GENOTYPIC AND PHENOTYPIC VARIABILITY IN CRANIOSYNOSTOSIS

颅缝早闭是一种相对常见的出生缺陷，可导致颅内压增高和头部畸形。这种情况需要在生命的最初几个月进行重建手术，因此是一个重大的公共卫生问题。颅缝早闭是100多种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，在颅面表型方面表现出相似性。颅缝早闭也可能作为一种明显孤立的现象发生。最近的综述指出，超过64个不同的突变的7个基因是负责颅缝早闭综合征和一个单一的，但高度可变的突变是负责大部分的非综合征冠状缝早闭。截至本文撰写之时，尚未发现与孤立矢状或孤立额突性骨性连接相关的特定突变。该项目的长期目标是确定与颅缝早闭相关的基因在产生颅面表型中的作用。这将通过获得上述颅缝早闭综合征的颅面表型的客观、定量测量以及对于额位、矢状和冠状缝早闭的孤立病例，并通过鉴定该人群中存在的基因突变来完成。个体表型表征将基于三维颅面图像数据。将对定量、三维、颅面特征进行分析，以确定仅基于皮肤、骨骼和/或CNS颅面形态定义的个体组。这些个体中存在的形态组和遗传突变之间的任何对应关系将提供无偏的基因型-表型相关性。我们的形态学组内的颅面表型变异的解释将寻求使用额外的临床数据。这些数据包括标准的人口统计学数据，与某些颅缝早闭症发生有关的流行病学因素，以及神经心理功能的临床评价。

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.