Severe craniosynostosis in an infant with deletion 22q11.2 syndrome.

We report a male infant with 22q11.2 deletion syndrome and very severe multi-sutural craniosynostosis associated with increased intracranial pressure, marked displacement of brain structures, and extensive erosion of the skull. While uni- or bi-sultural craniosynostosis is a recognized (though relatively uncommon) feature of 22q11 deletion syndrome, a severe multi-sutural presentation of this nature has never been reported. SNP Microarray was otherwise normal and the patient did not have common mutations in FGFR2, FGFR3, or TWIST associated with craniosynostosis. While markedly variable expressivity is an acknowledged feature of deletion 22q11 syndrome, herein we also consider and discuss the possibility that this infant may have been additionally affected with an undiagnosed single gene disorder.

Canadian College of Medical Geneticists guidelines for the indications, analysis, and reporting of cancer specimens.

The Canadian College of Medical Geneticists (ccmg) is a national organization of medical and laboratory geneticists. The mission of the ccmg is to establish and maintain high-quality professional and ethical standards for medical genetics services in Canada and to help to ensure that service of the highest quality is delivered to the Canadian public.Cancer cytogenetics is one of the sections of practice of the ccmg. The ccmg Cytogenetic Committee has, therefore, put forward guidelines to provide oncologists and ccmg cytogeneticists with a comprehensive review of the cytogenetic diagnostic tests that are recommended as a minimum standard of care for tumours of hematopoietic and lymphoid tissues and for tumours of soft tissue and bone. The guidelines were approved by the ccmg board of directors in June 2010.

CCMG guidelines: prenatal and postnatal diagnostic testing for uniparental disomy.

The aim of this statement is to provide clinicians, cytogeneticists and molecular geneticists of the Canadian College of Medical Geneticists (CCMG) a comprehensive review of the role of UPD in constitutional genetic diagnosis and to provide a guideline as to when investigation for UPD is recommended. Members of the CCMG Cytogenetics, Molecular Genetics, Clinical Practice, and Prenatal Diagnosis committees reviewed the relevant literature on uniparental disomy (UPD) in constitutional genetic diagnosis (May 2010). Guidelines were developed for UPD testing in Canada. The guidelines were circulated for comment to the CCMG members at large and following appropriate modification, approved by the CCMG Board of Directors (July 2010).

MYC gene amplification in double minute chromosomes in an aggressive large B-cell lymphoma with leukemic presentation: a case report.

Double-minute chromosomes (dmin) are small chromatin particles that lack a centromere. They represent extrachromosomal form of gene amplification. Dmin are very rarely encountered in lymphoid neoplasms. We describe a case of a leukemic presentation of large B-cell lymphoma with dmin. Fluorescence in situ hybridization analysis identified these dmin as comprising MYC genes.

Isodicentric Yp: prenatal diagnosis and outcome in 12 cases.

OBJECTIVES: 1. To present the prenatal cytogenetic findings and postnatal outcome of 12 cases with an isodicentric chromosome composed of the short arm of the Y chromosome.2. To review the literature and provide recommendations for cytogenetic analysis and counseling. METHODS: Prenatal and postnatal cytogenetic data and clinical findings of isodicentric Yp ascertained in six institutions were gathered and reviewed. RESULTS: Nine of the twelve cases were referred for advanced maternal age (AMA), one of which was a twin pregnancy with one twin having an increased nuchal translucency measurement. The remaining cases were referred owing to a family history of hemophilia and an abnormal maternal serum screen, respectively. Nine of these pregnancies resulted in the birth of a normal-appearing male infant with subsequent normal growth and psychomotor development. Follow-up ranged from birth to 7 years. In two cases, the pregnancy was terminated and the fetuses showed male external genitalia. In the case ascertained because of an increased nuchal translucency measurement, the prenatal diagnosis of 45,X was made. At birth, there were ambiguous genitalia, and postnatal cytogenetic studies found an isodicentric Yp. In 11 of the 12 cases, mosaicism was present. CONCLUSION: Our cases show that the prenatal finding of an isodicentric Yp, with or without 45,X mosaicism, is compatible with normal male phenotype in most cases, particularly in the absence of other anomalies. To ensure accuracy in cytogenetic reporting and prenatal counseling, the identification of a structurally abnormal or small Y chromosome, either alone or in the presence of 45,X colonies, should be followed immediately by confirmatory molecular cytogenetic investigations as well as by ultrasound determination of the phenotypic sex of the fetus.

Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation.

Infantile nephropathic cystinosis, an autosomal recessive disease characterized by a lysosomal accumulation of cystine, presents as failure to thrive, rickets and proximal renal tubular acidosis. The cystinosis gene, CTNS, which maps to chromosome 17p13, encodes a predicted 55 kDa protein with characteristics of a lysosomal membrane protein. We have conducted extensive linkage analysis in a French Canadian cystinosis cohort identifying a founding haplotype present in approximately half (21/40) of the chromosomes studied. Subsequent mutational analysis, in addition to identifying two novel mutations, has unexpectedly revealed a mutation which has been previously found in Irish (but not French) cystinotic families on these 21 French Canadian chromosomes. Haplotype analysis of two Irish families with this mutation supports the hypothesis that Celtic chromosomes represent an extensive portion of cystinosis chromosomes in French Canada. Our analysis underlines the genetic heterogeneity of the French Canadian population, reflecting a frequently unrecognized contribution from non-Gallic sources including the Irish.

Extracellular nucleotides stimulate leukocyte adherence to cultured pulmonary artery endothelial cells.

Adenosine, ATP, and various nucleotides were examined for their effects on the adherence of leukocytes to bovine pulmonary artery endothelial cells. Extracellular ATP enhanced adherence of HL-60 cells and human neutrophils to endothelial cells in a dose-dependent fashion. Maximal adherence occurred after 15 min coincubation of ATP and HL-60 cells or neutrophils with endothelial cells. ATP stimulation was mediated by direct effects on both HL-60 cells and endothelial cells. The potency profile of various nucleotides was ATP = 2-MeSATP > beta,gamma-CH2ATP, indicative of a P2y receptor. Interestingly, UTP was as potent as ATP in stimulating HL-60 cell adherence, suggesting the presence of a pyrimidine nucleotide receptor. Photoaffinity labeling of endothelial cells with 8-Az-[alpha-32P]ATP showed the presence of two ATP binding proteins of 48 and 87 kDa. ATP and 2-MeSATP inhibited binding by both proteins. Labeling of the 87-kDa protein was inhibited by beta,gamma-CH2ATP, whereas UTP blocked binding by the 48-kDa protein. Thus photoaffinity labeling experiments support the proposal that endothelial cells possess two ATP receptors, one of which is a P2u nucleotide receptor. These findings show that extracellular nucleotides enhance leukocyte adherence to endothelial cells. Nucleotide release into the extracellular space may be one mechanism of exacerbating vascular cell injury relevant to conditions such as adult respiratory distress syndrome and septic shock.

Hydrogen peroxide stimulates sodium-potassium pump activity in cultured pulmonary arterial endothelial cells.

Oxidant injury to pulmonary vascular endothelium is an important factor in the pathogenesis of acute lung injury. Oxidant injury to other cell types has been reported to alter the function of Na-K-adenosinetriphophatase (ATPase) an enzyme important in maintenance of cellular ionic homeostasis and in transport of ions across biological membranes. We investigated the effect of H2O2 (0.001-10 mM) or xanthine (X) (15.2 micrograms/ml) plus xanthine oxidase (XO) (0.0153 U/ml) on the Na-K pump activity of cultured bovine pulmonary arterial endothelial cells (PAECs). We used a functional assay, using 86RbCl as a tracer for K+ and expressing Na-K pump activity as ouabain-inhibitable K+ uptake. Our results demonstrate that H2O2 and X/XO stimulate Na-K pump activity of bovine PAECs, an effect prevented by catalase. In addition, we assessed the affinity, number, and turnover of [3H]ouabain binding sites on intact endothelial monolayers and found that H2O2 increased affinity to [3H]ouabain, decreased the number of binding sites, and increased the rate of pump turnover. Influx of 22Na increased in response to a nonlytic concentration of H2O2. Cell injury, as assessed by 51Cr release, adherent cell number, and phase-microscopic morphology, was not observed after 30-min incubations with the lowest dose (1 mM) of H2O2 effective in stimulating Na-K pump activity, or after incubation with X/XO. Na-K pump inhibition by ouabain significantly increased the 51Cr release caused by H2O2 or by X/XO, suggesting that the increase in Na-K pump activity may be a compensatory response to the cellular alterations produced by H2O2. Incubation with H2O2 decreased cell ATP content, an effect which was not prevented by coincubation with ouabain. In summary, these results show that H2O2 increases Na-K pump activity of PAECs, an effect mediated, at least in part, by increased intracellular [Na] and by an increased rate of pump turnover. It is possible that the increased pump activity may be an early marker of endothelial cell perturbation.