GENETIC STUDIES OF CRANIOFACIAL AND LIMB DISORDERS

颅缝早闭，颅骨缝过早融合，是一种常见的 导致头部形状异常的发育异常。 治疗中度至 严重者，颅内压增高，神经系统损害 后遗症，如果不手术治疗。 颅缝早闭是一个特征， 多达50种遗传综合症 肢体异常，如并指畸形 和短指畸形是这些病症的共同相关特征。 Crouzon、Jackson-Weiss和Pfeiffer综合征为常染色体显性遗传， 颅缝早闭病症，具有广泛的表达变异性。 我们 确定具有这些条件的家庭，以研究其染色体 和/或来自已建立的淋巴母细胞或成纤维细胞培养物的DNA。 已发现成纤维细胞生长因子受体2（FGFR 2）突变 在这种情况下。 我们研究了39例FGFR 2轴突的这三种情况之一， 伊利亚和IIIc突变。 在17个无关基因组中检测到11个突变。 例 先前在轴突伊利亚或轴突IIIc中的四个突变 仅在Crouzon综合征中报告，也存在于另一种 两种综合症 两个插入，一个在Crouzon综合征的轴突伊利亚中 另一个在Pfeiffer综合征患者的轴突IIIc中， 观察 lafter突变具有相同的选择性RNA剪接， 作为Crouzon综合征报告的同义突变。 一 错义突变，V359 F，检测到一个家庭，其中一名成员， 颅缝早闭和宽趾，诊断为普发综合征，以及 有两个成员的特征符合Crouzon综合征， 颅缝早闭无肢体畸形。 家庭间和家庭内 FGFR 2突变表达的变异性表明，这三种突变都可能导致FGFR 2突变。 综合征，假定是临床上不同的，而是 代表相关的颅缝早闭和指 紊乱 我们还研究了一种罕见的常染色体显性遗传疾病，其特征是： 回状皮肤的皱纹性皮肤病，疣状增生， 黑棘皮症，颅缝早闭， 颅面畸形、手指异常、脐部和肛门生殖器 异常和过早死亡。 我们检测到FGFR 2突变， BeareStevenson皮肤回状综合征 不像那些 上述突变（Y375 C和S372 C）在轴突中发现， 10，其包含跨膜结构域的近端区域或跨膜结构域 本身 这些突变可能影响所有FGFR 2亚型，除了 可溶性异构体。 BEK（IIIc）和角质形成细胞生长 因子受体，通过选择性地调节FGFR 2形成的FGFR 2的KGFR（IIIb）同种型 外显子lilc和lilb的拼接分别会受到影响， 这些外显子位于轴突10的上游。 Beare-Stevenson表型 综合征的时空表达模式是一致的 这两种异构体。 BEK同种型主要表达于 原始骨和KGFR亚型主要存在于上皮来源的 与皮肤发育有关的组织。

Craniosynostosis, the premature fusion of calvarial sutures, is a common developmental anomaly that causes abnormal head shape. In moderate to severe cases, there is increase intracranial pressure and neurological sequelae, if not surgically treated. Craniosynostosis is a feature of as many as 50 genetic syndromes. Limb abnormalities, such as syndactyly and brachydactyly, are common associated features of these conditions. Crouzon, Jackson-Weiss, and Pfeiffer syndromes are autosomal dominant, craniosynostotic conditions with a wide variability of expression. We ascertained families with these conditions to study their chromosomes and/or DNA from established lymphoblastoid or fibroblast cell cultures. Fibroblast growth factor receptor 2 (FGFR2) mutations have been found in these conditions. We studied 39 cases with one of these three conditions for FGFR2 axon IlIa and llIc mutations. Eleven mutations were detected in 17 unrelated cases. Four mutations in either axon IlIa or axon llIc previously reported only in Crouzon syndrome are present also in one of the other two syndromes. Two insertions, one in axon IlIa in a Crouzon syndrome patient and the other in axon llIc in a Pfeiffer syndrome patient, were observed. The lafter mutation has the same alternative RNA splicing effect as a reported synonymous mutation for Crouzon syndrome. A missense mutation, V359F, was detected in a family with one member with craniosynostosis and broad digits, diagnostic of Pfeiffer syndrome, and with two member with features consistent with Crouzon syndrome, craniosynostosis without limb anomalies. The inter- and intrafamilial variability in expression of FGFR2 mutations suggests that these three syndromes, presumed to be clinically distinct, are instead representative of a spectrum of related craniosynostotic and digital disorders. We also studied a rare, autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, verrucous hyperplasia with hyperpigmentation of acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. We detected FGFR2 mutations in this condition, BeareStevenson cutis gyrata syndrome. Unlike the syndromes mentioned above, these mutations (Y375C and S372C) were found in axon 10 which contains the proximal region of or the transmembrane domain itself. These mutations presumably affect all FGFR2 isoforms, except soluble isoforms. Both the BEK (IIIc) and the keratinocyte growth factor receptor, KGFR (Illb) isoforms of FGFR2 formed by alternative splicing of exons lilc and lilb, respectively, would be affected because these exons are upstream of axon 10. The phenotype of Beare-Stevenson syndrome is consistent with the spatiotemporal expression patterns of both of these isoforms. The BEK isoform is expressed primarily in primordial bone and KGFR isoform predominantly in epithelial-derived tissues involved in the development of the skin.