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We report the result of investigations from 20 families with 72 carriers of the paracentric inversion inv(11)(q21q23) in the Netherlands. There is no increase in the rate of spontaneous abortions among carriers of the inversion or their partners. Also, so far, there are no children with recombinant chromosomes arising from the inversion. It is doubtful whether prenatal diagnosis would be helpful to carriers of this inversion. The results of the genealogy study and geographical distribution are discussed; it is suggested that all the families have arisen from a single mutation.

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.

Chromosomal studies of the bone marrow and cultured peripheral blood cells in a 42-year-old female with the clinical and laboratory features typical for CML revealed a previously undescribed variant translocation involving chromosomes 12 and 22.

The clinical, hematological, and cytogenetic characteristics of a male patient with AMMoL are described. Before treatment a clone with the complex karyotype 45,X,del(7)(q32), t(8;21)(q22;q22) was present in the bone marrow. During partial remission induced by cytostatics, the percentage of normal cells increased, and a cell line having a 46,XY,del(7)(q32) karyotype was found. After four therapy courses, when remission was complete, only chromosomally normal cells were seen. The cytogenetic data suggest that in this case the 8/21 translocation and loss of the Y chromosome were only secondary events.

A family is described with three male sibs suffering from congenital adrenal hypoplasia (CAH). In the two surviving brothers the disease is clinically further characterized by a Duchenne type muscular dystrophy, growth failure and severe mental retardation. Laboratory investigations revealed deficient activities of gonadotrophin and glycerol kinase. The clinical, biochemical and genetic findings in ths exceptional family are reported and discussed.

In this report we describe a Dutch family with ten cases of X-linked recessive congenital hydrocephalus with a high perinatal mortality. In three cases necropsy has confirmed the diagnosis. In the best documented case the most striking features are absence of obstruction or stenosis of the aqueduct and congenital malformation of the cerebral cortex. On the basis of our findings and on reviewing the literature, the hypothesis is put forward that the defective gene on the X-chromosome is responsible for a pathological influence on cerebral cortex development and extraventricular CSF pathways. The expressivity of the genetic defect may be variable, causing extreme phenotypic variants (CHC and/or MR) under the influence of the different modifying genetic or environmental factors. Genetic counselling is difficult in families with no X-linked CHC precedent, since the mutant gene rather produces a communicating HC, secondarily complicated by narrowing of the aqueduct, and as at present there is no way of detecting beforehand heterozygote carriers.

The morphologic changes occurring in human chromosomes during R-banding by Ba(OH)2 treatment were followed with the aid of bright-field and Nomarski interference contrast microscopy. It was found that the hot Ba(OH)2 pretreatment alone, i.e., without staining, caused a pattern of transverse ridges in the chromosomes that clearly corresponded to positive R-band regions. No chromosomal collapse could be seen during any stage of the R-banding procedure. Thus these events contrast with those observed in G-band formation with trypsin, where complete chromosomal collapse occurs after pretreatment and where staining is necessary to induce G-band ridges. The possible mechanism of R-band induction by Ba(OH)2 is discussed. It is proposed that the R-band ridges arise as a result of chromatin loss from the interband regions during the hot alkaline pretreatment.

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.

Chromosome analysis was performed in 17 children with IgA-deficiency. In two patients a constitutional structural chromosome abnormality was found. A ring chromosome 22 was seen in one, while in the other a mosaicism of ring chromosome 18/18p+ was observed. Both patients were mentally retarded and showed distinct congenital defects. From ten asymptomatic patients, spontaneous as well as X-ray-induced chromosome instability was investigated. There was no increased spontaneous instability, and also after irradiation the induced chromosome damage was within normal control levels. A relationship between IgA-deficiency and X-ray hypersensitivity, as might be suggested by the frequently occurring coincidence of radiosensitivity and IgA-deficiency in ataxia telangiectasia patients, is not established.

Chromosomes were studied in a mentally retarded boy with microcephaly, growth retardation, facial erythema, café-au-lait spots, and IgA deficiency. In the lymphocytes there was a remarkable tendency to exchange parts of the chromosomes Nos. 7 and 14, the translocations almost exclusively taking place in bands 7p13, 7q32 and 14q11. Seven different types of rearrangements between Nos. 7 and 14, and some other chromosomal aberrations were found. No abnormalities could be detected in the bone marrow. The patient somewhat resembles those affected with ataxia-telangiectasia or with Bloom's syndrome, but on clinical and cytogenetic grounds these disorders could be excluded. 7/14 Translocations similar to those found in our patient's lymphocytes have been reported to occur very rarely in the lymphocyte cultures of individuals with apparently normal chromosome constitution. A relationship between these phenomena may exist.

The chromosomes of two mentally retarded probands were investigated because they were suspected of having the fragile X syndrome. However two other fragilities were detected. In one patient a fra(11)(q13) was found and in the other a fra(12)(q13). Family studies revealed that both fragile sites were real heritable ones. Besides these two heritable fragile sites, the common fragile site at 3p14 was frequently observed. The effects of BUdR, FUdR and methotrexate on the frequency of the three fragilities were studied. The two heritable fragile sites differed from the common fragile site at 3p14 with respect to their inducibility by FUdR and methotrexate.

This paper describes the unexpected transmission of a translocation (22;22)(p13;q11) from a mother to her phenotypically normal daughter (the proband). Both women had had multiple abortions. No signs of mosaicism with respect to chromosome No. 22 were found in the proband or in her mother. Until now, it has been generally assumed that carriers of a 22/22 translocation will have only abnormal conceptuses. The transmission of this translocation from a balanced carrier to a phenotypically normal daughter was therefore highly unexpected and is not easy to explain. Early postzygotic loss of a chromosome no. 22 from a trisomic zygote, or fertilization of an oocyte carrying the translocation by a sperm nullisomic for chromosome no. 22 could have led to the balanced chromosome pattern of the proband.

A translocation between a chromosome 15 and a chromosome 17 was found in the bone marrow of a 14-year-old boy who had clinical and laboratory symptoms of acute promyelocytic leukemia (APL). As far as we know, this is the sixth case of APL with 15/17 translocation to be reported in the literature. This observation gives further support to the hypothesis that there is an association between this chromosomal rearrangement and APL.

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.

In man a common fragile site is known to occur at 3p14. We studied the expression of this fragility in a group of 70 normal healthy subjects. Chromosome breaks, chromatid breaks and gaps at 3p14 could be observed in every examined individual, and in a total of 7000 metaphases they were seen in a mean of 4% of cells. Fluorescence studies in ten persons with chromosome No. 3 polymorphism showed that in all cases both Nos. 3 were about equally liable to breakage. A considerable variation in the fra 3p14 expression was found between individuals as well as in repeated cultures from the same person. Neither sex nor age influences could be detected. Cultures with a high percentage of lesions at 3p14 tended to have also a high number of lesions at other sites. Methotrexate and fluorodeoxyuridine markedly enhanced the expression of fra 3p14 and other fragilities. It is concluded that the chromosomal region at 3p14 represents man's most common fragile site, the expression of which seems to be influenced by environmental and heritable factors.

An X chromosome specific nucleic acid probe was used to study the positions of the X chromosomes in leukocyte nuclei by in situ hybridization to smears of peripheral blood. This autoradiographic approach allowed the first direct demonstration of the presence of X chromosomal material in the drumstick-like structures of female polymorphonuclear leukocytes.

Malignant histiocytosis (MH) was diagnosed on the cytologic and cytochemical features of the malignant cells present in bone marrow smears from an infant and a child. The diagnosis of MH was confirmed by light and electron microscopic studies on bone marrow and skin biopsy specimens, and bone marrow and liver biopsy specimens, respectively. Both patients showed a deterioration while receiving prednisone monotherapy, but they responded well to a combination of vincristine and cyclophosphamide. The infant has remained disease-free for 52+ months now, but the child died of a relapse 11 months after diagnosis. Cytogenetic studies of blood and/or bone marrow cells were performed before treatment. In the infant, a pathologic cell line with a translocation t(8;16)(p11;p13) was found; this abnormality was no longer present after remission was obtained. In the second patient, a hyperdiploid cell line with major karyotypic anomalies was found. When studied in relapse and shortly before death, additional chromosomal abnormalities were seen. The data from this study show that prednisone should be used with caution in MH, and that it should be omitted from combination chemotherapy when adverse effects are noted during short-term monotherapy. Also, cytogenetic studies should be performed more often in MH to determine the significance and possible nonrandomness of chromosomal abnormalities in this disease.

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.

Two maternal cousins are described with the connatal form of Pelizaeus-Merzbacher Disease (PMD) and congenital stridor. Study of brain biopsy material confirms the diagnosis of PMD. The neuropathological findings are suggestive for the transitional form of this disease. Quantitative morphology gives support to the hypothesis that PMD is a disturbance in maturation of neurons and in myelin formation rather than an active degenerative process. The hereditary transmission is most consistent with a sex-linked recessive pattern. Different X-linked signs seem combined in the presented cases.

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.

A patient is described with a karyotype 46,XX,del(9)(qter leads to p22:) and having the main clinical characteristics of pure monosomy for part of the short arm of chromosome No 9, among which craniosynostosis and trigonocephaly. She has also a few atypical features: a clearly advanced osseous maturation, marked congenital vertebral anomalies and unusual dermatoglyphics.

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.

A technique is described for the production of detailed and richly contrasting G-band patterns in human prometaphase chromosomes with the aid of the triphenylmethane dye basic fuchsin. The usefulness of this method is illustrated by its application for the precise analysis of two chromosome 11 rearrangements. It is also demonstrated that high-resolution banding with basic fuchsin can reveal bands not present in the international standard idiogram of human prophase chromosomes (ISCN 1981). The technique described can also be used for easy recognition of the late replicating X chromosome, which stains darker than its early replicating homologue. A preliminary analysis of the late replicating X chromosomes in a 49,XXXXY individual suggests that the three supernumerary X chromosomes do not necessarily replicate synchronously.

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.

A search for Y-specific DNA sequences has been performed in a sample of seven 46,XX true hermaphrodites and one 45,X mixed gonadal dysgenesis case and compared with a sample of 11 XX males. Using six Y-specific DNA probes no hybridization signal was obtained in the hermaphrodite group; in contrast, all XX males gave a positive signal with at least one probe. This difference is statistically highly significant. We conclude that the aetiology of true hermaphroditism is different from that of the XX male syndrome. As all cases of the hermaphrodite group are positive for the serological sex-specific antigen (Sxs) it is concluded that this antigen can be present even in the absence of Y-specific DNA.

The clinical and cytogenetic data are presented of four children with Bloom's syndrome, who belong to two unrelated Dutch families. The patients showed, in varying degrees, the clinical features most characteristic of the syndrome: stunted growth; telangiectatic facial erythema; sun-sensitivity of the skin; and decreased immuno-competence. In one child the skin lesions were only minor and the diagnosis would probably not have been made if her sib had not been recognized as having Bloom's syndrome. The cytogenetic characteristics of the syndrome were present in all patients. Each showed a high number of chromosomal aberrations and numerous sister-chromatid exchanges per cell.

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.

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.

A 10-year-old boy with microcephaly, stunted growth, mental retardation, café-au-lait spots and immunodeficiency is described. An older brother of the patient had the same clinical symptoms and a more severe immunodeficiency. Cytogenetic studies in the proband revealed a typical form of chromosome instability with multiple rearrangements of chromosomes 7 and 14. Such abnormalities were also present, though in very low frequencies, in the father and three of the phenotypically normal sibs. The similarity of the symptoms in the two sibs, the close consanguinity of their parents and the results of the cytogenetic studies in the family favour the hypothesis that the disorder is an inherited one. The clinical features and the chromosome aberrations as present in the proband are usually found in chromosomal breakage syndromes, but it was possible to exclude each of the classical chromosomal breakage syndromes on clinical and/or cytogenetic grounds.

Clinical and laboratory data are presented for two patients with a dyshaematopoietic disorder, and monosomy 7 in their bone marrow cells. The first patient, a 55-year-old woman, had been treated with chlorambucil for an ovarian carcinoma. After 4 years an oligoblastic myeloid leukaemia was diagnosed and she later died with an acute transformation of the disease. The second patient, a 21-year-old male, has had a dyserythropoietic anaemia with transient pancytopenia for over 5 years without any signs of malignancy. The possible relationship between therapy, the monosomy 7 and the other bone marrow abnormalities is briefly discussed. From an analysis of the data of these and comparable cases in the literature it appears that loss of chromosome No. 7 material is often associated with erythropoietic disorders such as erythroid hyperplasia and erythraemia. The reduction or absence of the Colton blood group antigens found in our patients and in a few other monosomy 7 cases also points to an abnormality of the red cell line.