Craniofacial Development and Stem Cell Biology, Comprehensive Biomedical Research Centre, Dental Institute, King's College London, Guy's Hospital, London, United Kingdom.
Am J Med Genet A. 2012 Nov;158A(11):2797-806. doi: 10.1002/ajmg.a.35598. Epub 2012 Sep 17.
Central nervous system anomalies in Pfeiffer syndrome (PS) due to mutations in the FGFR2 gene are poorly understood, even though PS is often associated with serious cognitive impairment. The aim of this study is to describe the neuropathological phenotype in PS. We present four severe fetal cases of sporadic PS with FGFR2 mutations who underwent termination followed by fetopathological and neuropathological examination. We studied the expression pattern of Fgfr2 in the mouse brain using radioactive fluorescence in situ hybridization. PS is associated with brain deformations due to the abnormal skull shape, but FGFR2 mutations also induce specific brain developmental anomalies: megalencephaly, midline disorders, amygdala, and hippocampus malformations, and ventricular wall alterations. The expression pattern of Fgfr2 in mice matches the distribution of malformations in humans. The brain anomalies in PS result from the combination of mechanical deformations and intrinsic developmental disorders due to FGFR2 hyperactivity. Several similarities are noted between these anomalies and the brain lesions observed in other syndromes due to mutations in FGF-receptor genes. The specific involvement of the hippocampus and the amygdala should encourage the precise cognitive screening of patients with mild forms of PS.
中枢神经系统异常在 Pfeiffer 综合征（PS）中由于 FGFR2 基因突变，尽管 PS 常与严重的认知障碍有关，但仍知之甚少。本研究旨在描述 PS 的神经病理学表型。我们介绍了 4 例散发性 PS 伴有 FGFR2 突变的严重胎儿病例，这些病例在终止妊娠后进行了胎儿病理学和神经病理学检查。我们使用放射性荧光原位杂交研究了 Fgfr2 在小鼠大脑中的表达模式。PS 与异常颅骨形状导致的脑畸形有关，但 FGFR2 突变也会引起特定的脑发育异常：巨脑症、中线障碍、杏仁核和海马畸形以及脑室壁改变。在小鼠中 Fgfr2 的表达模式与人类畸形的分布相匹配。PS 中的脑异常是由于 FGFR2 过度活跃引起的机械变形和内在发育障碍的组合。在这些异常与由于 FGF-受体基因突变引起的其他综合征中观察到的脑损伤之间存在一些相似之处。海马和杏仁核的特定参与应鼓励对轻度 PS 患者进行精确的认知筛查。
