Abstract：
Pathogenic biallelic variants in POL3RA have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann-Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Here we present the detailed clinical course of a 37-year-old woman in whom we identified a homozygous synonymous POLR3A variant c.3336G>A resulting in leaky splicing r.[3336ins192, =, 3243_3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS-like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported POLR3A-associated disorders, mostly mimicking the WRS. Thus, our study expands the POLR3A-mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic POLR3A variants.
摘要：
POL3RA中的致病性双等位基因变体与以进行性神经系统恶化为特征的不同疾病有关。这些包括4H脑白质营养不良综合征（髓鞘减少，低促性腺激素性性腺功能减退,和低度）和青春期发作的进行性痉挛性共济失调，以及Wiedemann-Rautenstrauch综合征（WRS），一种可识别的新生儿孕激素综合征。这些疾病之间的表型差异被认为主要是由于潜在的POLR3A变体的不同功能作用而发生的。在这里，我们介绍了一名37岁女性的详细临床过程，在该女性中，我们鉴定了纯合同义POLR3A变体c.3336G>A，导致泄漏剪接r。[3336ins192，=，3243_3336del94]。她出生时表现为宫内发育迟缓，脂肪营养不良,肌张力减退,和几个类似WRS的面部特征，虽然没有稀疏的头发和突出的头皮静脉。她没有发育迟缓或智力残疾的迹象。多年来,以上特征的面部特征，她表现出严重的产后发育迟缓，全球脂肪营养不良，关节挛缩,胸部发育不全,脊柱侧弯,无牙齿,痉挛性四肢瘫痪,双侧听力损失,失音,低促性腺激素性性腺功能减退,和小脑花梗在脑成像中的高强度。这些表现与先前报道的POLR3A相关疾病的临床特征部分重叠。主要是模仿WRS。因此，我们的研究扩展了POLR3A介导的表型谱,提示存在双等位基因POLR3A变异体的表型连续体.
