Thrombocytopenia-absent radius syndrome: a clinical genetic study.

The thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterised by bilateral absence of the radii and a thrombocytopenia. The lower limbs, gastrointestinal, cardiovascular, and other systems may also be involved. Shaw and Oliver in 1959 were the first to describe this condition, but it was Hall et al in 1969 who reported the first major series of patients. Since then most reports have been based on single or small numbers of cases. We report the results of a clinical study looking at the phenotype of 34 patients with TAR syndrome. All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies not previously described in association with TAR syndrome included facial capillary haemangiomata, intracranial vascular malformation, sensorineural hearing loss, and scoliosis. Karyotype analysis, chromosome breakage studies including premature centromeric separation and fluorescence in situ hybridisation studies looking for a deletion of chromosome 22q11 were undertaken. Two abnormal karyotypes were identified.

Increased chromosome translocations and aneuploidy in peripheral blood lymphocytes of patients having revision arthroplasty of the hip.

The long-term biological effects of wear debris are unknown. We have investigated whether there is any evidence of cumulative mutagenic damage in peripheral blood lymphocytes of patients undergoing revision arthroplasty of predominantly metal-on-plastic total hip replacements compared with those at primary arthroplasty. There was a threefold increase in aneuploidy and a twofold increase in chromosomal translocations which could not be explained by the confounding variables of smoking, gender, age and diagnostic radiographs. In the patients with TiVaAl prostheses there was a fivefold increase in aneuploidy but no increase in chromosomal translocations. By contrast, in patients with cobalt-chrome prostheses there was a 2.5-fold increase in aneuploidy and a 3.5-fold increase in chromosomal translocations. In six patients with stainless-steel prostheses there was no increase in either aneuploidy or chromosomal translocations. Our results suggest that future epidemiological studies of the putative long-term risks of joint replacement should take into account the type of alloy used in the prosthesis.

Genomic instability associated with limb defects: case report and review of the literature.

We report a child in whom we observed markedly increased genome-wide spontaneous chromosomal breakage in both leucocytes and fibroblasts associated with severe growth retardation, radial aplasia, leucopenia, mild hydrocephalus and an unusual trichodystrophy. Exposure to DNA cross-linking agents diepoxybutane, mitomycin-C and mustine hydrochloride in this case did not result in the increased chromosome breakage seen in Fanconi anaemia. It may be that this child has a defect in postreplicative DNA repair interacting with the protein components deficient in FA.

Preliminary observations on possible premalignant changes in bone marrow adjacent to worn total hip arthroplasty implants.

Previous epidemiologic studies have suggested that there may be a risk of malignancy, especially lymphoma and leukemia, after joint replacement, but the followup has been relatively short. This is a preliminary study to see if there is any biologic basis for such a risk. Blood and bone marrow samples from 71 patients at revision arthroplasty of a loose or worn prosthesis and 30 control patients at primary arthroplasty were analyzed with cytogenetic techniques and molecular biology. There was a higher chromosomal aberration rate in cells adjacent to the prosthesis at revision surgery compared with iliac crest marrow from the same patients or with femoral bone marrow at primary arthroplasty. Clonal expansion of lymphocytes without a serum paraprotein was seen in 2 of 21 patients at revision arthroplasty performed more than 10 years after primary arthroplasty. The results of this preliminary study suggest that future epidemiologic studies should concentrate on patients with longer postoperative intervals to see if there is any risk that would be pertinent to a young patient at primary arthroplasty.

Spontaneous graft-versus-host disease following autologous peripheral blood progenitor cell transplantation in chronic myeloid leukaemia.

Myeloablation followed by haemopoietic reconstitution using autologous peripheral blood progenitor cells (PBPC) is applicable to some patients with CML, particularly where there is no allogeneic stem cell donor available, and interferon alpha has failed to achieve a significant cytogenetic response. Cells lacking the Philadelphia (Ph) chromosome can be collected at the early phase of myeloid recovery after intensive chemotherapy, and reconstitution after autografting can be associated with prolonged suppression of the Ph positive clone. It is possible that mechanisms other than this "in vivo purge' may contribute to disease control, for example an autologous graft-versus-leukaemia effect. We report two patients in whom significant autologous graft-versus-host disease (auto-GVHD) has occurred, which has not previously been described as a spontaneous event after PBPC autograft for CML. We postulate that mononuclear cells collected in an early phase of recovery after intense myelosuppression have the capacity to produce self-reactivity after autografting. These cells, which may include autoreactive T lymphocytes or antigen-presenting dendritic cells, might mediate a useful graft-versus-leukaemia effect.

Developmental delay and dysmorphic features associated with a previously undescribed deletion on chromosome 1.

We report an 18 month old girl with developmental delay, dysmorphic features, and a karyotype 46,XX,del (1) (p32.1p32.3). To our knowledge the clinical features associated with this deletion have not been reported previously.

Testing the mutagenic potential of polyvinylpyrrolidone and methyl cellulose by sister chromatid exchange analysis prior to use in intracytoplasmic sperm injection procedures.

The treatment of infertility due to severe oligoasthenoteratozoospermia has been revolutionized by the introduction of the technique of intracytoplasmic sperm injection. However, techniques which involve injection into the oocyte of polyvinylpyrrolidone solution as a vehicle for the selected spermatozoon have caused concern since the possible harmful effects of polyvinylpyrrolidone have not been fully investigated. This study was performed to investigate the potential mutagenic effect of polyvinylpyrrolidone on cultured human somatic cells, at the concentration used for intracytoplasmic sperm injection, in addition to a possible alternative vehicle, methyl cellulose, using the technique of sister chromatid exchange analysis. The results showed no increase in the basal frequency of sister chromatid exchanges with polyvinylpyrrolidone (median 5.0, 95% interval 5.00-6.00) or with methyl cellulose (median 6.0, 95% interval 4.22-6.00) in comparison with the negative control (saline: median 6.0, 95% interval 5.00-7.00), and in contrast to the positive control (mitomycin C: median 25.0, 95% interval 22.23-28.77). This finding suggests that polyvinylpyrrolidone and methyl cellulose do not cause DNA lesions resulting in sister chromatid exchanges, and provides reassuring evidence concerning their use in sperm injection procedures.

Acute promyelocytic leukaemia (M3): relapse with acute myeloblastic leukaemia (M2) and dic(5;17) (q11;p11).

Secondary leukaemia following treatment of M3 acute promyelocytic leukaemia (APL) is a rare event. We describe a patient in remission following chemotherapy for APL who relapsed with M2 acute non-lymphoblastic leukaemia (ANLL). The original t(15;17) (q22;q21) chromosome translocation was lost and replaced by a clone containing a dic(5;17) (q11;p11) abnormality. Southern genomic analysis demonstrated re-arrangements of the retinoic acid receptor varies; is directly proportional to (RAR varies; is directly proportional to) and PML genes in the APL blasts at presentation but not in the M2 ANLL marrow at relapse. The significance of unbalanced 5;17 translocations as markers for therapy-related secondary leukaemia is discussed.

Diagnosis of Bloom's syndrome by sister chromatid exchange evaluation in chorionic villus cultures.

Cultures of a chorion biopsy taken from a pregnancy at risk of Bloom's syndrome revealed the high sister chromatid exchange frequency diagnostic of this rare disorder. To obtain the result, cultures were grown under standard conditions, with the addition of 10 microM 5'-bromodeoxyuridine for the final 48 h of incubation. This result demonstrates the feasibility of early prenatal diagnosis of Bloom's syndrome.

Germline and somatic abnormalities of chromosome 7 in Wilms' tumor.

Although a gene (WT1) located at chromosome 11p13 is implicated in the development of Wilms' tumor (WT), there is evidence that genes on other chromosomes are also involved. A WT patient presented with a constitutional balanced translocation between chromosomes 1 and 7, t(1;7)(q42;p15), the breakpoints of which could represent a WT predisposition gene in this patient. Cytogenetic analysis of the tumor from this patient revealed an acquired abnormality of the other chromosome 7, resulting in an isochromosome of the long arm and a 46,XY,t(1;7)(q42;p15)c,i(7)(q10) karyotype. The regions of the translocation breakpoints were investigated in a series of 24 WTs using Southern blot analysis. This confirmed the monosomy of 7p and trisomy of 7q in the tumor of the translocation patient, and in addition a loss of chromosome 7p alleles was identified in a WT of a bilaterally affected patient. In addition, two WTs were shown to have an extra copy of chromosome 7 alleles. Multiple copies of chromosome 1q alleles, probably resulting from secondary changes, were observed in two WTs, one of which was also associated with a trisomy of chromosome 7. These results indicate that 7p may contain a tumor suppressor gene involved in WT development, and that duplications of 7q also may play a role in WT development.

Elucidation of structural abnormalities of the X chromosome using fluorescence in situ hybridisation with a Y chromosome painting probe.

Particular regions of the X and Y chromosomes share DNA sequence homology to the extent that cross hybridisation occurs. Thus, chromosome painting with a whole Y chromosome probe consistently results in fluorescence on specific regions of the X chromosome as well as the complete Y chromosome. This phenomenon has been exploited to elucidate the structure of unusual X chromosome rearrangements, without Y involvement, in two females.

Acute non-lymphocytic leukemia with t(16;21).

A patient with ANLL FAB subtype M1 was found to possess a t(16;21)(p11;q22) and trisomy 10. The 16;21 translocation has been reported in 12 other cases of ANLL, of various subtypes, and its relationship to the disease profile is discussed.

Telomeric associations in a patient with B-cell prolymphocytic leukaemia.

Telomeric associations were determined in bone marrow preparations from a patient with B-cell prolymphocytic leukaemia and a clonal isochromosome of the long arm of chromosome 17. Thirteen associations involved 16 chromosome arms, with preferential involvement of the short arm of chromosome 19 and the long arm of 17.

Sister chromatid exchange evaluation as an aid to the diagnosis and exclusion of Fanconi's anaemia by induced chromosome damage analysis.

Evaluation of chromatid aberrations induced in culture by DNA cross linking agents provides the most reliable method currently available for the diagnosis and exclusion of Fanconi's anaemia. However, at appropriate concentrations of clastogenic agent the aberration frequency in an unaffected subject may be very low and thus it may be difficult to confirm that the treatment was effective. Data are presented to show that sister chromatid exchange analysis can be used to monitor the effectiveness of the clastogen treatment and thereby increase the reliability and efficiency of the assay.

Dicentric chromosome in the bone marrow of a child with megakaryoblastic leukaemia and Down's syndrome.

A two year old girl with Down's syndrome (constitutional karyotype: 47 + 21), presenting with pancytopenia, developed acute megakaryoblastic leukaemia (AMKL). Her bone marrow contained an abnormal clone with a novel dicentric chromosome derived from chromosomes 5 and 7 (karyotype 46, XX, -5, -7, +dic (5;7) (p 13; p 11.2), +21. This case provides further evidence for a connection between chromosome 21 and this unusual form of childhood leukaemia, and raises questions about the loss of short arm material from chromosomes 5 and 7 compared with the more usual monosomy or long arm loss.