PORCN基因嵌合突变致男性局灶性真皮发育不全1例并文献复习

PORCN gene mosaic mutation cause focal dermal hypoplasia:A case report and literature review

目的报道1例PORCN基因嵌合突变致男性局灶性真皮发育不全(FDH)患儿并文献复习,为该病的临床诊断提供参考。方法总结患儿的临床表现、辅助检查和基因测序结果。在Pubmed、万方数据库和中国知网中检索建库至2017年9月30日报道的PORCN突变致FDH综合征的病例,归纳该病的临床表现,筛选并总结存活男性患儿的基因型和临床表型。结果患儿男,12岁2月,因"身材矮小"就诊。当地医院检查胰岛素样生长因子1(IGF1)343.8 ng·m L^(-1),胰岛素样生长因子结合蛋白3(IGFBP3)4.9μg·m L^(-1);垂体MR增强扫描未见异常;B超检查双侧睾丸、肾上腺未见异常。身高142cm(-1.4 SD),体重36.1 kg;左侧第4脚趾明显小于右侧;左侧腹部和腿部有沿Blaschko线的色素减退,左侧臀部及阴茎左侧面有浅黄色脂肪膨出;双足X线正位片示,左足第1、4、5跖骨和左拇趾第1趾骨较细,第4趾骨细小,左拇趾末节趾骨短、末端细尖。性激素6项未见异常。韦氏儿童智力量表测试显示语言、总分分值偏低。基因检测显示PORCN基因c.178G>A嵌合突变,确诊为PORCN基因嵌合突变致FDH。共检索到36篇英文文献报道了经基因检测确诊为PORCN突变导致的FDH综合征205例,其中男性22例(3例在出生后死亡);临床表现以皮肤(72.7%)、骨骼系统(66.8%)和颅面部(58.5%)最常见。20例(包括本文1例)存活的PORCN突变导致的FDH综合征男性患儿中除1例为46,XXY Klinefelter综合征外,余均为嵌合体或合子后嵌合;均存在皮肤发育不全,其他临床表现多样。结论 FDH不仅可表现为肢体和皮肤异常,还可导致智力发育迟滞。PORCN基因突变所致FDH为X连锁显性遗传病,男性杂合患者多为胚胎致死性,存活男性多为嵌合突变且临床表现异质性高,临床易漏诊,对存在皮肤相似病变怀疑该病者应做基因检测以辅助诊断。

Objective To report one case of male focal dermal hypoplasia( FDH) caused by mosaic mutation of PORCN for clinical diagnosis reference. Methods The clinical manifestations,laboratory measurements and gene sequencing results were summarized.PORCN mutations from Pubmed,Wanfang Database and China National Knowledge Infrastructure up to September30 th,2017 were searched,the related features along with the clinical and gene mutation spectrums of the survived FDH male cases were summarized.Results A 12 years and 2 months old boy with height 142 cm(-1.4 SD) and weight 36.1 kg was referred to our clinic due to short stature. The serum IGF1 level was 323.8 ng·m L^(-1) and IGFBP3 level was 4.9 μg·m L^(-1).No abnormalities were found in his pituitary and bilateral testes and adrenal gland. However,typical features were found as short left fourth toe,skin hypopigmentation at his left leg and abdomen along Blaschko line,and fat herniation in buttocks and penis. Bipedal X-ray showed that the 1 st,4 th,5 th metatarsal of left foot,left great toe and the 4 th phalanges were small,the phalanges of left great toe were short with small end. Six steroid sex hormones were within normal range. WISC-R intellectual test demonstrated that language and total scores are marginally low. Mosaic c.178 G> A mutation of PORCN gene was detected by whole exon sequencing and confirmed by Sanger sequencing,then the diagnosis of FDH was made. A total of 205 reported patients confirmed having PORCN mutations were reported in 36 literatures and only 22 were males( 3 cases died soon after birth). The most frequently reported symptoms were skin hypoplasia( 72.7%),skeletonabnormalities( 66.8%) and craniofacial anomalies( 58. 5%). The survived male patients were all mosaic or postzygotic mosaic mutations except one 46,XXY Klinefelter syndrome whose clinical manifestations showed great heterogeneity but all with skin hypoplasia. Conclusion The FDH patient we reported not only presented with limb and skin abnormalities,but also with mental retardation. Male patients could be misdiagnosed by Sanger sequencing because of the failure of detection of mosaic mutation and great heterogeneity of clinical manifestations.WES test could significantly improve the positive rate of diagnosis for those suspected male patients.