Lillian H. Lockhart

Position Effects Due to Chromosome Breakpoints that Map ∼900 Kb Upstream and ∼1.3 Mb Downstream of SOX9 in Two Patients with Campomelic Dysplasia

Campomelic dysplasia (CD) is a semilethal skeletal malformation syndrome with or without XY sex reversal. In addition to the multiple mutations found within the sex-determining region Y–related high-mobility group box gene (SOX9) on 17q24.3, several chromosome anomalies (translocations, inversions, and deletions) with breakpoints scattered over 1 Mb upstream of SOX9 have been described. Here, we present a balanced translocation, t(4;17)(q28.3;q24.3), segregating in a family with a mild acampomelic CD with Robin sequence. Both chromosome breakpoints have been identified by fluorescence in situ hybridization and have been sequenced using a somatic cell hybrid. The 17q24.3 breakpoint maps ∼900 kb upstream of SOX9, which is within the same bacterial artificial chromosome clone as the breakpoints of two other reported patients with mild CD. We also report a prenatal identification of acampomelic CD with male-to-female sex reversal in a fetus with a de novo balanced complex karyotype, 46,XY,t(4;7;8;17)(4qter→4p15.1::17q25.1→17qter;7qter→7p15.3::4p15.1→4pter;8pter→8q12.1::7p15.3→7pter;17pter→17q25.1::8q12.1→8qter). Surprisingly, the 17q breakpoint maps ∼1.3 Mb downstream of SOX9, making this the longest-range position effect found in the field of human genetics and the first report of a patient with CD with the chromosome breakpoint mapping 3′ of SOX9. By using the Regulatory Potential score in conjunction with analysis of the rearrangement breakpoints, we identified a candidate upstream cis-regulatory element, SOX9cre1. We provide evidence that this 1.1-kb evolutionarily conserved element and the downstream breakpoint region colocalize with SOX9 in the interphase nucleus, despite being located 1.1 Mb upstream and 1.3 Mb downstream of it, respectively. The potential molecular mechanism responsible for the position effect is discussed.

Oyster Ciliary Inhibition by Cystic Fibrosis Factor

Ciliary inhibition in oysters serves as an assay in identifying a serum factor in cystic fibrosis patients and heterozygotes. Seriums from 47 patients With cystic fibrosis antd 19 heterozygotes caused ciliary cessation within 35 minutes, whereas serums from only 2 of 64 individuals without cystic fibrosis inhibited ciliary activity within this time.

Nonrandom distribution of chromosomal aberrations induced by three chemicals

The G-band locations of 3244 breakpoints induced by cis-platinum (II) diamminedichloride (PDD), 1460 breakpoints induced by cytosine arabinoside (ara-C), and 1257 breakpoints induced by triethylenemelamine (TEM) in human lymphocyte chromosomes were identified. The breakpoints induced by each of these chemicals demonstrated a significantly nonrandom distribution within the human karyotype. The overall pattern of the interarm distribution was dependent upon the chemical used, but certain chromosomes arms exhibited similar responses to all 3 chemicals. Comparison of the frequencies of breakpoints within individual G-bands indicated that (1) certain bands were susceptible to damage induced by all 3 chemicals; (2) certain bands were resistant to damage by all 3 chemicals; (3) certain bands demonstrated variable susceptibility to induced damage dependent upon the chemical agent; and (4) other bands demonstrated near expected frequencies of damage (by length) to all 3 agents.

Maternal phenylketonuria pregnancy outcome: a preliminary report of facial dysmorphology and major malformations

ConclusionIt is clear from the preliminary data that major malformations, i.e. intrauterine growth retardation, microcephaly and cardiac defects, tend to decrease in frequency as the blood phenylalanine level drops, but not enough to suggest that phenylalanine levels of 600µmol/L are safe levels. The facial dysmorphic features may be used as a sensitive indicator that blood phenylalanine levels should be below 360µmol/L. It is hoped that at the end of the collaborative study more data will be available to suggest blood phenylalanine levels which will prevent the deleterious effects of maternal PKU syndrome.

Cystic Fibrosis: Characterization of the Inhibitor to Ciliary Action in Oyster Gills

The inhibitor to oyster ciliary activity was isolated from serumof cystic fibrosis patients and heterozygotes.The inhibitinig protein fraction wast a cation as judged by electrophoresis; it had a molecuer weight of 125,000 to 200,000 as judged by gel filtration; antd oil diethylaminoethyl-cellulose chromatography it eluted with the immunoglobulin G fraction. The analogous fraction in normal individuals did not inhibit oyster cillary activity.

Clinical experience in prevention of candidiasis by nystatin in children with acute lymphocytic leukemia

for the prevention of renal oSteodystrophy. In addition, fluid intake was restricted (he was anephric) and an anticholinergic drug was prescribed, both of which probably contributed to the constipation. It is difficult to know which factor played .the major part in the eventual bowel obstruction, but it would seem reasonable to exert due caution when any patient requires chronic usage of aluminum hydroxide. Efforts to lessen constipation, such as liberal fluid intake, use of laxatives, and, if renal function is not compromised, alternate use of magnesium containing antacids may reduce the risk of a fecal impaction. An appropriate history for constipationshould be a part of the ongoing care of these patients while they are receiving antacid therapy.

Cytogenetic effects of cis-platinum(II)diamminedichloride on human lymphocyte cultures.

Human lymphocytes were treated with the antitumor agent cis-platinum)II)diamminedichloride (PDD) during either the last 24 h or 48 h of incubation. A dose-dependent effect was observed for both inhibition of mitotic activity and increased frequency of metaphases with chromosomal aberrations. The aberrations observed consisted primarily of chromatid breaks. Statistical analysis of 3244 PDD-induced breakpoints demonstrated a significantly nonrandom distribution of breakpoints between chromosomes. The pattern of distribution varied with the type of aberration. Only chromosome number 9 had a significant increase of breakpoints for each type of aberration analyzed. The breakpoints were located predominantly in lightly staining G-gands. Certain individual bands had relatively high frequencies of breakpoints, indicating a specific interaciton occurs between PDD and the DNA of human lymphocytes in vitro.

Familial autism and the fragile-X chromosome

This report presents two male siblings in whom the diagnosis of infantile autism was found in association with a fragile site on the X chromosome. In addition to their marked autistic characteristics, formal examinations indicated that both boys were severely mentally retarded and had several physical features commonly observed in association with the fragile-X syndrome. The mother of these two siblings also gave birth to identical twin boys, who were developmentally delayed and showed several autistic features prior to their untimely death in a house fire. The possible role of the fragile-X chromosome as an etiological factor in families where there is a clustering of autism and related developmental disturbances is discussed.

A Rapid and Noninvasive Method for Detecting Tissue-Limited Mosaicism: Detection of i(12)(p10) in Buccal Smear from a Child with Pallister-Killian Syndrome

Pallister-Killian syndrome (PKS), a rare disorder, is characterized by tissue-limited or tissue-specific mosaicism. The characteristic chromosome abnormality associated with PKS is i(12p), which is seen predominantly in skin fibroblast cultures. Diagnosis of i(12p) has been carried out on buccal smears before and was shown to be an easy and feasible method. All previously published studies used alpha-satellite probes for the diagnosis and as such have several pitfalls. Our approach, using dual-color, locus-specific probes, has high specificity and sensitivity for the diagnosis of i(12p). Using statistical analysis, we have also confirmed that the signal pattern in interphase nuclei is consistent with isochromosome 12p.

Prenatal Diagnosis of a Fetus with Unbalanced Translocation (4;13)(p16;q32) with Overlapping Features of Patau and Wolf-Hirschhorn Syndromes

Wolf-Hirschhorn syndrome (WHS) and Patau syndrome are two of the most severe conditions resulting from chromosome abnormalities. WHS is caused by a deletion of 4p16, while Patau syndrome is caused by trisomy for some or all regions of chromosome 13. Though the etiologies of these syndromes differ, they share several features including pre- and postnatal growth retardation, microcephaly, cleft lip and palate, and cardiac anomalies. We present here a female fetus with deletion of 4p16 → pter and duplication of 13q32 → qter due to unbalanced segregation of t(4;13)(p16;q32) in the father. She displayed overlapping features of both of these syndromes on ultrasound. To the best of our knowledge, this is the first report of a fetus with both partial trisomy 13 and deletion of 4p16, the critical region for WHS.