背景:17q11.2微删除,其中包括1型神经纤维瘤病(NF1)基因区域,负责NF1微缺失综合征,在所有NF1患者中观察到4.2%。与NF1普通人群相比,NF1基因及其侧翼区的大缺失与更严重的NF1表型相关。
方法:我们特此描述两个女孩的临床和分子特征(2岁和4岁,分别),具有非马赛克非典型缺失。患者1显示15个咖啡色斑点和腋窝雀斑,以及左眼的Lisch结节,斜视,高拱形腭,错牙合,严重脊柱侧后凸,双侧跟骨外翻足,轻度广泛性低张力,多动症和言语相关能力的缺陷。通过多重连接依赖性探针扩增(MLPA)的NF1基因组重排检测到整个NF1基因的杂合缺失。阵列比较基因组杂交(a-CGH)分析定义了约1Mb的17q11.2缺失(位于位置29,124,299和30,151,654的断点),涉及不同的基因(部分CRLF3,ATAD5,TEFM,ADAP2,RNF135,OMG,EVI2B,EVI2A,RAB11FIP4),包括NF1。患者2显示生长和发育迟缓,肺动脉瓣上狭窄,二十五个咖啡点,腋窝雀斑,颅面畸形特征,短颈伴翼状胬肉,脑磁共振成像(MRI)的肢体异常和神经发育不良的病灶。MLPA检测到NF1的杂合缺失,由a-CGH详细说明,指出位置29,124,299和30,326,958为其断点,除了患者1中删除的基因外,还包括COPRS,UTP6和部分SUZ12。父母的荧光原位杂交(FISH)分析记录了两种情况下缺失的从头起源。
结论:本报告可能为NF1微缺失综合征提供进一步的见解和更好的表征。
BACKGROUND: 17q11.2 microdeletions, which include the neurofibromatosis type 1 (NF1) gene region, are responsible for the NF1 microdeletion syndrome, observed in 4.2% of all NF1 patients. Large deletions of the NF1 gene and its flanking regions are associated with a more severe NF1 phenotype than the NF1 general population.
METHODS: We hereby describe the clinical and molecular features of two girls (aged 2 and 4 years, respectively), with non-mosaic atypical deletions. Patient 1 showed fifteen café-au-lait spots and axillary freckling, as well as a Lisch nodule in the left eye, strabismus, high-arched palate, malocclusion, severe kyphoscoliosis, bilateral calcaneovalgus foot, mild generalized hypotonia, hyperactivity and deficits of speech-related abilities. NF1 genomic rearrangements through multiplex ligation-dependent probe amplification (MLPA) detected an heterozygous deletion of the whole NF1 gene. Array comparative genomic hybridization (a-CGH) analysis defined a 17q11.2 deletion of about 1 Mb (breakpoints at positions 29,124,299 and 30,151,654), which involved different genes (partially CRLF3, ATAD5, TEFM, ADAP2, RNF135, OMG, EVI2B, EVI2A, RAB11FIP4), including NF1. Patient 2 showed growth and developmental delay, supravalvular pulmonary stenosis, twenty-five café-au-lait spots, axillary freckling, craniofacial dysmorphic features, short neck with pterygium, limb abnormalities and foci of neural dysplasia on brain magnetic resonance imaging (MRI). MLPA detected an heterozygous deletion of NF1, which was detailed by a-CGH indicating the positions 29,124,299 and 30,326,958 as its breakpoints, and which included aside from the genes deleted in Patient 1 also COPRS, UTP6 and partially SUZ12. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletions in both cases.
CONCLUSIONS: The present report will likely provide further insights and a better characterization of NF1 microdeletion syndrome.