Periacinar Retraction Clefting in Nonneoplastic and Neoplastic Prostatic Glands: Artifact or Molecular Involvement

A space between neoplastic acini and prostatic stroma is not rare and studies have interpreted this as an artifact, considering the absence of endothelial cells indicating vascular invasion. Thus, the aims of this work were to characterize and correlate the occurrence and extent of retraction clefting with the reactivities of alpha and beta dystroglycan (alpha DG, beta DG), laminin, matrix metalloproteinase 2 (MMP-2), p63, insulin-like growth factor 1(IGF-1), vimentin, and fibroblast growth factor 2 (FGF-2). The study was based on nonneoplastic and neoplastic prostatic tissues obtained from necropsies and retropubic radical prostatectomies. The results showed that periacinar retraction clefting was significantly more frequent in prostatic carcinoma samples than in normal prostatic acini. Most of the neoplastic acini (72.0%) showed retraction clefting of more than 50% of circumference, which were significantly more frequent in Gleason score 7 and 6. Decreased collagen and reticular and elastic fibers were verified in the stroma around neoplastic acini. Weak and discontinuous alpha DG, beta DG, and laminin immunoreactivities and intensified MMP-2, vimentin, IGF-1 and FGF-2 immunoreactivities were verified in the neoplastic acini; p63 immunoreactivity was negative in all carcinomas. Thus, these findings showed that the lack of epithelial basal cells, DGs, and laminin and increased MMP-2, IGF-1, and FGF-7 could be considered important pathways in periacinar retraction occurrence. This study demonstrated the origin of and the biological mechanisms responsible for periacinar retraction clefting in prostatic carcinoma.

Ectodermal dysplasia, ectrodactyly, clefting, anophthalmia microphthalmia, and genitourinary anomalies: nosology of goltz-gorlin syndrome versus eec syndrome

We report on two unrelated Brazilian girls born to normal and nonconsanguineous parents and presenting ectodermal dysplasia, ectrodactyly, clefting, tear duct anomalies, and micro/anophthalmia. The clinical picture presented by these patients suggests the diagnosis of Goltz-Gorlin (Focal dermal hypoplasia) syndrome and EEC syndrome.

Blepharo-cheilo-dontic (BCD) syndrome: Report on four new patients

We report on four Brazilian patients with, among other signs, cleft lip and palate, dental anomalies, ectropion of the lower eyelids, euryblepharon, and lagophthalmia, Two were sporadic cases and two were familial cases, a mother and her equally affected son, Recently, the reports with different combination of these signs were reviewed by Gorlin et al, [1996; Am J Med Genet 65:109-112] and named blepharo-cheilo-dontic (BCD) syndrome, Variable expressivity and autosomal dominant inheritance were observed. (C) 1998 Wiley-Liss, Inc.

X-chromosome inactivation patterns in monozygotic twins and sib pairs discordant for nonsyndromic cleft lip and/or palate

Nonsyndromic clefts of the lip and/or palate are common birth defects with a strong genetic component. Based on unequal gender ratios for clefting phenotypes, evidence for linkage to the X chromosome and the occurrence of several X-linked clefting syndromes, we investigated the role of skewed X chromosome inactivation (XCI) in orofacial clefts. Our samples consisted of female monozygotic (MZ) twins (n = 8) and sister pairs (n = 152) discordant for nonsyndromic clefting. We measured the XCI pattern in peripheral blood lymphocyte DNA using a methylation based androgen receptor gene assay. Skewing of XCI was defined as the deviation in inactivation pattern from a 50:50 ratio. Our analysis revealed no significant difference in the degree of skewing between twin pairs (P = 0.3). However, borderline significant differences were observed in the sister pairs (P = 0.02), with the cleft lip with cleft palate group showing the most significant result (P=0.01). We did not find evidence for involvement of skewed XCI in the discordance for clefting in our sample of female MZ twins. However, results from the paired sister study suggest the potential contribution of skewed XCI to orofacial clefting, particularly cleft lip and palate. (C) 2007 Wiley-Liss, Inc.

Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome

Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic Mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons oil samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. Oil the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect oil interferon regulatory factor 6 function. Genet Med 2009:11(4):241-247.

Genomic Strategy Identifies a Missense Mutation in WD-Repeat Domain 65 (WDR65) in an Individual With Van der Woude Syndrome

Genetic variation in the transcription factor interferon regulatory factor 6 (IRF6) causes and contributes risk for oral clefting disorders. We hypothesized that genes regulated by IRF6 are also involved in oral clefting disorders. We used five criteria to identify potential IRF6 target genes; differential gene expression in skin taken from wild-type and Irf6-deficient murine embryos, localization to the Van der Woude syndrome 2 (VWS2) locus at 1p36-1p32, overlapping expression with Irf6, presence of a conserved predicted-binding site in the promoter region, and a mutant murine phenotype that was similar to the Irf6 mutant mouse. Previously, we observed altered expression for 573 genes; 13 were located in the murine region syntenic to the VWS2 locus. Two of these genes, Wdr65 and Stratifin, met 4 of 5 criteria. Wdr65 was a novel gene that encoded a predicted protein of 1,250 amino acids with two WD domains. As potential targets for Irf6 regulation, we hypothesized that disease-causing mutations will be found in WDR65 and Stratifin in individuals with VWS or VWS-like syndromes. We identified a potentially etiologic missense mutation in WDR65 in a person with VWS who does not have an exonic mutation in IRF6. The expression and mutation data were consistent with the hypothesis that WDR65 was a novel gene involved in oral clefting. (C) 2011 Wiley-Liss, Inc.

Oral cleft prevention program (OCPP)

Background: Oral clefts are one of the most common birth defects with significant medical, psychosocial, and economic ramifications. Oral clefts have a complex etiology with genetic and environmental risk factors. There are suggestive results for decreased risks of cleft occurrence and recurrence with folic acid supplements taken at preconception and during pregnancy with a stronger evidence for higher than lower doses in preventing recurrence. Yet previous studies have suffered from considerable design limitations particularly non-randomization into treatment. There is also well-documented effectiveness for folic acid in preventing neural tube defect occurrence at 0.4 mg and recurrence with 4 mg. Given the substantial burden of clefting on the individual and the family and the supportive data for the effectiveness of folic acid supplementation as well as its low cost, a randomized clinical trial of the effectiveness of high versus low dose folic acid for prevention of cleft recurrence is warranted.Methods/design: This study will assess the effect of 4 mg and 0.4 mg doses of folic acid, taken on a daily basis during preconception and up to 3 months of pregnancy by women who are at risk of having a child with nonsyndromic cleft lip with/without palate (NSCL/P), on the recurrence of NSCL/P. The total sample will include about 6,000 women (that either have NSCL/P or that have at least one child with NSCL/P) randomly assigned to the 4 mg and the 0.4 mg folic acid study groups. The study will also compare the recurrence rates of NSCL/P in the total sample of subjects, as well as the two study groups (4mg, 0.4 mg) to that of a historical control group. The study has been approved by IRBs (ethics committees) of all involved sites. Results will be disseminated through publications and presentations at scientific meetings.Discussion: The costs related to oral clefts are high, including long term psychological and socio-economic effects. This study provides an opportunity for huge savings in not only money but the overall quality of life. This may help establish more specific clinical guidelines for oral cleft prevention so that the intervention can be better tailored for at-risk women.

MICHELS SYNDROME IN A BRAZILIAN GIRL BORN TO CONSANGUINEOUS PARENTS

We report on a Brazilian girl born to consanguineous parents and presenting with craniosynostosis, telecanthus, blepharophimosis, blepharoptosis, epicanthus inversus, cleft lip and palate, skeletal defects, and hearing loss. This combination of anomalies appears to constitute the Michels syndrome. (C) 1995 Wiley-Liss, Inc.

Oral clefts and vitamin supplementation

Objectives: the evidence linking low levels of folic acid and orofacial clefting (OFC) is presently equivocal, There is stronger evidence for the role of folic acid supplementation in protection against the occurrence and recurrence of neural tube defects. The present investigation tested the hypotheses that cleft lip, cleft palate, or both are inversely associated with maternal intake of dietary and supplemental vitamins during the periconceptional period and first 4 months of pregnancy in a Brazilian population.Design: A population-based, case-control study of cleft lip with or without cleft palate (CL(P)) and isolated cleft palate (CP) in a Brazilian population. in structured interviews, case histories were taken from the mothers of a consecutive sample of 450 infants born with nonsyndromic OFC,Results: Mothers who had children with CL(P) were less likely to have been supplemented during the periconceptional period. The statistical significance of the difference in prevalence of the use of supplements between mothers of patients and of controls was greater for the CL(P) group: p < .05 for CP and p < .001 for CL(P). Multivariate analysis confirmed this finding of a protective effect for both types of orofacial cleft,Conclusions: the use of vitamin supplements in the first 4 months of pregnancy was suggestive of a protective effect against the occurrence of CP and CL(P) in this population, the significance of an association between multivitamin supplementation and OFC and the possible role of gene/environment interaction are discussed.

As interrogativas de conteúdo na história do Português brasileir o: uma abordagem discursivo-funcional

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)