Thiel Christian, Wilken Martin, Zenker Martin, Sticht Heinrich, Fahsold Raimund, Gusek-Schneider Gabriele-Charlotte, Rauch Anita
Insitute of Human Genetics, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
Am J Med Genet A. 2009 Jun;149A(6):1263-7. doi: 10.1002/ajmg.a.32837.
Neurofibromatosis-Noonan syndrome (NFNS), an entity which combines both features of Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), was etiologically unresolved until recent reports demonstrated NF1 mutations in the majority of patients with NFNS. The phenotypic overlap was explained by the involvement of the Ras pathway in both disorders, and, accordingly, clustering of the NF1 mutations in the GTPase-activating protein (GAP) domain of neurofibromin was observed in individuals with NFNS. We report on an 18-month-old girl with typical findings suggestive of NS in combination with multiple café-au-lait spots and bilateral optic gliomas suggestive of NF1. The patient was found to carry a de novo PTPN11 mutation p.T2I as well as the maternally inherited NF1 mutation c.4661+1G>C. Her otherwise healthy mother and brother, who also had the NF1 mutation, showed few café-au-lait spots as the only sign of neurofibromatosis. Since our patient's unique NF1 mutation results in skipping of exon 27a and thus involves the same region, Gap-related domain, that had been shown to be associated with NFNS, her phenotype could have been misleadingly attributed to the NF1 mutation only. Contrarily, absence of both cutaneous neurofibromas and NS features in her relatives with the same NF1 mutation, suggests that the index patient's typical NFNS phenotype is caused by an additive effect of mutations in both NF1 and PTPN11. In contrast to previous findings, we speculate that absence of cutaneous neurofibromas is not solely associated with the recurrent 3-bp in-frame deletion in exon 17.
神经纤维瘤病-努南综合征（NFNS）是一种兼具努南综合征（NS）和1型神经纤维瘤病（NF1）特征的疾病，在最近有报告显示大多数NFNS患者存在NF1突变之前，其病因一直未得到解决。两种疾病表型上的重叠可通过Ras信号通路在二者中的参与来解释，因此，在NFNS患者中观察到神经纤维瘤蛋白的GTP酶激活蛋白（GAP）结构域中存在NF1突变聚集。我们报告了一名18个月大的女孩，她有典型的提示NS的表现，同时伴有多个咖啡牛奶斑和双侧视神经胶质瘤，提示NF1。该患者被发现携带一个新发的PTPN11突变p.T2I以及母亲遗传的NF1突变c.4661+1G>C。她原本健康的母亲和哥哥也有NF1突变，仅表现出少数咖啡牛奶斑，这是神经纤维瘤病的唯一迹象。由于我们患者独特的NF1突变导致外显子27a跳跃，因此涉及与NFNS相关的同一区域，即Gap相关结构域，她的表型可能会被错误地仅归因于NF1突变。相反，她具有相同NF1突变的亲属既没有皮肤神经纤维瘤也没有NS特征，这表明该索引患者典型的NFNS表型是由NF1和PTPN11突变的累加效应引起的。与之前的发现不同，我们推测皮肤神经纤维瘤的缺失不仅仅与外显子17中反复出现的3bp框内缺失有关。
