Interstitial 7q deletion [46,XY,del (7) (pter----cen::q112----qter)] in a retarded quadriplegic boy with normal beta glucuronidase.

A 14-year-old severely retarded male with deletion of chromosomal band 7 cen----q112 is described. Clinical features include short stature, microcephaly, unusual facies with narrow forehead, short nose, malar hypoplasia, protruding alveolar ridges and incisors, receding chin, relatively long philtrum, and large ears. In addition, he had bilateral inguinal herniae cryptorchidism with hypogonadism, pulmonic stenosis, and spastic quadriplegia. Normal activity of beta-glucuronidase was found in the patient's leukocytes. This finding suggests that the gene is not in the deleted region, narrowing the smallest region of overlap to 7q112----q22.

Fragile X expression in Martin-Bell syndrome, intellectually normal individuals, and neoplasia, interpreted by a viral hypothesis.

We present data on fragile X expression in lymphocytes obtained from the following patients: a university student, an infertile couple, 6 of 22 prostatic cancer patients, a meningioma patient, and members of families with meningioma and familial gliomas. All patients were of normal intelligence. In addition, we report 3 cases of central nervous system (CNS) tumors in more typical fragile X families. We suggest that the fragile X expression as well as the clinical findings may be caused by a viral (or similar) infection. The virus may require a receptor protein coded by one allele of a gene on the X chromosome.

Interstitial deletion 2q14q21.

A girl with multiple congenital anomalies and a tendency to severe pyogenic infections was found to have an interstitial deletion of chromosome band 2q14----q21. Unusual facial manifestations included enophthalmos, long philtrum, micrognathia, narrow forehead, prominent glabella, and depressed nasal bridge. Unilateral corneal clouding, with Peters-like anomaly; agenesis of the corpus callosum; brain atrophy; and heart, kidney, hand, and dermatoglyphic anomalies were additional findings. Eye anomalies were observed in five of 22 patients with deletions of chromosome 2q. In comparing these cases, it seems that deletions of bands 2q21 and 2q31 are variably associated with microphthalmia, corneal clouding, cataracts, and Peters anomaly. Measurement of protein C and interleukin-1 (IL-1) did not show a gene dose effect, but the pyogenic infections and low IgA found in this patient may reflect an abnormality of IL-1 not detectable by our methods.

New complex Ph' translocation t (10; 14; 22) in bone marrow cells and in PHA-stimulated peripheral blood cultures in chronic myelocytic leukaemia.

A patient with chronic myelocytic leukaemia (CML) and a new complex Philadelphia chromosome (Ph') translocation, t (10; 14; 22), is described. This three way Ph' translocation not involving chromosome 9 was present in the majority of the bone marrow cells, as well as in a great proportion of metaphases from phytohaemagglutinin (PHA) stimulated peripheral blood cultures. The possibility that the Ph' translocation was present also in lymphocytes is discussed and at this regard the involvement of chromosome 14 is of interest considering the documented non random involvement of chromosome 14 in lymphoid malignancies.

A hypodiploid clone and its duplicate in acute lymphoblastic leukemia.

Examination of the bone marrow of a 63-year-old man who had acute lymphoblastic leukemia revealed a population of cells with 32 chromosomes and another population with 64 chromosomes, the karyotypical exact duplicate of the first clone. The karyotypic evolution was studied and the findings compared with those described in two similar cases previously reported. It is postulated that severe hypodiploidy is associated with reduced capability of cellular survival, promoting a strong tendency for duplication.

Studies of banded chromosomes in patients with acute lymphocytic leukemia, including one patient with the Burkitt-type (L3).

Studies on banded chromosomes of 10 patients with acute lymphocytic leukemia (ALL) are reported. The group is small but quite representative. 60% of the patients had a clonal abnormality: a Philadelphia chromosome and chromosome #7 abnormalities were seen in one patient; a marked hypodiploid clone (32 chromosomes) and its duplicate was seen in another; hyperploidy of 49 chromosomes (+4 +17 +21) was seen in a third patient, and 3 patients were found to have a 6q-abnormality. One of these patients had an L3, Burkitt-type of ALL. A translocation t(8;14) has frequently been found in this type of ALL. The findings confirm the nonrandomness of particular cytogenetic abnormalities in ALL and the possibility of the existence of different aberrations in apparently identical clinical entities.

On the meaning of fragile sites in cancer risk and development.

In the last few years, there has been increasing concern about the possible involvement of fragile sites in cancer risk and development. Patients with malignancies and family histories of cancer who presented with constitutional fragile sites are reported here. These findings are discussed with regard to the familial risk for cancer and the tissue specificity of the malignancy in relation to the different fragile sites. The hypothesis is advanced that these may be sites of viral DNA modification, probably representing areas where genes that are important for the metabolism of the virus are located. On the other hand, these genes may well be cellular (proto)oncogenes. We believe that fragile sites may increase the risk for cancer, not by being break-prone points at oncogene locations, but through more complex mechanisms that are not easy to predict.

Familial fragile 8q22 involved as a cancer breakpoint in cells of a large bowel tumor.

A familial fragile 8q22 and an interferon-induced fragile 16q22 were found in two sisters. Eight years previously, both sisters developed an endometrial adenocarcinoma and now one of them presented with an adenocarcinoma of the colon. An 8q22 deletion was found in all the cells of the colonic tumor and seemed to be the primary initiating change. Other nonrandom and possibly promoting aberrations were also present, among others, a 16q22 deletion. The possibility exists that a familial fragile 8q22 may predispose to cancer and a fragile 16q22 may have promoting capacities.

Involvement of chromosome 22 in a Merkel cell carcinoma in a patient with a previous meningioma.

The relatively simple cytogenetic findings in an aggressive metastatic Merkel cell carcinoma are reported. Deletion 2p was found in 100% of the cells. Nevertheless, this was considered a secondary (metastatic?) change because the same aberration has been found in several other kinds of malignancy. The involvement of chromosome 22 [del(22q) and -22] in 85% of the cells seemed more intriguing, considering the fact that the Merkel cell carcinoma followed a previous meningioma.

Inversion (16)(p13q22) in tumor cells of sigmoid colon.

We report on the cytogenetic findings in direct preparations of two tumors of the sigmoid colon. Respectively, they had a near-triploid and a near-tetraploid constitution and relative numerical and other inconstant chromosomal imbalances. The only constant chromosomal structural anomaly apparently was inversion of chromosome #16, inv(16)(p13q22), which was found in all the cells examined. This rearrangement has been found to be associated with a type of acute myelomonocytic leukemia type M4. We suggest that an etiologic clastogenic (and oncogenic) agent responsible for this rearrangement may eventually be the cause of various kinds of malignancy.

Marker chromosomes in a family with high incidence of cancer.

Two young sisters presenting with malignant or premalignant conditions inherited two marker chromosomes (a 13p- and a 16 with a fragile site at q22). Malignancy was reported in the family on both the mother's and father's side. According to data from the literature on similar markers and from our personal observations, a possible significance may be suggested for these markers. Search for markers must be encouraged in families with high incidence of cancer. Eventually, we may find markers which will help in understanding the processes of carcinogenesis and possibly indicate individuals at risk.

Cytogenetic study of patients with carcinoma of the colon and rectum: particular C-band variants as possible markers for cancer proneness.

A possible involvement of chromosomal heterochromatic polymorphisms in propensity to cancer has been considered and discussed by several investigators who studied groups of patients presenting with different forms of malignancy. We report a cytogenetic study on the circulating lymphocytes of patients suffering from colorectal carcinoma, most of whom were of European origin. Significantly increased incidence of polymorphisms of chromosomes #1 and #9 was found, especially partial inversions (PI). Emphasis is given to the problem of selecting adequate controls, which must be as homogeneous as possible.

Chronic Myelogenous Leukemia Associated with Extranodal B-Cell Lymphoma.

A 75-year-old man is reported with a 10 year-history of villous adenoma of the colon and carcinoma in situ treated by hemicolectomy. Seven years later, he developed chronic myelogenous leukemia (CML). After a 3-month course of busulfan he was kept off chemotherapy for a one year period. Two years after the diagnosis of CML, an extranodal B-cell lymphoma developed in the left ankle region. A clonal pericentric inversion of chromosome 20 was shown in the lymphoma cells, but without Philadelphia (Ph') chromosome. The possible relation between the two malignant disorders is discussed in the light of current knowledge on the clonal origin of CML.

Juxta-centromeric fragility of chromosomes 1, 2, 9, 16, and immunodeficiency. Special reference to the fragility of chromosome 2 and its oncogenic potential.

Juxta-centromeric fragility of chromosomes 1, 2, 9, 16, has been described at least thrice in unrelated patients in association with combined immunodeficiency. This association has been confirmed by our findings in both immunodeficient and cancer patients. In our opinion, both the fragility and the immunodeficiency are the results of persistent viral infections by certain DNA (i.e.: Herpes-, Papova-) viruses or RNA (retro-) viruses (i.e. HTLV), which are lymphotropic. The immunodeficiency may be due to virus-cell, cell to cell, or virus-virus interactions. According to our findings, centromeric fragility of chromosome 2 appears to have a particular oncogenic potential probably because of its location in proximity to immunoglobulins genes. We suggest that centromeric fragility of chromosomes 1, 2, 9, 16, may be one of the symptoms of an incipient Acquired Immunodeficiency Syndrome (AIDS) which will not necessarily develop fully.

Ca antagonist verapamil and tumor promoter 12-O-tetradecanoylphorbol-13- acetate (TPA) induce chromosomal aberrations in human lymphocytes.

Lymphocytes from 8 healthy donors were cultured for 3 days in the presence of phytohemagglutinin. Addition of the Ca antagonist verapamil or the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) increased chromosomal aberrations in comparison with control cultures. The effects of TPA and verapamil were additive. Although the Ca ionophore A23187 had no effect per se, it did abolish the effect of verapamil. Five patients with supraventricular tachycardia were treated clinically with verapamil for 1 week. Their lymphocytes were cultured for 3 days in vitro in the presence of phytohemagglutinin. These lymphocytes showed higher chromosomal aberrations in comparison with lymphocytes isolated from the patients before treatment. The clinical significance is still unclear. We suggest that calcium ions may be necessary for the intactness of chromosomes of human lymphocytes and presumably of other cells.

Chromium chloride induces chromosomal aberrations in human lymphocytes via indirect action.

The aim of this study was to examine the possible clastogenic effects of trivalent chromium chloride (CrCl3) as the results in the literature are non-conclusive. Under the conditions used in this study Cr(III) induces chromosomal aberrations in phytohemagglutinin(PHA)-stimulated human lymphocytes. This activity, however, is suppressed by the antioxidants superoxide dismutase (SOD) (scavenger of O-.2), the SOD-like agents, catalase and mannitol (specific scavenger of OH.). The possibility that oxygen free radicals could evolve through stimulation of the arachidonic acid cascade is suggested using suitable inhibitors.

Fibrous dysplasia and cherubism as an hereditary familial disease. Follow-up of four generations.

Five cases of dysplasia of the jaws in one family which has been under our observation since 1970 are reported. The disease appeared as a mixed display of jaw lesions, in some members as fibrous dysplasia and in others as cherubism. We were able to trace the disorder through an unbroken line of four generations, and thus to demonstrate autosomal dominant inheritance. Cytogenetic analysis performed on three members of this family revealed a significantly increased rate of chromosomal breakage.

Leber's optic neuropathy--a cytogenetic study of a family.

The present report describes a family with Leber's optic neuropathy. The cytogenetic findings in this family, as well as some clinical features, are suggestive of a slow viral infection with vertical transmission as a possible cause of the disease.

Risk of malignancy and chromosomal polymorphism: a possible mechanism of association.

A significantly increased incidence of heterochromatic chromosomal variants, particularly of A1 and C9, has been found in a group of 120 patients with malignant or premalignant diseases. People presenting with such a kind of polymorphism usually have an increased chromosomal breakage rate. Genetically increased susceptibility to breaking agents may be the unifying concept explaining the increased incidence of heterochromatic variants found in couples with sterility or abortions, in karyotypically normal malformed or retarded children, and in patients suffering from different malignant or premalignant diseases. Chromosomal imbalance is probably the basis for initiation of malignancy whose development is influenced by many different factors.

An unusual case of hemoglobin Bart's hydrops fetalis.

A baby with alpha-chain thalassemia hydrops fetalis was born to an Iraqian Jewish couple of Iraqi-Kurdish extraction. Hemoglobin Bart's constituted only 40% of the total hemoglobin, much less than usually found in alpha-thalassemia hydrops fetalis. That this is a particular expression of hemoglobin H disease is considered. The likelihood of two alpha-chain loci, rather than one alpha-chain locus, in this family, is also discussed.