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This report describes a case of a neonate presenting with many of the typical phenotypic characteristics of chromosome 3p deletion including hypertelorism, flat nasal bridge, flat philtrum, thin lips and low-set ears. The hands and feet showed post axial polydactyly, single palmar creases and rocker bottom feet. A karyotype confirmed chromosome 3p25.3-pter deletion with normal parental karyotypes. A high TSH was noted on newborn screening and congenital hypothyroidism was confirmed on thyroid function tests. Thyroid nuclear imaging was suggestive of dyshormonogenesis. This is the first reported case of congenital hypothyroidism in an infant with chromosome 3p deletion. © 2011 by Walter de Gruyter * Berlin * Boston.

This report describes a case of a neonate presenting with many of the typical phenotypic characteristics of chromosome 3p deletion including hypertelorism, flat nasal bridge, flat philtrum, thin lips and low-set ears. The hands and feet showed post axial polydactyly, single palmar creases and rocker bottom feet. A karyotype confirmed chromosome 3p25.3-pter deletion with normal parental karyotypes. A high TSH was noted on newborn screening and congenital hypothyroidism was confirmed on thyroid function tests. Thyroid nuclear imaging was suggestive of dyshormonogenesis. This is the first reported case of congenital hypothyroidism in an infant with chromosome 3p deletion. © 2011 by Walter de Gruyter * Berlin * Boston.

The ophthalmic features are reported of a member of an Australian pedigree with three affected individuals spanning two generations with a hereditary endotheliopathy syndrome resulting in retinopathy, leukoencephalopathy and nephropathy. The index case initially presented with asymptomatic retinopathy, cerebral microvascular disease, nephropathy and raised inflammatory markers. The clinical, neuro-radiological, biochemical and histopathological findings in this patient are consistent with a diagnosis of hereditary endotheliopathy, retinopathy, nephropathy and stroke (HERNS). Linkage analysis has identified a locus for HERNS on chromosome 3p21.1-p2l.3. This locus is shared with two other diseases: hereditary vascular retinopathy (HVR) and cerebroretinal vasculopathy (CRV). Although peripheral retinal involvement is a feature of HVR, it has not previously been described in HERNS. This case represents a novel phenotype of HERNS, and serves to blur the distinction between the vasculopathies mapping to chromosome 3p21. Although previously thought to be distinct clinical entities, it is possible that HERNS, HVR and CRV simply represent different phenotypes of the same disease. This will only be clarified with the identification of the gene or genes. This case also raises the question of how best to manage rare forms of vascular retinopathy.

Objective. To undertake a systematic wholegenome screen to identify regions exhibiting genetic linkage to rheumatoid arthritis (RA). Methods. Two hundred fifty-two RA-affected sibling pairs from 182 UK families were genotyped using 365 highly informative microsatellite markers. Microsatellite genotyping was performed using fluorescent polymerase chain reaction primers and semiautomated DNA sequencing technology. Linkage analysis was undertaken using MAPMAKER/SIBS for single-point and multipoint analysis. Results. Significant linkage (maximum logarithm of odds score 4.7 [P = 0.000003] at marker D6S276, 1 cM from HLA-DRB1) was identified around the major histocompatibility complex (MHC) region on chromosome 6. Suggestive linkage (P < 7.4 × 10-4) was identified on chromosome 6q by single- and multipoint analysis. Ten other sites of nominal linkage (P < 0.05) were identified on chromosomes 3p, 4q, 7p, 2 regions of 10q, 2 regions of 14q, 16p, 21q, and Xq by single-point analysis and on 3 sites (1q, 14q, and 14q) by multipoint analysis. Conclusion. Linkage to the MHC region was confirmed. Eleven non-HLA regions demonstrated evidence of suggestive or nominal linkage, but none reached the genome-wide threshold for significant linkage (P = 2.2 × 10-5). Results of previous genome screens have suggested that 6 of these regions may be involved in RA susceptibility.

Cervical cancer derives from a series of pre-invasive cervical neoplastic lesions termed CIN I-III (Cervical Intraepithelial Neoplasia) via typical multiple-step processes. In contrast to premalignant disorders in other organs, different degrees of CIN possess a distinct biological behaviour where a proportion spontaneously regress or persist, whereas some progress to invasive cancer. A meticulous examination of pathological, genetical and viological aspects of the mechanisms for this dynamic event was performed. Clonality and clonal lineages of CIN and invasive cancer were studied on microdissected single or multiple synchronous lesions. Independent CIN lesions were both monoclonal and polyclonal, whereas invasive cancer and adjacent CIN inevitably were monoclonal in origin. Mostly when multiple lesions were analyzed, the invasive cancer shared an identical clonality pattern with the co-existing CIN but one third of multiple CIN lesions were multifocal and their clonal origin was not identical to synchronous invasive cancer. The data suggest that CIN lesions vary in their biological behaviour although they are morphologically similar. Polyclonal CIN may represent a benign proliferation,whereas monoclonal CIN more likely progresses to an invasive stage. Multifocal origin of CIN suggests that multiple cells from the cervix undergo transformation simultaneously, implying an essential role of a "field defect" (HPV?) in cervical carcinogenesis. Genetic deletions (LOH) of chromosome 3p, 6p and 6q were investigated in CIN and SCC. The detection of allelic losses and the deletion mapping suggested that the alterations of 3p22-21.3, 3p21.1, HLA region on 6p and 6q16.1-21 were frequent and early genetic events in cervical cancer and imply that these chromosome regions harbour potential tumor suppressor genes important in thecervical carcinogenesis. HPV 16 E6 and L1 gene variations were analyzed in CIN lesions independent or synchronous with invasive cancer. Distribution of H

Loss of tumor suppressor genes (TSGs) represent critical molecular events in the development and progression of breast cancer. Based on loss of heterozygosity (LOH) studies as well as direct cytogenetic studies of breast tumors, one or more TSGs most likely resides on the short arm of chromosome 3 (3p) and appears to be involved in nearly 50% of breast cancers. Four distinct regions within 3p P12, P14, P21 (PROXIMAL) AND P21 (DISTAL) undergo recurrent deletions in human carcinomas and are the most likely sites for a breast cancer TSG. Recently, we demonstrated recurrent homozygous deletion or rearrangement in breast cancer cell lines involving 3p14. A set of DNA clones spanning the critical region has now been sequenced revealing several potential gene coding segments. YACs containing the critical region have been modified with the Neomycin resistance gene for selective retention in mammalian cells. Introduction of YACs into a homozygously deleted breast cancer cell line should provide direct evidence concerning the presence of a functioning tumor suppressor gene. The progress made in 3p14 has now allowed us to evaluate the other candidate gene regions for involvement in breast cancer as originally proposed using deletion detection, DNA sequence analysis, gene isolation and expression assays.

Loss of tumor suppressor genes by genetic mechanisms represent critical molecular events in the development and progression of breast cancer. One or more of these tumor suppressor genes likely resides on the short arm of chromosome 3 (3p) and appears to be involved in nearly 50% of breast cancers. We have identified a region in 3pl4 which undergoes recurrent homozygous deletion or rearrangement in breast cancer cell lines. A set of cloned DNA molecules spanning the target region has been established and a gene search is underway. In order to develop a functional tumor suppressor test of the 3pl4 and other target regions, we have begun to modify specific YACs with the Neomycin resistance gene that will permit their selective retention in mammalian cells. The identification of this homozygous deletion region is an exciting development that has resulted in a modification of the order for our Specific Aims.