Kazal 5型丝氨酸蛋白酶抑制剂基因突变致新生儿Netherton综合征一例并文献复习

Netherton syndrome caused by serine protease inhibitor of Kazal type 5 gene mutation:a case report and literature review

目的探讨Kazal 5型丝氨酸蛋白酶抑制剂(serine protease inhibitor of Kazal type 5,SPINK5)基因突变致新生儿Netherton综合征(Netherton syndrome,NS)的临床特征及分子遗传学特点。方法回顾性分析2018年11月上海交通大学附属儿童医院收治的1例新生儿NS病例的临床资料,采用高通量测序及Sanger测序对其SPINK5基因进行分析。在万方数据库、中国知网和PubMed数据库中检索2月龄以内确诊且有SPINK5基因分析结果的NS病例。结合本例患儿和文献报道的病例,总结新生儿NS的临床特点、基因突变情况、治疗及随访情况。采用描述性统计分析。结果本例患儿生后陆续出现全身皮肤弥漫性红斑及脱屑、毛发稀疏、反复感染等表现,实验室检查发现血IgE升高(111 IU/ml),光学显微镜下毛发呈"竹节发"。SPINK5基因分析发现患儿存在c.2468dup(p.Lys824Glufs^(*)4)和c.377_378del(p.Tys126^(*))复合杂合突变,家系分析发现患儿的2个突变分别遗传自其父亲和母亲,确诊为SPINK5基因突变致NS。经抗感染、注射丙种球蛋白、皮肤护理等综合治疗后皮疹好转,但反复感染,后放弃治疗自动出院,生后2月龄死于感染。共检索到NS病例报道11例,合并本例共12例NS新生儿。总结12例患儿最常见临床表现发现,有早期皮肤弥漫性红斑及脱屑12例、感染8例、毛发干结7例、高钠血症性脱水7例、高IgE 5例、生长迟缓4例、呼吸衰竭3例、特应性体质2例、腹泻2例及吞咽不协调、低体温、喘息、高血压、肝衰竭、代谢性碱中毒各1例。结论NS由SPINK5基因突变导致,新生儿期NS临床表现多不典型。生后早期出现全身皮肤弥漫性红斑及脱屑、反复感染、毛发干结,尤其血IgE偏高的患儿,应考虑NS可能,基因检测有助于早期诊断、指导治疗,并为遗传咨询提供依据。

Objective To investigate the clinical and molecular genetic features of neonatal congenital Netherton syndrome(NS)caused by mutations in serine protease inhibitor of Kazal type 5(SPINK5)gene.Methods This study retrospectively analyzed the clinical data of an NS neonate admitted to Shanghai Children's Hospital in November 2018.SPINK5 gene was analyzed using high-throughput sequencing and Sanger sequencing.Relevant articles were retrieved from various databases including China National Knowledge Infrastructure,Wanfang and PubMed,and the reported cases who were diagnosed as NS within two months after birth with SPINK5 gene sequencing results were reviewed.Clinical features,gene mutations,treatment and follow-up results of NS were summarized using descriptive statistical analysis.Results The patient presented with diffuse erythema and desquamation,sparse hair and repeated infections shortly after birth.Laboratory tests revealed elevated IgE(111 IU/ml)and"invagination-like"change in the hair under optical microscope.SPINK5 gene analysis found that there were compound heterozygous mutations of c.2468dup(p.Lys824Glufs^(*)4)and c.377_378del(p.Tys126^(*))in the child.The pedigree analysis found that the two mutations were respectively inherited from the father and the mother,which supported the diagnosis of NS caused by SPINK5 gene mutation.Though skin rash improved after comprehensive treatments including anti-infection therapy,gamma globulin injection and skincare,the patient suffered from recurrent infection and was discharged from the hospital after giving up treatment and died of infection at two months old.Eleven NS cases were retrieved from literature and altogether 12 cases were analyzed here.The most common clinical manifestations in the 12 patients were early skin diffuse erythema and desquamation(12/12),infection(8/12),dry hair(7/12),hypernatremia dehydration(7/12),high IgE(5/12),growth retardation(4/12),respiratory failure(3/12),atopic constitution(2/12),diarrhea(2/12),dysphagia(1/12),hypothermia(1/12),wheezing(1/12),hypertension(1/12),liver failure(1/12)and metabolic alkalosis(1/12).Conclusions NS is caused by SPINK5 gene mutation with atypical manifestations in neonates.Neonates with diffuse erythema and desquamation of the skin,repeated infections,dry hair and especially with high blood IgE should be considered the possibility of NS.Genetic testing is conducive to early diagnosis,guiding treatment decisions and providing a basis for genetic counseling.