Mild craniosynostosis with 1p36.3 trisomy and 1p36.3 deletion syndrome caused by familial translocation t(Y;1)

We report on a 20-year-old man and a 16-year-old woman with a chromosomal imbalance derived from a balanced translocation, t(Y;1)(q12;p36.3) of the father. The man had a partial trisomy for 1p36.3-pter [46,X,der(Y)t(Y:1)(q12;p36.3)] and mild craniosynostosis of metopic and sagittal sutures as well as a borderline mental impairment, while the woman with a deletion for 1p36.3-pter [46,XX,der(1)t(Y;1)(q12;p36.3)] showed dysmorphic face with large anterior fontanel and severe developmental delay. Fluorescence in situ hybridization (FISH) showed that his trisomy spanned the 5.3-Mb region from 1p telomere harboring the critical region for craniosynostosis. To our knowledge, the man is the first case of a pure type of simple 1p36.3 trisomy as the effect of heterochromatic Yq12-qter deletion likely does not affect phenotype.     

Unique t(Y;1)(q12;q12) reciprocal translocation with loss of the heterochromatic region of chromosome 1 in a male with azoospermia due to meiotic arrest: a case report

A de novo reciprocal translocation 46,X,t(Y;1)(q12;q12) was found in an azoospermic male with meiotic arrest. Cytogenetics and fluorescent in situ hybridization (FISH) were used to define the karyotype, translocation breakpoints and homologue pairing. SRY (Yp), Yq11.2-AZF regions, DAZ gene copies and the distal Yq12 heterochromatin were studied by PCR and restriction analysis using sequence-tagged sites and single nucleotide variants. High resolution GTL, CBL and DA-DAPI staining revealed a (Y;1) translocation in all metaphases and a normal karyotype in the patient's father. FISH showed the presence of the distal Yq12 heterochromatic region in der(1) and loss of the heterochromatic region of chromosome 1. PCR demonstrated the intactness of the Y chromosome, including the SRY locus, AZF regions, DAZ genes and distal heterochromatin. A significant decrease (P = 0.005) of Xp/Yp pairing (18.6%), as compared with controls (65.7%), was found in arrested primary spermatocytes, and cell culture and mRNA expression studies confirmed an irreversible arrest at meiosis I, with induction of apoptosis and removal of germ cells by Sertoli cells. We characterized a de novo t(Y;1)(q12;q12) balanced reciprocal translocation with loss of the heterochromatic region of chromosome 1, that caused unpairing of sex chromosomes followed by meiosis I arrest, apoptotic degeneration of germ cells and azoospermia.     

An identical t(Y;1)(q12;q21) in two patients with myelodysplastic syndromes

Two male patients with myelodysplastic syndromes, one with refractory anemia with excess blasts (RAEB), the other with chronic myelomonocytic leukemia both had in their bone marrow and peripheral blood cells the same abnormal karyotype 46,X,-Y, + der (Y)t(Y;1)(q12;q21). This abnormality produced trisomy for the 1q21-1qter region of chromosome 1. In addition to the t(Y;1), the patient with RAEB had a del(20)(q11) abnormality in separate CFU-GM and BFUe progenitor cell populations. The t(Y;1) clone of this patient underwent chromosomal evolution with the acquisition of trisomies for chromosomes 2, 6, 8, and 9. Cytogenetic analysis of serial peripheral blood samples showed that the t(Y;1) clone and its derivatives gradually replaced that with the 20q- abnormality. Metaphase cells trisomic for chromosomes 2, 6, 8, and 9 were found predominantly in the CFU-GM population and only rarely in BFUe colonies, suggesting that chromosomal evolution was largely confined to the granulocytic lineage.     

Imatinib resistance in a novel translocation der(17)t(1;17)(q25;p13) with loss of TP53 but without BCR/ABL kinase domain mutation in chronic myelogenous leukemia

We describe here two novel translocations, t(7;14)(p22;q13) and der(17)t(1;17)(q25;p13), in a 41-year-old man with an accelerated phase (AP) of chronic myelogenous leukemia (CML). Chromosome analysis initially showed 46,XY,t(7;14)(p13;q22),t(9;22)(q34;q11.2)[20]. In 3 years, the karyotype evolved to 45,X,−Y,der(7)t(7;14)(p13;q22),t(9;22)(q34;q11.2),−14,der(17)t(1;17)(q25;p13),+der(22)t(9;22)[20], accompanied with a resistance to imatinib mesylate. The TP53 was deleted from the der(17)t(1;17)(q25;p13), but there was no mutation of TP53 in the remaining allele. Mutations in the BCR/ABL kinase domain could not be detected as well. Morphologically, dysplastic changes including pseudo-Pelger–Huët anomaly appeared in the bone marrow cells. These findings suggest that the t(7;14)(p22;q13) translocation had a crucial role in the progression to CML-AP, and that the resistance to imatinib may be due to the additional cytogenetic abnormalities, including der(17)t(1;17)(q25;p13), but not to BCR/ABL mutations.     

Characterization of breakpoints in the GABRG3 and TSPY genes in a family with a t(Y;15)(p11.2;q12)

We report the clinical, cytogenetic, and molecular findings in a family in which a t(Y;15)(p11.2;q12) is segregating. The Y chromosome breakpoint disrupts the DYZ5 sequence containing the TSPY genes that are exclusively expressed in the testes while the chromosome 15 breakpoint is within the GABRG3 gene. The father and his son who both carried the balanced form of the translocation are clinically normal. A daughter who carried the der Y had the clinical features of Prader-Willi syndrome while a son who carries the der 15 has mild developmental delay and hypogonadism. The relationship of the translocation to the clinical phenotypes is discussed.     

Molecular cytogenetic investigations in a novel complex variant of t(8;21)(q22;q22) with ins(15;21)(q15;q22.2q22.3) in a patient with AML-M2 subtype

Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease characterized by the aberrant proliferation of myeloid stem cells, reduced apoptosis and blockage in cellular differentiation. The present report describes the results of hematological, cytogenetic, and fluorescence in situ hybridization (FISH) analysis in a 25-year-old man diagnosed with AML-M2. Cytogenetic as well as FISH analysis revealed a complex translocation involving four chromosomes, with the karyotype 45,−Y,der(X)t(X;8)(p21;q22),der(8)t(8;21)(q22;q22),ins(15;21)(q15;q22.2q22.3),der(21)t(8;21)(q22;q22). The breakpoints at 8q22 and 21q22 suggested a rearrangement of the RUNX1T1 (alias ETO) and RUNX1 (previously AML1) genes, respectively. Using a dual-color FISH test with RUNX1T1 and RUNX1 probes, we demonstrated an RUNX1/RUNX1T1 fusion signal on the derivative chromosome 8, establishing this translocation as a novel complex variant of t(8;21)(q22;q22).     

Unbalanced translocation der(11)t(11;12)(q23;q13): a new recurrent cytogenetic aberration in myelodysplastic syndrome with a complex karyotype

Cytogenetic abnormalities are observed in approximately one half of cases of myelodysplastic syndrome (MDS). Partial or complete chromosome losses and chromosome gains are frequently found, but there is a relatively high incidence of unbalanced translocations in MDS. We describe here two cases of MDS with an unbalanced translocation, der(11)t(11;12)(q23;q13). Both patients were 69 years of age and diagnosed with refractory anemia with excess of blasts in transformation (RAEB-t) according to the high percentage of blasts in the peripheral blood. Cytoplasmic hypogranulation of neutrophils was evident as a dysplastic change. The blasts were positive for CD4 and CD41a as well as CD13, CD33, CD34 and HLA-DR in both cases. Chromosome analysis showed complex karyotypes including a der(11)t(1;11)(q11;p15)t(11;12)(q23;q13) in case 1 and der(11)t(11;12)(q23;q13) in case 2 plus several marker chromosomes. Spectral karyotyping confirmed the der(11)t(11; 12)(q23;q13) and clarified the origin of marker chromosomes, resulting in del(5q) and del(7q). Fluorescence in situ hybridization (FISH) analyses with a probe for the MLL gene demonstrated that the breakpoints at 11q23 were telomeric to the MLL gene in both cases. FISH also showed that the breakpoint at 11p15 of the case 1 was telomeric to the NUP98 gene. Considering another reported case, our results indicate that the der(11)t(11;12)(q23;q13) is a recurrent cytogenetic abnormality and may be involved in the pathogenesis of advanced-stage MDS.     

Trisomy 1q, 2, and 20 in a case of hepatoblastoma: possible significance of 2q35-q37 and 1q12-q21 rearrangements

Combined cytogenetic, chromosome painting, and spectral karyotyping (SKY) analyses in a case of hepatoblastoma revealed a karyotype of 49,XY,+Y,+der(2)t(2;3)(q35;q25),der(3)t(1;3)(q12; q25),+20. Trisomy 1q, 2, and 20 identified in the present case are consistent with the previously reported cytogenetic alterations in hepatoblastoma. The breakpoints at 1q12 and 2q35 identified in this case have also been reported previously as nonrandom changes. The frequent occurrence of these rearrangements in hepatoblastoma suggests that they may be of pathogenic significance.     

Disruption of the ETV6 gene as a consequence of a rare translocation (12;12)(p13;q13) in treatment-induced acute myeloid leukemia after breast cancer

We describe a case of treatment-induced acute myeloid leukemia M2 after breast cancer with a rare reciprocal t(12;12)(p13;q13) as a secondary cytogenetic abnormality in addition to the t(11;19)(q23;p13.1). Fluorescence in situ hybridization analysis revealed that both ETV6 genes (previously TEL) were located on the same der(12)t(12;12) as a result of t(12;12). Interestingly, the translocated ETV6 gene was disrupted, indicating the breakpoint on the large der(12)t(12;12) to be within the ETV6 gene and thus the possible formation of a new fusion gene. CHOP gene at 12q13, was found to be translocated intact to the other homologue chromosome 12, indicating that the breakpoint on the small der(12) is proximal to CHOP. To the best of our knowledge, our patient represents the first report of the rare t(12;12)(p13;q13) described in treatment-induced leukemia and the possible formation of a new fusion gene.     

Ring (Y) in two azoospermic men

We have identified two azoospermic men with r(Y) in 312 infertile men presenting with non-obstructive azoospermia or oligozoospermia. Their karyotypes were 45,X [9]/46,X, r(Y)(p11q11) [11] (case 1), and 46,X,r(Y)(p11q11) (case 2), respectively. In both cases, the Yp breakpoints were located within the pseudoautosomal region. Both cases had extensive deletions of azoospermia factors (AZFs). Case 1 also had deletion of the putative growth controlling gene (GCY) and the Yq breakpoint was located between sY741 and USP9Y. The Yq breakpoint was located between sY105 and sY109 in case 2. Both cases did not have Turner stigmata except short stature in case 1. By a combination of cytogenetic and molecular genetic tools, we showed r(Y) arose from breakage in both arms of the chromosome with subsequent fusion of two broken ends of the centric fragment to form a continuous ring. Spermatogenic defects in men with r(Y) may result from deletion of Y-linked AZFs combined with synaptic failure.     

一例母源性46,Y,der(X)t(X;Y)(p22;q11)染色体非平衡易位患儿的遗传学分析

目的对1例临床表征为身材矮小、鼻根部内陷、双侧隐睾、智力低下患儿进行遗传学分析,探讨该染色体结构异常与临床表征之间的关系。方法应用G显带染色体核型分析及染色体微阵列分析(chromosomal microarray analysis,CMA)技术对患儿进行遗传学检测,并对其父母进行外周血染色体核型分析。结果G显带分析结果显示患儿染色体核型为46,Y,der(X)t(X;Y)(p22;q11),mat。CMA检测结果提示患儿X染色体短臂Xp22.33p22.31存在约8.3 Mb片段缺失,Y染色体长臂Yq11.221qter存在约43.3 Mb片段重复。其父亲染色体核型正常,母亲染色体核型结果为46,X,der(X)t(X;Y)(p22;q11)。结论患儿携带母源性der(X)t(X;Y)(p22;q11)染色体非平衡易位,携带者的表型与其性别以及X染色体缺失片段的大小和位置密切相关。男性携带者智力障碍、生长发育落后等异常表型较女性更为严重。     

Cytogenetic and molecular cytogenetic studies of a variant of t(21;22), ins(22;21)(q12;q21q22), with a deletion of the 3' EWSR1 gene in a patient with Ewing sarcoma

Ewing sarcoma is the second most common malignant bone tumor in children and young adults. Cytogenetic analysis to identify a common t(11;22)(q23;q12) or less frequently a t(21;22)(q22;q12) or t(7;22)(p22;q12) plays an important role in the confirmation of the clinical diagnosis. We report a case of a 10-year-old female who had extraskeletal Ewing sarcoma. Conventional cytogenetic analysis revealed that 11 out of 20 cells had a derivative chromosome 22, possibly due to an insertion of the long arm of the 21q21 approximately q22. This finding was confirmed by fluorescence in situ hybridization (FISH) utilizing whole chromosome paint probes specific for chromosomes 21 and 22. Hybridization utilizing LSI EWSR1, dual-color break-apart rearrangement probe unexpectedly revealed that the 3' EWSR1 gene was lost on the derivative chromosome 22. This finding suggests that the insertion of chromosome 21 is another mechanism that could lead to EWS-ERG gene fusion. To our knowledge, this is the first case report of an insertion of a segment of 21q21 approximately q22 into the long arm of 21q12 with a loss of a DNA segment around the breakpoint on the derivative chromosome 22 in Ewing sarcoma.     

Novel clonal der(8)t(8;14)(p11;q11),del(9)(q13q22) and t(14;22) (q13;q13) in a patient with fulminant adult T-cell leukemia/lymphoma

We describe a 70-year-old man with fulminant adult T-cell leukemia/lymphoma. He died of progressive disease 1 week after the onset of symptoms. The integrated viral DNA of human T-lymphotropic virus type I was detected in the bone marrow aspirate by polymerase chain reaction. Cytogenetic analysis of bone marrow cells showed novel clonal aberrations consisting of 46,XY,der(8)t(8;14)(p11;q11),del(9) (q13q22),t(14;22)(q13;q13).     

Structural analysis of a rare rearranged Y chromosome and its bearing on genotype–phenotype correlation

We report on a 9‐year‐old boy with a rare rearranged Y chromosome and borderline short stature (−2.0 SD). Standard metaphase chromosome analysis indicated a 46,X,i(Y)(q10) karyotype, but high resolution G‐banding showed an asymmetric band pattern for the rearranged Y chromosome. FISH and DNA studies for a total of 15 different Y chromosomal loci or regions showed that the rearranged Y chromosome was accompanied by: 1) a partial deletion of the short arm pseudoautosomal region (PAR1) involving SHOX, with the breakpoint distal to DXYS85; and 2) a partial duplication of Yq, with the breakpoint proximal to DAZ. The karyotype was determined as 46,X,?i(Y)(q10).ish der(Y)(Yqter→ Yp11.3::Yq11.2→Yqter)(DAZ++,DYZ3+,SRY+, SHOX−). The X chromosome and the autosomes were normal. The results suggest that haploinsufficiency of SHOX is primarily responsible for the borderline short stature, and that the deletion of the PAR1 may result in spermatogenic failure due to defective X‐Y pairing and recombination in the PAR1. Am. J. Med. Genet. 92:256–259, 2000. © 2000 Wiley‐Liss, Inc.     

Intravenous leiomyomatosis is characterized by a der(14)t(12;14)(q15;q24)

Intravenous leiomyomatosis (IVL) is a rare smooth-muscle proliferation that is of special interest because of its quasi-malignant behavior. Our finding of a specific chromosomal aberration, a der(14)t(12;14)(q15;q24), in a second case of IVL suggests that it may be characteristic of IVL. We propose that IVL arises from a uterine leiomyoma with a t(12;14)(q15;q24). The presence of an extra copy of 12q15-qter and/or loss of 14q24-qter may be a critical genetic event(s) leading to intravascular intrusion and proliferation.     

The first recurring chromosome translocation in hepatoblastoma: Der(4)t(1;4)(q12;q34)

We report four cases of hepatoblastoma with a derivative chromosome 4 from an unbalanced translocation between the long arms of chromosomes 1 and 4, an aberration reported only rarely in isolated cases of other types of neoplasms. The abnormality in three hepatoblastomas was der(4)t(1;4)(q12;q34), whereas the fourth case appeared to have a der(4)t (q25;q32). All had hyperdiploid tumor karyotypes; however, in the case with t(q25;q32), the der(4) was the only abnormality in the stemline. We speculate that the oncogenetic event in our cases may be the loss of a gene or genes on distal 4q or their alteration by juxtaposition to 1q12 heterochromatin. Genes Chromosom. Cancer 19:291–294, 1997. © 1997 Wiley-Liss, Inc.     

Translocation t(12;22)(q13;q12.2–12.3) in a clear cell sarcoma of tendons and aponeuroses

Cytogenetic analysis of a short-term culture from a clear cell sarcoma revealed a complex karyotype with the mainline of 49,XY,t(7;18)(p11.2;q21.3), + der(7)t(7;18)(p11.2;q21.3), + 8, + der(8;17)(q10;q10),t(12;22)(q13;q12.2–12.3),add(13)(p13). An apparently identical translocation t(12;22) has been described recently in four clear cell sarcomas, indicating that this constitutes a primary cytogenetic change specific for this type of tumor. In our case, the breakpoint on chromosome 22 could be assigned to band 22q12.2 or 22q12.3. Together with the present case, trisomy or tetrasomy 8 has been found in six of nine clear cell sarcomas, suggesting that, as in Ewing's sarcoma and myxoid liposarcoma, trisomy/tetrasomy 8 represents a nonrandom secondary aberration. We conclude that the finding of the specific translocation t(12;22) may prove to be an important marker in the differential diagnosis of clear cell sarcoma from some other soft tissue sarcomas and malignant melanoma. © 1993 Wiley-Liss, Inc.     

Array-CGH characterization of a prenatally detected de novo 46,X,der(Y)t(X;Y)(p22.3;q11.2) in a male fetus

We report on an apparently normal 5-month-old boy with a X;Y complex rearrangement identified first on prenatal diagnosis and found on array-CGH to have a 7.6?Mb duplication of Xp22.3 chromosome and a deletion of Yq chromosome, distal to the AZFa locus. Karyotype analysis on amniotic fluid cell cultures revealed a de novo homogenous chromosome marker that we interpreted as an isochromosome Yp. FISH analysis using SRY probe revealed only one signal on the derivative Y chromosome. The final karyotype was interpreted as 46,X,der(Y)t(X;Y)(p22.31;q11.22). Translocation Xp22;Yq11 in male are very rare event and only 4 cases have been published, all showing mental retardation and malformations. Herein we discussed some possible explanation for this apparent phenotypic variability.     

一例伴有der(Y)t(Y;1)异常的多发性骨髓瘤的临床和实验研究

目的 对1例伴有不平衡染色体易位der(Y)t(Y;1)的多发性骨髓瘤(multiple myeloma,MM)患者进行细胞遗传学、中期荧光原位杂交、免疫学及临床研究.方法 采用细胞遗传学G显带行中期染色体核型分析;用1号染色体涂抹探针、Y染色体异染色质区探针进行中期荧光原位杂交检测;免疫分型检测CD38、CD138、ZAP70等的表达及免疫电泳检测免疫球蛋白类型等.结果 细胞遗传学分析结果 发现患者具有高度复杂的异常克隆,其核型为:92,XXYY[3]/49,X,der(Y)t(Y;1)(q12;q21),t(11;14)(q13;q32),+18,+20,+21[47]/49,X,idem,del(13q22),ace[1]/98,XX,der(Y)t(Y;1)×2,+18,+18,+20,+20,+21,+21[10]/46,XY[19].中期荧光原位杂交结果 证实der(Y)t(Y;1)的G显带结果 ,为1q部分三体与Y染色体长臂的不平衡易位.其异常的单克隆免疫球蛋白为IgD,定量6.24 g/L;免疫分型结果 为表达CD38、CD138,不表达ZAP70,考虑为异常克隆浆细胞的表达.结论 Y染色体的结构异常在血液系统肿瘤中非常罕见,本文报道1例发生于多发性骨髓瘤中的伴der(Y)t(Y;1)的核型异常、实验室及临床特点.