Aniridia,male pseudohermaphroditism,gonadoblastoma, mental retardation,and del 11p13

Summary A 20-month-old male patient was referred because of severe growth and mental retardation, bilateral glaucoma, hypospadias, and cryptorchidism. Karyotyping revealed a de novo complex three-chromosome rearrangement as well as deletion of band 11p13:46,XY,t(4;7;15)(q212;p14;q26),del(11) (p13p14). Trabeculectomia revealed bilateral aniridia. Surgery on the genitalia revealed male pseudohermaphroditism and bilateral gonadoblastoma. The kidneys were normal. A deficiency in catalase (CAT) activity allowed the regional assignment of the CAT gene to band 11p13.     

16种罕见的人类染色体异常核型报告

通过对患有闭经、自发流产、死胎、死产等患者外周血淋巴细胞染色体检查,发现16种新的罕见人类染色体异常核型,它们是46,XY,t(6;11)(q25;p15);46,XY,inv(3)(p25;q29);46,XY,t(7;18)(q10;p10);46,X,t(X;13)(q24;q14);46,XY,t(4;7)(q33;q22);46,XY,t(8;15)(q24;q15);46,XY,t(2;17)(q33;q25);46,XX,t(4;7)(q34;q11);46,XX,t(1;3)(p36;p23);46,XX,t(4;6)(q35;p11);46,X,inv(X)(q22;q28);46,XX,t(7;10)(p11;q26);46,XX,t(3;6)(p21;q23);46,XX,t(8;16)(p21;p13);46,XX,t(8;9)(q21;q34);46,XY,t(17;22)(q21;q11)。描述了患者的临床表现,并对生殖异常患者染色体畸变与其表型效应关系进行探讨。Abstract：By examining the lymphocytic chromosomes of peripheral blood from patients with amenorrhea,spontaneous abortion and stillbirth history, .the 16 rare species of human chromosomal abnormal karyotypes were discovered. They wre 46,XY,t(6;11)(q25;p15);46,XY,inv(3)(p25;q29);46,XY,t(7;18)(q10;p10);46,X,t(X;13)(q24;q14);46,XY,t(4;7)(q33;q22);46,XY,t(8;15)(q24;q15);46,XY,t(2;17)(q33;q25);46,XX,t(4;7)(q34;q11);46,XX,t(1;3)(p36;p23);46,XX,t(4;6)(q35;p11);46,X,inv(X)(q22;q28);46,XX,t(7;10)(p11;q26);46,XX,t(3;6)(p21;q23);46,XX,t(8;16)(p21;p13);46,XX,t(8;9)(q21;q34);46,XY,t(17;22)(q21;q11). Their clinical situation were described. Discussion on the relationship between the chromosomal aberrations and phenotype effect indicates the importance of chromosome karyotyping in patients with abnormal reproductive history.     

Regional assignment of catalase (CAT) gene to band 11p13. Association with the aniridia-Wilms' tumor-Gonadoblastoma (WAGR) complex

A gene dosage effect for catalase (CAT) was investigated in three individuals : one with 11p13 deletion, aniridia, ambiguous genitalla, and gonadoblastoma ; one trisomic for 11p with the exception of 11p13; and one trisomic for 11p13. Results were compatible with the assignment of CAT to 11p13 and its linkage with the aniridia-gonadoblastoma or Wilms' tumor complex (WAGR).     

Partial Turner's syndrome in four girls with Xq duplication and Xp deficiency

Summary Four girls with some clinical symptoms of Turner's syndrome had Xq duplication and Xp deficiency, their karyotypes being 46,X,dup(X)(p113;q11), 46,X,dup(X)(p212;q211), 46,X,dup(X)(p225;q13), and 46,X,dup(X)(p222;q213). No mosaicism was found.The major clinical findings, short stature, lack of pterygium colli, and no continuous gamete production, are compared with those in three previously published cases.     

131例原发性闭经女性的细胞遗传学分析(含世界首报异常核型3例)

原发性闭经是一种原因复杂的疾病, 染色体异常则是发病的主要原因。通过对131例原发性闭经患者的外周血淋巴细胞染色体的G带核型分析, 发现其中83例为正常女性核型, 占63.36%; 各种异常核型48例,占36.64%, 其中包括3例世界首次报道的异常核型[46,X,t(X;1)(q22;p34); 46,X,t(X;5;6)(p11.2;q35;q16); 46,XX,t(4; 9)(q21;p22),t(6;10)(p25;q25),t(11;14)(q23;q32)]。另外, 将33例Turner’s综合征患者的主要异常体征及核型分布分别与Elsheikh等的报道进行比较, 发现矮身材、蹼颈、后发迹低和肘外翻的发生率与文献资料存在显著差异, 说明东西方Turner’s综合征患者临床体征的表现可能存在差异。通过对2例X-常染色体易位携带者的分析, 认为Xp11.2和Xq22区域可能与原发性闭经有关。     

Familial aniridia and translocation t(4;11)(q22;p13) without Wilms' tumor

A family with dominantly inherited aniridia in three generations is presented. All three patients had an apparently balanced chromosome translocation t(4;11)(q22;p13). The patients were otherwise clinically normal and without signs of Wilms' tumor; their erythrocyte catalase activities were within the normal range. We suggest that in this family aniridia is caused either by a submicroscopic deletion at the translocation breakpoint 11p13 or by a position effect on the same chromosome segment. Furthermore, the loci for aniridia and Wilms' tumor susceptibility are separate. It follows that the WAGR complex is caused by a mutation of more than one gene located at 11p13. The theoretical implications of a presumably defective allele causing a mendelian dominant phenotype are discussed.     

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

Summary 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.     

Array-CGH characterization of a de novo t(X;Y)(p22;q11) in a female with short stature and mental retardation

We report the clinical and molecular investigations in a girl with 46,X,-X,+der(X)t(X;Y)(p22;q11) de novo karyotype who presented an intricate phenotype characterized by mental retardation and facial dysmorphisms in combination with short stature. The structure of the derivative X chromosome was studied using BAC array-CGH which disclosed the Xp22 breakpoint between the STS and the VCX3A gene and the presence of the Yq11.1qter chromosome. It is common that females with Xp;Yq translocations present only short stature and are normal in every other aspect. Thus, this would be the first case in which a girl with Xp;Yq translocation presents an unusual phenotype with intermediate male clinical features with Xp;Yq translocations. The risk of developing gonadoblastoma in females with Y chromosome material is also discussed and, to this effect, different explanations related to this apparent variation are also presented.     

Paternal reciprocal translocation t(11;16)(p13;q24.3) in a Silver-Russel syndrome patient

We describe a 7-month-old male child with Silver-Russel syndrome (SRS) phenotype, presented with two major clinical features: low birth weight, short stature, and minor features, such as macrocephaly, clinodactyly, essential for the diagnosis of SRS. Routine cytogenetic studies with GTG-banding showed 46,XY,t(11;16)(p13;q24.3). Fluorescence in situ hybridisation (FISH) with single copy probes BAC (11p13) and PAC (16q24.3), showed a reciprocal translocation. Chromosomal analysis of the mother was normal and the phenotypically normal father had apparently identical translocation t(11;16)(p13;q24.3). The disruption of growth factor genes at 11p and 16q breakpoint regions due to reciprocal translocation in the father might have caused SRS phenotype in the child.     

Chromosome duplications and deletions and their mechanisms of origin.

Duplications and deletions of the same gene loci or chromosome regions are known to produce different clinical manifestations and are significant factors in human morbidity and mortality. Extensive cytogenetic and molecular cytogenetic studies with cosmid and YAC probes in two patients with unique mosaicism for reciprocal duplication-deletion allowed us to further understand the origin of these abnormalities. The first patient's mosaic karyotype was 46,XX, inv dup(11) (q23q13)/46,XX,del(11)(q13q23). The second patient had a 46,XY,dup(7)(p11.2p13)/46,XY,del(7)(p11.2p13)/46,XY karyotype. Fluorescence in situ hybridization studies on the first patient placed the two breakpoints near the folate-sensitive fragile sites FRA11A and FRA11B. The presence of repeated sequences responsible for these fragile sites may have been involved in the patient's duplication-deletion. Our investigation leads us to conclude that, in addition to known mechanisms (such as unequal crossovers between homologs, unequal sister chromatid exchanges, excision of intrachromatid loops, and meiotic recombination within a single chromatid), duplication-deletion can also arise by the formation of an overlying loop followed by an uneven crossover at the level of the DNA strand.     

A highly polymorphic locus cloned from the breakpoint of a chromosome 11p13 deletion associated with the WAGR syndrome

Children with constitutional deletions of chromosome 11p13 suffer from aniridia, genitourinary malformations, and mental retardation and are predisposed to develop bilateral Wilms tumor (the WAGR syndrome). The critical region for these defects has been narrowed to a segment of band 11p13 between the catalase and the beta-follicle-stimulating hormone genes. In this report, we have cloned the endpoints from a WAGR patient whose large cytogenetic deletion, del(11)(p14.3::p13), does not include the catalase gene. The deletion was characterized using DNA polymorphisms and found to originate in the paternally derived chromosome 11. The distal endpoint was identified as a rearrangement of locus D11S21 in conventional Southern blots of the patient's genomic DNA, but was not detected in leukocyte DNA from either parent or in sperm DNA from the father. The proximal endpoint was isolated by cloning the junction fragment and was mapped in relation to other markers and breakpoints. It defines a new locus in 11p13-delta J, which is close to the Wilms tumor gene and the breakpoint cluster region (TCL2) of the frequent t(11;14)(p13;q11) translocation in acute T-cell leukemia. An unusual concentration of base pair substitutions was discovered at delta J, in which 9 of 44 restriction sites tested (greater than 20%) vary in the population. This property makes delta J one of the most polymorphic loci on chromosome 11 and may reflect an underlying instability that contributed to the original mutation. The breakpoint extends the genetic map of this region and provides a useful marker for linkage studies and the analysis of allelic segregation in tumor cells.     

9种新的人类染色体异常核型报告

发现９种新的人类染色体异常核型,分别为：４６,ＸＸ,ｔ（２;１０）（ｑ３３;ｑ１１）;４６,ＸＹ,ｔ（１０;１２）（ｑ２６;ｑ２２）;４６,ＸＹ,ｔ（６;１５）（ｐ２３;ｑ２３）;４６,ＸＹ,ｔ（１;６）（ｐ３６;ｑ２１）;４６,ＸＹ,ｔ（１;１９）（ｐ３２;ｐ１３）;４６,ＸＹ,ｔ（１６;１８）（ｑ２２;ｑ２１）;４６,ＸＹ,ｉｎｖ（１）（ｐ３６ｑ２５）;４６,ＸＹ,ｔ（１３;１７）（ｑ１２;ｑ２５）;４６,ＸＹ,ｔ（１５;２１）（ｑ２６;ｑ１１）。异常核型是导致自然流产和不育的原因。     

Sex reversal due to Xp disomy by t(X;Y)(p21;q11).

A 20-month-old infant exhibiting psychomotor retardation, dysmorphisms and ambiguous external genitalia was found to have a 46-chromosome karyotype including a normal X chromosome and a marker Y with most of Yq being replaced by an extra Xp21-->pter segment. The paternal karyotype (G and C bands) was 46,XY. The marker Y composition was verified by means of FISH with a chromosome X painting, an alphoid repeat and a DMD probe. Thus, the final diagnosis was 46,X,der(Y)t(X;Y)(p21;q11)de novo.ish der(Y)(wcpX+,DYZ3+,DMD+). The patient's phenotype is consistent with the spectrum documented in 13 patients with similar Xp duplications in whom sex reversal with female or ambiguous genitalia has occurred in spite of an intact Yp or SRY gene. A review of t(X;Y) identifies five distinct exchanges described two or more times: t(X;Y)(p21;q11), t(X;Y)(p22;p11), t(X;Y)(p22;q11-12), t(X;Y) (q22;q12), and t(X;Y)(q28;q12). These translocations probably result from a recombination secondary to DNA homologies within misaligned sex chromosomes in the paternal germline with the derivatives segregating at anaphase I.     

Partial trisomy 11,46,XX,-3,-20,+der3,+der20,t(3:11:20), resulting from a complex maternal rearrangement of chromosomes 3, 11, 20

Summary Clinical findings of partial trisomy 11p are described in a patient bearing t(3;11;20) (p13;p11;q13). The translocation was present in balanced form in her mother (46,XX)t(3;11;20)(p13;p11;q13).     

Molecular cytogenetic analysis of follicular lymphoma (FL) provides detailed characterization of chromosomal instability associated with the t(14;18)(q32;q21) positive and negative subsets and histologic progression

We analyzed a cohort of 61 follicular lymphomas (FL) with an abnormal G-banded karyotype by spectral karyotyping (SKY) to better define the chromosome instability associated with the t(14;18)(q32;q21) positive and negative subsets of FL and histologic grade. In more than 70% of the patients, SKY provided additional cytogenetic information and up to 40% of the structural abnormalities were revised. The six most frequent breakpoints in both SKY and G-banding analyses were 14q32, 18q21, 3q27, 1q11-q21, 6q11-q15 and 1p36 (15-77%). SKY detected nine additional sites (1p11-p13, 2p11-p13, 6q21, 8q24, 6q21, 9p13, 10q22-q24, 12q11-q13 and 17q11-q21) at an incidence of >10%. In addition to the known recurring translocations, t(14;18)(q32;q21) [70%], t(3;14)(q27;q32) [10%], t(1;14)(q21;q32) [5%] and t(8;14)(q24;q32) [2%] and their variants, 125 non-IG gene translocations were identified of which four were recurrent within this series. In contrast to G-banding analysis, SKY revealed a greater degree of karyotypic instability in the t(14;18) (q32;q21) negative subset compared to the t(14;18)(q32;q21) positive subset. Translocations of 3q27 and gains of chromosome 1 were significantly more frequent in the former subset. SKY also allowed a better definition of chromosomal imbalances, thus 37% of the deletions detected by G-banding were shown to be unbalanced translocations leading to gain of genetic material. The majority of recurring (>10%) imbalances were detected at a greater (2-3 fold) incidence by SKY and several regions were narrowed down, notably at gain 2p13-p21, 2q11-q21, 2q31-q37, 12q12-q15, 17q21-q25 and 18q21. Chromosomal abnormalities among the different histologic grades were consistent with an evolution from low to high grade disease and breaks at 6q11-q15 and 8q24 and gain of 7/7q and 8/8q associated significantly with histologic progression. This study also indicates that in addition to gains and losses, non-IG gene translocations involving 1p11-p13, 1p36, 1q11-q21, 8q24, 9p13, and 17q11-q21 play an important role in the histologic progression of FL with t(14;18)(q32;q21) and t(3q27).     

A locus for isolated cleft palate, located on human chromosome 2q32.

We present evidence for the existence of a novel chromosome 2q32 locus involved in the pathogenesis of isolated cleft palate. We have studied two unrelated patients with strikingly similar clinical features, in whom there are apparently balanced, de novo cytogenetic rearrangements involving the same region of chromosome 2q. Both children have cleft palate, facial dysmorphism, and mild learning disability. Their karyotypes were originally reported as 46, XX, t(2;7)(q33;p21) and 46, XX, t(2;11)(q33;p14). However, our molecular cytogenetic analyses localize both translocation breakpoints to a small region between markers D2S311 and D2S116. This suggests that the true location of these breakpoints is 2q32 rather than 2q33. To obtain independent support for the existence of a cleft-palate locus in 2q32, we performed a detailed statistical analysis for all cases in the human cytogenetics database of nonmosaic, single, contiguous autosomal deletions associated with orofacial clefting. This revealed 2q32 to be one of only three chromosomal regions in which haploinsufficiency is significantly associated with isolated cleft palate. In combination, our data provide strong evidence for the location at 2q32 of a gene that is critical to the development of the secondary palate. The close proximity of these two translocation breakpoints should also allow rapid progress toward the positional cloning of this cleft-palate gene.     

Familial isolated aniridia associated with a translocation involving chromosomes 11 and 22 [t(11;22)(p13;q12.2)]

Summary Isolated aniridia segregated as an autosomal dominant trait in a family with 11 affected members spanning five generations. Four of the eight individuals studied had aniridia associated with glaucoma and cataracts. Cytogenetic studies revealed an apparently balanced reciprocal translocation between chromosomes 11 and 22 [t(11;22)(p13;q12.2)], while four unaffected relatives had normal karyotypes. There is no evidence of Wilms tumor or genitourinary abnormalities in any members of the family. Restriction enzyme analysis of the human catalase gene revealed no abnormalities in the individuals with the translocation. A summary of phenotypic abnormalities in 61 cases associated with aniridia is presented, as well as a comparison of breakpoints in 44 cases of 11p deletion. These data indicate that single breaks at 11p13 are associated with isolated aniridia, while deletion of 11p13 results in aniridia combined with Wilms tumor, genitourinary abnormalities, and/or mental retardation.     

Familial (11;21)(p13;q22)pat balanced reciprocal translocation in a female child with regression of milestones

The role of balanced translocations in the human morphogenesis is difficult to interpret. A balanced reciprocal translocation (BRT) was observed in a female child referred with a history of regression of milestones. The cytogenetic findings by GTG-banding and fluorescence in situ hybridization revealed a BRT involving chromosomes 11p and 21q, i.e. 46,XX, t(11;21)(p13;q22). The father was found to be a carrier of the same BRT. This is the first report of reciprocal translocation involving 11p and 21q. The possible reasons for the manifestation of clinical features in the proband due to inherited BRT are discussed.     

Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia

Seventy-seven patients with aniridia, referred for cytogenetic analysis predominantly to assess Wilms tumor risk, were studied by fluorescence in situ hybridization (FISH), through use of a panel of cosmids encompassing the aniridia-associated PAX6 gene, the Wilms tumor predisposition gene WT1, and flanking markers, in distal chromosome 11p13. Thirty patients were found to be chromosomally abnormal. Cytogenetically visible interstitial deletions involving 11p13 were found in 13 patients, 11 of which included WT1. A further 13 patients had cryptic deletions detectable only by FISH, 3 of which included WT1. Six of these, with deletions <500 kb, share a similar proximal breakpoint within a cosmid containing the last 10 exons of PAX6 and part of the neighboring gene, ELP4. Two of these six patients were mosaic for the deletion. The remaining four had chromosomal rearrangements: an unbalanced translocation, t(11;13), with a deletion including the WAGR (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation) region, and three balanced rearrangements with what appear to be position effect breakpoints 3' of PAX6: (a) a t(7;11) with the 11p13 breakpoint approximately 30 kb downstream of PAX6, (b) a dir ins(12;11) with a breakpoint >50 kb from PAX6, and (c) an inv(11)(p13q13) with a breakpoint >75 kb downstream of PAX6. The proportion and spectrum of chromosome anomalies in familial (4/14, or 28.5%) and sporadic (26/63, or 41%) cases are not significantly different. An unexpectedly high frequency of chromosomal rearrangements is associated with both sporadic and familial aniridia in this cohort.     

Molecular analysis of a reciprocal translocation t(5;11)(q11;p13) in a WAGR patient

Summary Most patients with the complex association aniridia — predisposition to Wilms' tumor (WAGR syndrome) present with a de novo constitutional deletion of band 11p13. We report a patient with WAGR syndrome and a reciprocal translocation between chromosomes 5 and 11 t(5;11)(q11;p13). High resolution banding cytogenetic analysis and molecular characterization using 11p13 DNA markers showed a tiny deletion encompassing the gene for CAT but sparing the gene for FSHB. This suggests that syndromes associated with apparently balanced translocations may be due to undetectable loss of material at the breakpoint(s) rather than to breakage in the gene itself.