先天性类脂质性肾上腺增生症临床及StAR基因突变分析

摘要

目的 探讨先天性类脂质性肾上腺皮质增生症患儿的临床及类固醇生成急性调控蛋白(steroidogenic acute regulatory protein,StAR)基因突变特点.方法 收集2例先天性类脂质性肾上腺皮质增生症患儿临床资料,采集患儿及其父母静脉血2 mL,用二代测序技术对2例患儿44个肾上腺皮质功能减退相关基因的外显子及其相邻内含子进行检测,对所检出的 StAR 基因突变用 sanger 测序验证,并对患儿父母 StAR 基因进行验证分析;对StAR基因突变相关文献进行复习.结果 2例患儿均为46XX 女性,均为新生儿期发病;以皮肤色素沉着、呕吐、体重不增等肾上腺皮质功能减退症状为主要表现;实验室检查示血低钠高钾、促肾上腺皮质激素显著增高,皮质醇及17羟孕酮降低,睾酮、雄烯二酮、脱氢表雄酮等各雄性激素不高;经皮质激素氢化可的松及9α-氟氢可的松替代治疗后生长正常;母妊娠史及患儿出生史、家族史无特殊.StAR基因突变分析显示病例1为 c.229 G>A(p.Q77X)及 c.772G>A(p.Q258X)复合杂合已知致病突变;病例2为 c.707_708delAG ins CTT(p.K236Tfs*47)纯合已知致病突变;2例患儿父母均为突变携带者.结合中国已报道13例 StAR基因突变患儿,c.772G>A(p.Q258X)突变发生率为53.3%(8/15),c.707_708delAG ins CTT(p.K236Tfs*47)发生率为33.3%(5/15).结论 17羟孕酮及雄性激素不高的原发性肾上腺皮质功能减退患儿,尤其是女性表型者,应行染色体及 StAR 基因检测;c.772C>T(p. Q258X)及 c.707_708delAG ins CTT(p.K236Tfs*47)突变可能为中国 StAR 基因突变热点;适当皮质激素替代治疗可使患儿长期生存、生长正常.%Objective To analyze the clinical features and steroidogenic acute regulatory protein (StAR)gene mutation in children with lipoid congenital adrenal hyperplasia.Methods The clinical data of 2 children with lipoid congenital adrenal hyperplasia were collected in detail. Two milliliters venous blood of the children and their parents were collected and the exons and adjacent introns of 44 adrenal cortical dysfunction related genes of the 2 children were detected by second generation sequencing.The detected StAR gene mutation was confirmed by sanger sequencing.The StAR gene of children's parents was verified and analyzed.Literatures related to StAR gene mutation were reviewed.Results Both the 2 cases were 46XX females and neonatal onset.The main symptoms were skin pigmentation,vomiting and no weight gain;Laboratory examination showed hyponatremia and hyperkalemia,elevated adrenocorticotrophic hormone levels,decreased serum cortisol and 1 7 hydroxyprogesterone and androgens levels.The growth were normal after hydrocortisone and 9α-fluorocortisone replacement therapy.There were no special events in the maternal pregnancy history or the childern's birth history as well as family history.StAR gene analysis showed that case 1 was c.229G>A(p.Q77X )and c.772G>A(p. Q258X )compound heterozygous mutation.Case 2 was c.707_708delAG ins CTT(p.K236Tfs*47)homozygous mutation.All are known pathogenic mutations.Both parents were mutated carriers.Together with the reported 1 3 cases of StAR gene mutation in China,the incidence of c. 772G>A(p.Q258X)and c.707_708delAG ins CTT(p.K236Tfs*47)mutation were 53.3%(8/15) and 33.3% (5/15)respectively.Conclusion The chromosome and StAR gene should be detected in patients with primary adrenocortical dysfunction with low 1 7 hydroxyprogesterone and androgens,especially in female phenotypes.The mutation of c.772G>A(p.Q258X )and c.707_708delAG ins CTT(p.K236Tfs*47)may be the hot spots of StAR gene mutation in China. Children with lipoid congenital adrenal hyperplasia can survive for a long time and grow normally after appropriate corticosteroid replacement therapy.