Der(22)t(11;22) resulting from a paternal de novo translocation, adjacent 1 segregation, and maternal heterodisomy of chromosome 22

The t(11;22) (q23;q11) translocation is the most frequently identified familial reciprocal translocation in humans. In translocation carriers, 3:1 meiotic segregation with tertiary trisomy can occur resulting in abnormal progeny with the der(22) as the supernumary chromosome. Affected children have a distinct phenotype with multiple anomalies and severe mental retardation. We have identified a child with developmental delay and multiple anomalies consistent with the der(22) phenotype. Cytogenetic analysis showed an abnormal chromosome complement of 47,XX,+der(22)t(11;22)(q23; q11) in all 50 cells analysed. FISH analysis using chromosome 11 and 22 painting probes showed a pattern consistent with a reciprocal translocation of the distal bands 11q23 and 22q11 respectively. Parental karyotypes were normal. RFLP analysis of locus D22S43, which maps above the t(11;22) breakpoint, showed that the der(22) was paternal in origin and indicated that the normal chromosomes 22 were the probable result of maternal heterodisomy. RFLP analysis of locus D22S94, which maps below the t(11;22) breakpoint, also suggested that both normal chromosomes 22 of the child represented the two maternal homologues. Non-paternity was excluded through the analysis of 10 microsatellite markers distributed on 10 different chromosomes and three VNTRs on three different chromosomes. To the best of our knowledge, this is the first reported case of a patient with an abnormal karyotype resulting from a de novo translocation in the paternal germline with probable unbalanced adjacent 1 segregation and maternal non-disjunction of chromosome 22 in meiosis I.     

A cytogenetic survey of 200 unclassifiable mentally retarded children with congenital anomalies and 200 normal controls

A cytogenetic survey was carried out on 200 patients with mental retardation and multiple congenital anomalies, and on 200 normal adult controls. Patients with a known syndrome were excluded from the survey. Chromosome analyses were carried out on 'blind-coded' slides using the ASG banding technique as the routine stain. After the initial analyses (at least 15 cells per person) the slides were decoded, destained and reused for C and Q band polymorphism studies. Five major chromosome abnormalities were detected in the patient group during the survey. They included three patients with de novo, apparently balanced, reciprocal translocations, karyotypes 46,XY,rcp(3;16)(q21;p12); 46,XX,rcp(5;8)(p15;q22); and 46,XX,rcp(5;12)(p11;q24); one with karyotype 47,XX,+mar and one with karyotype 46,XX,der(13),t(13;?)(q34;?). One additional patient whose karyotype in lymphocytes was 46,XX,inv(9)(p11;q13) was found to have a mosaic karyotype 46,XX,inv(9)(p11;q13)/46,XX,inv(9) (p11;q13), der(12),t(12;?)p13;?) in cultured skin fibroblasts. None of the 200 controls had a major chromosome abnormality. From the combined results of this and previous surveys it is now apparent that about 6.2% of the unclassifiable mentally retarded patients with three or more congenital anomalies and about 0.7% of the controls reveal major chromosome abnormalities.     

Prenatal detection of short arm deletion and isochromosome 18 formation investigated by molecular techniques

A patient was referred for amniocentesis because of advanced maternal age and polyhydramnios. The fetal karyotype was a mosaic 46,XX,del(18)(p11.1)/46,XX,-18,+i(18q)de novo. The deletion appeared to encompass the whole short arm as evidenced by G banding and in situ hybridisation. However, telomere sequences were found on both ends of the deleted chromosome as well as the isochromosome. The normal 18 and the isochromosome showed more alphoid sequences than the del(18). Subsequent passages of the cell lines showed an increase in the frequency of the isochromosome from 20% to about 30%. Possible mechanisms are discussed.     

Karyotypic changes in phyllodes tumors of the breast

Cytogenetic analysis of short-term cultures of five phyllodes tumors of the breast-classified as benign (one tumor), borderline malignant (two tumors removed from the same breast in 1991 and 1993), and malignant (two tumors)--revealed clonal changes with simple structural abnormalities in the benign tumor, the borderline malignant tumors, and one malignant tumor in which benign areas and areas of borderline malignancy were also present. In contrast, the malignant tumor without admixed borderline malignant or benign areas had a complex karyotype. The karyotype of the benign phyllodes tumor was 46,XX,del(12)(p11p12)/46,XX,t(8;18)(p11;p11)/46,XX. The first borderline malignant phyllodes tumor had t(3;20)(p21;q13) as the sole abnormality. When the tumor recurred, this was no longer the only clone detected and the tumor karyotype was now 46,XX,t(3;20)(p21;q13)/46,XX,t(9;10)(p22;q22)/46,XX,t(1;8) (p34;q24)/46,XX,del(11)(q22-23)/46,XX. The malignant/borderline malignant/benign tumor had t(1;6)(p34;p22) as the sole clonal abnormality. Finally, the karyotype of the malignant phyllodes tumor which contained no benign or borderline malignant areas was 42,XX,der(1)t(1;4)(q21;q21),der(3)t(3;17)(q29;q21), -4,i(8)(q10), -10, -13,i(13)(q10),der(14)t(1;14)(q21;p11),der(14)t(4;14) (p12;p11), -17/80-90,idemx2, +del(1)(q12), +i(1)(p10), +dic(5;5)(p14;p14), +i(6)(p10), +del(7)(p11), +dup(7)(q11q36), +i(15)(q10),inc/46,XX. The findings indicate some cytogenetic similarities between benign/borderline malignant phyllodes tumors and fibroadenomas of the breast, presumably reflecting similar pathogenetic mechanisms in the two types of mixed-lineage tumors.     

Agonist and antagonist actions of (-)pindolol at recombinant, human serotonin1A (5-HT1A) receptors

Prenatal diagnosis and clinical follow up of a patient with mosaicism for anomalies of chromosome 18 are reported. The fetus appeared on ultrasound to have multiple anomalies, including clubbed feet, abnormal hand positioning, edema of the scalp, cleft palate, and polyhydramnios. The karyotype on amniocytes was 47,XY,+i(18p). Postnatally, the peripheral blood karyotype was 46,XY,+i(18q), whereas the skin fibroblast karyotype was 47,XY,+i(18p). The infant had many features consistent with those previously described in cases of tetrasomy 18p and some that were consistent with trisomy 18q.     

Are duodenal ulcer seasonal fluctuations paralleled by seasonal changes in 24-hour gastric acidity and Helicobacter pylori infection?

Short-term cultures from two histologically benign chemodectomas, one from the carotid body and one from the vagal nerve, were analyzed cytogenetically. The former had a small abnormal clone with the karyotype 46,XX,t(3;19)(q21;q13),t(12;15) (p13;q12-14), whereas the majority of the cells from the latter tumor displayed two related abnormal clones: 46,XY,i(I)(q10)/ 46,iderm,add(2)(q37). The findings add to the evidence that chemodectomas are heterogeneous neoplasms and suggest that the heterogeneity may possibly be associated with the site of origin.     

N-ras mutation in acute myeloid leukemia: incidence, prognostic significance and value as a marker of minimal residual disease

The combined use of qualitative and quantitative analysis of 11p13 polymorphic markers together with chromosomal in situ suppression hybridization (CISS) with biotin labeled probes mapping to 11p allowed us to characterize a complex rearrangement segregating in a family. We detected a pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in the family: an insertion of brand 11p13-p14 carrying the genes for predisposition to Wilms' tumor, WT1, and for aniridia, AN2, into the long arm of chromosome 11 in 11q13-q14. Asymptomatic balanced carriers were observed over three generations. Classical cytogenetics had failed to detect this anomaly in the balanced carriers, who were first considered to be somatic mosaics for del(11)(p13). Two of these women gave birth to children carrying a deleted chromosome 11, most likely resulting from the loss of the 11p13 band inserted in 11q. Although in both cases the deletion encompassed exactly the same maternally inherited markers, there was a wide variation in clinical expression. One child, with the karyotype 46,XY, del(11)(p13p14), presented the full-blown WAGR syndrome with aniridia, mental retardation, Wilms' tumor, and pseudohermaphroditism, but also had proteinuria and glomerular sclerosis reminiscent of Drash syndrome. In contrast, the other one, a girl with the karyotype 46,XX,del(11)(p13), only had aniridia. Although a specific set of mutational sites has been observed in Drash patients, these findings suggest that the loss of one copy of the WT1 gene can result in similar genital and kidney abnormalities.     

Chromosomes and causation of human cancer and leukemia. XLVIII. T-cell acute leukemia in ataxia telangiectasia

Cytogenetic and immunologic studies were performed on the cells of an 18-year-old female with ataxia telangiectasia (AT) associated with acute lymphocytic leukemia (ALL). At the onset of the leukemia 15.4% of peripheral blood cells stimulated with phytohemagglutinin (PHA) contained a tandem translocation of the long arm of chromosome #14, i.e., t(14;14). To ascertain if these karyotypically abnormal cells and the leukemic cells had a common lineage, chromosome analyses were performed on bone marrow cells. Examination of the marrow cells on the seven occasions when leukemic cells were present in the marrow, including times when they were predominant, showed only a normal karyotype without the presence of t(14;14). However, an abnormal clone, which had the karyotype 45,XX,-9,t(9;6)(q12;q13), was identified in the marrow cells on the last examination during the terminal phase of the leukemia. Immunologically, the ALL was classified as an atypical type which had characteristics in common with certain T-cell subsets. We suggest that the malignant cells did not originate from the preexisting cells with a tandem duplication of the 14q.     

De novo unbalanced translocation resulting in monosomy for proximal 14q and distal 4p in a fetus with intrauterine growth retardation, Wolf-Hirschhorn syndrome, hypertrophic cardiomyopathy, and partial hemihypoplasia

We present the perinatal findings of a fetus with a de novo unbalanced chromosome translocation that resulted in monosomy for proximal 14q and monosomy for distal 4p. Prenatal sonographic examination at 27 weeks of gestation showed intrauterine growth retardation, microcephaly, cardiomegaly with arrhythmia, and asymmetry of the upper limbs. Genetic amniocentesis showed an abnormal karyotype of 45,XX,der(4)t(4;14)(p16.3;q12),-14. Linkage analysis of the family confirmed the maternal origin of the deletions. Molecular refinement of the deletion breakpoints indicated that the breakpoints at 4p16.3 and 14q12 were located between loci D4S403 (present) and D4S394 (absent), and between loci D14S252 (present) and D14S64 (absent), respectively. Necropsy showed dysmorphic features compatible with Wolf-Hirschhorn syndrome, hypertrophic cardiomyopathy, partial hemihypoplasia, and a normal brain without evidence of holoprosencephaly. Our case adds to the list of clinical phenotypes associated with the proximal regions of 14q.     

A de nevo complex t(7;13;8) translocation with a deletion in the TRPS gene region

Molecular cytogenetic analyses have resolved the pathogenetic aberration of an 8-year-old girl with tricho-rhino-phalangeal syndrome type I (TRPS I), normal intelligence, and a karyotype originally described as 46,XX,t(8;13)(q24;q21). R- and Q-banding and high resolution R-banding analyses have also disclosed a seemingly mosaic abnormality of the distal short arm of chromosome 7 but have not fully characterized this abnormality. Combined primed in situ labelling and chromosome painting, and three-colour chromosome painting have revealed a complex, apparently balanced translocation t(7;13;8). Fluorescence in situ hybridization with yeast artificial chromosome and cosmid clones from 8q24.1 has shown an interstitial deletion of at least 3 Mb covering most of the TRPS I critical region.     

Emergent endoluminal repair of delayed abdominal aortic rupture after blunt trauma

A 72-year-old man with increased monocytes and eosinophils in the bone marrow was found to have an isochromosome, i(14q), as the sole abnormality on bone-marrow cytogenetics. Follow-up over 12 months with repeat cytogenetic testing of bone marrow specimens on three further occasions showed an additional abnormality consisting of an apparently balanced translocation, t(6;21)(p21.1; q22). This abnormality, together with other features, indicated disease progression. A review of seven reported cases of i(14q) revealed limited follow-up information.     

Effects of tenoxicam on neutrophil chemotaxis in rheumatoid arthritis and healthy controls

Craniosynostosis (CRS) is frequently seen in the del(7p) syndrome, and the gene for this cranial anomaly (CRS1) has been assigned to 7p21. We present a 3-year-old boy with CRS involving the sagittal and coronal sutures, who had a de novo and apparently balanced translocation, t(6;7)(q16.2;p15.3). Southern blot analysis of several loci on 7p14-->pter showed that the patient was heterozygous for HOX1I and IL6, possibly homozygous for D7S149, but hemizygous for D7S135 with a loss of the paternal allele. These findings suggest the localization of a candidate gene for CRS1 to be on 7p15.3 in the close proximity to the D7S135 locus.     

Correlation of cytogenetic, molecular cytogenetic, and clinical findings in 59 patients with ANLL or MDS and abnormalities of the short arm of chromosome 12

Abnormalities of the short arm of chromosome 12 (12p) are found in about 5% of acute nonlymphocytic leukaemias (ANLL) and myelodysplastic syndromes (MDS). They are described to be characteristic of secondary leukaemias, especially after prior mutagenic exposure, and to be associated with a poor prognosis. In our series of 59 patients with 12p abnormalities and ANLL or MDS, exposure to genotoxic agents was proven only in five patients, but in 13/44 patients ANLL evolved from an MDS. Patients with a small deletion del(12)(p11.2p13) having a mild clinical course were distinguished from those with a large del(12)(p11.2), additional chromosomal anomalies, and a poor clinical course. Among the 31 patients with translocations or dicentric chromosomes involving 12p, a group of eight with t/dic(12;13) was the most frequent and was associated with a poor prognosis. The clinical outcome was adverse in the majority of patients with complex karyotype abnormalities, but in some patients a milder clinical course seems likely. A new, hitherto undescribed, abnormality in an MDS case with a duplication dup(12)(p11.2p13) was the amplification of the signal of the yeast artificial chromosome (YAC) clone 964c10 (D12S736). In 38 cases with deletions or unbalanced translocations/dicentrics one YAC signal was lost. Five patients with balanced translocations demonstrated breakpoints within the YAC, containing the ETV6 (TEL) gene. The breakpoints were telomeric to the YAC 964c10 in seven cases and centromeric in one patient.     

Diagnosis of an occipital condyle fracture using MRI

In the application of the fluorescence in situ hybridization (FISH) technique for prospective prenatal screening of common aneuploidies involving the autosomes 13, 18, and 21, and sex chromosomes, six cases of inconsistency between the results of FISH analysis and the results of karyotyping of cultured amniocytes have been observed, including two cases of translocation involving the Y-chromosome and chromosome 15 in a total of 904 cases of amniocentesis studied. In one case, the translocation was of maternal origin, and in the other, of paternal origin. In both cases, the couples decided to continue the pregnancy and normal babies were delivered. The data show the usefulness of applying the FISH technique in prospective prenatal screening of common trisomies for the possible detection of rare chromosome rearrangements involving the Y-chromosome.     

Clinical relevance of the i(12p) marker chromosome in germ cell tumors

BACKGROUND: Germ cell tumors in men are curable at all stages and are among the most sensitive of all cancers to chemotherapy. An isochromosome of the short arm of chromosome 12, i(12p), has been reported to be a frequent marker of these tumors and to have diagnostic and prognostic significance. PURPOSE: We evaluated the possible association between this cytogenetic marker and clinical outcome for men with germ cell tumors. METHODS: One hundred seventy-eight germ cell tumor samples from 150 men were studied using conventional and molecular cytogenetic techniques. Of these samples, 171 were evaluable. Patient characteristics, disease stage, treatment outcome, and disease status were correlated with the observed cytogenetic changes. In addition, 28 biopsy specimens obtained from 28 patients with tumors of uncertain histogenesis were evaluated to determine whether the presence of i(12p) could serve as a diagnostic marker of a germ cell origin for these tumors. RESULTS: Of the 171 evaluable tumor accessions, 101 (59%) yielded abnormal karyotypes. i(12p) was determined to be present in 79 of the 101 (79%) abnormal karyotypes, which were derived from all cell types and primary sites. An abnormal karyotype was more frequently obtained from nonseminomatous tumors (91/137 [81%]) than from seminomas (10/34 [30%] [P < .001]). Tumors resulting in a cytogenetic failure were more likely to respond completely to chemotherapy than tumors with an abnormal karyotype (P = .004). i(12)p copy number was not associated with response or survival. Fluorescence in situ hybridization using a chromosome 12 centromere-specific probe detected i(12p) in 47 of 47 tumors (100%) already shown to have i(12p) by cytogenetic analysis and in 13 of 49 tumors (27%) exhibiting either an abnormal karyotype or a cytogenetic failure. One or more copies of i(12p), excess 12p copy number, or a deletion on the long arm of chromosome 12 was found in seven of 28 (25%) midline tumors of uncertain histogenesis, thus establishing a diagnosis of a germ cell tumor in these patients. One partial and five complete responses were observed in these seven patients. Only two partial responses were seen in the 17 patients who had no detectable germ cell tumor-related cytogenetic marker (P = .009). CONCLUSIONS: i(12p) is a highly nonrandom chromosomal marker seen in about 80% of male germ cell tumors with evaluable cytogenetic abnormalities. The presence of this isochromosome has diagnostic and possibly prognostic importance for patients with these tumors. IMPLICATIONS: Cytogenetic studies of germ cell tumors in prospective clinical treatment trials are warranted to define more precisely the relationship between histologic subtype, serum tumor marker production, and prognosis.     

Unbalanced t(3;12) in a case of juvenile myelomonocytic leukemia (JMML) results in partial trisomy of 3q as defined by FISH

Juvenile myelomonocytic leukemia (JMML) is a rare disorder of early childhood, to which no recurrent chromosome rearrangement has been yet associated. We report a case where leukemic cells harbored a 46,XX,der(12)t(3;12) (q21 approximately 22;p13.33) karyotype, resulting in partial trisomy of 3q. The origin of chromosome material translocated to chromosome 12 was assessed by chromosome painting using a whole chromosome 3-specific probe. The breakpoint regions were defined by FISH using YAC probes from 3q and 12p chromosomal regions. Interestingly, partial trisomy of 3q has been detected in a previously reported JMML case, consequent to the presence of a der(15)t(3;15)(q13.1;q26). The involvement of a similar chromosome 3 rearrangement in these two JMML cases suggests the hypothesis that either the resulting duplication of some gene/s on 3q or the loss of heterozygosity (LOH) of some gene/s on 3p may be involved in one of the steps leading to JMML. On the other hand, it cannot be ruled out that the relevant mutation in our case might be consequent to the particular breakpoints at bands 3q21 approximately 22 and 12p13.3, that may alter the structure and/or expression of the involved gene/s.     

Cytogenetic aberrations in Ewing sarcoma: are secondary changes associated with clinical outcome?

BACKGROUND: Ewing sarcoma is associated with a nonrandom pattern of primary and secondary chromosomal aberrations. Whereas the finding of rearrangements of chromosome 22, usually in the form of a balanced translocation t(11;22)(q24;q12), is important diagnostically, nothing is known about the potential prognostic impact of the secondary chromosomal aberrations. PROCEDURE: During a 1 3-year-period, short-term cultured tumor samples from 21 children and young adults with Ewing sarcoma were cytogenetically analyzed successfully. RESULTS: Clonal chromosome aberrations were detected in 18 patients, 17 of whom had the characteristic t(11;22)(q24;q12) or variants thereof. The most frequent secondary change was +8, followed by +12, +2, +5, +9, +15, and gain of material from the long and short arms of chromosome 1. The only recurrent secondary change that was restricted to tumors from the ten patients that were dead at latest follow-up was gain of 1q material. Furthermore, all three patients with tumors with chromosome numbers over 50 had died, and the only patient with a tumor karyotype lacking chromosome 22 rearrangement was alive without evidence of disease. CONCLUSIONS: These data and previously published results indicate that the karyotypic pattern not only may be of diagnostic significance but also may be important prognostically.     

Neuroprotective effect of eliprodil: attenuation of a conditioned freezing deficit induced by traumatic injury of the right parietal cortex in the rat

We report on a familial three way translocation involving chromosomes 3, 6, and 15 identified by prometaphase banding and fluorescence in situ hybridisation (FISH). Two mentally retarded sibs with different phenotypic abnormalities, their phenotypically normal sister and mother, and two fetuses of the phenotypically normal sister were analysed. The terminal regions of chromosomes 3q, 6q, and 15q were involved in a reciprocal translocation, in addition to a paracentric inversion of the derivative chromosome 15. Conventional cytogenetic studies with high resolution GTG banding did not resolve this rearrangement. FISH using whole chromosome paints (WCPs) identified the chromosomal regions involved, except the aberrant region of 3q, which was undetectable with these probes. Investigation of this region with the subtelomeric FISH probe D3S1445/D3S1446 showed a balanced karyotype, 46,XX,t(3;15;6) (q29;q26.1;q26), inv der(15) (q15.1q26.1) in two adult females and one fetus. It was unbalanced in two sibs, showing two different types of unbalanced translocation resulting in partial trisomy 3q in combination with partial monosomy 6q in one patient and partial trisomy 15q with partial monosomy 6q in the other patient and one fetus. These represent apparently new chromosomal phenotypes.     

Prenatal diagnosis of supernumerary chromosome derivative (22) due to maternal balanced translocation in association with diaphragmatic hernia: a case report

An aneuploid fetus was detected prenatally by cordocentesis at 27 weeks' gestation following ultrasonographic diagnosis of severe fetal growth retardation and a large diaphragmatic hernia. The fetal karyotype was revealed to be 47,XX,der(22)t(11;22)(q23.3;q11.2) after parental bloods confirmed a balanced reciprocal translocation in the mother. Approximately 85 cases with an unbalanced karyotype 47,XX(or XY),+der(22),t(11;22) due to 3:1 meiotic disjunction in the parental translocation carrier have been reported in the world literature and only one of them was diagnosed prenatally. This is the first detailed case report of a supernumerary derivative (22) chromosome abnormality diagnosed prenatally in association with diaphragmatic hernia.     

Cytogenetic profile of lymphoma of follicle mantle lineage: correlation with clinicobiologic features

Conventional chromosome analysis (CCA) and interphase fluorescence in situ hybridization (FISH) was performed in 42 patients with mantle-cell lymphoma (MCL), with BCL1 rearrangement. The t(11;14)(q13;q32) or 11q abnormalities were detected by CCA in 34 cases, 20 of which had additional aberrations. A normal karyotype was observed in 8 cases. Probes detecting the chromosome aberrations that were observed in at least 3 cases by CCA, ie, +12, 13q14 deletion, and 17p deletion, were used for interphase FISH analysis. FISH detected total or partial +12, 13q14 deletion and 17p- in 28.5%, 52.4%, and 26% of the cases, respectively. The presence of these anomalies was not a function of karyotype complexity. Based on the results of CCA/FISH, three groups of increasing karyotype complexity were recognized: group 1, including 11 patients without detectable aberrations in addition to BCL1 rearrangement; group 2, including 14 patients with 1 to 2 additional anomalies; and group 3, including 17 patients with three or more additional anomalies. Clinical parameters associated with shorter survival were male sex (P =.006) and primary lymph-node involvement compared with primary bone marrow involvement (P =.015). Trisomy 12 was the only single cytogenetic parameter predictive of a poor prognosis (P =.006) and the best prognostic indicator was the derived measure of karyotype complexity (P <.0001), which maintained statistical significance in multivariate analysis (P<.0001). We arrived at the following conclusions: 13q14 deletion occurs at a high incidence in MCL; 17p deletion and total/partial +12 are relatively frequent events in MCL, the latter aberration being associated with a shorter survival; and the degree of karyotype complexity has a strong impact on prognosis in this neoplasia.