Functional disomy of Xp: prenatal findings and postnatal outcome

We report on trisomy of the short arm of the X chromosome (Xp11.2 --> pter) due to a de novo unbalanced X;13 translocation diagnosed prenatally in a female fetus. Amniocentesis was performed at 20-weeks' gestation following ultrasound finding of a Dandy-Walker malformation. The trisomy of Xp11.2 --> pter was confirmed with fluorescence in situ hybridization (FISH), using an X chromosome painting probe and telomeric FISH probes specific for the short arm of chromosome X. The karyotype was defined as 46,XX,der(13)t(X;13)(p11.2;p11.2). Molecular analysis suggested that the extra Xp material was of paternal origin. FISH analysis with an XIST probe showed that the derivative chromosome 13 did not include the XIST locus at the X-inactivation center (XIC). A complex phenotype was seen at birth including macrosomia, facial dysmorphism with preauricular tag, congenital heart defects, and structural brain malformations. Because the derivative chromosome was not subject to X inactivation, functional disomy of Xp11.2 --> pter most likely accounts for the abnormal phenotype in this patient.     

Identification of de novo chromosome rearrangements: five cases analyzed with differential chromosome painting

We report on five cases of de novo structural chromosome rearrangements that were difficult to identify by conventional G-banding analysis. In all five cases, differential chromosome painting (DCP) provided evidence for the presence of an additional segment and its origin. A combination of DCP with subsequent conventional fluorescence in situ hybridization (FISH) analysis using adequate locus-specific probes and reexamination of G-banding patterns resulted in successful identification of the rearrangements. Their karyotypes were finally interpreted as 46,XY,der(1)(qter --> q42.1::p36.3 --> qter) in case 1; 46,XY,der(8)(8pter -->8q24.3::8q24.3 --> 8q23.2::?p11.2 --> ?ps) in case 2; 47,XY,+der(10)(pter --> q11) in case 3; 46,XX,der(3)(17pter --> 17p11.2::3p26 --> 3qter) in case 4; and 46,XY,dup(1) (pter --> q32::q25 --> qter) in case 5.     

Axenfeld-Rieger anomaly, hypertelorism, clinodactyly, and cardiac anomalies in sibs with an unbalanced translocation der(6)t(6;8)

We describe two sibs with the unbalanced translocation der(6)t(6;8)(p25.1;q24.23), making them monosomic for 6p25.1-->6pter and trisomic for 8q24.23-->8qter. The siblings both possess Axenfeld-Rieger Anomaly (ARA), hypertelorism, clinodactyly, and cardiac anomalies, but otherwise vary in the phenotypic manifestations of this unbalanced translocation. We compare them to previously described cases and a recently proposed syndrome of ARA, atrial septal defect, and sensorineural deafness.     

Pediatric renal cell carcinoma: clinical, pathologic, and molecular abnormalities associated with the members of the mit transcription factor family

We describe the clinical features, outcome, pathology, cytogenetics, and molecular aspects of 13 pediatric papillary renal cell carcinomas during a 19-year period. Seven cases (54%) had translocations involving Xp11.2 (TFE3). They were identified by cytogenetic, molecular, and/or immunohistochemical analyses. All Xp11.2+ translocations were TFE3+ by immunostaining. Cytogenetic and/or polymerase chain reaction analyses identified 3 cases with t(X17) and 1 case with t(1;17), and all had additional translocations. Histologic features in common in TFE3+ tumors also were present in some TFE3- tumors. One TFE3- tumor had complex cytogenetic abnormalities, 55XY,+2,del(3)(p14),+7,+8,+12,+13,+16,+17,+20[11 ], and 2 cases had normal karyotypes. None had t(6;11)/TFEB+ immunostaining. Five cases had focal, weak MITF tumor immunostaining. The key clinical findings were as follows: (1) The presence of an Xp11.2 (TFE3) translocation frequently is associated with advanced stage at initial examination. (2) All patients who underwent complete, partial nephrectomy with clear margins (adequate only for stage 1) and resection of metastases were alive and relapse-free at last follow-up. (3) The mean +/- SD event-free survival and overall survival rates at 5 years were both 92% +/- 7.4%. (4) One patients with a TFE3+ and MITF+ tumor and 66-87,XXY,der(1)t(1;8)del(4)(q?) der(11)t(11;15)der17t(X;17 abnormalities died 9 months after diagnosis.     

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。     

A double cryptic chromosome imbalance is an important factor to explain phenotypic variability in Wolf-Hirschhorn syndrome

A total of five Wolf-Hirschhorn syndrome (WHS) patient with a 4p16.3 de novo microdeletion was referred because of genotype-phenotype inconsistencies, first explained as phenotypic variability of the WHS. The actual deletion size was found to be about 12 Mb in three patients, 5 Mb in another one and 20 Mb in the last one, leading us to hypothesize the presence of an extrachromosome segment on the deleted 4p. A der(4)(4qter --> p16.1::8p23 --> pter) chromosome, resulting from an unbalanced de novo translocation was, in fact, detected in four patients and a der(4)(4qter --> q32::4p15.3 --> qter) in the last. Unbalanced t(4;8) translocations were maternal in origin, the rec(4p;4q) was paternal. With the purpose of verifying frequency and specificity of this phenomenon, we investigated yet another group of 20 WHS patients with de novo large deletions (n = 13) or microdeletions (n = 7) and with apparently straightforward genotype-phenotype correlations. The rearrangement was paternal in origin, and occurred as a single anomaly in 19 out of 20 patients. In the remaining patient, the deleted chromosome 4 was maternally derived and consisted of a der(4)(4qter --> 4p16.3::8p23 --> 8pter). In conclusions, we observed that 20% (5/25) of de novo WHS-associated rearrangements were maternal in origin and 80% (20/25) were paternal. All the maternally derived rearrangements were de novo unbalanced t(4;8) translocations and showed specific clinical phenotypes. Paternally derived rearrangements were usually isolated deletions. It can be inferred that a double, cryptic chromosome imbalance is an important factor for phenotypic variability in WHS. It acts either by masking the actual deletion size or by doubling a quantitative change of the genome.     

Axenfeld‐Rieger anomaly,hypertelorism, clinodactyly,and cardiac anomalies in sibs with an unbalanced translocation der(6)t(6;8)

We describe two sibs with the unbalanced translocation der(6)t(6;8)(p25.1;q24.23), making them monosomic for 6p25.1→6pter and trisomic for 8q24.23→8qter. The siblings both possess Axenfeld‐Rieger Anomaly (ARA), hypertelorism, clinodactyly, and cardiac anomalies, but otherwise vary in the phenotypic manifestations of this unbalanced translocation. We compare them to previously described cases and a recently proposed syndrome of ARA, atrial septal defect, and sensorineural deafness. © 2001 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.     

Beckwith-Wiedemann syndrome due to 11p15.5 paternal duplication associated with Klinefelter syndrome and a "de novo" pericentric inversion of chromosome Y

We report on an infant who had been prenatally diagnosed with Klinefelter syndrome associated with a "de novo" pericentric inversion of the Y chromosome. A re-evaluation at 3 years of age suggested that he was also affected by Beckwith-Wiedemann syndrome (BWS). Karyotype was repeated and fluorescence in situ hybridisation (FISH) analysis revealed trisomy for 11p15.5-->11pter and a distal monosomy 18q (18q23-->qter). Parental cytogenetic studies showed that the father carried a balanced cryptic translocation between chromosomes 11p and 18q. Furthermore, the child had an extra X chromosome and a "de novo" structural abnormality of chromosome Y. Thus, his karyotype was 47,XX, inv (Y) (p11.2 q11.23), der(18) t (11;18) (p15.5;q23) pat. ish der(18) (D11S2071+, D18S1390-). Two markers on the X chromosome showed that the extra X of the child was paternally inherited. No deletions were observed on the structurally abnormal Y chromosome from any of the microsatellites studied. Clinical findings of patients with BWS due to partial trisomy 11p reveal that there is a distinct pattern of dysmorphic features associated with an increased incidence of mental retardation when comparing patients with normal chromosomes. This fact reinforces that FISH study have to be performed in all BWS patients, specially in those with mental retardation since small rearrangements cannot be detected by conventional cytogenetic techniques.