BRAIN STRUCTURE AND FUNCTION IN CHILDREN WITH ORAL CLEFTS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 口腔裂是人类病态出生缺陷的重要组成部分。唇腭裂影响了大约1/700的新生儿，与地理来源和社会经济地位有关的差异很大。这些口裂是发育中的颅面畸形，至少部分原因是神经脊细胞未能正确迁移。作为一个群体，70%的裂隙障碍包括那些仅限于面部裂隙的疾病(非综合征)，30%的裂隙是明确定义的额外异常综合征的一部分。在高加索人中，大约每1000名活产儿中就有一名发生非综合征性口腔裂，从解剖学上又分为唇腭裂(CLP)和单纯腭裂(CPO)。 非综合征性唇腭裂(NSCLP)的病因是复杂的，遗传和环境因素都有作用。遗传流行病学研究表明，包括一个主基因在内的多个相互作用的基因与NSCLP的病因有关，可能约占家族性发病的一半。根据NSCLP的表达、转基因动物的表型、突变以及小鼠或人类的连锁/关联，许多候选基因已被确定为与NSCLP有关。关于它们在NSCLP中的作用，似乎有三个基因的数据最强，它们是MSC1(同源结构域基因)、TGFA和TGFB3(生长因子基因)。 本研究有以下假设：1)与年龄和性别匹配的健康对照组相比，NSCLP儿童会有异常的脑形态结构。2)与健康对照组相比，NSCLP儿童表现出认知功能障碍，总体上表现为一般智商的轻度抑郁，而在表达语言和执行功能方面表现出更具体的缺陷。相当大一部分人也会表现出明显的社会压抑。3)脑形态异常与认知功能异常的关系如下：(1)智商与前脑体积呈负相关，与后脑体积呈正相关。(2)语言功能障碍与左颞叶结构异常有关。(C)此外，额叶皮质腹侧的形态将与社会功能有关。4)脑结构和功能的异常程度与口腔裂隙程度有关。5)脑结构异常与TGFA、TGFB3、Msx1基因变异有显著相关性。6)女性的大脑异常模式与男性相同，但程度较轻。女性也会表现出较轻程度的语言障碍和社交障碍。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Oral clefts comprise a significant component of morbid human birth defects. Clefts of the lip and palate affect about 1/700 births with wide variability related to geographic origin and socioeconomic status. These oral clefts are developmental craniofacial abnormalities that result, at least in part, from a failure of neural crest cells to migrate properly. As a group, 70% of clefting disorders are comprised of those that are isolated to facial clefts only (non-syndromic), and 30% are those in which the facial cleft is part of a well-defined syndrome of additional anomalies. Nonsyndromic oral clefts occur in approximately 1 per 1,000 live births among Caucasians and are further divided anatomically into clefts of the lip and/or palate (CLP) and clefts of the palate only (CPO). The etiology of non-syndromic clefts of the lip and/or palate (NSCLP) is complex with both genetic and environmental factors having a role. Genetic epidemiological studies have shown that several interacting loci, including a major gene, are involved in the etiology of NSCLP, possibly accounting for approximately one-half of the familial occurrences. A number of candidate genes have been identified as being involved in NSCLP based on expression, phenotype in transgenic animal, mutations, and linkage/associations in mice or humans. Three genes that appear to have the strongest data regarding their role in NSCLP are MSC1 (a homeodomain gene), TGFA and TGFB3 (growth factor gene). This study has the following hypotheses: 1) Children with NSCLP will have abnormal brain morphology compared to age and sex matched healthy controls. 2) Children with NSCLP will show cognitive dysfunction compared to healthy controls with a pattern of overall mild depression of general IQ, and more specific deficits in expressive language and executive functions. A substantial proportion will also show significant social inhibition. 3) The abnormalities in brain morphology will correlate with abnormalities in cognitive function in the following manner: (a) There will be an inverse correlation between IQ and anterior cerebral volume and a positive correlation between IQ and posterior cerebral volume. (b) Disturbed language function will be associated with abnormalities of left temporal lobe structures. (c) In addition, morphology of the ventral aspect of the frontal lobe cortex will be related to social function. 4) Degree of brain abnormality (structure and function) will be associated with degree of oral clefting. 5) There will be a significant correlation between abnormalities in brain structure and genetic variation in TGFA, TGFB3 and MSX1. 6) Females will have the same pattern of brain abnormalities as males, but to a lesser degree. Females will also show a milder degree of language impairment and social dysfunction.