진성반음양과 혼합 생식샘 발생장애를 가진 환자 생식샘의 조직학적 및 분자유전학적 분석

Abstract

True hermaphroditism (ovotesticular DSD) and mixed gonadal dysgenesis (MGD) have an overlapping clinical feature including ambiguous genitalia, endocrinologic data, and karyotypes, however, differential diagnosis between the two conditions is clinically important because the risk of malignant germ cell tumor, fertility potential, and surgical treatment methods are quite different. Although the pathogenesis of the two conditions remains unclear, the occurrence of both conditions in the same family or in the twins have been reported, which led us to hypothesize that these two conditions could be genetically related. To clarify the genetic relationship between the two condition, we analyzed the clinicopathologic features and molecular genetic profiles of gonadal tissue in patients with ovotestis (n=13) and MGD (n=12) by whole exome sequencing. Cytogenetic results of the 13 patients with ovotestis showed 46, XX (n=9) or 46, XX/46, XY chimerism (n=4), whereas 12 patients with MGD showed 45, X/46, XY (n= 5) most commonly and other mosaic cell lines, which could be derived from 46, XY through mitotic or meiotic errors, suggesting that the two conditions are not genetically related. Histologically, the most significant difference was the presence or absence of well-developed ovarian tissue in ovotestis and MGD, respectively, however, there were previously undescribed minor component of additional dysgenetic gonadal tissue at the peripheral portion of the ovotestis. In whole exome sequencing, various types of somatic and germline mutations were identified in both groups, but clinical significance or gene function have not been clarified yet. Four patients (30.8%) with ovotestis in our study had 46, XX/ 46, XY chimerism, which could be the cause of ovotesticular development. One of eight patients with 46, XX/SRY-negative ovotestis revealed WNT4 and WNT7A mutation, which might have downregulated beta-catenin pathway, and subsequent testicular differentiation, but remaining seven patients with 46, XX/SRY-negative, the cause of ovotestis development could not be explained. Based on the gene ontology analysis, the mutated genes in ovotestis, including FASN, ACADVL, and ME1 gene were significantly enriched in pathway associated with lipid metabolism, whereas those in patients with MGD were associated with cytokine production, small molecule metabolism, endocrine process, steroid biosynthesis. In conclusion, ovotestis and MGD appear to have different pathogenetic mechanisms, although some of the clinical and histopathologic features are overlapping. Functional relationship between the mutated genes and the abnormal sexual development need to be further clarified.