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John J Mulvihill

Publications and source records attributed to John J Mulvihill.

At least 19 recordsLinked to original sources
PubMed2006

Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta.

Classic osteogenesis imperfecta, an autosomal dominant disorder associated with osteoporosis and bone fragility, is caused by mutations in the genes for type I collagen. A recessive form of the disorder has long been suspected. Since the loss of cartilage-associated protein (CRTAP), which is required for post-translational prolyl 3-hydroxylation of collagen, causes severe osteoporosis in mice, we investigated whether CRTAP deficiency is associated with recessive osteogenesis imperfecta. Three of 10 children with lethal or severe osteogenesis imperfecta, who did not have a primary collagen defect yet had excess post-translational modification of collagen, were found to have a recessive condition resulting in CRTAP deficiency, suggesting that prolyl 3-hydroxylation of type I collagen is important for bone formation.

Collagen Type I↗
PubMed2006

Investments in cancer genomics: who benefits and who decides.

The Cancer Genome Atlas--formerly the Human Cancer Genome Project--provides an opportunity for considering how social concerns about resource allocation are interrelated with practical decisions about specific research strategies--part of a continuing convergence between scientific and public evaluations of priorities for biomedical research funding. For example, the manner, order, and extent that The Cancer Genome Atlas selects tumor types and populations to be sampled will determine who benefits most from its findings. Those choices will be determined on the basis of both scientific and social values. By soliciting public involvement and conducting rigorous policy analysis in the design of large scientific projects such as The Cancer Genome Atlas, cancer researchers can help democratize the allocation of scientific resources and foster public confidence in biomedical research.

Atlases as Topic↗
PubMed2006

Trisomy 1q in a patient with severe aplastic anemia.

Aplastic anemia is a rare, serious disease characterized by hypocellular bone marrow and pancytopenia in the peripheral blood. Most cases are acquired, idiopathic, and without gross cytogenetic abnormalities. A few chromosome abnormalities have recurred among a small subset of patients, most commonly trisomy 8 and monosomy 7. Some of these chromosome abnormalities have prognostic and therapeutic significance, although for most the clinical relevance is not known. We present the case of a 40-year-old man with idiopathic severe aplastic anemia in bone marrow cells with trisomy of the whole long arm of chromosome 1 due to an unbalanced translocation between chromosomes 1 and 15 at breakpoints of q10 and 15q10. This clonal abnormality (which, to our knowledge, has not been previously reported in a patient with aplastic anemia) suggests that genes on 1q may be involved in marrow aplasia.

Adult↗
PubMed2006

Cryptic and complex chromosomal rearrangements and the deletion of TP53 gene in a patient with leukemic mantle cell lymphoma.

We present a case of leukemic mantle cell lymphoma with cryptic and complex chromosomal rearrangements, including multiple-way translocations involving chromosomes 8q24, 14q11/q32, 17p13.3, 17p13.1, 21q22, and 21q22; a deletion of the long arm of chromosome 10 [del(10)(q24)]; and a deletion of the TP53 gene in addition to t(11;14). We speculate that this series of chromosomal changes may disrupt the IgH gene, activate the c-MYC oncogene, inactivate the p53 tumor suppressor gene, and disrupt other cancer-related genes either within or flanking the chromosomal breakpoints. This combinational effect causes the progression of mantle cell lymphoma.

Bone Marrow↗
PubMed2006

A computer-aided method to expedite the evaluation of prognosis for childhood acute lymphoblastic leukemia.

This study presented a fully-automated computer-aided method (scheme) to detect metaphase chromosomes depicted on microscopic digital images, count the total number of chromosomes in each metaphase cell, compute the DNA index, and correlate the results to the prognosis of childhood acute lymphoblastic leukemia (ALL). The computer scheme first uses image filtering, threshold, and labeling algorithms to segment and count the number of the suspicious "chromosome," and then computes a feature vector for each "detected chromosome." Based on these features, a knowledge-based classifier is used to eliminate those "non-chromosome" objects (i.e., inter-phase cells, stain debris, and other kinds of background noises). Due to the possible overlap of the chromosomes, a classification criterion was used to identify the overlapped chromosomes and adjust the initially counted number of the total chromosomes in each image. In this preliminary study with 60 testing images (depicting metaphase chromosome cells) acquired from three pediatric patients, the computer scheme generated results matched with the diagnostic results provided by the clinical cytogeneticists. The results demonstrated the feasibility or potential of using a computerized method to replace the tedious and the reader-dependent diagnostic methods commonly used in genetic laboratories to date.

Algorithms↗
PubMed2006

Perform a gene test on every patient: the medical family history revisited.

The medical family history is the most practical personalized genomic tool, yet healthcare professionals often undervalue and underutilize it. Collecting and interpreting the medical family history is an important task for all clinicians. It can shed light on the complex interactions of genetic, environmental, and behavioral factors that determine a patient's present problem and can also indicate a patient's risk for common chronic conditions. Physicians can use a medical family history to diagnose disease, optimize therapy, plan screening, and avoid disease. The medical family history is dynamic so it must be updated regularly. Referral to a genetic specialist needs to be made when a moderate to high risk is identified or there is need for specific gene testing. A reproducible template is provided to expedite family history collection and interpretation.

Family Health↗
PubMed2005

Ring chromosome 9 [r(9)(p24q34)]: a report of two cases.

We report clinical and molecular cytogenetic studies in two patients with ring chromosome 9. Cytogenetics and fluorescent in situ hybridization (FISH) analysis using the p16 gene probe on 9p21, the ABL gene on 9q34, chromosome 9 alpha satellite-centromeric probes, and TelVision 9p and 9q probes which identify subtelomere-specific sequences on chromosome 9p and 9q, revealed 46,XX,r(9)(p24q34).ish r(9)(305J7-T7-,p16+,ABL+, D9S325-) and 46XY,r(9)(p24q34).ish r(9)(305J7-T7-,p16+,ABL+, D9S325-). Based on FISH analysis at least 115 kb was deleted on terminal 9p, and at least 95 kb from terminal 9q. In comparison with other reports of r(9), deletion 9p, and deletion 9q, both patients had clinical characteristics of ring 9 and additional features of deletion 9q or deletion 9p syndrome. The variability between the two cases with r(9) despite similar breakpoints identified by GTG-banding and FISH may be explained by submicroscopic differences between deletion breakpoints, ring instability, interaction of other genes on the phenotype, and variation in fetal environmental conditions.

Adolescent↗
PubMed2005

Ring chromosome 4 in a patient with early onset type 2 diabetes, deafness, and developmental delay.

To date, most ring formations of chromosome 4 lose distal 4p and usually include the Wolf-Hirschhorn syndrome region [WHS]. We describe a case with r(4) in a girl who presented without features of WHS; she had mild developmental delay, deafness, short stature, obesity, and the onset of type 2 diabetes in adolescence, a distinctive phenotype. Although 4p was significantly deleted on Giemsa banding, the 4p junction was distal to the WHS and FGFR3 but proximal to the D4S3360 marker. The 4q breakpoint was close to the telomere. The phenotype appears different from previous patients with 4p- or r(4), which have had more extensive 4p deletion.

Abnormalities, Multiple↗
PubMed2005

A variant t(8;10;21) in a patient with pathological features mimicking atypical chronic myeloid leukemia.

We report the case of an 11-year-old girl who was initially diagnosed with a chronic myeloproliferative disorder, possibly chronic myelogenous leukemia (CML), based on laboratory and blood and marrow morphological findings. The patient's high leukocyte count did not respond to hydroxyurea, a standard initial therapy for CML. Chromosomal analysis revealed that the patient did not have t(9;22), but a complex t(8;10;21)(q22;q24;q22), a variant of t(8;21). The treatment regime was switched to an acute myeloid leukemia (AML) protocol; the patient responded well and is now in remission. This case demonstrates again that routine clinical cytogenetic analysis plays an important role in the clinical diagnosis, guidance of treatment, and prognostication in hematological disorders.

Child↗
PubMed2005

Cytogenetic and molecular cytogenetic studies of a variant of t(21;22), ins(22;21)(q12;q21q22), with a deletion of the 3' EWSR1 gene in a patient with Ewing sarcoma.

Ewing sarcoma is the second most common malignant bone tumor in children and young adults. Cytogenetic analysis to identify a common t(11;22)(q23;q12) or less frequently a t(21;22)(q22;q12) or t(7;22)(p22;q12) plays an important role in the confirmation of the clinical diagnosis. We report a case of a 10-year-old female who had extraskeletal Ewing sarcoma. Conventional cytogenetic analysis revealed that 11 out of 20 cells had a derivative chromosome 22, possibly due to an insertion of the long arm of the 21q21 approximately q22. This finding was confirmed by fluorescence in situ hybridization (FISH) utilizing whole chromosome paint probes specific for chromosomes 21 and 22. Hybridization utilizing LSI EWSR1, dual-color break-apart rearrangement probe unexpectedly revealed that the 3' EWSR1 gene was lost on the derivative chromosome 22. This finding suggests that the insertion of chromosome 21 is another mechanism that could lead to EWS-ERG gene fusion. To our knowledge, this is the first case report of an insertion of a segment of 21q21 approximately q22 into the long arm of 21q12 with a loss of a DNA segment around the breakpoint on the derivative chromosome 22 in Ewing sarcoma.

Calmodulin-Binding Proteins↗
PubMed2004

Oligogenic combinations associated with breast cancer risk in women under 53 years of age.

Common, but weakly penetrant, functional polymorphisms probably account for most of the genetic risk for breast cancer in the general population. Current polygenic risk models assume that component genes act independently. To test for potential gene-gene interactions, single nucleotide polymorphisms in ten genes with known or predicted roles in breast carcinogenesis were examined in a case-control study of 631 Caucasian women diagnosed with breast cancer under the age of 53 years and 1,504 controls under the age of 53 years. Association of breast cancer risk with individual genes and with two- and three-gene combinations was analyzed. Sixty-nine oligogenotypes from 37 distinct two- and three-gene combinations met stringent criteria for significance. Significant odds ratios (ORs) covered a 12-fold range: 0.5-5.9. Of the observed ORs, 17% differed significantly from the ORs predicted by a model of independent gene action, suggesting epistasis, i.e., that these genes interact to affect breast cancer risk in a manner not predictable from single gene effects. Exploration of the biological basis for these oligogenic interactions might reveal etiologic or therapeutic insights into breast cancer and other cancers.

Adolescent↗
PubMed2004

Chromosome 2q terminal deletion: report of 6 new patients and review of phenotype-breakpoint correlations in 66 individuals.

We report a new patient with terminal deletion of chromosome 2 with breakpoint at 2q36 and five additional new patients with 2q terminal deletion with breakpoint at 2q37. Hemidiaphragmatic hernia is a novel finding in one patient with a breakpoint at 2q37.1. In comparing these patients to 60 previously reported individuals with 2q terminal deletions, certain physical abnormalities are loosely associated with positions of breakpoint. For example, facial features (e.g., prominent forehead, depressed nasal bridge, and dysmorphic ears and nose), short stature, and short hands and feet were frequent in patients with breakpoints at or proximal to 2q37.3. Reports of horseshoe kidney and Wilms tumor were limited to patients with a breakpoint at 2q37.1, and structural brain anomalies and tracheal anomalies were reported only in patients with breakpoints at or proximal to 2q37.1. Cleft palate was reported only in patients with the most proximal breakpoints (2q36 or 2q35). Neurological effects including developmental delay, mental retardation, autistic-like behavior, and hypotonia were typical in this patient population but did not stratify in severity according to breakpoint. Terminal deletion of the long arm of chromosome 2 should be considered in the infant with marked hypotonia, poor feeding, gastroesophageal reflux, and growth delay, and the older child with developmental delay, autistic behavior, and the characteristic facial and integumentary features described herein. Assignment of clinical features to specific breakpoints and refinement of predictive value may be useful in counseling.

Abnormalities, Multiple↗
PubMed2004

Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: a population-based study.

Ionizing radiation and many cancer drugs have the potential to produce germ-cell mutations that might lead to genetic disease in the next generation. In a population-based study, we identified, from records in the Danish Cancer Registry, 4,676 children treated for cancer. Their 6,441 siblings provided a comparison cohort. The results of a search of the Central Population Register identified 2,630 live-born offspring of the survivors and 5,504 live-born offspring of their siblings. The occurrence of abnormal karyotypes diagnosed in these offspring and also in any pregnancies terminated following prenatal diagnosis of a chromosome abnormality was determined from the Danish Cytogenetic Registry. After exclusion of hereditary cases and inclusion of the prenatal cases, after correction for expected viability, the adjusted proportion of live-born children in survivor families with abnormal karyotypes (5.5/2,631.5 [0.21%]) was the same as that among the comparison sibling families (11.8/5,505.8 [0.21%]). There were no significant differences in the occurrence of Down syndrome (relative risk [RR]=1.07; 95% CI 0.16-5.47) or Turner syndrome (RR=1.32; 95% CI 0.17-7.96) among the children of cancer survivors, compared with the children of their siblings. These reassuring results are of importance to the survivors, to their families, and to genetic counselors.

Adolescent↗
PubMed2004

Double trisomy.

Explore the source record for details and available documents.

Abnormalities, Multiple↗
PubMed2004

Leiomyosarcoma of the breast: a pathologic and comparative genomic hybridization study of two cases.

Leiomyosarcoma is an extremely rare form of primary breast sarcoma. We present the pathologic and genetic findings of two cases of leiomyosarcoma of the breast. The patients were 44 and 52 years of age and they presented with circumscribed masses of 3.0 and 4.5 cm, (greatest dimension) respectively. Microscopically, the two tumors showed diffuse proliferation of spindle cells with oval and blunt-ended nuclei arranged in short fascicles or bundles. There was moderate cytologic atypia in both cases, and 6 and 12 mitotic figures per 10 high power fields, respectively. No epithelial component was identified. The tumor cells were strongly immunoreactive for markers of smooth-muscle differentiation, including desmin, muscle-specific actin, and smooth-muscle actin. Comparative genomic hybridization analysis showed losses of 10q (two of two cases), 13q (two of two cases), 17p (one of two cases), and gains of 1q (one of two cases) and 17p (one of two cases). The patterns of chromosomal imbalances identified in leiomyosarcoma of the breast are similar to those reported in leiomyosarcoma of soft tissue and uterus and are different from those reported for leiomyoma, indicating that these alterations may be important for development of malignant smooth-muscle tumors regardless of site or organ of origin.

Adult↗
PubMed2003

Genetic effects of radiotherapy for childhood cancer.

Radiation-induced heritable diseases have not been demonstrated in humans and estimates of genetic risks for protection purposes are based on mouse experiments. The most comprehensive epidemiologic study is of the Japanese atomic bomb survivors and their children, which found little evidence for inherited defects attributable to parental radiation. Studies of workers exposed to occupational radiation or of populations exposed to environmental radiation appear too small and exposures too low to convincingly detect inherited genetic damage. In contrast, survivors of childhood cancer form the largest group of people exposed to high doses of ionizing radiation before reproduction and offer unique advantages for studying trans-generation effects. A wide range of gonadal doses are possible, several comparison groups are readily available (including siblings), and there is a strong willingness among cancer survivors to participate in health studies. Cancer patients also have detailed medical records that facilitate both the accurate estimation of gonadal doses and the assessment of potentially confounding factors, such as intercurrent illness, personal and family medical histories, lifestyle characteristics such as tobacco use, and circumstances at delivery. An international study is nearing completion of over 25,000 survivors of childhood cancer in the United States and Denmark who gave birth to or fathered over 6,000 children. Doses to gonads are being reconstructed from radiotherapy records with 46% over 100 mSv and 16% over 1,000 mSv. Adverse pregnancy outcomes being evaluated include major congenital malformations, cytogenetic abnormalities, stillbirths, miscarriages, neonatal deaths, total deaths, leukemia and childhood cancers, altered sex ratio, and birth weight. The main analyses are based on dose-response evaluations. Blood studies of trios (cancer survivor, spouse or partner and offspring) have been initiated to evaluate mechanistic evidence for the transmission of any radiation-induced genetic damage such as minisatellite mutations. Markers of cancer susceptibility such as chromosomal radiosensitivity and genotype profile will also be examined. In the United States series to date, 4,214 children were born to cancer survivors among whom 157 (3.7%) genetic diseases were reported in contrast to 95 (4.1%) reported conditions among 2,339 children born to sibling controls. In the Denmark series the comparable figures were 82 (6.1%) birth defects among 1,345 children of cancer survivors and 211 (5.0%) among 4,225 children of sibling controls. Coupled with prior studies, these preliminary findings, if sustained by ongoing dose-response analyses, provide reassurance that cancer treatments including radiotherapy do not carry much if any risk for inherited genetic disease in offspring conceived after exposure.

Abnormalities, Radiation-Induced↗