Clinical and Mutational Spectrum of Neurofibromatosis Type 1-like Syndrome
Clinical and Mutational Spectrum of Neurofibromatosis Type 1-like Syndrome
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DOI：
10.1001/jama.2009.1663
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发表时间：
2009-11-18
影响因子：
120.7
通讯作者：
Legius, Eric
中科院分区：
文献类型：
--
作者：
Messiaen, Ludwine;Yao, Suxia;Legius, Eric
背景最近在主要表现为咖啡色Au lait斑（CALM）、腋窝雀斑和大头畸形的个体中描述了常染色体显性失活与发芽相关的EVH 1蛋白1结构域（SPRED 1）突变。这种新的疾病的临床谱的程度需要进一步delineation. ObjectiveTo确定的频率，突变谱，和表型神经纤维瘤病1型样综合征（NFLS）在一个大型队列的patients.Design，设置，和参与者在一个横断面研究，23名通过临床试验确定的携带SPRED 1突变的无关先证者与他们的家族一起参加了基因型-表型研究（2007-2008年）。在第二个横断面研究中，收集了1318个不相关的匿名样本，在2003-2007年从患者的广泛的迹象通常发现在1型神经纤维瘤病（NF 1），但没有检测到NF 1种系突变进行SPRED 1突变analysis.Main结果测量比较汇总的临床特征的患者或不SPRED 1或NF 1突变。结果42例SPRED 1阳性患者中，有20例（48%; 95%可信区间[CI]，32%-64%）符合美国国立卫生研究院（NIH）的NF 1诊断标准，诊断标准基于5例以上的CALM伴或不伴雀斑或NF 1家族史。42例SPRED 1阳性个体（0%; 95%CI，0%-7%）均无离散性皮肤或丛状神经纤维瘤、典型NF 1骨病变或症状性视路胶质瘤。在1318名个体的匿名队列中，在43名先证者中确定了34种不同的SPRED 1突变：34名先证者中有27种致病性突变，9名先证者中有7种可能的非致病性错义突变。在94例有或无雀斑且无其他NF 1特征的家族性CALM先证者中，69例（73%; 95% CI，63%-80%）有NF 1突变，18例（19%; 95% CI，12%-29%）有致病性SPRED 1突变。在匿名队列中，1.9%（95%CI，1.2%-2.9%）的个人与临床诊断的NF 1根据NIH标准有NFLS。结论发现高SPRED 1突变的检测率在NF 1突变阴性的家庭与常染色体显性表型的CALM有或没有雀斑，没有其他NF 1功能。在本研究的个体中，NFLS与NF 1中观察到的外周和中枢神经系统肿瘤无关。JAMA. 2009; 302（19）：2111-2118
Context Autosomal dominant inactivating sprouty-related EVH1 domain containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with cafe au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation.Objective To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1-like syndrome (NFLS) in a large cohort of patients.Design, Setting, and Participants In a cross-sectional study, 23 unrelated probands carrying a SPRED1 mutation identified through clinical testing participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1318 unrelated anonymous samples collected in 2003-2007 from patients with a broad range of signs typically found in neurofibromatosis type 1 (NF1) but no detectable NF1 germline mutation underwent SPRED1 mutation analysis.Main Outcome Measures Comparison of aggregated clinical features in patients with or without a SPRED1 or NF1 mutation. Functional assays were used to evaluate the pathogenicity of missense mutations.Results Among 42 SPRED1-positive individuals from the clinical cohort, 20 (48%; 95% confidence interval [CI], 32%-64%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas. In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 27 pathogenic mutations in 34 probands and 7 probable nonpathogenic missense mutations in 9 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73%; 95% CI, 63%-80%) had an NF1 mutation and 18 (19%; 95% CI, 12%-29%) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS.Conclusions A high SPRED1 mutation detection rate was found in NF1 mutation negative families with an autosomal dominant phenotype of CALMs with or without freckling and no other NF1 features. Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1. JAMA. 2009; 302(19): 2111-2118