GENETIC STUDIES OF CRANIOFACIAL AND LIMB DISORDERS

该建议的总体假设是遗传和环境因素参与了正常的人类颅面和肢体发育，并且是这些疾病的危险因素。本提案的目标是确定涉及人类颅面和肢体发育的遗传和环境因素。在接下来的五年里，我们将在中大西洋地区的500多名患者中研究颅缝闭合、口腔裂和下颌面骨不全等常见的人类颅面疾病及其相关的肢体异常。在1997年1月12日至1998年11月30日期间，我们研究了颅面综合征，saethree - chotzen。对32例具有saethree - chotzen综合征（一种常见的颅缝闭锁和肢体异常的常染色体显性遗传病）特征的不相关患者进行TWIST、FGFR2和FGFR3突变筛查。在12个家族中发现9个新的和3个复发的TWIST突变。七个家庭被发现有FGFR3 P250R突变，一个个体被发现有FGFR2 VV269-270缺失。迄今为止，我们在saethree - chotzen综合征患者中TWIST或FGFR突变的检出率为68%，包括我们在其他地方报告的5例TWIST突变患者。目前在文献中已知超过35种不同的TWIST突变。超过三分之一的TWIST突变患者最常见的表型特征是冠状结膜紧闭、头短、前额发际线低、面部不对称、上睑下垂、远端远视、大脚趾宽和拇趾斜突。TWIST突变或FGFR突变均存在显著的家族内和家族间表型变异。临床特征的重叠和在同一基因中存在不止一种颅缝闭锁疾病（如saethree - chotzen， Crouzon和Pfeiffer综合征）的突变，支持了TWIST和fgfr是参与调节人类颅面和肢体发育的相同分子途径的组成部分的假设。

The overall hypothesis of this proposal is that genetic and environmental factors are involved in normal human craniofacial and limb development and are risk factors for these disorders. The goal of this proposal is to determine those genetic and environmental factors involved in human craniofacial and limb development. The common human craniofacial conditions of craniosynostosis, oral clefts, and mandibulofacial dysostosis, and their associated limb abnormalities will be studied in over 500 patients in the Mid-Atlantic Region during the next five year period. During the last period from 12/1/97 through 11/30/98, we studied a craniofacial syndrome, Saethre-Chotzen. Thirty-two unrelated patients with features of Saethre-Chotzen syndrome, a common autosomal dominant condition of craniosynostosis and limb anomalies, were screened for mutations in TWIST, FGFR2, and FGFR3. Nine novel and three recurrent TWIST mutations were found in 12 families. Seven families were found to have the FGFR3 P250R mutation, and one individual was found to have an FGFR2 VV269-270 deletion. To date, our detection rate for TWIST or FGFR mutations is 68% in our Saethre-Chotzen syndrome patients, including our five patients elsewhere reported with TWIST mutations. More than 35 different TWIST mutations are now known in the literature. The most common phenotypic features, present in more than a third of our patients with TWIST mutations, are coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition-such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes-support the hypothesis that TWIST and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans.