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Abstract：
Noonan syndrome is a congenital disorder characterized by distinctive facial appearance, congenital heart defects, short stature, and skeletal dysplasia. Although boys with Noonan syndrome frequently exhibit cryptorchidism, a mild form of 46,XY disorders of sex development (DSD), they barely manifest more severe genital abnormalities. Here, we report a boy with ambiguous genitalia, short stature, and non-specific dysmorphic features. He had no cardiac abnormalities or skeletal dysplasia. His score in the Noonan syndrome diagnostic criteria (36 of 157 points, 23%) was lower than the cutoff for diagnosis (50%). Whole-exome sequencing identified a de novo heterozygous variant (c.922A>G: p.Asn308Asp) in PTPN11 and a maternally inherited hemizygous variant (c.1439C>T: p.Pro480Leu) in FLNA. The PTPN11 variant was a known causative mutation for Noonan syndrome. FLNA is a causative gene for neurodevelopmental and skeletal abnormalities and has also been implicated in 46,XY DSD. The p.Pro480Leu variant of FLNA was assessed as deleterious by in silico analyses. These results provide evidence that whole-exome sequencing is a powerful tool for diagnosing patients with atypical disease manifestations. Furthermore, our data suggest a possible role of digenic mutations as phenotypic modifiers of Noonan syndrome.
摘要：
Noonan综合征是一种先天性疾病，其特征是独特的面部外观，先天性心脏缺陷,身材矮小,和骨骼发育不良。尽管患有Noonan综合征的男孩经常表现出隐睾，轻度的46，XY性发育障碍（DSD），他们几乎没有表现出更严重的生殖器异常。这里,我们报告了一个生殖器模棱两可的男孩，身材矮小,和非特异性的变形特征。他没有心脏异常或骨骼发育不良。他在努南综合征诊断标准中的得分(157分中的36分，23%）低于诊断截止值（50%）。全外显子测序鉴定了PTPN11中的从头杂合变体（c.922A>G：p.Asn308Asp）和FLNA中的母系遗传半合子变体（c.1439C>T：p.Pro480Leu）。PTPN11变体是Noonan综合征的已知致病突变。FLNA是神经发育和骨骼异常的致病基因，也与46，XYDSD有关。通过计算机模拟分析评估FLNA的p.Pro480Leu变体是有害的。这些结果提供了证据，表明全外显子组测序是诊断具有非典型疾病表现的患者的有力工具。此外，我们的数据提示双基因突变可能作为Noonan综合征的表型修饰因子发挥作用.
