Giemsa-11 staining of chromosome 1: a newly described heteromorphism.

Sequential Giemsa-11 and C-band staining of the heterochromatic region of chromosome 1 from 30 unrelated individuals revealed a high degree of variability within this region, more than was identifiable with either stain alone. The Giemsa-11 stained material usually appeared as a single band of only slightly varying size within the heterochromatic region. The position of this band ranged from a location immediately adjacent to the centromere, to one farther along the long arm or at the junction of the C-band heterochromatin and euchromatin. Two individuals had a chromosome 1 with no detectable Giemsa-11 band but an average-size C-band. Two others with a large heterochromatic segment by C-banding had two Giemsa-11 positive bands. Additional studies of five members of one family were consistent with transmission of these hetermorphisms in codominant Mendelian fashion.

Emerging phenotype of duplication (7p): a report of three cases and review of the literature.

Here we report on three patients with dup (7p) and review the previously published 17 cases. Characteristic manifestations include severe/profound psychomotor retardation, dolichocephaly or microbrachycephaly, gaping fontanels and wide sagittal and metopic sutures, hypertelorism, large apparently low-set ears, micrognathia, choanal atresia/stenosis, hyperextensible joints subject to dislocation, joint contractures, and a high rate of cardiac septal defects. Our analysis suggests that dup(7p) is associated with a recognizable characteristic phenotype.

Transmission of ring 14 chromosome from mother to two sons.

We report on a family with transmission of a ring chromosome 14 from an affected mother to her 2 sons. The mother was mosaic, 46,XX,r(14)/45,XX,t(14q21q). Both of her sons, affected by seizures and mental retardation, have the karyotype 46,XY,r(14). In considering the association of translocation 14:21 in the mother with ring 14, we postulate that either the ring chromosome was formed first and then opened with translocation of the partially deleted chromosome 14 to chromosome 21, or the 14:21 translocation was present first, then the chromosomes 14 and 21 broke apart, and the partially deleted 14 formed the ring. The published literature of cases of ring 14 is reviewed.

De novo 21q interstitial deletion in a retarded boy with ulno-fibular dysostosis.

A 9-year-old boy was referred for evaluation of multiple anomalies and mental retardation. Skeletal abnormalities had been noted at birth: joint contractures, right acetabular "dysplasia," ulno-fibular dysostosis, and bilateral talipes equinovarus with calcaneocuboid fusion. Additional findings at 9 years included short stature, unusual facial appearance, camptodactyly of several digits, undescended testes, and syndactyly of toes 4 and 5. On psychological testing he was found to be moderately retarded. Cytogenetic analysis of chromosome bands using Q, GTG, R, and C banding showed an interstitial deletion of 21q; karyotype designation: 46,XY, del (21)(pter----q11.2::q22.1----qter). Parental chromosomes were normal. Manifestations in this boy, including the joint contractures, are similar to those described in the monosomy 21 syndrome. Ulno-fibular dysostosis has not been reported previously with abnormalities of chromosome 21. To our knowledge, this is the second patient reported with an interstitial deletion of chromosome 21, and the patients are phenotypically dissimilar.

Partial duplication of Xp: a case report and review of previously reported cases.

We report clinical and cytogenetic findings on a 24-year-old woman with short stature, irregular menses, and other anomalies suggestive of Ullrich-Turner syndrome (UTS). Chromosome analysis documented a de novo duplication of Xp21 without any apparent microscopic deletion. DNA studies showed that part of band Xp22.1 is also duplicated. The clinical findings are compared with 5 other patients with dup(Xp).

46,XY/47,XYY male with the fragile X syndrome: cytogenetic and molecular studies.

We report the first case of a 46,XY/47,XYY mosaic male with fragile X [Fra(X)] expression in both cell lines. Cytogenetic analysis, DNA linkage analysis, and direct detection of the pre- and full mutation for the affected individual and his at-risk female relatives were performed. Southern analysis of PstI-digested DNA with probe pX6 clearly distinguished the normal genotype, the premutation, and the full mutation in various individuals in the patient's family. Fra(X) carriers who had normal cytogenetic results were clearly identified by direct mutation analysis.

Interstitial deletion involving most of Yq.

Males with a Yq deletion are well described, but few have been studied with both cytogenetic and molecular techniques to define the deletion and relate it to the phenotype. This study reports an analysis of cells obtained from a college student with azoospermia, short stature, and a small penis. Cytogenetic analysis indicated that the entire Yq was deleted, but DNA hybridization showed that a portion of Yq12 remained. We conclude that the deletion is interstitial.

Tandem duplication/deletion in a maternally derived chromosome 9 supernumerary derivative resulting in 9p trisomy and partial 9q tetrasomy.

A 19-week stillborn female fetus with bilateral cleft palate, horseshoe kidney, bicornuate uterus, low-set ears, and intrauterine growth retardation (IUGR) was found to have a supernumerary derivative chromosome 9 (der(9)) with an apparent tandem duplication in the long arm. PCR analysis at five polymorphic loci confirmed the duplication and showed an adjacent deletion, while whole chromosome FISH demonstrated only chromosome 9 to be involved. Further FISH studies of der(9) found the 9qh region to be duplicated, telomeric sequences to be intact, and subtelomeric sequences to be absent. Thus, the fetus was determined to be trisomic for 9pter-->9q12 and 9q34.3-->9qter, tetrasomic for 9q12--> 9q33, and disomic for 9q33-->9q34.3. These results are consistent with a tandem duplication of 9q12-->9q33 and adjacent distal deletion as designated by the karyotype, 47,XX,+der(9)dup(9) (q12q33)del(9) (q33q34.3).ish der(9)(WCP9+,D9Z1x2,STP9q-, AHT+) de novo. In addition to characterizing der(9), the combined PCR and cytogenetic studies refined the Genome Database Map of three loci (D9S907, D9S155, and D9S302) approximately to the distal 9q33 region. Without the attempt to refine breakpoints by PCR analysis, the deletion in distal 9q would not have been detected. Tandem direct duplication/deletion chromosomes have been reported in fewer cases than inverted duplication/deletions. We propose mechanisms of origin, consistent with those for recurrent inter stitial microdeletion and microduplication syndromes, shown to arise by recombination at homologous, flanking DNA sequences.

Symmetric replication of an unstable isodicentric Xq chromosome derived from isolocal maternal sister chromatid recombination.

An amniocyte culture was found to be mosaic for 45,X/46,X, idic(X)(p11.2)/ 47,X, idic(X)(p11.2),idic(X)(p11.2) cell lines, reflecting mitotic nondisjunction of the idic(X)(p11.2) chromosome. Upon learning of abnormal karyotype and ultrasound findings, the parents decided to discontinue the pregnancy. Subsequent cultures of fetal skin, kidney, and lung were mosaic 45,X/46,X,idic(X)(p11.2) reflecting mitotic loss of the unstable idic(X)(p11.2) chromosome. C-banding and in situ hybridization of X chromosome-specific alpha-satellite probe to metaphase fetal cells confirmed two centromeres on the idic(X)(p11.2) chromosome with both centromeres appearing to be active in two-thirds of cells. This result was confirmed by centromere protein-E (CENP-E) antibody staining which delineated 80% of scored cells with two active centromeres and 20% with 1 active centromere. Bromodeoxyuridine (BrdU) incorporation and acridine orange staining characterized the DNA replication pattern of the idic(X)(p11.2) chromosome as late and symmetrically replicating. Polymerase chain reaction analysis of highly polymorphic loci determined that the normal X chromosome carried paternal alleles and the idic(X)(p11.2) chromosome carried maternal alleles from only one grandparental chromosome. Overall, the results suggest that recombination occurred between two maternal sister chromatids both in the same chromosome band Xp11.2 (isolocal) prior to maternal meiosis II anaphase to generate an unstable maternal idic(X)(p11.2) chromosome. Additional factors that could contribute to i(Xq) and idic(X) formation and instability are discussed along with a mechanism to explain the high frequency of intrauterine loss in 45,X pregnancies.

Characterization of a duplication in the terminal band of 4p by molecular cytogenetics.

An infant with multiple anomalies including small head, large apparently low-set ears, beaked nose, micrognathia, choanal stenosis, proptosis, atrial-septal defect, and left inguinal hernia was found, on chromosome analysis, to have a longer than normal terminal band 4p16 by G and R-banding. In situ hybridization of biotin-labeled DNA probes C39, BJ14, BJ54, BJ19, BJ7, and BJ11 showed them to be duplicated. Probes I14, A157.1, and the telomeric sequence, (TTAGGG)n, which hybridized to the more distal part of 4p16.3, were not duplicated. These results confirm the impression by G and R-banding of a duplication within band 4p16, a region extending from approximately 2.1 Mb from the telomere, proximally, to the junction of 4p16.1 and 4p15.3. This is the smallest confirmed duplication of distal 4p reported to date, with many of the classical findings of dup(4p) syndrome.

Chromosome deletion of Xq25 in an individual with X-linked lymphoproliferative disease.

High resolution chromosome analysis was done on lymphoblastoid cell lines, established during the past decade from affected males with X-linked lymphoproliferative disease (XLP) or from obligate female carriers, from 14 families. One cell line, from a male with XLP, has a partial deletion of band Xq25. The constitutional nature of the deletion is confirmed in chromosome studies of peripheral blood from the affected individual and represents the first such structural defect to be described in this disorder. Cell lines from the remaining 13 families do not have cytogenetically detectable deletions. This observation will facilitate precise localization, cloning and sequencing of the gene causing XLP.

Summary of the 1993 ASHG ancillary meeting "recent research on chromosome 4p syndromes and genes".

The following is a summary of presentations given during an ancillary meeting to the 1993 American Society of Human Genetics Meeting in New Orleans, LA. This ancillary meeting, entitled "Recent Research on Chromosome 4p Syndromes and Genes," reviewed the history of the Wolf-Hirschhorn syndrome (WHS), the natural history of patients with WHS, and the smallest region of deletion associated with the WHS. The proximal 4p deletion syndrome and the duplication 4p syndrome were also described and advice was offered regarding detection of chromosome 4p deletions, duplications, and rearrangements. The current status of the physical map of chromosome 4p with emphasis on the genes that map to the 4p16 region was presented along with a preliminary phenotypic map of 4p16. The goal of this format was to provide a comprehensive review of the clinical presentations, diagnostic capabilities, and genetic mapping advances involving chromosome 4p.

Trisomy 15 mosaicism and uniparental disomy (UPD) in a liveborn infant.

We describe a liveborn infant with uniparental disomy (UPD) with trisomy 15 mosaicism. Third trimester amniocentesis yielded a 46,XX/47,XX,+15 karyotype. Symmetrical growth retardation, distinct craniofacies, congenital heart disease, severe hypotonia and minor skeletal anomalies were noted. The infant died at 6 weeks of life. Peripheral lymphocyte chromosomes were "normal" 46,XX in 100 cells. Parental lymphocyte chromosomes were normal. Skin biopsy showed 47,XX,+15 in 80% of fibroblasts and results were equivalent in fibroblasts from autopsy lung tissue. Molecular analysis revealed maternal uniparental heterodisomy for chromosome 15 in the 46,XX cell line. We describe an emerging phenotype of trisomy 15 mosaicism, confirm that more than one tissue should be studied in all cases of suspected mosaicism, and suggest that UPD be considered in all such cases.

Trisomy 18/trisomy 13 mosaicism in an adult with profound mental retardation and multiple malformations.

We report on an adult woman with profound mental retardation and multiple anomalies who consists of 3 cell lines: one with trisomy 18, one with trisomy 13, and a normal cell line. Her phenotype includes manifestations of both trisomy syndromes. The origin of these cell lines could have been a doubly aneuploid (48,XX + 13, + 18) or singly aneuploid (47,XX + 18 or 47,XX + 13) zygote with subsequent mitotic nondisjunctions, or a normal zygote with multiple mitotic nondisjunctions. There have been four previous reports of mosaicism involving both trisomy D and trisomy E; all died in the first six months of life. Two of these cases had a doubly aneuploid (48,XX, + D + E) cell line. Our patient illustrates the need for study of several tissues in patients with complex aneuploidy syndromes or atypical manifestations of a given syndrome (such as prolonged survival), as well as the need for caution in counseling families about prognosis for survival in autosomal trisomies which usually are lethal.

Report of a variant t(1;15;17)(p36;q22;q21.1) in a patient with acute promyelocytic leukemia.

Chromosome analysis of bone marrow aspirate from a 46-year-old man with acute promyelocytic leukemia (APL) revealed a variant translocation, 46,XY,t(1:15;17)(p36;q22;q21.1). The breakpoints in chromosomes 15 and 17 appear to be the same as those in the more common translocation, t(15;17), associated with APL. The common translocation has been reported in up to 80% of cases of APL. Seventeen cases with variant translocations have been reported involving 15 alone, 17 alone, or 15, 17, and some other chromosome.

Cytogenetic studies of eight squamous cell carcinomas of the head and neck. Deletion of 7q, a possible primary chromosomal event.

Cytogenetic analysis was performed on the metaphase spreads obtained from primary cultures of eight squamous cell carcinomas (SCCa) of the head and neck. Despite a variety of tumor sites and clinical stages, four of eight tumors studied showed the same interstitial deletion of a portion of the q arm of chromosome 7, i.e., del(7)(q22q34). In one tumor, this was the sole chromosome abnormality present. Three tumors showed multiple chromosome rearrangements, including deletion at 7q. Three tumors showed multiple rearrangements but did not have del(7q). One tumor had an apparently, normal karyotype. The implications for del(7q) as a primary chromosomal event in SCCa are discussed.

Familial supernumerary chromosome and malignancy.

No familial marker chromosome associated with a malignancy has been reported to date. We used fluorescence in situ hybridization (FISH) to characterize a supernumerary marker chromosome 15 ascertained during prenatal diagnosis. This supernumerary chromosome 15 was found to span three generations of a family. Three family members carrying the supernumerary chromosome 15 have also had malignancies, namely, a cystic glioma, leukemia, and thyroid cancer.

Abnormalities of chromosome 22 in meningiomas and confirmation of the origin of a dicentric 22 by in situ hybridization.

We report three cases of meningioma. Case 1 had a dicentric chromosome number 22 resulting in partial monosomy for a portion of the q-arm, i.e., 46,XX,idic(22)(pter-->q11.2::q11.2-->pter) and 46,XX,psu dic(22)(pter-->q11.2::q11.2-->pter), which was the sole clonal abnormality. The origin of the dicentric chromosome from 22 was confirmed by in situ hybridization studies, using biotin-labeled alpha centromeric DNA probes for the acrocentric chromosomes. Case 2 had two distinct clonal abnormalities: deletion of 22q and monosomy of 22. Case 3 also had a deleted 22q.

Acquired Robertsonian translocations in two leukemia patients.

Robertsonian translocations were observed in two leukemia patients. The first case was a patient with chronic lymphocytic leukemia, who was found to have a rare Robertsonian translocation der(14;15)(q10;q10). The second case, a patient with acute myeloid leukemia, had multiple Robertsonian translocations: der(15)t(13;15)(q11.1;p11.1), der(14;22)(q10;q10), and dic(21;22)(p11.1;p11.1). Acquired multiple Robertsonian translocations have not been reported previously in leukemia.

Gamma heavy chain disease: report of a case associated with trisomy of chromosome 7.

A case of gamma heavy chain disease is reported in a 52-year-old white male who presented with fever and generalized lymphadenopathy. A lymph node biopsy showed malignant lymphoma. A partial transient response was obtained with cyclophosphamide, vincristine, prednisone, and doxorubicin. He died 3 months after diagnosis from disease progression and infectious complications. Chromosome analysis of cells from an involved lymph node showed the presence of trisomy 7. Chromosome abnormalities have been reported in three of ten previously published cases of gamma heavy chain disease. Trisomy of chromosome #7 has not previously been reported.