Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination

Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination

Pathogenic mutations in genes (SASH1 and PTPN11) can cause a rare genetic disorder associated with pigmentation defects and the well-known LEOPARD syndrome, respectively. Both conditions presented with lentiginous phenotypes. The aim of this study was to arrive at definite diagnoses of three Chinese boys with clinically suspected lentigines-related syndromes. ADAR1, ABCB6, SASH1 and PTPN11 were candidate genes for mutational screening. Sanger sequencing was performed to identify the mutations, whereas bioinformatic analysis was used to predict the pathogenicity of novel missense mutations. Two novel mutations c.1537A>C (p.Ser513Arg) and 1527_1530dupAAGT (p.Leu511Lysfs*21) in SASH1 and a common p.Thr468Met mutation in PTPN11 were detected in three pediatric patients with lentiginous phenotypes, respectively. Comparisons between clinical presentations showed that SASH1-related phenotypes can exhibit hyper- and hypopigmentation on the trunk and extremities, similar to dyschromatosis, while scattered cafe au-lait spots usually appeared in PTPN11-related LEOPARD syndrome. Furthermore, the similarity in the clinical presentations of Peutz-Jeghers syndrome, Laugier-Hunziker syndrome, xeroderma pigmentosum, neurofibromatosis type I, suggesting that these conditions should be added into the differential diagnoses of lentiginous phenotypes.

基因（SASH1和PTPN11）中的致病性突变可分别导致一种与色素沉着缺陷相关的罕见遗传病以及众所周知的豹皮综合征。这两种病症都呈现出雀斑样表型。本研究的目的是对三名临床上疑似雀斑相关综合征的中国男孩做出明确诊断。ADAR1、ABCB6、SASH1和PTPN11是进行突变筛查的候选基因。通过桑格测序来识别突变，同时利用生物信息学分析来预测新的错义突变的致病性。在三名具有雀斑样表型的儿科患者中，分别在SASH1中检测到两个新的突变c.1537A>C（p.Ser513Arg）和1527_1530dupAAGT（p.Leu511Lysfs*21），在PTPN11中检测到一个常见的p.Thr468Met突变。临床表现之间的比较表明，SASH1相关表型可在躯干和四肢表现出色素沉着过度和色素减退，类似于色素异常症，而散在的咖啡牛奶斑通常出现在PTPN11相关的豹皮综合征中。此外，黑斑息肉综合征、劳吉尔 - 亨齐克综合征、着色性干皮病、I型神经纤维瘤病临床表现的相似性表明，这些病症应被纳入雀斑样表型的鉴别诊断中。