Balanced complex rearrangement involving chromosomes 8, 9, and 12 in a normal mother,derivative chromosome 9 with recombinant chromosome 12 in her daughter with minor anomalies

We report on a 19-month-old girl with a derivative chromosome 9 and a recombinant chromosome 12 resulting from a maternal balanced complex rearrangement involving chromosomes 8, 9, and 12. The karyotype of the phenotypically normal mother was 46,XX,t(8;12) (9;12) (8qter→8p23::12q12→12q15::9q32→9qter;9pter→9q32::12q15→12qter;12pter→12q12::8p23→8pter). The child's karyotype was 46,XX,?9,?12, +der(9) (9pter→9q32::12q15→12qter),+rec(12) (12pter→12q15::9q32→9qter) mat. The child had severe growth retardation, minor anomalies including trigonocephaly, hypertelorism, broad nasal root, apparently low-set and posteriorly angulated ears, triangular face, pectus carinatum, clinodactyly of fifth fingers, and almost normal psychomotor development. To the best of our knowledge, there have been only 3 previous reports of recombination derived from parental complex chromosome rearrangements. In the recombination products, the chromosomes were apparently balanced and the offspring had no clinical abnormalities. The present case exhibited abnormalities and may have a submicroscopic aberration of 12q arising from crossing over during maternal meiotic pairing, although her chromosomes appeared to be balanced. © 1993 Wiley-Liss, Inc.     

Syndromal frontonasal dysostosis in a child with a complex translocation involving chromosomes 3, 7, and 11

We report on a 4-year-old boy with typical frontonasal dysostosis and an apparently balanced de novo translocation involving chromosomes 3, 7, and 11, and four breakpoints. The karyotype was 46,XY,t(7;3)(3;11) (7pter→7q21.3::3q27→3qter;3pter→3q23::11q21→11qter;11pter→11q21::3q23→3q27::7q21.3→7qter). In situ hybridization with a chromosome 3 painting probe confirmed the interpretation from GTG banding. The child had a widow's peak, marked hypertelorism, absence of the nasal tip, and widely separated nares. He also had an atrial septal defect, micropenis, small testes, clubfeet, scoliosis, block C2–4, and structural brain abnormalities on MRI. In review we found two other cases of frontonasal dysostosis with chromosome abnormalities, neither of which was similar to our case. The presence of a denovo (apparently) balanced translocation in our patient may help to locate the gene(s) for frontonasal dysplasia and perhaps other midline craniofacial malformations. © 1995 Wiley-Liss, Inc.     

Maternal balanced translocation leading to partial duplication of 4q and partial deletion of 1p in a son: Cytogenetic and FISH studies using band-specific painting probes generated by chromosome microdissection

A 9-month-old boy with pre- and post-natal growth retardation, microcephaly, plagiocephaly, and several minor anomalies had the initial karyotype: 46,XY,der(1)t(1;?)(p36.1;?). Further analysis showed that the der(1) was derived from an unfavorable segregation of a maternal complex chromosome rearrangement, i.e., 46,XX,der(1)t(1;?)(p36.1;?), der(4)t(4;?)(q?;?). Whole chromosome fluorescence in situ hybridization (FISH) and chromosome microdissection were used to clarify the maternal karyotype as: 46,XX,der(1)t(1;4)(4qter→4q33::1p36.13→1qter),der(4)t(1;4)inv(4)(4pter→ 4q31.3::1p36.33→1p36.13::4q33→4q31.3::1p36.33→1pter). Therefore, the karyotype of the boy actually was 46,XY,der(1)t(1;4)(p36.13;q33). Clinical comparison of the patient's clinical findings showed similarities to individuals with partial del(1p) and dup(4q). To our knowledge the above cytogenetic abnormalities have not been described previously. This case further demonstrates the advantages of chromosome microdissection and FISH in the identification of anomalous chromosome regions and breakpoints. Am. J. Med. Genet. 71:160–166, 1997. © 1997 Wiley-Liss, Inc.     

A complex chromosome rearrangement with at least five breakpoints studied by fluorescence in situ hybridization

A newborn infant with multiple congenital anomalies was diagnosed with an unbalanced translocation of chromosomes 1 and 5. Studies of parental chromosomes revealed a complex rearrangement in the patient's mother involving the exchange of terminal long arms between chromosomes 1 and 5 and the insertion of an interstitial segment from the same chromosome 5q into chromosome 2q by high-resolution G-banding. Further study of the mother's chromosomes by fluorescent in situ hybridization (FISH) detected an additional insertion between the rearranged chromosomes 2 and 5, which was not revealed by G-banding. This led to the identification of a complex translocation-insertion between 3 chromosomes with at least 5 breaks [t(1;5;2)(1pter→1q42.3::5q23.2→5qter;5pter→5q21.2::2q33→2q35::1q42.3→1qter;2pter→2q33::5q21.2→5q23.2::2q35→2qter)] and illustrates the value of FISH as an adjunct to standard cytogenetics, particularly in cases of complex rearrangements. Am. J. Med. Genet. 68:417–420, 1997. © 1997 Wiley-Liss, Inc.     

Complex chromosome rearrangement and recombinant balanced translocation in a mother and a daughter with the same phenotypic abnormalities

We report on the diagnosis of a complex chromosome rearrangement in a mother and the transmission of a simplified translocation in her fetus. The mother had mental retardation, short stature, facial dysmorphism, and hydronephrosis, but was never investigated before she was pregnant. A blood sample was taken for karyotyping at the time of amniocentesis for advanced maternal age. The mother's karyotype revealed two translocations involving chromosome 5, chromosome 16 twice, and chromosome 20 as follow: 46,XX,t(5;16;20)(5pter-->5q11.2::16q12.1-->16q23::20p11.2-->20pter;16pter-->16q12.1::5q11.2-->5qter;16qter-->16q23::20p11.2-->20qter). The amniocentesis revealed a female karyotype with an apparently balanced translocation: 46,XX,t(16;20)(q23;p11.2). The translocation of the fetus probably resulted from a meiotic recombination between the derived 5 and the normal 16 in the mother. The baby was born and presented the same facial dysmorphism and hydronephrosis. The simplification of a complex rearrangement through recombination into a balanced product has only been rarely described and it is to our knowledge the first time that both the carrier of the complex rearrangement and her descendant with a simplified rearrangement share phenotypic abnormalities.     

Molecular cytogenetic analysis of a nontumorigenic human breast epithelial cell line that eventually turns tumorigenic: Validation of an analytical approach combining karyotyping,comparative genomic hybridization,chromosome painting,and single-locus fluorescence in situ hybridization

The immortalized, nontumorigenic human breast epithelial cell line HMT-3522 has been used as a model for premalignant and, eventually, malignant development. During cultivation, the karyotype evolution was followed. At an early stage, a very long constant phase showed a near-diploid karyotype, with only five marker chromosomes. DNA from this phase was used for comparative genomic hybridization (CGH) analysis, confirming a previously known MYC amplification, and the integration sites were subsequently determined by single-locus fluorescence in situ hybridization (FISH). Furthermore, gains of 5q22-qter and 20q11-qter and deletion of most of chromosome 6 (6p23-qter) were detected by CGH. Because of uncertainty about some of the indicated changes, including a deletion of 1p35-pter, the CGH findings were investigated more closely by chromosome painting, leading to a revision of the karyotype: 45,XX,del(1)(p35),−6,dup(8)(pter→qter::qter→q24),der(12) t(6;12)(p23;p13),der(14)t(5;14)(q22;q32.3),der(17)t(8;17;20)(17pter→17q25::8qter→8q23::8q24→8qter::8q24→8qter::8q23→8q24.1::20q11→20qter). Some karyotypic changes were confirmed by CGH; others had to be revised; and, in the 1p35 region, classical cytogenetics seems superior to CGH. However, CGH revealed a karyotypically unsuspected dup(20q) that might be of special relevance to breast tumor initiation or progression. Our study confirms that CGH is supplementary to current technologies, e.g., karyotyping and Southern analysis, but cannot replace them. In addition, our cell line turned out to be an excellent model for comparison among the different methods. The results imply that future cytogenetic analyses of complex karyotypes should be based on a combination of karyotyping, CGH, and FISH. Genes Chromosom. Cancer 20:30–37, 1997. © 1997 Wiley-Liss, Inc.     

Unique karyotypes in two patients with Prader-Willi syndrome

A physical disruption of the Prader-Willi syndrome (PWS) chromosome region is thought to cause PWS. We describe 2 girls with PWS phenotype, who had unique chromosome 15 abnormalities. The first patient showed mosaicism: 45,XX,t(15;15)(qter→p11.1::q11.200→ qter)/46,XX,t(15;15)(qter → p11.1::q11.200→ qter), + mar. The band 15q11.2 apparently remained intact in the t(15;15) chromosome, and the mar chromosome was considered as r(15) (p11.1q11.1). The second patient had a karyo-type of 47,XX,del(15)(q11.200→q11.207), + idic (15)(pter → q11.1::q11.1→pter). The complex breakage and reunion involving the 15q11.2 regions of the father's homologous chromosomes 15 at meiosis appeared to have resulted in the idic(15) and the del(15) chromosomes. These cytogenetic findings suggest that the PWS chromosome region may be localized on the very proximal portion of band 15q11.2.     

Clonal chromosome aberrations in a keratoacanthoma and a basal cell papilloma

Clonal chromosome abnormalities were found in short-term cultures from two epithelial skin tumors, a basal cell papilloma and a keratoacanthoma. The three-way translocation t(2;6;11)(q21;q27;p13) was the sole clonal rearrangement in the basal cell papilloma. The karyotype of the keratoacanthoma was more complex: 46,XX,der(2)(2pter----2p13::2p11----cen----2q37: :5q33----5qter),der(2) (:2p13----cen----2q37::6q23----6qter),der(5)t(2; 7;5)(q37;q11;q33),der(6) (6pter----cen----6q23::2p13----2pter),der(7)t(2; 7;5)(q37;q11;q33), del(13)(q11q14). In addition, several nonclonal structural changes were seen in both tumors.     

Complex karyotypic anomalies in a bizarre leiomyoma of the uterus

Cytogenetic investigation of short-term cultures from a bizarre leiomyoma of the uterus, a tumor type not hitherto karyotypically characterized, revealed two abnormal clones with multiple complex rearrangements. Three-fourths of the aberrant cells were hypodiploid with the composite karyotype 38–44, XX,?6,?7,?10,?11,+20,?22, r(1), der(2) (:2p23→cen→2q13::1q21→1qter), der(2)t(2;9)(p21;q13), t(5;?)(q35;?), t(5;?),(q35;?), + der(5)t(5;15)(q11;q15), der(8)t(8;11)(q24;q13), t(15;?)(p12;?), der(16)t(12;16)(q13;p13),+r,+mar. The remaining abnormal mitoses were hypotetraploid, with chromosome numbers ranging from 74 to 86. These massively rearranged cells showed the same markers that were found in the hypodiploid clone, but in duplicate, indicating that this clone had arisen through polyploidization of hypodiploid cells. Flow cytometry revealed a DNA index of 1.03.     

Ph-negative chronic myelocytic leukemia with a complex translocation involving chromosomes 7 and 11

A complex translocation t(7;11)(7qter----7p15::11q13----11qter;11pter ----11p15::11q13----11p15::7p15----7pter) was detected in the leukemic cells from a 67-year-old woman with Ph chromosome negative chronic myelocytic leukemia. This translocation has not been previously reported in Ph-negative CML.     

Multiple apparently unrelated clonal chromosome abnormalities in a squamous cell carcinoma of the tongue

We have cytogenetically examined short-term cultures from a squamous cell carcinoma of the tongue, a tumor type in which chromosome aberrations hitherto have not been reported. No less than 12 pseudodiploid clones were detected, giving the tumor karyotype 46,X,der(X)t(X;1)(q26;p32),der(1)(Xqter→Xq26::1p32→cen→1q42:),del(13)(q11q21),t(15;?) (q26;?)/46,XX,t(1;?)(p34;?),inv(2)(p21q11)/46,XX,t(1;10)(p32;q24)/46,XX,+der(1)(12pter→ 12p11::1p11→cen→1q32::11q13→11q32→1q42:),del(11)(q13q22), - 12, der(17)t(1:17) (q42;p13)/46,XX,inv(1)(p22q44)/47,XX,del(1)(q32),der(17)t(1:17)(p22;q25),der(1)inv(1) (q25q44)t(1;17)(p22;q25),ins(14;7)(q11;q22q36), + 14/46,XX,t(1;4)(q23;q35)/46,XX,t(1;21) (q25;q22),t(2;10)(q31;q26),t(22;?)(q12;?)/46,XX,del(1)(q32)/46,XX,t(1;8)(q44;q21)/46,XX, t(2;21)(q11;p11)/46,XX,t(9;11)(q34;q13). The large number of apparently unrelated abnormalities leads us to suggest that the carcinoma may have been of multiclonal origin.     

Nonendemic Burkitt's lymphoma with complex chromosome abnormalities involving chromosomes 2 and 8

A long surviving patient with nonendemic Burkitt's lymphoma and complex cytogenetic findings is presented. Chromosome abnormalities were seen as a minor clone in peripheral blood and were considered consistent with the t(2;8)(p12;q24) variant. The karyotype was 47,XY, -2, -8, + der2(8qter-8q24::2p12-2qter), + der8(8pter-8q23::2p12-2pter) + der8(8qter-8cen::1q21-1qter). This case illustrates the value of extensive chromosome analysis in hematologic disorders and, at the time of writing, is the first example in Britain of the t(2;8) variant in Burkitt's lymphoma.     

A complex,five breakpoint intrachromosomal rearrangement ascertained through two recombinant offspring

Intrachromosomal rearrangements usually result from three or fewer breaks. We report a complex intrachromosomal rearrangement resulting from five breaks in one chromosome 10 of a phenotypically normal father of two developmentally delayed children. GTG-banding analysis of the father's rearranged chromosome 10 suggested an initial pericentric inversion followed by an insertion from the short arm into the terminal band of the long arm [der(10)(pter→p13::q21.2→p12.2::q22.1→q26.3::q22.1→q21.2::p12.2→p13::q26.3→qter)]. To our knowledge, this rearrangement is the most complex ever reported in a single chromosome. Both children inherited a recombinant chromosome 10 with loss of the insertion and the segment distal to it [rec(10)der(pter→p13::q21.2→p12.2::q22.1→q26.3:)]. Mechanisms for both rearrangements are proposed. © 1996 Wiley-Liss, Inc.     

Meiotic segregation in familial reciprocal translocation t(8q;22q)

We studied the chromosomes of a mentally retarded boy with minor anomalies and of his parents using a G-band stained high-resolution chromosome method. This documented dup (8q24.1 → 8qter) and dup(22pter → 22q11.2) in the boy due to a maternal balanced reciprocal translocation of chromosomes 8 and 22 and 3:1 disjunction during meiosis I. The karyotype of the boy is 47, XY, + der(22) (22pter → 22q11.2::8q24.1 → 8qter). The der(22) was involved in satellite associations and stained positively with AgNO₃ in mother and child. The case is compared to similar cases in the literature and the function of the small acrocentric marker chromosome during meiosis is discussed.     

Application of fluorescence in situ hybridization for early prenatal diagnosis of partial trisomy 6p/monosomy 6q due to a familial pericentric inversion

Wauters JG, Bossuyt PJ, Roelen L, van Roy B, Dumon J. Application of fluorescence in situ hybridization for early prenatal diagnosis of partial trisomy 6p/monosomy 6q due to a familial pericentric inversion. Clin Genet 1993: 44: 262–269. © Munksgaard, 1993
We report the prenatal diagnosis of a karyotype 46,XY,rec(6)dup p, inv(6) (p23q27) mat detected by fluoroscence in situ hybridization using chromosome 6pter and 6qter specific DNA markers. This partial duplication-deletion (6p12→pter; 6q27→qter) emanated from a balanced pericentric inversion 46,XX inv(6) (p23q27)pat present in the mother. The phenotypes of two relatives with the same unbalanced anomaly are described. This report illustrates the sensitivity and specificity of fluorescence in situ hybridization (FISH) and its benefit in rapid and unequivocal prenatal diagnosis of subtle chromosomal rearrangements.     

Cytogenetic,spectral karyotyping,fluorescence in situ hybridization,and comparative genomic hybridization characterization of two new secondary leukemia cell lines with 5q deletions,and MYC and MLL amplification

Cytogenetic studies of patients with therapy-induced acute myeloid leukemia (t-AML) have demonstrated whole chromosome loss or q-arm deletion of chromosomes 5 and/or 7 in a majority of cases. We have established two cell lines, SAML-1 and SAML-2, from two patients who developed t-AML after radiation and chemotherapy for Hodgkin disease. In both cases, the leukemia cells contained 5q deletions. SAML-1 has 58 chromosomes and numerous abnormalities, including der(1)(1qter-->1p22::5q31-->5qter), der(5)(5pter-->5q22::1p22-->1pter), +8, der(13)i(13)(q10)del(13)(q11q14.1), and t(10;11). Fluorescence in situ hybridization (FISH) with unique sequence probes for the 5q31 region showed loss of IL4, IL5, IRF1, and IL3, and translocation of IL9, DS5S89, EGR1, and CSFIR to 1p. SAML-2 has 45 chromosomes, del(5)(q11.2q31) with a t(12;13)ins(12;5), leading to the proximity of IRF1 and RB1, and complex translocations of chromosomes 8 and 11, resulting in amplification of MYC and MLL. Comparative genomic hybridization and spectral karyotyping were consistent with the G-banding karyotype and FISH analyses. Because a potential tumor suppressor(s) in the 5q31 region has yet to be identified, these cell lines should prove useful in the study of the mechanisms leading to the development of t-AML.     

Monosomy 9p24→pter and trisomy 5q31→qter: Case report and review of two cases

Partial deletion of the short arm of chromosome 9 (p24→pter) and partial duplication of the long arm of chromosome 5 (q32→qter) were observed in an abnormal boy who died at age 8 weeks of a complex cyanotic cardiac defect. He also had minor anomalies, sagittal craniosynostosis, triphalangeal thumbs, hypospadias, and a bifid scrotum. Two other infants with similar cytogenetic abnormalities were described previously. These patients had severe congenital heart defect, genitourinary anomalies, broad nasal bridge, low hairline, apparently low-set ears, short neck, and triphalangeal thumbs, in common with our patient. We suggest that combined monosomy 9p23,24→pter and trisomy 5q31,32→qter may constitute a clinically recognizable syndrome. © 1995 Wiley-Liss, Inc.     

Four cases with complex Philadelphia translocations, including one with appearance de novo of a "masked" Ph

Four cases of chronic myelogenous leukemia (CML) with complex Philadelphia (Ph) translocations are described. The first case was that of a 50-year-old woman in the chronic phase of CML. Her leukemic cells showed a complex Ph translocation involving chromosomes #9, #11, and #22 [i.e., t(9;9;22;11)(11qter----11q11::9q11----9q34:: 9p11----9pter;22qter----22q11::9q34?;11 pter----11q11::22q11----22qter)]. In addition to the complex Ph translocation, the leukemic cells contained del(10)(p13). The second case was that of a 21-year-old man whose leukemic cells contained a translocation involving chromosomes #5, #9, and #22 [i.e., t(5;22;9)(q31;q11;q34)], resulting in a "masked" Ph chromosome. The third case was that of a 37-year-old man whose leukemic cells had a complex Ph translocation involving chromosomes #8, #9, and #22 [i.e., t(8;9;22)(q13;q34;q11)]. The fourth patient was a 41-year-old woman diagnosed as having CML in myeloid blastic phase, at which time the first specimen was examined by us. This blood sample showed a karyotype of 45,XX, -9, -17, -22, +mar1, +mar2,9q+. No Ph chromosome was present. A standard Ph translocation was detected in the cells obtained from the spleen, when the patient underwent splenectomy for treatment of the blastic crisis. Subsequent specimens obtained from the blood and bone marrow showed that the leukemic cells contained three clones: 45,XX, -9, -17, -22, +mar1, +mar2,9q+/46,XX, -17, +mar1,t(9;22)(q34;q11)/46,XX,t(9;22)(q34;q11). Cells with the "masked" Ph chromosome were thought to have been derived from the clone with the standard Ph translocation. We postulate that some variant Ph translocations, including those with a "masked" Ph chromosome, may be generated by a stepwise process following the genesis of a standard Ph translocation.     

Molecular cytogenetic analysis of breast cancer: a combined multicolor fluorescence in situ hybridization and G-banding study of uncultured tumor cells

In six patients with breast cancer, uncultured tumor cells were investigated with G-banding and multicolor fluorescence in situ hybridization (M-FISH). A large number of numerical and structural aberrations could be analyzed. Among other structural abnormalities, reciprocal, hidden and complex translocations were found. Recurrent t(1;10) and t(6;16), not previously described, were identified, as well as t(15;22). The latter was also found in additional cases among our unpublished breast carcinomas. The significance of t(15;22) for breast cancer is discussed, taking into account also data drawn from the literature. Reciprocal translocations were a prominent feature in a pseudodiploid lobular carcinoma. Hidden translocations on 6p22-p24 were detected with M-FISH. Involvement of 6p22-p24 was observed in five cases. The analysis of various other translocations and different structural abnormalities revealed the following common breakpoints (according to frequency of involvement): 1p34-p36, 3p12-p13, 4p13-->q11, 14p11-->q11, 1q42, 8p11, 8q24, 10q22, 11q13, 11q23-q24, 13q13, and 18p10-p11. Loss of 3p and 1p34-p36-->pter and complete or partial loss of 13q and chromosome 17 were also found. With the combination of G-banding and M-FISH techniques, chromosome misclassification is avoided and the characterization of complex tumor karyotypes is more effective.