High incidence of progressive postnatal cerebellar enlargement in Costello syndrome: brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities.
High incidence of progressive postnatal cerebellar enlargement in Costello syndrome: brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities.
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DOI：
10.1002/ajmg.a.33391
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发表时间：
2010-05
期刊：
影响因子：
--
通讯作者：
Dobyns WB
中科院分区：
文献类型：
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作者：
Gripp KW;Hopkins E;Doyle D;Dobyns WB
Costello综合征是一种由原癌基因HRAS的生殖细胞突变引起的肾病。它的表现包括无法茁壮成长的大头畸形、特征性面部特征、肥厚性心肌病、乳头状瘤、恶性肿瘤和认知障碍。在一项系统回顾中，我们发现27/28例患者的绝对或相对大头畸形（100%）、脑室扩大（50%）和其他脑和脊髓成像异常。在27/28例（96%）中观察到后颅窝拥挤伴小脑扁桃体疝（CBTH），在10/17例（59%）中观察到后颅窝拥挤进展。后颅窝拥挤和CBTH的后遗症包括需要分流或脑室造口术的脑积水（25%），基亚里1畸形（32%）和空洞形成（25%）。我们的数据显示，大头畸形与进行性额叶隆起和CBTH，记录了一个持续的过程，而不是静态的先天性异常。将婴儿的影像与随后的研究进行比较，证实了出生后颅窝拥挤的发展。这种巨脑畸形和小脑增大的演变过程与小鼠模型数据一致，描述了神经元和神经胶质的异常发生，导致星形胶质细胞数量增加和脑体积增大。在Costello综合征和巨脑-毛细血管畸形综合征中，脑发育不均衡是导致出生后CBTH和基亚里1畸形的主要因素。
Costello syndrome is a rasopathy caused by germline mutations in the proto-oncogene HRAS. Its presentation includes failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. In a systematic review we found absolute or relative macrocephaly (100%), ventriculomegaly (50%), and other abnormalities on brain and spinal cord imaging studies in 27/28 individuals. Posterior fossa crowding with cerebellar tonsillar herniation (CBTH) was noted in 27/28 (96%), and in 10/17 (59%) with serial studies posterior fossa crowding progressed. Sequelae of posterior fossa crowding and CBTH included hydrocephalus requiring shunt or ventriculostomy (25%), Chiari 1 malformation (32%) and syrinx formation (25%). Our data reveal macrocephaly with progressive frontal bossing and CBTH, documenting an ongoing process rather than a static congenital anomaly. Comparison of images obtained in young infants to subsequent studies demonstrated postnatal development of posterior fossa crowding. This process of evolving megalencephaly and cerebellar enlargement is in keeping with mouse model data, delineating abnormal genesis of neurons and glia, resulting in an increased number of astrocytes and enlarged brain volume. In Costello syndrome and macrocephaly-capillary malformation syndrome disproportionate brain growth is the main factor resulting in postnatal CBTH and Chiari 1 malformation.