A practical guide for evaluating gonadal germ cell tumor predisposition in differences of sex development

Abstract

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.

A Case of 45,X/46,XY Mosaicism Presenting as Swyer Syndrome

“…Swyer syndrome, like all cases of gonadal dysgenesis associated with the presence of a Y chromosome, is associated with a high incidence of gonadoblastoma and germ cell malignancies. 4 As seen in our case, the presence of dysgerminoma and gonadoblastoma might be associated with hormone production that results in the development of secondary sexual characteristics and intermittent vaginal bleeding. 46,XY CGD is a genetically heterogeneous group of disorders that affect early gonadal development.…”

“…3 In all cases of gonadal dysgenesis, the presence of the Y chromosome increases the risk of germ cell neoplasms. 4 However, the presence or absence of a 45,X lineage is also important for prognosis.…”

46, XX Ovotesticular disorder of sex development (true hermaphroditism) with seminoma

“… [15] The risk for tumor development depends on many parameters, including gonadal morphology, germ cell location, presence of germ cells, genital morphology, patient age, and presence of TSPY. [ 4 16 ] Furthermore, the risk for GCT development varies among different DSDs. Cools and colleagues divided DSDs into several risk groups for the development of type II GCT [4] and reported that OT-DSD patients were at a low risk of GCT development.…”

Clinical and Genetic Characteristics of 17 α-Hydroxylase/17, 20-Lyase Deficiency: c.985_987delTACinsAA Mutation of CYP17A1 Prevalent in the Chinese Han Population

“…SRY gene was detected in the seven patients with XY karyotype, suggesting that testicle should be present in the body, likely to be located in inguinal region. Given the potential risk of malignancy in the suspected testicles which do not descend into the scrotum, surgical exploration is suggested in order to search the testicles which should be removed when necessary (13). In our study, testicles could be found in only 2 out of 7 XY patients by US or MRI.…”

“…The chromosome karyotype was 46, XY, and SRY gene was detected. However, B-type ultrasound (US) and MRI showed no uterus and ovaries, also no testis was detected in groin and abdominal cavity.Therefore, surgical exploration and orchiectomy were performed to avoid the potential risk of malignancy in the suspected testicles(13). Histopathological findings showed the undeveloped testis.…”