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At 6 years of age, a boy with bilateral sensorineural deafness, lateral displacement of inner canthi, a bulbous nasal tip, synophrys, and cryptorchidism was clinically diagnosed as having Waardenburg's syndrome type I (WS-1). In addition, he had a lumbar spina bifida with hydrocephalus shunted on the second day of life and severe mental retardation with a head circumference at the fifth percentile. Neither parent showed signs of WS-1, and the family history was negative. Because of the WS-1 features, attention was focused on the PAX3 location in 2q, at which time a de novo paracentric inversion of 2q23-q37.1 was noted. Subsequent high-resolution chromosome analysis 8 years later indicated a complex rearrangement involving regions 2q31-q35 and 2q13-q21. Whole chromosome painting and high-resolution comparative genomic hybridization yielded negative results for any translocation, duplication, or deletion of any chromosome segments. Sequencing of the PAX3 gene yielded no detectable mutation. Fluorescent in situ hybridization (FISH) studies with human BAC clones revealed five breakpoints in chromosome 2q resulting in two paracentric inversions and one insertion, the karyotype being interpreted as 46,XY,der(2)inv(2)(q13q21)inv(2)(q21q24.2)ins(2)(q24.2q33q35). In this extremely rare chromosomal rearrangement, the FISH result showed a breakpoint at 2q35 being proximal to and without involvement of the PAX3 gene. While further studies continue, possible interpretations include involvement of a regulatory gene(s) for PAX 3 and other genes at the other breakpoints related causally to the spina bifida and mental retardation.

Analyzable G-banded metaphases were normal in bone marrow from a 26-year-old male having 80% blasts. Fluorescence in situ hybridization (FISH) using the centromeric probe, D7Z1, revealed 85% of interphase cells with one signal for chromosome 7. Chromosome painting revealed a chromosome 7 rearrangement in a few metaphases that were otherwise unanalyzable. A repeat bone marrow confirmed 3 of 20 metaphases, by G-banding, to have multiple rearrangements and aneuploidy, including a large derivative chromosome involving a complex rearrangement of chromosomes 5, 7, and 9; that is, der(5)t(5;9)(q31;q13)ins(5;7)(p15;q?31q?34), with loss of most of chromosome 7 (7 pter-->7q?31); one normal 7 was present. Immunophenotyping characterized the patient's condition as an early T-cell acute lymphocytic leukemia (ALL), with a population of cells suggesting biphenotypic leukemia. He attained a complete clinical remission with chemotherapy. Six months after the initial presentation he received an allogeneic bone marrow transplant. Three months later a CNS relapse was followed by a bone marrow relapse. At this time, eight months after transplant, repeat study of his bone marrow revealed the majority of metaphases had structural and numerical chromosome abnormalities similar to the small clone in the earlier study, including der(5)t(5;9)ins(5;7), but with two normal 7s. FISH showed two 7-centromere signals in interphase. The patient expired one month later.

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.

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.

Cytogenetic findings in the third reported case of adrenal cortical carcinoma are described. In contrast to the two previous cases, hypodiploidy characterized almost all cells, which had as many as eight abnormal chromosomes in each cell analyzed.

We report three cases of amniocentesis in which mosaicism for trisomy 12 was detected in two or more independent cultures. The parents elected to terminate the pregnancy in all three cases. Follow-up studies in two of the cases confirmed the mosaicism in fetal tissues (in subcutaneous tissue in one case; in fetal lung in the other), but not in blood. No fetal anomalies were evident by ultrasound or at autopsy. These results along with other reported cases demonstrate the difficulty in counselling for mosaic trisomy 12.

A ring chromosome No. 13 was found in a 21-year-old female with multiple anomalies suggestive of 13q--syndrome. Chromosomes of the girl and her parents, studied by quinacrine staining, revealed the ring to be of paternal origin. Detailed study of the quinacrine banding pattern of the ring indicated loss of the most distal band of the long arm (13q34) and possible partial loss of the next adjacent long arm band (13q33). The short arm (13q11) was present but the stalk (13p12) and satellite (13p13) regions appeared to be missing.

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.

An infant with multiple anomalies and developmental delay during his first year was found to have an intersitital deletion of band p14 from the proximal short arm of chromosome 3. Examination of the father's chromosomes indicates an "inserted paracentric inversion" in chromosome 3 as the probable origin of the deletion in the child.

A 5-year-old male with mild mental retardation showed a chromosomal rearrangement involving duplication of part of 2q (2q33.3 leads to 2wter) in 70% of metaphases from peripheral blood; the remaining 30% of cells had a rearrangement of chromosome 2 in the form of a ring, viz., r(2)(2p25.2 leads to 2q33.2). Both configurations appeared to be missing a tiny portion of 2p (p25.3 leads to pter). All metaphases examined from cultured skin fibroblasts from the child had the abnormal rod configuration of chromosome 2; none had the ring. The pattern of the 2q duplication/2p deletion in the rod is that expected if there were an inversion in a No. 2 in one of the parents. Q-, G-, and R-banding studies, however, revealed both parents to be chromosomally normal. Furthermore, the finding of an inversion would not explain the origin of the ring. The most probable explanation is that neither parent is mosaic for an inversion, but that the rod and ring configurations arose simultaneously from a de novo, prezygotic or early zygotic exchange in a No. 2, either between complementary DNA strands in G1 or by intrachromosomal exchange in S or G2. Differential selection against cells with the ring chromosome in blood and skin probably occurred during subsequent embryological development. Cytoplasmic malate dehydrogenase (MDH1) was excluded from the terminal band of 2p (i.e., 2p25.3) by deletion mapping.

A patient with multiple exostoses, mental retardation, and unusual facies has an interstitial deletion of the long arm of chromosome 8, or 46,XX, del (8) (pter leads to q22::q24.1 leads to qter). She has some features of the Langer-Giedion syndrome, but her facies are not characteristic and she does not have cone-shaped phalangeal epiphyses. Of the eight previous reports of partial deletion of the long arm of chromosome 8, four patients had exostoses and unusual facies, three of whom had characteristics of the Langer-Gieldion syndrome. The deleted segments in the patients with exostoses are not identical, although there are areas of deletion that are seen in more than one patient. Among the explanations of the relationship of the 8q deletions to exostoses is the presence of several loci on 8q that are involved in bone formation, the deletion of any of which may give rise to a similar skeletal defect.

Chromosomal analysis on a 15-year-old girl with amenorrhea and lack of secondary sexual development showed a normal X chromosome and an isodicentric X chromosome, 46,X, idic(x) (pter leads to q23::q23 leads to pter). Thus the patient has duplicated and deleted X chromosome material. There was no evidence of 45,X mosaicism. Brd U-labeling revealed the abnormal X to be late-replicating.