GENOTYPIC AND PHENOTYPIC VARIABILITY IN CRANIOSYNOSTOSIS

脑颅缝过早闭合，即颅缝早闭，是一种比较常见的先天性畸形，会导致颅内压升高和头部形状异常。这种情况需要在生命的头几个月进行重建手术，因此是一个重大的公共卫生问题。颅缝融合是100多个综合征的临床特征之一。其中一些综合征，特别是Crouzon、Apert、Jackson-Weiss、Pfeiffer和Saethre-Chotzen，在颅面表型上表现出相似之处。颅缝融合也可以作为一种明显孤立的现象发生。最近的综述指出，在身上，七个基因的不同突变导致了颅性融合综合征，而一个单一但高度可变的突变导致了很大比例的非综合征冠状融合。在撰写本文时，尚未发现与孤立性矢状面或孤立性后视性联会相关的特定突变。拟议项目的长期目标是确定与颅缝融合相关的基因在产生颅面部表型中的作用。这将通过获得上述颅缝融合综合征的头面部表型以及特位、矢状位和冠状融合的个别病例的客观、定量的测量，并通过鉴定该人群中存在的基因突变来完成。个体的表型特征将基于三维头面部图像数据。将对定量的三维颅面特征进行分析，以确定完全基于皮肤、骨骼和/或中枢神经系统颅面形态定义的个体组。这些个体中存在的形态群体和基因突变之间的任何对应关系都将提供无偏见的基因-表型相关性。我们将使用更多的临床数据来解释我们的形态组中的颅面部表型变异。这些数据包括标准人口学数据、与某些颅缝早闭的发生有关的流行病学因素，以及神经心理功能的临床评估。

Premature closure of the neurocranial sutures, craniosynostosis, is a relatively common bir6th defect that results in increased intracranial pressure and abnormal head shape. The condition necessitates reconstructive surgery during the first months of life and therefore represents a significant public health problem. Craniosynostosis is one of a number of clinical features in over 100 syndromes. Some of these syndromes, specifically Crouzon, Apert, Jackson-Weiss, Pfeiffer, and Saethre-Chotzen, exhibit similarities in craniofacial phenotypes. Craniosynostosis can also occur as an apparently isolated phenomenon. Recent reviews note that over 64 different mutations of seven genes are responsible for craniosynostosis syndromes and that a single, but highly variable mutation is responsible for a large proportion of non-syndromic coronal synostosis. As of this writing, no specific mutations have been found to be associated with isolated sagittal or isolated metopic synostosis. The long-term goal of the proposed project is to determine the role of genes associated with craniosynostosis in producing craniofacial phenotypes. This will be done by obtaining objective, quantitative measures of the craniofacial phenotypes of the craniosynostosis syndromes named above and for isolated cases for metopic, sagittal, and coronal synostosis, and by identifying the genetic mutations present in this population. Individual phenotypic characterizations will be based on three-dimensional craniofacial image data. The quantitative, three-dimensional, craniofacial characterizations will be analyzed to determine groups of individuals defined solely on the basis of cutaneous, skeletal, and/or CNS craniofacial morphology. Any correspondence between the morphological groups and the genetic mutations present in these individuals will provide an unbiased genotype-phenotype correlation. Explanations of the craniofacial phenotypic variability within our morphological groups will be sought using additional clinical data. These data include standard demographic data, epidemiological factors implicated in the occurrence of some craniosynostosis conditions, and clinical evaluations of neuropsychological function.