Gong Yan, Yin Xiaoqin, Xu Jing, Li Yan, Liu Qingxu, Zhou Shasha, Wang Fei, Lyu Yiqing, Guo Sheng, Huang Wenyan, Li Pin
Department of Endocrinology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Urology, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, China.
Front Endocrinol (Lausanne). 2025 May 23;16:1571467. doi: 10.3389/fendo.2025.1571467. eCollection 2025.
46,XX testicular/ovotesticular differences/disorders of sexual development (TDSD/OTDSD) are rare in childhood and exhibit marked distinctions compared to those in adulthood. This study aimed to summarize the clinical characteristics and outcomes of 46,XX TDSD/OTDSD in childhood.
The sexual development characteristics, hormone profiles, chromosomal analysis, fluorescence hybridization analysis (FISH) sex-determining region Y () analysis (peripheral blood and tissues), molecular genetic etiology, gonadal pathology, risk of gonadal tumors, and assigned gender of 52 patients were collected and analyzed.
The median age at initial presentation was 18 months, and external masculinization score(EMS) within the range of 3 < EMS ≤ 6 was more prevalent. There were no statistical differences in hormone levels [luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T)] between the different age groups. Among the 52 children, 4 showed positive in peripheral blood, whereas none of the 8 children exhibited positive in tissue samples. A total of 29 children underwent whole exome sequencing (WES) and copy number variant (CNV) analysis, but no genetic variants were identified. A total of 47 children underwent gonadal biopsy and showed no evidence of tumors. However, immunohistochemical analysis revealed that 2 of 16 children were OCT3/4 positive. The most frequent type of gonadal pathology (17/47) was bilateral seminiferous tubules. After the assessment, gender assignment was revised in six cases: five individuals originally assigned as female at birth were reassigned as male, while one individual assigned as male was changed to female. In seven cases, the gender of rearing remained undetermined pending further longitudinal psychosocial assessment. Among the female-reared cohort, three children were more than 11 years old. As a result of undergoing bilateral gonadectomy at an early age, the patients were unable to spontaneously enter puberty. However, given their short stature, they are receiving growth hormone (GH) treatment and have not yet received sufficient sex hormone replacement therapy (HRT). Among the male-reared cohort, seven children had entered puberty. The average age at puberty onset was 12 ± 0.87 years, the average testicular volume was 5.14 ± 1.57 mL, the mean basal LH level was 6.44 ± 4.19 IU/L, the mean basal FSH level was 13.18 ± 10.22 IU/L, and the mean basal T was 3.40 ± 1.63 nmol/L.
Compared to adults, children with 46,XX testicular/ovotesticular DSD were very different. -negative children were predominant and tended to have more severe external genital abnormalities during childhood. Peripheral blood or tissue mosaicism was not a prevalent cause and the intricate genetic pathways behind these cases were unknown. There were no statistical differences in hormone levels (LH, FSH, and T) between the different age groups. The assigned gender is mainly male, and the incidence of gonadal tumor risk markers was modest. During adolescence, their testosterone levels could normalize despite elevated FSH and LH levels.
46,XX性睾丸发育异常/卵睾性发育异常（TDSD/OTDSD）在儿童期较为罕见，与成人期表现出明显差异。本研究旨在总结儿童期46,XX TDSD/OTDSD的临床特征及转归。
收集并分析52例患者的性发育特征、激素水平、染色体分析、荧光原位杂交分析（FISH）Y染色体性别决定区（SRY）分析（外周血和组织）、分子遗传学病因、性腺病理学、性腺肿瘤风险及指定性别。
首次就诊的中位年龄为18个月，外生殖器男性化评分（EMS）在3＜EMS≤6范围内更为常见。不同年龄组之间的激素水平[促黄体生成素（LH）、促卵泡生成素（FSH）和睾酮（T）]无统计学差异。52例儿童中，4例外周血SRY呈阳性，而8例儿童的组织样本中均未出现SRY阳性。共有29例儿童接受了全外显子测序（WES）和拷贝数变异（CNV）分析，但未发现基因变异。共有47例儿童接受了性腺活检，未发现肿瘤证据。然而，免疫组化分析显示，16例儿童中有2例OCT3/4呈阳性。最常见的性腺病理类型（17/47）是双侧生精小管。评估后，6例患者的性别指定进行了修订：出生时原指定为女性的5例患者重新指定为男性，而1例原指定为男性的患者改为女性。7例患者的抚养性别在进一步的纵向社会心理评估之前仍未确定。在女性抚养队列中，3例儿童年龄超过11岁。由于早年接受了双侧性腺切除术，这些患者无法自然进入青春期。然而，鉴于其身材矮小，他们正在接受生长激素（GH）治疗，尚未接受足够的性激素替代疗法（HRT）。在男性抚养队列中，7例儿童已进入青春期。青春期开始的平均年龄为12±0.87岁，平均睾丸体积为5.14±1.57 mL，平均基础LH水平为6.44±4.19 IU/L，平均基础FSH水平为13.18±10.22 IU/L，平均基础T为3.40±1.63 nmol/L。
与成人相比，46,XX性睾丸/卵睾性发育障碍的儿童差异很大。SRY阴性儿童占主导，儿童期往往有更严重的外生殖器异常。外周血或组织SRY嵌合体不是常见原因，这些病例背后复杂的遗传途径尚不清楚。不同年龄组之间的激素水平（LH、FSH和T）无统计学差异。指定性别主要为男性，性腺肿瘤风险标志物的发生率适中。在青春期，尽管FSH和LH水平升高，他们的睾酮水平仍可恢复正常。
