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Biomedical subjects

M W Steele

Publications and source records attributed to M W Steele.

At least 19 recordsLinked to original sources
PubMed1996

A molecular anatomical analysis of mosaic trisomy 16.

A one-month-old child presenting with an aortic coarctation was found to have a left single transverse palmar crease and proportionate growth delay on physical examination, prompting a peripheral blood chromosome analysis. This showed a mosaic trisomy of chromosome 16, subsequently observed to decrease with the passage of time. As her phenotype was relatively benign, further analysis was performed to define more precisely the extent of her mosaicism given the supposedly lethal nature of the aneuploid cell line. Fluorescence in situ hybridisation and CA repeat polymorphism studies demonstrated the aneuploidy in multiple tissues, including the structurally affected aorta. Molecular analysis showed both maternal chromosomes 16 to be present in the trisomic cells, but maternal heterodisomy was not present in the diploid cells. Given the increasing number of individuals described with aneuploid mosaicism, we suggest that the study of multiple tissues is a necessary approach, the eventual goal being the appreciation of the relationship between the characteristics of a somatic mosaicism and the phenotype it imparts.

Alleles↗
PubMed1996

A simplified six-item checklist for screening for fragile X syndrome in the pediatric population.

OBJECTIVE: In our general experience, about 2% of samples referred for fragile X testing showed positive results on Southern blot analysis. The aim of this project was to determine whether screening criteria could be developed to increase the proportion of positive test results without sacrificing sensitivity. STUDY DESIGN: We retrospectively analyzed nine clinical characteristics from patient records of 273 male and 62 female pediatric probands (average age, 5.7 years) referred for fragile X testing. The characteristics included mental retardation, family history of mental retardation, large or prominent ears, elongated face, attention deficit hyperactivity disorder, autistic-like behavior, simian crease, macroorchidism, and hyperextensible joints. These were scored as 2 if present, 1 If borderline present, and 0 if absent. RESULTS: Analysis of the nine characteristics identified three (simian crease, macroorchidism, and hyperextensible joints) with low frequency and statistical insignificance, which were therefore eliminated. With the use of the remaining six characteristics, If a score of 5 or more was used as the criterion for requesting fragle X testing, then close to 60% of those tests from our patient population could have been eliminated without missing any positive cases. The validity of our threshold score of 5 was subsequently confirmed among an additional six cases of fragile X syndrome. CONCLUSION: With our simplified six-item clinical checklist, 60% of testing could have been eliminated, thereby improving the cost-effectiveness of fragile X testing and increasing the proportion of cases with positive results by threefold.

Cost-Benefit Analysis↗
PubMed1995

Infundibulopelvic stenosis, multicystic kidney, and calyectasis in a kindred: clinical observations and genetic analysis.

Congenital obstructive anomalies of the urinary tract usually occur sporadically. We describe inheritance in a three-generation kindred of a spectrum of kidney anomalies consistent with an autosomal-dominant mode of transmission, with incomplete penetrance, calyectasis (maternal grandmother), infundibulopelvic stenosis (uncle), and multicystic kidney (male proband, age 4 years). The proband's mother, father and half sister had normal renal imaging studies. Inheritance of informative polymorphic markers (3'-HVR, GGG1, GGG9, SM-7, KG8, and CW3) mapping close to the adult polycystic kidney disease type 1 (PKD-1) and tuberous sclerosis (TSC-2) loci on chromosome 16p was evaluated by Southern blot studies and by PCR-based, fluorescent genotyping for linkage to phenotype. The 3 affected individuals, as well as the unaffected mother (obligate carrier) and unaffected half-sister, inherit a common chromosome haplotype linked to the PKD1 locus. Our findings support the hypothesis that these anomalies may be part of a spectrum of obstructive renal dysplasia which are inherited as a simple Mendelian trait exhibiting an autosomal-dominant mode of transmission with variable expression and incomplete penetrance.

Adult↗
PubMed1995

Down syndrome consequent to a cryptic maternal 12p;21q chromosome translocation.

A 9-year-old, mildly mentally retarded girl presented with phenotypic manifestations of Down syndrome. G-banded chromosomal analyses of peripheral blood lymphocytes from the patient and her parents, and skin fibroblasts from the patient, did not detect any abnormality. Molecular analysis of 15 highly polymorphic chromosome 21 dinucleotide repeat markers demonstrated a partial duplication of the Down syndrome critical region (D21S55, subband 21q22.2) of maternal origin in the patient. The segmental trisomy was confirmed by FISH analysis using the cosmid probe D21S55. Further analysis demonstrated that the trisomy was due to segregation of an apparently balanced cryptic translocation from the mother. The patient's karyotype is 46,XX,-12,tder(12)t(12;21)(p13.1;q22.2)mat.

Child↗
PubMed1995

Chromosomal abnormalities in a psychiatric population.

Over a 3.5 year period of time, 345 patients hospitalized for psychiatric problems were evaluated cytogenetically. The patient population included 76% males and 94% children with a mean age of 12 years. The criteria for testing was an undiagnosed etiology for mental retardation and/or autism. Cytogenetic studies identified 11, or 3%, with abnormal karyotypes, including 4 fragile X positive individuals (2 males, 2 females), and 8 with chromosomal aneuploidy, rearrangements, or deletions. While individuals with chromosomal abnormalities do not demonstrate specific behavioral, psychiatric, or developmental problems relative to other psychiatric patients, our results demonstrate the need for an increased awareness to order chromosomal analysis and fragile X testing in those individuals who have combinations of behavioral/psychiatric, learning, communication, or cognitive disturbance.

Adolescent↗
PubMed1995

"Balanced" karyotypes in six abnormal offspring of balanced reciprocal translocation normal carrier parents.

Among 6800 consecutive blood samples studied for clinical cytogenetic diagnosis, we identified 30 families in which one parent of the proband had a balanced reciprocal autosomal translocation (excluding Robertsonian rearrangements). Twenty-eight of the 30 families had a malformed and/or mentally retarded proband: 19 with an unbalanced derived chromosome, 3 with abnormalities involving chromosomes other than those in the translocation, 5 with a "balanced" reciprocal translocation, and 1 with a normal karyotype. We hypothesize that the latter 6 affected probands with "balanced" karyotypes could be abnormal due to submicroscopic deletions and duplications as was originally suggested by Jacobs [1984]. Particularly in these 6 families, 83% of translocation breakpoints were associated with fragile sites, more than expected by chance (P < 0.025). This supports the report of an association between fragile sites and constitutional chromosome breakpoints by Hecht and Hecht [1984]. To explain these findings, we propose that autosomal fragile sites are unstable areas which predispose to breaks and unequal crossing over near the fragile site breakpoints creating minute duplications and deletions. Consequently, newborn infants inheriting a seemingly "balanced" karyotype from a normal parent with a balanced reciprocal translocation may still be at an increased risk of being malformed and/or developmentally delayed because of submicroscopic chromosomal imbalances.

Abnormalities, Multiple↗
PubMed1994

Research squeeze.

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Academic Medical Centers↗
PubMed1994

Three unrelated cases of paracentric inversions of 1p in individuals with abnormal phenotypes.

Paracentric inversions, involving a rearrangement within one chromosome arm, are rare. Although carriers of balanced paracentric inversions should theoretically not be at risk for abnormal offspring, such cases have been reported. We report on 2 unrelated cases of inherited paracentric inversions of 1p with breakpoints at p32 and p36.1 and p32.3 and p36.22 in individuals with abnormal phenotypes. Another case of 2 abnormal monozygotic twins with a de novo paracentric inversion of 1p with breakpoints at p22 and p34 is presented as well.

Abnormalities, Multiple↗
PubMed1994

Cytogenetic characterization of cat eye syndrome marker chromosome.

Cat eye syndrome is associated with a partial tetrasomy 22q and can be inherited. The authors have evaluated the marker chromosome in a proband and his mother by cytogenetic banding techniques to verify the dicentric chromosomal rearrangement and by fluorescence in situ hybridization to confirm the involvement of 22. The mother also had an affected offspring with an unrelated aneuploidy, trisomy 21.

Abnormalities, Multiple↗
PubMed1993

Broad-spectrum Möbius syndrome associated with a 1;11 chromosome translocation.

The authors report a case of Möbius syndrome with Poland syndrome, cleft palate, dextrocardia, mandibular hypoplasia, and multiple areas of diffuse brain volume loss. Karyotype demonstrated a t(1;11)(p22;p13) translocation in the patient and his phenotypically normal father and brother. This case extends the spectrum of congenital disorders that are associated with Möbius syndrome and raises the possibility of genetic heterogeneity for the Möbius disorder.

Abnormalities, Multiple↗
PubMed1992

Acrometageria: a spectrum of "premature aging" syndromes.

A child with manifestations of acrogeria and metageria, two "premature aging" syndromes, is presented. Because of his indistinct phenotype and because the question has been previously raised as to whether these conditions are separate, we propose the designation of acrometageria to describe this phenotypic continuum. As there is much in common clinically between acrometageria and the syndrome of type III procollagen deficiency (Ehlers-Danlos type IV), it might be presumed that a similar pathogenesis for acrometageria exists. This possibility has been tested previously, without demonstrating specific quantitative or qualitative deficits, but with some indirect evidence that collagen metabolism is deranged in these patients. One such crude indicator is the elevation of urinary hyaluronic acid levels, demonstrated in our patient and also observed in the phenotypically distinct Werner and Hutchinson-Gilford premature aging syndromes. On one hand, it could be argued that this supports the concept that premature aging syndromes exist as a biological continuum. On the other hand, it is equally valid to argue that syndromes of premature aging are so described merely because they include recognizable changes of normal aging and that the demonstration of an underlying mutation in a collagen gene, for example, invalidates their study as models of accelerated normal aging.

Cells, Cultured↗
PubMed1992

X inactivation and dystrophin studies in a t(X;12) female: evidence for biochemical normalization in Duchenne muscular dystrophy carriers.

A 4-year-old girl was identified with high creatine kinase (CK) values, and mild muscle weakness in a limb-girdle distribution. Results of dystrophin analysis of the muscle biopsy were consistent with a manifesting heterozygote for Duchenne muscular dystrophy. In peripheral lymphocytes she had a t(X;12) (p21.2;q24.33). Late DNA replication studies demonstrated inactivation of the normal X chromosome in 99.4% of cells. Dystrophin immunofluorescence showed 64% dystrophin-negative muscle fibers. Dystrophin content of muscle by immunoblot was approximately 5% of normal. The discordance between the percent of normal X inactivation and percent of dystrophin-negative cells may be explained by compensatory protection of dystrophin by rare nuclei with the normal X active in multi-nucleated muscle fibers with shared cytoplasm.

Child, Preschool↗
PubMed1991

X/Y translocations resulting from recombination between homologous sequences on Xp and Yq.

Several regions of sequence homology between the human X and Y chromosomes have been identified. These segments are thought to represent areas of these chromosomes that have engaged in meiotic recombination in relatively recent evolutionary times. Normally, the X and Y chromosomes pair during meiosis and exchange DNA only within the pseudoautosomal region at the distal short arms of both chromosomes. However, it has been suggested that aberrant recombination involving other segments of high homology could be responsible for the production of X/Y translocations. We have studied four X/Y translocation patients using molecular probes detecting homologous sequences on X and Y chromosomes. In one translocation the breakpoints have been isolated and sequenced. The mapping data are consistent with the hypothesis that X/Y translocations arise by homologous recombination. The sequencing data from one translocation demonstrate this directly.

Base Sequence↗
PubMed1991

Assessment of X bends in patients with atypical X chromosome phenotypes.

Several patients with X chromosome structural abnormalities have been more severely affected clinically than expected. Since bends at Xq13-21 have been associated with inactivation, the authors scored bends retrospectively in 62 patients with X chromosome aneuploidy and 21 cases with structural abnormalities of the X chromosome. They found that patients with 2 X inactivation sites where one X was structurally abnormal had significantly fewer cells with X bends than normal 46,XX. In addition, these patients also showed X bends on the normal X more often than would be expected if non-random X inactivation of the abnormal X chromosome was occurring. Five of the 6 patients with a short or long arm deletion or paracentric inversion of Xq were mentally retarded or had other congenital anomalies not usually associated with Turner syndrome. This suggests to them that these clinical findings may be related to interference with X inactivation patterns in cells with a structurally abnormal X chromosome.

Aneuploidy↗
PubMed1990

Chromosome mosaicism in hypomelanosis of Ito.

Our finding of chromosome mosaicism with a ring 22 in a retarded black boy with hypomelanosis of Ito prompted a review of this "syndrome." Most patients have a variety of non-dermal defects, particularly those affecting CNS function. Among karyotyped patients, most are chromosome mosaics of one sort or another. Hypomelanosis of Ito turns out to be a causable non-specific phenotype, i.e., a clinical marker for chromosome mosaicism of all different types in individuals with a dark enough skin to show lighter patches. Consequently, cytogenetic evaluation is indicated in all patients with this skin finding.

Abnormalities, Multiple↗
PubMed1990

Mosaicism in Pallister i(12p) syndrome.

The clinical diagnosis of Pallister syndrome in a 1-day-old white boy was confirmed by the presence of i(12p) in 100% of cells on direct bone marrow analysis. This is the second Pallister syndrome case in which cytogenetic diagnosis was made in bone marrow cells during the neonatal period. Other tissues analyzed in our patient included peripheral blood PHA-stimulated cultured lymphocytes and postmortem skin and lung cultured fibroblasts with 3%, 98.5%, and 97.5% of cells containing the i(12p), respectively. Serial skin fibroblast cultures re-established from frozen cells were analyzed sequentially over time for the isochromosome. There was slight reduction in the proportion of i(12p) cells until passage 15 with plateauing of the proportion of i(12p) cells at about 80% until culture senescence. Our review of such cytogenetic analyses suggests that in vivo and perhaps also in vitro isochromosome loss best explains the intra- and inter-tissue specific chromosomal mosaicism in the i(12p) syndrome. In any event, our results indicate that confirmation of the diagnosis in the neonatal period is possible by direct cytogenetic analysis of bone marrow.

Bone Marrow Cells↗