GENOTYPIC AND PHENOTYPIC VARIABILITY IN CRANIOSYNOSTOSIS

颅神经缝合线过早闭合是一种相对常见的先天性缺陷，可导致颅内压升高和头部形状异常。这种情况需要在出生后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。颅缝闭合是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saethree - chotzen，在颅面表型上表现出相似性。颅缝闭合也可以作为一种明显孤立的现象发生。最近的综述指出，7种基因的64种不同突变可导致颅缝闭塞综合征，而一个单一但高度可变的突变可导致很大比例的非综合征性冠状缝闭塞。在撰写本文时，尚未发现特异性突变与孤立矢状面或孤立异位性骨膜粘连有关。该项目的长期目标是确定与颅缝闭合相关的基因在颅面表型产生中的作用。这将通过获得上述颅缝闭塞综合征的颅面表型的客观、定量测量，以及对异位、矢状和冠状缝闭塞的孤立病例进行测量，并通过识别该人群中存在的基因突变来实现。个体表型特征将基于三维颅面图像数据。定量的、三维的颅面特征将被分析，以确定仅根据皮肤、骨骼和/或中枢神经系统颅面形态定义的个体群体。形态学组和这些个体中存在的基因突变之间的任何对应关系都将提供无偏倚的基因型-表型相关性。解释颅面表型变异在我们的形态学组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数据，与某些颅缝闭锁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.