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C Shuman

Publications and source records attributed to C Shuman.

At least 19 recordsLinked to original sources
PubMed2006

New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome demonstrating heterogeneous molecular alterations of two imprinted domains on chromosome 11p15. The most common molecular alterations include loss of methylation at the proximal imprinting center, IC2, paternal uniparental disomy (UPD) of chromosome 11p15 and hypermethylation at the distal imprinting center, IC1. An increased incidence of female monozygotic twins discordant for BWS has been reported. The molecular basis for eleven such female twin pairs has been demonstrated to be a loss of methylation at IC2, whereas only one male monozygotic twin pair has been reported with this molecular defect. We report here two new pairs of male monozygotic twins. One pair is discordant for BWS; the affected twin exhibits paternal UPD for chromosome 11p15 whereas the unaffected twin does not. The second male twin pair is concordant for BWS and both twins of the pair demonstrate hypermethylation at IC1. Thus, this report expands the known molecular etiologies for BWS twins. Interestingly, these findings demonstrate a new epigenotype-phenotype correlation in BWS twins. That is, while female monozygotic twins with BWS are likely to show loss of imprinting at IC2, male monozygotic twins with BWS reflect the molecular heterogeneity seen in BWS singletons. These data underscore the need for molecular testing in BWS twins, especially in view of the known differences among 11p15 epigenotypes with respect to tumor risk.

Beckwith-Wiedemann Syndrome↗
PubMed2001

Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1.

Dysregulation of imprinted genes on human chromosome 11p15 has been implicated in Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome associated with congenital malformations and tumor predisposition. The molecular basis of BWS is complex and heterogeneous. The syndrome is associated with alterations in two distinct imprinting domains on 11p15: a telomeric domain containing the H19 and IGF2 genes and a centromeric domain including the KCNQ1OT1 and CDKNIC genes. It has been postulated that disorders of imprinting in the telomeric domain are associated with overgrowth and cancer predisposition, whereas those in the centromeric domain involve malformations but not tumor development. In this study of 125 BWS cases, we confirm the association of tumors with constitutional defects in the 11p15 telomeric domain; six of 21 BWS cases with uniparental disomy (UPD) of 11p15 developed tumors and one of three of the rare BWS subtype with hypermethylation of the H19 gene developed tumors. Most importantly, we find that five of 32 individuals with BWS and imprinting defects in the centromeric domain developed embryonal tumors. Furthermore, the type of tumors observed in BWS cases with telomeric defects are different from those seen in BWS cases with defects limited to the centromeric domain. Whereas Wilms' tumor was the most frequent tumor seen in BWS cases with UPD for 11p15 or H19 hypermethylation, none of the embryonal tumors with imprinting defects at KCNQ1OT1 was a Wilms' tumor. This suggests that distinct tumor predisposition profiles result from dysregulation of the telomeric domain versus the centromeric domain and that these imprinting defects activate distinct genetic pathways for embryonal tumorigenesis.

Beckwith-Wiedemann Syndrome↗
PubMed2001

GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson-Golabi-Behmel syndrome.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome caused by deletions in glypican 3 (GPC3). SGBS is characterized by pre- and postnatal overgrowth, a characteristic facial appearance, and a spectrum of congenital malformations which overlaps that of other overgrowth syndromes. We performed GPC3 deletion screening on 80 male patients with somatic overgrowth in the following categories: SGBS (n = 19), possible SGBS (n = 26), including families in which individuals had previously been diagnosed with other overgrowth syndromes, and Wiedemann-Beckwith syndrome (WBS) (n = 35). Using exon-specific PCR and Southern blot analysis, we identified seven GPC3 deletions. In most cases a clear X-linked family history was not present. In two cases, GPC3 deletions were identified in patients belonging to pedigrees published previously as other overgrowth syndromes: one with a diagnosis of Sotos syndrome and the other Perlman syndrome with nephroblastomatosis. A third patient developed hepatoblastoma, a tumor type not previously described in SGBS. No GPC3 deletions were identified among the WBS patients. Direct sequencing of all GPC3 exons in the remaining 13 SGBS patients without GPC3 deletions did not identify any further mutations, raising the possibility of alternative silencing mechanisms and/or other genes in the pathogenesis of SGBS. Our results validate the clinical specificity of the facial appearance, skeletal/hand anomalies, and supernumerary nipples in patients with GPC3 deletions. Our data also suggest that nephroblastomatosis and hepatoblastoma are included in the phenotypic spectrum of GPC3 deletions and SGBS, underscoring the importance of tumor surveillance in these children.

Abnormalities, Multiple↗
PubMed2001

Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations.

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by somatic overgrowth, congenital malformations, and predisposition to childhood tumors. Aberrant expression of multiple imprinted genes, including H19, IGF2, KCNQ1OT1, and CDKN1C, has been observed in BWS patients. It has been estimated that mutations in CDKN1C occur in 12-17% of BWS patients. We have screened 10 autosomal dominant pedigrees and 65 sporadic BWS cases by PCR/heteroduplex analysis and DNA sequencing and have identified four mutations, two of which were associated with biallelic IGF2 expression and normal H19 and KCNQ1OT1 imprinting. One patient demonstrated phenotypic expression of paternally transmitted mutation in this maternally expressed gene, a second proband is the child of one of a pair of monozygotic twin females who carry the mutation de novo, and a third patient exhibited unusual skeletal changes more commonly found in other overgrowth syndromes. When considered with other studies published to date, this work reveals the frequency of CDKN1C mutations in BWS to be only 4.9%. This is the first report of an analysis of the imprinting status of genes in the 11p15 region where CDKN1C mutations were associated with loss of IGF2 imprinting and maintenance of H19 and KCNQ1OT1 imprinting.

Amino Acid Sequence↗
PubMed2000

Analphoid 3qter markers.

Two cases of marker chromosomes derived from a non-centromeric location were studied to determine the characteristics of these markers with respect to the presence of functional centromeres and whether an associated phenotype could be described. The markers were characterized by fluorescence in situ hybridization and centromeric protein studies. Assessments were done to identify clinical features. Case 1 is a girl referred at age 1.5 years with swirly areas of hyperpigmentation, bilateral preauricular pits, hypotonia, developmental delay, and seizures. Case 2 is a male first evaluated as a newborn and then later during the first year of life. He had streaky hypopigmentation, right preauricular pit, accessory nipples, postaxial polydactyly, asymmetric cerebral ventricles, duplicated right kidney, a right pulmonary artery stenosis, and seizures. Mosaicism for an extra marker from the 3qter region was present in both cases. Both markers had a constriction near one end and were C-band negative. Centromeric protein studies indicated absence of CENP-B, presence of CENP-C (data for case 1 only), and presence of CENP-E. Marker chromosomes were thus identified with a chromosomal origin far from their usual centromeric region and yet appeared to have functional centromeres. These two cases did not permit a specific clinical phenotype to be ascribed to the presence of tetrasomy for 3q26.2 approximately 3q27.2-->3qter.

Autoantigens↗
PubMed2000

Presence and localization of connexins 43 and 26 in cell cultures derived from myometrial tissues from nonpregnant and pregnant women and from leiomyomas.

OBJECTIVE: Our objective was to study the appearance and distribution of connexins 43 and 26 in various human myometrial cell cultures. STUDY DESIGN: Scrape loading, Western blotting, and immunohistochemical techniques were applied to cultured cells derived from myometrial tissues obtained from nonpregnant and pregnant women (upper and lower uterine segments) and from leiomyomas (tumor and analogous myometrial tissues). RESULTS: Scrape loading revealed the presence of metabolic coupling in all tissues. Indirect immunohistochemical studies showed membrane localization of connexin 43 in all myometrial cultures. Western blots and indirect immunohistochemical studies showed the presence and localization of the connexin 26 protein and associated gap junctions in tissues from myomas and from nonpregnant and pregnant women except for those derived from the upper segment of the pregnant uterus. CONCLUSION: These results show that human myometrial cultures express various gap junction proteins and that there are regional differences in expression of connexins in tissues from pregnant women.

Blotting, Western↗
PubMed2000

Serum alpha-fetoprotein levels in Beckwith-Wiedemann syndrome.

We conducted a retrospective study that compared serial alpha-fetoprotein (AFP) concentrations obtained from 22 children with Beckwith-Wiedemann syndrome (BWS) with levels established for healthy children. The AFP concentration is greater in patients with BWS and declines during the postnatal period at a significantly slower rate than what is reported in healthy children. AFP levels obtained in the course of routine tumor screening in children with BWS should be interpreted with a normal curve established specifically for BWS rather than with previously published data for healthy infants and children.

Beckwith-Wiedemann Syndrome↗
PubMed1996

FISH detection of chromosome 15 deletions in Prader-Willi and Angelman syndromes.

We have evaluated fluorescence in situ hybridization (FISH) analysis for the clinical laboratory detection of the 15q11-q13 deletion seen in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) using probes for loci D15S11, SNRPN, D15S10, and GABRB3. In a series of 118 samples from patients referred for PWS or AS, 29 had deletions by FISH analysis. These included two brothers with a paternally transmitted deletion detectable with the probe for SNRPN only. G-banding analysis was less sensitive for deletion detection but useful in demonstrating other cytogenetic alterations in four cases. Methylation and CA-repeat analyses of 15q11-q13 were used to validate the FISH results. Clinical findings of patients with deletions were variable, ranging from newborns with hypotonia as the only presenting feature to children who were classically affected. We conclude that FISH analysis is a rapid and reliable method for detection of deletions within 15q11-q13 and whenever a deletion is found, FISH analysis of parental chromosomes should also be considered.

Angelman Syndrome↗
PubMed1993

Intravenous regional anesthesia for outpatient foot and ankle surgery: a prospective study.

A prospective study was undertaken in 39 patients undergoing 48 foot and ankle procedures using intravenous regional anesthesia (IVRA). IVRA was administered using 35 cc of 0.33% or 0.5% lidocaine. Single tourniquets inflated to 250 mm Hg were used at the ankle level. No supplemental analgesia or sedation was used. Those requiring supplemental local anesthetic infiltration were defined as IVRA failures. Thirty-one of the 39 patients (79.5%) tolerated the procedures with little or no discomfort, and 8 (20.5%) required additional local infiltration with 1% lidocaine. All 39 patients completed the procedures at the outpatient surgical unit without requiring conversion to other forms of anesthesia. Patchy non-anesthetic areas were noted in 14 patients (36.8%). In 7 patients, because the non-anesthetic areas were excluded from the operative fields, the procedures were completed without discomfort. However, in 8 patients where the non-anesthetic areas were directly involved in the operative fields, supplemental local anesthesia was required. Only 1 of the 39 patients complained of tourniquet pain. IVRA compared favorably with other methods of regional anesthesia in the lower extremity with respect to ease of technique, speed of onset, safety, and patient acceptance. However, it appears that it is less reliable than IVRA in the upper extremity. The reasons for this difference will require further investigation.

Adult↗
PubMed1990

First trimester prenatal diagnosis of Tay-Sachs disease using the sulfated synthetic substrate for hexosaminidase A.

Uncultured and cultured embryonic trophoblastic tissue obtained by chorionic villus sampling (CVS) displays enzyme activity towards 4-methylumbelliferyl-2-acetamido-2-deoxy-beta-D-glucopyranosyl-6-sulfate (MUGS), a specific substrate for Hexosaminidase A (Hex A), the enzyme deficient in Tay-Sachs disease (TSD). Specific activity is comparable to that found in cultured amniocytes and fibroblasts. The enzyme activity has a pH optimum of 4.1 and an apparent Km of 6 x 10(-4) mol/L. Thirteen pregnancies in eight families at risk for TSD were monitored by CVS using MUGS as the Hex A substrate. Four fetuses were proven affected by enzyme analysis of fetal tissues and cultured fetal fibroblasts obtained at the time of termination of the pregnancies. Nine fetuses were judged to be unaffected. Eight babies were clinically normal while the other pregnancy is continuing. The use of MUGS as substrate for Hex A makes prenatal diagnosis by CVS of families at risk for TSD simple, direct and accurate.

Cells, Cultured↗
PubMed1979

Long-term results of 474 arterial reconstructions for severely ischemic limbs: a fourteen year follow-up.

A retrospective study of 474 femoropopliteal and femorotibial bypasses performed for limb salvage with a follow-up of up to 14 years is presented. The overall operative mortality rate was 4.2%. Initial limb salvage rate for femoropopliteal was 82.8% and for femorotibial, 67.9%. Cumulative limb salvage rate, as calculated by the life-table method, at 1, 5, 10, and 14 years for femorpopliteal was 67.6%, 59.7%, 54.0%, and 31.5%; for femorotibial 53.9%, 46.9%, 42.2%, and 42.2%. Initial and long-term salvage of severely ischemic lower extremities can be achieved in a large number of patients by revascularization to the popliteal and more distal arterial tree. Therefore we conclude that arterial reconstruction for salvage of severely ischemic limbs should be considered in lieu of primary amputation in all patients with popliteal or tibial run-off.

Adolescent↗
PubMed1976

Femorotibial bypass in the elderly for revascularization of the severely ischemic lower extremity.

In the elderly, revascularization of a severely ischemic lower extremity with occlusion of both femoral and popliteal arteries often can be achieved by surgical construction of a distal bypass to the tibial or peroneal arteries. An aggressive diagnostic and therapeutic approach is necessary, in an attempt to prevent recourse to primary amputation. Femoroperoneal or femorotibial bypass can be performed safely and is recommended in elderly patients with advanced ischemia of a lower extremity with absolute indications for surgical intervention, e.g., gangrene, gangrenous ulceration or rest pain. A significant number of limbs can be salvaged by this method. Although the mortality rate in the older age groups is predictably higher, the overall rate for this operation compares favorably with that for primary amputation.

Adult↗