Biomedical subjects
Publications and source records attributed to L Y Hsu.
An unbalanced translocation, 46,XX,der(5)t(5;11) (p15;q25)mat was ascertained by prenatal diagnosis. The mother previously had a liveborn child with cri du chat syndrome. The subtlety of the chromosome rearrangement in this case illustrates the need for the most detailed cytogenetic investigations in cri du chat cases when deletion or translocation are not immediately obvious.
Chromosome rearrangement is a relatively common finding in cultured amniotic fluid cells. When cytogenetic abnormalities are confined to one cell or cells from a single culture, they are generally assumed to have arisen in culture (pseudomosaicism). To determine whether or not there might be some specificity in chromosome break-points in balanced translocation multiple cell pseudomosaicism, data has been pooled for 18 cases studied at PDL and 30 cases from the U.S. survey on mosaicism and pseudomosaicism (Hsu & Perlis 1984). Out of a total of 97 break-points, 87 were assigned to Giemsa-staining light bands and 12 to Giemsa-staining dark bands. An excess of break points (29%) were assigned to terminal bands. Two loci appeared to be preferentially involved in rearrangement: six break-points (4 PDL cases and 2 others) were assigned to band 6p21; the region to which the major histocompatibility complex (HLA) has been assigned; Four break-points (all PDL cases) were assigned to 13q14, the region associated with the retinoblastoma locus. This preliminary evidence for specific break-points needs confirmation and long-term follow-up information is needed to determine whether or not there is any clinical significance to these observations.
The Prenatal Diagnosis Laboratory of New York City (PDL) is a regional program for the prevention of genetic diseases. The administrative aspects of the establishment of the laboratory were described in papers I [Hsu, 1981] and II [Hsu and Benn, 1981] in this series. We now report our experience of the first 7,000 referrals to the laboratory. The laboratory achieved a success rate of 99.5% in obtaining a diagnosis. The frequency with which a repeat amniocentesis was required was 1.9%, usually attributable to inadequate initial amniotic fluid volume or condition. Cases were completed in an average time of 20.82 days. A total of 149 (2.13%) cytogenetic abnormalities were detected. There were 59 nonmosaic autosomal trisomies and 29 sex chromosome abnormalities. The incidence of unbalanced structural abnormalities (0.186%) was much higher than that reported in surveys of newborn infants largely because of the prenatal detection of cases with supernumerary chromosomes. The incidence of balanced structural abnormalities was also considerably higher than that found in surveys of the newborn population, in part because of the detection of subtle familial pericentric inversions of common chromosome regions (inv(Y)(p11q11), inv(2) (p11q13), and inv(1)(p11q13)). The incidence of cases with multiple independent chromosome abnormalities was no higher than expected by chance. A high incidence of mosaicism, pseudomosaicism, and maternal cell contamination was found. Screening for neural tube defects accounted for the detection of a further 16 abnormalities. Nearly all women with severely abnormal fetuses (trisomy 13, 18, 21) elected to terminate their pregnancy whereas only 62% of patients with a prenatally diagnosed sex chromosome abnormality elected to terminate their pregnancies. Full details of follow-up and confirmatory studies for unusual diagnoses are reported. Utilization of prenatal diagnosis in the New York City area has increased sharply since PDL became operational. The laboratory's success illustrates the role of a prenatal diagnosis laboratory that provides a service independent of the patient's financial status. The experience further shows the high degree of acceptance of prenatal diagnosis by individuals at high risk for a child with a genetic disorder.
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The survey of the incidence of chromosome mosaicism and pseudomosaicism detected in prenatal diagnosis included data from approximately 60 000 genetic amniocenteses in the United States. There were 59 participating cytogenetic laboratories nationwide. The overall incidence of chromosome mosaicism was 0.25 per cent (range of 0-0.89 per cent). The average frequency of pseudomosaicism involving multiple cells or clones was 0.7 per cent (range of 0-11.21 per cent). The frequency of single cell or clone pseudomosaicism was 2.47 per cent (range of 0-11.49 per cent). In cases of pseudomosaicism with trisomy, the most frequently involved chromosome was number 2; occurrence rates of trisomies 7,X,9,17 and 20 were also relatively high. In cases of pseudomosaicism with structural abnormalities, this survey showed an association between relative chromosome size and the frequency of involvement in structural rearrangement. Data on a total of 185 cases of chromosome mosaicism collected in this survey as well as from other documented sources showed 89 cases involved an autosome, 73 cases a sex chromosome, and 23 a marker chromosome. The frequency of noticeable phenotypic abnormalities was highest (37.8 per cent) in the autosomal mosaics and lowest (10.5 per cent) in the sex chromosome mosaics. The average rate for cytogenetic confirmation was 70 per cent.
The finding of a supernumerary marker chromosome in amniotic fluid cells poses a considerable counseling dilemma. In 6,500 cases referred to our laboratory over a 4 1/2-year period, eight such cases were identified (0.123% of all cases). In five of the eight cases, a diagnosis of true mosaicism between cells with 46 and 47 chromosomes was made. In the remaining three cases, the marker was present in 100% of the cells. In three cases, the marker was determined to be familial in nature with mosaicism present in the parents of two of these cases. Detailed cytogenetic findings for each case are provided. In no cases were abnormalities noted in either abortuses or live borns. The high incidence of mosaicism in these cases seems to indicate a propensity for supernumerary chromosomes to be lost. Familial markers may not be passed on for many generations, and they may arise as new mutations relatively frequently. There is an urgent need for more information on the risks associated with the prenatal detection of supernumerary chromosomes. We recommend that in considering the implications of the prenatal detection of marker chromosomes cases be considered in at least four distinct groups: type 1--familial and nonmosaic; type 2--familial with mosaicism in either the amniotic fluid cells, a parent, or both; type 3--de novo markers and nonmosaic; and type 4--de novo with mosaicism present in the amniotic fluid cells.
Crystalline cholesterol undergoes a phase transition a few degrees below human body temperature. The high-temperature form has an unusually complex structure with 16 independent molecules. In the transition two molecules change side chain conformation, four reorient about their long axes, and ten remain unchanged. The transition mechanism implies relatively nonspecific intermolecular interactions, qualitatively consistent with the behavior of cholesterol in biomembranes. The transition preserves a remarkably closely obeyed pseudosymmetry present in the structure.
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A fetus was identified by prenatal cytogenetic diagnosis as having a karyotype 46,XY,r(13) (p11q13). Termination of the pregnancy yielded a severely malformed fetus. Fetal abnormalities included anencephaly, imperforate anus and urethral meatus, severe talipes, syndactyly, cardiac defects and other anomalies. Confirmatory studies on cultured placental villi cells indicated a second cell line, 46,XY, -13,+13qter leads to cen::13q13 leads to qter. This cell line was not detectable in cells derived from the fetus despite extensive studies. It seems likely that the two cell lines arose simultaneously with selection favouring the 46,XY,r(13) line. How the chromosome rearrangements may have arisen is discussed. We are unaware of other cases where a cell line identifiable by a chromosome abnormality appeared to be confined to placental tissue. However, studies on placental tissue may be helpful in understanding the origin of other unbalanced de novo rearrangements.
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This study demonstrated that the GTG banding technique is not sufficient for the precise localization of breakpoints in translocations. Multiple banding techniques are required in cases with complex rearrangements before describing a so called "new syndrome'. Nevertheless, it is concluded that each banding technique has certain advantages, but GTG technique is the poorest choice.
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The increasing demand in New York City for prenatal diagnosis of genetic disorders has necessitated the development of a large-scale, centralized prenatal genetic screening program. The objective of this program is eventually to serve 3,000 to 4,000 at-risk New York City pregnant women annually. Through the teamwork of a task force comprising representatives from the New York Scientists' Committee for Public Information (SCPI), the Medical and Health Research Association of New York City Departments of Health, and five different advisory committees, the centralized Prenatal Diagnosis Laboratory of New York City (PDL) was designed and established. While this program aims to provide high quality, centralized laboratory service for the prenatal detection of chromosome abnormalities and open neural tube defects, it also emphasizes quality-controlled services in genetic counseling, aminocentesis, ultrasound monitoring, obstetric care, and patient follow-up. Genetic counseling by PDL-employed counselors is made available to patients whenever the participating hospital lacks such service or cannot handle their patient load. In addition, PDL has launched a vigorous public health education program. A detailed guideline for the program was prepared describing the highest standards of quality for each component. The initial step was th developmental phase that included establishing the advisory committees, searching for sponsors, preparing guidelines, developing the health education program, renovating the laboratory site, purchasing and installing equipment, and recruiting of staff. The experience gained from this endeavor will be of value in the development of similar large-scale prenatal diagnosis programs.
Prenatal diagnosis of genetic disorders is now being made available to an increasing number of New York City women through the establishment of a large centralized laboratory. This laboratory contracts to provide genetic diagnostic services to municipal and private hospitals throughout the New York City area. It is the first project of such magnitude in the United States. Prior to the receipt of samples for diagnostic purposes, the laboratory was required to meet the highest technical standards, as established by a Cytogenetics Advisory Committee. A set of guidelines was drawn up detailing the procedure and protocols for all the analyses and the reporting of results, including a timetable according to which results were to be obtained. The Cytogenetics Advisory Committee continues to review cases on a regular schedule. One of the unique aspects of the laboratory has been the development of back-up agreements with other area laboratories to assist in dealing with any problem that might disrupt the routine diagnostic service. The first year of operation of the laboratory has shown that financial, legal, and physical problems associated with designing and instituting a megacenter can be over-come. Similar programs should be encouraged.
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Three cases of trisomy 20 mosaicism in amniotic fluid cell cultures are described. Two of the pregnancies resulted in normal full-term infants. The third pregnancy was terminated and revealed a phenotypically normal fetus. A review of five previously reported cases is presented. Explanations of these findings include in vitro nondisjunction, culture of extraembryonic tissue, and true fetal mosaicism. The diagnostic dilemma this presents is discussed.
We have identified trisomy 13 in two additional patients with hematologic malignancies involving the hematopoietic stem cell: a 75-year-old female with acute myelocytic leukemia and a 64-year-old female with agnogenic myelofibrosis and myeloid metaplasia. Chromosome analysis of the direct bone-marrow preparation showed 100% of cells with trisomy 13 in the first and 10% of cells in the second. We also previously reported a patient with Ph1 negative chronic myelogenous leukemia in whom 100% of the marrow cells showed an identical trisomy. The probability of finding three such patients in our case material was calculated to be 0.05--0.08, implying that trisomy 13 may be another nonrandom chromosomal aberration associated with malignancies of hematopoietic pluri-potent stem cell.