一新的雄激素受体突变致雄激素不敏感综合征1例并文献复习

A novel mutation of the androgen receptor gene causes androgen insensitivity syndrome： a case report and literature review

目的 对1例46，XY性腺发育异常的患儿进行雄激素受体（AR）基因检测，以提高对雄激素不敏感综合征（AIS）的认识和诊断水平。方法 对患儿临床资料进行分析，包括体格检查、相关实验室检查、染色体核型分析、盆腔B超、盆腔磁共振成像（MRI）等。同时进行AR基因突变分析，抽取患儿及其父母外周血样本，对患儿、患儿父母AR基因所有外显子进行扩增，然后直接测序。结果 患儿7岁2个月，女性外阴，阴蒂2.0 cm×0.8 cm，阴道口可见，双侧腹股沟区可及大小约1.5 cm×0.8 cm包块。人绒毛膜促性腺激素（HCG）激发试验结果：激发前睾酮、雄烯二酮及双氢睾酮水平分别为0 nmol/L、1.78 nmol/L、0.07 nmol/L，HCG激发后其血清水平分别为4.69 nmol/L、2.10 nmol/L、0.33 nmol/L。染色体核型为46，XY。盆腔B超：盆腔内未显示正常子宫、卵巢声像，未显示明显阴道回声，双侧腹股沟管内环处分别显示低回声团块，边界欠清，左侧1.4 cm×1.0 cm×0.8 cm，右侧1.5 cm×0.7 cm×0.8 cm，团块回声均匀，低回声团内显示稀疏点状血流信号，超声诊断为双侧腹股沟管低回声团，考虑为睾丸。双侧肾、输尿管、膀胱、肾上腺、腹膜后B超未见异常。盆腔MRI平扫＋增强显示直肠与膀胱之间见一管道影，长度40 mm，考虑为阴道，但其末端未见正常形态及结构的子宫、卵巢影。DNA测序结果显示患儿AR基因第2外显子上发生c.1685T〉C杂合突变，造成该基因编码氨基酸的第562位由异亮氨酸改变为苏氨酸。检索国内外文献及相关数据库未见该突变报道，经计算机软件预测该突变为有害突变。对患儿母亲进行该位点的Sanger验证，发现同样位点突变；而患儿父亲该位点未见异常。结论 AR基因第2外显子c.1685 T〉C（p.Ile562Thr ）突变，是一个新的AR基因突变位点，结合患儿临床表现及计算机软件预测结果推断该位点的突变可导致AIS的发生。

Objective To explore the mutation of androgen receptor（AR） gene in a patient with 46, XY disorder of sex development（DSD）and to improve the diagnostic level and understanding of androgen insensitivity syndrome（AIS）.Methods The clinical data of the child was analyzed, including physical examination, relevant laboratory examination, karyotype, pelvic B ultrasound, pelvic magnetic resonance imaging（MRI） and AR gene mutation.The peripheral blood of the child and his parents were drawn, and peripheral blood DNA was extracted.The polymerase chain reaction（PCR）-DNA sequencing method was used to amplify all exons of the AR gene in the child and his parents.Then, they were directly sequenced.Results A 7-years and 2-months old child who suffered from DSD, revealed physical examination that the child had normal female external genitalia, as the clitoris length was 2.0 cm×0.8 cm, with visible vaginal opening, and there were masses at bilateral inguinal region, with a size of 1.5 cm×0.8 cm.The results of human chorionic gonadotropin（HCG） stimulation test： testosterone was 0 nmol/L, androstenedione was 1.78 nmol/L, dihydrotestosterone was 0.07 nmol/L before HCG was injected; but testosterone was 4.69 nmol/L, androstenedione was 2.10 nmol/L, dihydrotestosterone was 0.33 nmol/L after HCG was injection.Sex chromosome analysis reported 46, XY karyotype.Pelvic B ultrasound revealed the absence of a uterus and ovaries and the presence of bilateral testes like gonad at each side of internal inguinal ring, with a size of 1.4 cm×1.0 cm×0.8 cm in the left, 1.5 cm×0.7 cm×0.8 cm in the right; but the kidney, ureter, urinary bladder, adrenal gland and retroperitoneal for B ultrasound revealed no abnormality.Pelvic MRI（non-enhanced and enhanced） showed the presence of a blind ending vagina between rectum and urinary bladder（40 mm in depth） and the absence of uterus and ovarian tissue.DNA sequencing found one c. 1685T〉C heterozygous mutation（p.Ile562Thr ） on exon 2 of AR gene in the child.But retrieving and summarzing documents of the domestic and foreign information databases and websites, the locus mutation of AR gene had never been reported.The structure prediction of the mutated protein（ Polyohen2 and SIFT software） was significantly changed.By verifying the locus site of the parents of this child, it was found that his mother carried the same mutation, but his father was found to be normal.Conclusions A c. 1685 T〉C mutation（ p. Ile562Thr ） on exon 2 of AR gene is a novel mutation.Combined with the patient′s clinical manifestations and computer prediction results, it may suggest that the novel mutation of AR gene can lead to the occurrence of AIS.