Pyle Louise C, Nathanson Katherine L
Translational Medicine/Human Genetics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Am J Med Genet C Semin Med Genet. 2017 Jun;175(2):304-314. doi: 10.1002/ajmg.c.31562. Epub 2017 May 25.
Differences of Sex Development (DSD) includes a wide spectrum of etiologies and phenotypes. A subset of individuals with DSDs are predisposed to gonadal germ cell tumor (GCT). In this setting, GCT risk varies widely, depending on the DSD molecular etiology and penetrance. Prognostication based on molecular diagnosis remains challenging, as natural history data specific to recently identified molecular causes of DSD is lacking. In this review, we provide a framework for the clinical geneticist to consider GCT tumor risk in the patient with DSD. We discuss germ cell development and etiology of GCT growth, along with parameters to consider when recommending prophylactic gonadectomy including fertility, hormonal output, and malignant GTC treatment outcomes. Shortly after the 2006 reorganization of DSD nomenclature, literature reviews of natural history publications stratified GCT risk by a chromosomal, pathological, and hormonal taxonomy. Our 2017 literature review reveals a larger body of publications. However, the broad DSD GCT risk stratification within the 2006 taxonomy remains stable. We discuss precise GCT risk assessment for specific diagnoses, including androgen insensitivity, Smith-Lemli-Opitz, and 46,XY with MAP3K1 mutations and gonadal dysgenesis, as examples. We also examine the GCT risk in non-DSD syndromes, in addition to the cancer risks in DSD patients with dimorphic gonads and genitalia. This review is intended to provide a nuanced assessment of relative germ cell tumor risk in the DSD patient, including modern precise molecular diagnosis, for use by the clinical geneticist.
性发育差异（DSD）涵盖了广泛的病因和表型。一部分患有DSD的个体易患性腺生殖细胞肿瘤（GCT）。在这种情况下，GCT风险差异很大，取决于DSD的分子病因和外显率。基于分子诊断的预后评估仍然具有挑战性，因为缺乏针对最近确定的DSD分子病因的自然病史数据。在本综述中，我们为临床遗传学家提供了一个框架，以便在DSD患者中考虑GCT肿瘤风险。我们讨论了生殖细胞发育和GCT生长的病因，以及在推荐预防性性腺切除术时需要考虑的参数，包括生育能力、激素分泌和恶性GTC治疗结果。2006年DSD命名法重新组织后不久，对自然病史出版物的文献综述根据染色体、病理和激素分类对GCT风险进行了分层。我们2017年的文献综述揭示了更多的出版物。然而，2006年分类法中的广泛DSD GCT风险分层仍然稳定。我们以雄激素不敏感、史密斯-利姆利-奥皮茨综合征以及具有MAP3K1突变和性腺发育不全的46,XY为例，讨论了针对特定诊断的精确GCT风险评估。我们还研究了非DSD综合征中的GCT风险，以及具有两性性腺和生殖器的DSD患者的癌症风险。本综述旨在为临床遗传学家提供对DSD患者相对生殖细胞肿瘤风险的细致评估，包括现代精确分子诊断。
