Pasmant E, Sabbagh A, Hanna N, Masliah-Planchon J, Jolly E, Goussard P, Ballerini P, Cartault F, Barbarot S, Landman-Parker J, Soufir N, Parfait B, Vidaud M, Wolkenstein P, Vidaud D, France R N F
UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
J Med Genet. 2009 Jul;46(7):425-30. doi: 10.1136/jmg.2008.065243. Epub 2009 Apr 14.
Germline loss-of-function mutations in the SPRED1 gene have recently been identified in patients fulfilling the National Institutes of Health (NIH) diagnostic criteria for neurofibromatosis type 1 (NF1) but with no NF1 (neurofibromin 1) mutation found, suggesting a neurofibromatosis type 1-like syndrome.
61 index cases with NF1 clinical diagnosis but no identifiable NF1 mutation were screened for SPRED1 mutation.
We describe one known SPRED1 mutation (c.190C>T leading to p.Arg64Stop) and four novel mutations (c.637C>T leading to p.Gln213Stop, c.2T>C leading to p.Met1Thr, c.46C>T leading to p.Arg16Stop, and c.1048_1060del leading to p.Gly350fs) in five French families. Their NF1-like phenotype was characterised by a high prevalence of café-au-lait spots, freckling, learning disability, and an absence of neurofibromas and Lisch nodules in agreement with the original description. However, we did not observe Noonan-like dysmorphy. It is noteworthy that one patient with the p.Arg16Stop mutation developed a monoblastic acute leukaemia.
In our series, SPRED1 mutations occurred with a prevalence of 0.5% in NF1 patients and in 5% of NF1 patients displaying an NF1-like phenotype. SPRED1 mutated patients did not display any specific dermatologic features that were not present in NF1 patients, except for the absence of neurofibromas that seem to be a specific clinical feature of NF1. The exact phenotypic spectrum and the putative complications of this NF1 overlapping syndrome, in particular haematological malignancies, remain to be further characterised. NIH diagnostic criteria for NF1 must be revised in view of this newly characterised Legius syndrome in order to establish a specific genetic counselling.
最近在符合美国国立卫生研究院（NIH）1型神经纤维瘤病（NF1）诊断标准但未发现NF1（神经纤维瘤蛋白1）突变的患者中鉴定出SPRED1基因的种系功能丧失突变，提示一种1型神经纤维瘤病样综合征。
对61例临床诊断为NF1但未发现可识别的NF1突变的索引病例进行SPRED1突变筛查。
我们在五个法国家庭中描述了一个已知的SPRED1突变（c.190C>T，导致p.Arg64Stop）和四个新突变（c.637C>T，导致p.Gln213Stop；c.2T>C，导致p.Met1Thr；c.46C>T，导致p.Arg16Stop；以及c.1048_1060del，导致p.Gly350fs）。他们的NF1样表型的特征是咖啡牛奶斑、雀斑、学习障碍的高患病率，以及与最初描述一致的无神经纤维瘤和Lisch结节。然而，我们未观察到努南样畸形。值得注意的是，一名携带p.Arg16Stop突变的患者发生了单核细胞性急性白血病。
在我们的系列研究中，SPRED1突变在NF1患者中的发生率为0.5%，在表现出NF1样表型的NF1患者中为5%。除了无神经纤维瘤似乎是NF1的一种特定临床特征外，SPRED1突变患者未表现出任何NF1患者中不存在的特定皮肤特征。这种NF1重叠综合征的确切表型谱和可能的并发症，尤其是血液系统恶性肿瘤，仍有待进一步明确。鉴于这种新发现的勒吉尤斯综合征，必须修订NIH的NF1诊断标准，以便建立特定的遗传咨询。
