. We propose that our patient belongs to the expanding category of "AT-related" genetic disorders, probably to the Nijmegen breakage syndrome.

Variegated aneuploidy related to premature centromere division (PCD) is expressed in vivo and is a cancer-prone disease.

We present three patients with variegated aneuploidy and premature centromere division (PCD), a rare chromosomal abnormality in humans. Comparison of these three and eight other patients with variegated aneuploidy related to PCD demonstrates a phenotype comprising most frequently microcephaly, CNS anomalies (with cerebellar affection and migration defects), mental retardation, pre-and postnatal growth retardation, flat and broad nasal bridge, apparently low-set ears, eye and skin abnormalities, and ambiguous genitalia in male patients. The occurrence of Wilms tumor in three patients, rhabdomyosarcoma in two others and acute leukemia in a fifth characterizes this condition as a chromosome or genome instability disorder with a high risk of malignancy. FISH studies in uncultured blood and buccal smear cells demonstrate that the random aneuploidies are not limited to cultured cells, but also occur in vivo.

Further delineation of the Nijmegen breakage syndrome.

We report on five independent families with a chromosome instability disorder that earlier had been called the Nijmegen breakage syndrome (NBS). These families, two from the Netherlands and three from Czechoslovakia, had a total of eight patients, five of whom are still alive. The main clinical manifestations were microcephaly, short stature, a "bird-like" face, immunological defects involving both the humoral and cellular system. In four of the five living patients it has been possible to study the chromosomes of cultured lymphocytes. The basic karyotype in these patients were normal, but in 17% to 35% of the metaphases rearrangements were found, preferentially involving chromosomes 7 and/or 14 at the sites 7p13, 7q34, and 14q11. The chromosomes of all five living patients were very sensitive to ionizing radiation. In addition, the DNA synthesis in their cultured lymphocytes and fibroblasts was more resistant to X-rays than in cells from controls. The NBS shares a number of important features with ataxia telangiectasia (AT). Both syndromes are characterized by the occurrence of typical rearrangements of chromosomes 7 and/or 14, cellular and chromosomal hypersensitivity to X-irradiation, radioresistance of DNA replication and immunodeficiency. However, there are also obvious differences: NBS patients have microcephaly but neither ataxia nor telangiectasia, and in contrast to the situation in AT the alpha-fetoprotein level in their serum is normal.

Possible involvement of unstable sites on chromosomes 7 and 14 in human cancer.

Specific sites on human chromosomes appear to have a tendency to rearrange in so-called "sporadic translocations," which are found in approximately 1 of 1000 metaphases from peripheral blood lymphocyte cultures. We now present data that implicates four sites in the human genome as displaying this distinct type of chromosomal instability (7p13, 7q34, 14q11, and 14q32). Chromosome 14q11 was found to be involved in sporadic translocations most often, followed by 7p13 greater than 7q34 greater than 14q32. The 14q11 locus also shows the highest frequency of spontaneous sister chromatid exchange. It is proposed that these sporadic translocations involving chromosomes #7 and #14 arise following recombinational errors occurring at sites of T- and B-cell genes known to be located at these four sites. Evidence is presented that in some cases "fixation" of a sporadic translocation might be involved in malignancy of lymphoid origin.

Specific translocation t(1;3) in acute myelomonocytic leukemia: a further case.

We describe herein a translocation, t(1;3)(p36;q21), that was found in the bone marrow of a patient with acute myelomonocytic leukemia preceded by a long lasting myelodysplastic phase. An identical translocation has been reported in three other myelodysplastic patients. one of whom also developed an acute myelomonocytic leukemia. The possible significance of this specific translocation is briefly discussed.

Isochromosome 1q as the sole chromosomal abnormality in two fetal teratomas. Possible trisomic or tetrasomic zygote rescue in fetal teratoma with an additional isochromosome 1q.

An isochromosome of the long arm of chromosome 1 leading to tetrasomy 1q was detected as the sole chromosomal aberration in two cases of fetal teratoma arising from the oral cavity. This type of teratoma is extremely rare and has seldom been investigated cytogenetically. Studies of DNA markers in the tumor, normal fetal skin, and parental cells demonstrated that in both cases the additional 1q material was of maternal origin. In one of the patients, the teratoma had maternal 1q marker alleles that were not found in the fetal body cells. This implies that the tumor was not derived in a direct way from the fetal body tissue; instead, the chromosomally-normal fetus might be the result of some trisomic or tetrasomic zygote rescue mechanism.

Translocation 1;7 in hematologic disorders: a brief review of 22 cases.

A translocation t(1;7)(p11;p11), previously reported in patients with myelodysplasia or leukemia has been found in seven new cases. The present report briefly reviews the cytogenetic and clinical features of 22 patients with this translocation. The majority of these patients had a history of occupational or therapeutic exposure to toxic substances or radiation. Trisomy 8 or 21 were the most common additional abnormalities, especially in leukemic patients. The t(1;7) should be added to the group of specific cytogenetic abnormalities observed frequently in secondary myelodysplasia and leukemia.

Translocation 1;7 in dyshematopoiesis: possibly induced with a nonrandom geographic distribution.

Eight patients with various hematologic disorders had an identical chromosomal aberration in their bone marrow or unstimulated peripheral blood, a translocation t(1;7) interpreted as t(1;7)(p11;p11). The translocation chromosome replaced one normal chromosome #7; therefore, the karyotype of the abnormal cells was trisomic for 1q and monosomic for 7q. Including four cases from the literature, a total of 12 patients (4 women, 8 men) with this translocation are known at the moment. The translocation does not seem to be associated with a specific disorder, but almost all patients had a preleukemic syndrome during some stage of their disease. It is very remarkable that 11 of the 12 patients lived in the Netherlands, and 7 patients had a history of iatrogenic exposure to alkylating agents or irradiation; one patient was a radiation worker and another one had a history of toxic exposure to chloramphenicol. It is suggested, therefore, that the t(1;7) is a possibly induced chromosomal aberration with a clearly nonrandom geographic distribution.

Epidermodysplasia verruciformis: Langerhans cells, immunologic effect of retinoid treatment and cytogenetics.

A case study is presented of a 44-year-old negroid male with epidermodysplasia verruciformis (EV), cutaneous carcinomas, and impaired cell-mediated immunity (CMI), infected with human papillomavirus type 8 and 17. Analysis was made of (a) T6+ and HLA-DR+ Langerhans cells (LCs) by immunoperoxidase staining in lesional and clinically normal skin before and during retinoid treatment, (b) the effect of retinoid treatment on CMI in vivo and in vitro, and (c) cytogenetic aspects related to chromosomal instability. The results showed the virtual absence of T6+ and HLA-DR+ LCs in koilocytic areas of epidermis involved with EV. Light-exposed, clinically normal skin also demonstrated microscopic EV lesions largely devoid of T6+ and HLA-DR+ LCs. Retinoid treatment with etretinate (Ro 10-9359) appeared both to increase the CMI response in vitro to T-cell mitogens and to influence the in situ pattern of T6+ and HLA-DR+ LCs. The cytogenetic study did not show evidence of spontaneous or UV-induced chromosomal instability.

Sister-chromatid exchanges induced in vitro by cyclophosphamide without exogenous metabolic activation in lymphocytes from three mammalian species.

The induction of sister-chromatid exchanges (SCEs) by cyclophosphamide (CP) in human, rat and rabbit lymphocytes was studied in vitro without exogenous metabolic activation. In contrast with published reports, CP induced SCEs in lymphocytes from all three species, indicating that cultured lymphocytes possess the metabolic capacity to convert this indirect-acting mutagen.

Hypersensitivity to ionizing radiation, in vitro, in a new chromosomal breakage disorder, the Nijmegen Breakage Syndrome.

The Nijmegen Breakage Syndrome (NBS) is a new chromosomal instability disorder different from ataxia telangiectasia (AT) and other chromosome-breakage syndromes. Cells from an NBS patient appeared hypersensitive to X-irradiation. X-rays induced significantly more chromosomal damage in NBS lymphocytes and fibroblasts than in normal cells. The difference was most pronounced after irradiation in G2. Further, NBS fibroblasts were more readily killed by X-rays than normal fibroblasts. In addition, the DNA synthesis in NBS cells was more resistant to X-rays and bleomycin than that in normal cells. The reaction of NBS cells to X-rays and bleomycin was similar to that of cells from patients with ataxia telangiectasia. Our results indicate that NBS and AT, which also have similar chromosomal characteristics, must be closely related.

Precarious acrocentric short arm in prenatal diagnosis: no chromosome 14 polymorphism, but trisomy 17p.

Precarious acrocentric short arm in prenatal diagnosis: no chromosome 14 polymorphism, but trisomy 17p: We report on a girl with multiple congenital abnormalities and a prenatally diagnosed 46,XX,14p+ de novo karyotype. Fluorescence in situ hybridization (FISH) demonstrated that the extra material on the short arm of chromosome 14 was not just a polymorphism, but that it originated from chromosome 17. The phenotypic findings of this patient with pure trisomy 17p are compared with those of ten previously published cases.

[Immunodeficiency and chromosome instability]. / Immunodeficiëntie en chromosoominstabiliteit.

In this paper, a survey is given of the immunological disturbances in some chromosome instability disorders (e.g. Bloom syndrome, ataxia teleangiectasia and Nijmegen Breakage syndrome). Further, the clinical symptoms and the diagnostic approach will be discussed.

[Down's syndrome in the Netherlands]. / Het syndroom van Down in Nederland.

In 348 patients with Down syndrome (DS) born in the Netherlands in 1981 and 1982 chromosome studies had been performed before December 1st 1984. Prenatal chromosome studies had revealed 22 cases who could have been born in 1981 and 1982 taking into account a pregnancy duration of 40 weeks. DS rates are determined for five-yearly maternal age classes. These frequencies are compared with those from a reference group, consisting of a compilation of five epidemiological studies which are comparable in their way of presentation of the results and in the ascertainment of the DS cases. The most conspicuous finding in this comparison is that the frequency of DS among children of older mothers (greater than or equal to 40 years) in our study is relatively low. Therefore we presume that a number of patients born in the years 1981 and 1982, particularly from the maternal age groups 40-44 and greater than or equal to 45, are not (yet) referred for cytogenetic characterization. The great majority (+/- 90%) of the postnatally studied cases was presented within the first two months of life. In nearly 95% a standard trisomy 21 was detected and in about 5% a translocation or mosaicism.

[Immunologic and cytogenetic aspects of ataxia telangiectasia]. / Immunologische en cytogenetische aspecten van ataxia telangiectasia.

Immunological and cytogenetic studies were performed in 6 patients with ataxia telangiectasia (AT). Immunological disturbances were found in these patients: immunoglobulin deficiencies (IgA, IgE, IgG2 and IgG4), decreased cellular immunity and a defect in the synthesis of specific antibodies. Cytogenetic studies revealed chromosome 7 and/or 14 abnormalities in all patients. X-irradiation of AT cells induced an excessive increase in chromosome and chromatid breaks. The DNA synthesis inhibition after X rays was less in AT patients compared to controls. The possibilities of early diagnosis and the eventual relationship between immunological and cytogenetic findings are discussed.

CT banding of human chromosomes: description of the banding technique and some of its modifications.

A technique is described for staining centromeric areas and reverse, mainly telomeric bands in human chromosomes. With this "CT" technique karyotyping of C-banded metaphases is possible without previous or subsequent use of other banding methods. The method consists of an alkaline pretreatment at 60 degrees C with Ba(OH)2, followed by salt incubation in 2 X SSC at 60 degrees C and staining with the cationic dye "Stains-all". In a series of experiments the influence of the variables in the procedure was studied, with the following main results: 1) Ba(OH)2 treatment alone and subsequent staining produces a distinct reverse banding pattern in which the secondary constriction of chromosome 9 is positive. 2) The 2 X SSC incubation in the CT procedure causes the Ba(OH)2 induced reverse bands to become weaker; the centromeric regions, however, become very prominent. 3) If the temperature of the 2 X SSC treatment is raised to 85 degrees C, the CT technique results in a specific staining of the short arm regions of some probably variant acrocentric chromosomes. The interphase nuclei of individuals possessing such acrocentrics usually show very distinct chromocentres after this treatment; in the polymorphs these chromocentres are often situated along the nuclear membrane. The mechanisms which may form the basis of the staining results obtained, and the possible significance in human cytogenetics of the techniques described, are discussed briefly.

CT banding of human chromosomes. The role of cations in the alkaline pretreatment.

This paper describes a study of the role of certain cations in the alkaline pretreatment step used in the CT technique for chromosome band formation. Treatment of human chromosomes with ammonium bases or with the hydroxides of the monovalent alkali metals Na, K, or Li resulted in their rapid disintegration, unless very short treatment periods or diluted solutions were used. In the latter cases a subsequent staining produced a weak G-banding pattern. The chromosomes appeared to be much less sensitive to treatment with the hydroxides of the divalent alkaline earth metals Ba, Sr, Ca, and Mg. Staining after exposure to these hydroxides yielded R-banding patterns. The reduced alkali sensitivity of the chromosomes and the reverse banding pattern formation observed are probably the result of a chromatin stabilization by the divalent cations of the alkaline earth metals. It is proposed that not only in the R-band formation with the hydroxides of the alkaline earth metals but also in that obtained by other techniques, chromosome stabilization plays an important role.