We report on a new patient with immunodeficiency, centromeric heterochromatin instability, and facial anomalies (the ICF syndrome). Studies with traditional cytogenetic methods demonstrate that aberrations in this syndrome primarily involve the centromeric regions of chromosomes 1 and 16. We applied fluorescence in situ hybridization (FISH) using "painting" probes for chromosomes 1 and 16 to document the progression of centromeric instability from simple decondensation aberrations to the subsequent formation of complex multibranched chromosomes 1, and finally to the interphase aberrations of nuclear projections and micronuclei involving both chromosomes 1 and 16. The loss of the large multibranched chromosome 1 configurations from the cells as micronuclei suggests that the centromeric aberrations subsequently interfere with normal chromosome movement at anaphase in ICF syndrome. Circular areas of counterstained chromatin were observed by FISH in the micronuclei corresponding to the intertwined segments of centromeric heterochromatin seen involving multibranched chromosomes 1 in the patient's G-banded chromosome study. The current hypothesis of recessive inheritance for this disorder suggests that the chromosomal aberrations are not a causative event in this syndrome; however, the chromosome aberrations are clearly an important basic diagnostic criterion.
Kawasaki disease (KD) is an acute inflammatory disorder of children frequently associated with the development of coronary artery abnormalities. Although a great deal is known about inflammatory and immune responses in acute KD, the mechanisms linking the immune response to vascular changes are not known. To gain further insight into this process, we performed a microarray gene expression analysis on RNA isolated from the peripheral blood mononuclear cells of four patients with KD during both their acute and convalescent phases. Forty-seven genes of 7129 genes examined showed an increased expression in three or all four patients in the acute compared with the convalescent phase of KD. Fourteen of these genes were significantly (p Ͻ 0.05) up-regulated, including several inflammatory response genes (e.g. S-100 A9 protein) and also anti-inflammatory genes (e.g. TSG-6). Of greatest interest, the adrenomedullin (ADM) gene, known to be associated with coronary artery vasodilation, was up-regulated in the acute phase of KD (p ϭ 0.024). Up-regulation of ADM in the acute phase of KD was confirmed in peripheral blood mononuclear cells of 11 additional KD patients by reverse transcriptase-PCR (p Ͻ 0.01). Isolated blood monocytes but not lymphocytes were demonstrated by realtime PCR to have increased ADM mRNA (p ϭ 0.01). Plasma ADM protein level in 32 additional KD patients was also confirmed to be higher in acute KD compared with convalescent KD (p Ͻ 0.032). It is interesting that from microarray results, other molecules known to be associated with coronary dilation, including nitric oxide, prostacyclin, acetylcholine, bradykinin, substance P, and serotonin, were not elevated in acute KD. Our current study suggests that ADMexpressing monocytes that infiltrate the coronary vascular wall may be the cause of coronary dilation in the acute phase of KD. Kawasaki disease (KD) is an acute vasculitis that affects mainly infants and young children (1). Ten to 15% of patients with untreated KD develop coronary arterial lesions, and a greater proportion of patients develop coronary arterial dilation (ectasia) (2,3). Many studies have demonstrated that the acute phase of KD is associated with activation of T cells and monocyte/macrophages (4 -6). However, the mechanisms linking the systemic immune response to vascular abnormalities are unknown.Using new approaches such as the DNA microarray method (7), it is possible to examine thousands of genes, which may be up-or down-regulated during acute compared with convalescent KD, for identification of novel disease processes (mechanisms
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