Juniarto A Zulfa, van der Zwan Yvonne G, Santosa Ardy, Ariani Mahayu Dewi, Eggers Stefanie, Hersmus Remko, Themmen Axel P N, Bruggenwirth Hennie T, Wolffenbuttel Katja P, Sinclair Andrew, White Stefan J, Looijenga Leendert H J, de Jong Frank H, Faradz Sultana M H, Drop Stenvert L S
Division of Human Genetics, Center for Biomedical Research Faculty of Medicine Diponegoro University (FMDU), Semarang, Indonesia.
Department of Paediatrics, Division of Endocrinology, Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, The Netherlands.
Clin Endocrinol (Oxf). 2016 Aug;85(2):247-57. doi: 10.1111/cen.13051. Epub 2016 Apr 4.
The objective of this study was to determine the aetiological spectrum of disorders of sex development (DSD) in a large cohort of underprivileged and undiagnosed patients from Indonesia.
A total of 286 patients with atypical external and/or internal genitalia were evaluated using clinical, hormonal, molecular genetic and histological parameters.
The age (years) at presentation was 0-0·5 in 41 (14·3%), >0·5-12 in 181 (63·3%) and >12 in 64 cases (22·4%). 46,XY DSD was most common (68·2%, n = 195), 46,XX DSD was found in 23·4% (n = 67) and sex chromosomal DSD in 8·4% (n = 24). In 61·2% of 46,XX DSD patients, 17·9% of 46,XY DSD patients and all sex chromosome DSD patients (29·4% in total), a final diagnosis was reached based on genetic or histological gonadal tissue evaluation. 17-hydroxyprogesterone and androstenedione levels were the most distinctive parameters in 46,XX DSD patients. In 46,XY DSD, diagnostic groups were identified based on the external masculinization score: androgen action disorder (AAD), unknown male undermasculinization (UMU), and gonadal dysgenesis (GD). LH, FSH and testosterone levels were most informative especially in the older age group. HCG tests were of no additional value as no patients with androgen synthesis disorders were found. Hormonal profiles of patients with sex chromosome DSD and a Y-chromosome sequence containing karyotype showed high levels of LH and FSH, and low levels of AMH, inhibin B and testosterone compared with the normal male range. Gene mutations were found in all patients with CAH, but in only 24·5% and 1·8% of patients with AAD and UMU. In 32% of 46,XY GD patients, copy number variants of different genes were found.
A stepwise diagnostic approach led to a molecularly or histologically proven final diagnosis in 29·4% of the patients. The most informative parameters were serum levels of 17-hydroxyprogesterone and androstenedione in 46,XX DSD patients, and serum LH, FSH and testosterone levels in 46,XY DSD patients.
本研究的目的是确定来自印度尼西亚的一大群贫困且未确诊患者的性发育障碍（DSD）的病因谱。
使用临床、激素、分子遗传学和组织学参数对总共286例具有非典型外生殖器和/或内生殖器的患者进行评估。
就诊时年龄（岁）为0至0.5岁的有41例（14.3%），>0.5至12岁的有181例（63.3%），>12岁的有64例（22.4%）。46,XY DSD最为常见（68.2%，n = 195），46,XX DSD占23.4%（n = 67），性染色体DSD占8.4%（n = 24）。在46,XX DSD患者的61.2%、46,XY DSD患者的17.9%以及所有性染色体DSD患者（总计29.4%）中，基于遗传或组织学性腺组织评估得出了最终诊断。17-羟孕酮和雄烯二酮水平是46,XX DSD患者中最具特征性的参数。在46,XY DSD中，根据外生殖器男性化评分确定诊断组：雄激素作用障碍（AAD）、不明男性性发育不全（UMU）和性腺发育不全（GD）。促黄体生成素（LH）、促卵泡生成素（FSH）和睾酮水平最具参考价值，尤其是在年龄较大的患者组中。人绒毛膜促性腺激素（HCG）检测没有额外价值，因为未发现雄激素合成障碍患者。与正常男性范围相比，性染色体DSD且核型包含Y染色体序列的患者的激素谱显示LH和FSH水平高，抗苗勒管激素（AMH）、抑制素B和睾酮水平低。所有先天性肾上腺皮质增生症（CAH）患者均发现基因突变，但AAD和UMU患者中分别只有24.5%和l.8%发现基因突变。在46,XY GD患者的32%中，发现了不同基因的拷贝数变异。
逐步诊断方法使29.4%的患者获得了分子或组织学证实的最终诊断。最具参考价值的参数是46,XX DSD患者的血清17-羟孕酮和雄烯二酮水平，以及46,XY DSD患者的血清LH、FSH和睾酮水平。
