Denys-Drash syndrome (DDS) is caused by germ line mutations in the WT1 gene, affecting both 46XY and 46XX patients and resulting in abnormal gonadal and renal phenotypes. The WT1 transcription factor plays an essential role on both gonadal and kidney development, through a delicate balance between its two major isoforms, +KTS and -KTS. WT1 mutations in DDS affect the DNA-binding site, most frequently involving exons 8 and 9, and result in impairment of WT1 function as a transcription factor without altering the +KTS/-KTS.
The type of renal lesion observed in DDS is very characteristic, with diffuse mesangial sclerosis associated with hypertrophied vacuolized podocytes, markedly dilated tubules and interstitial fibrosis, similar to Finnish type congenital nephrotic syndrome. The nephrotic syndrome in DDS is rapidly progressive and occurs at an early age (usually before 4 years), sometimes during the first weeks of life. An additional important feature of DDS is the increased risk for the development of Wilms tumors and the presence of nephroblastomatosis.
In DDS, 46XX patients show a normal gonadal phenotype. However, 46XY individuals present with abnormal testicular development reflected by dysgenetic testes. Morphologically, dysgenetic testes are thought to represent partial or defective testicular differentiation. The main histological landmark is an abnormal tunica albuginea with irregular collagenization and variable thickness; occasionally, seminiferous cords penetrate through it, opening up at the testicular surface. In addition, areas of ovarian-like stroma are commonly seen. The seminiferous cords may be normal or near normal, with reduced germ cells, irregular shapes and intra-tubular calcifications, and are intermixed with areas of more immature cords. The existence of bilateral dysgenetic testes, as observed in DDS, characterizes a spectrum of clinical manifestations known as partial gonadal dysgenesis, previously referred to as dysgenetic male pseudo-hermaphroditism. The external phenotype will depend on the amount of gonadal differentiation towards a normal testis, and manifestations will range from normal male genitalia to different degrees of ambiguous genitalia and persistent Müllerian structures. Cryptorchidism is nearly always present.
DDS should be differentiated from Frasier syndrome (FS), also caused by mutations in the WT1 gene; in FS, mutations occur on intron 9 with resulting abnormal splicing and decreased +KTS/-KTS ratio. In contrast to DDS, FS presents with complete gonadal dysgenesis in XY patients, reflected by male-to-female sex reversal and a normal female genitalia. Morphologically, gonads on FS are streak gonads with no evidence of differentiation towards testicular tissue. In addition, FS patients show a distinct renal lesion, with focal and segmental glomerulosclerosis. The typical clinical picture in FS is that of a phenotypically female teenager patient who presents with primary amenorrhea, abnormal secondary sexual development and/or steroid-resistant nephrotic syndrome.
Dysgenetic gonads containing Y chromosome material in their genome (specially the "GBY" region, encoding the TSPY gene) are at increased risk for the development of neoplasms. The presence of SRY or other sex determining genes is irrelevant in this context. Germ-cell tumors are by far the most frequently occurring tumors in those patients, always preceded by the presence of an in situ neoplastic lesion (either CIS/ITGCNU or gonadoblastoma). The finding of other types of gonadal tumors in dysgenetic testes is extremely uncommon.
The occurrence of testicular JGCT is much rarer than its ovarian counterpart, and affects mainly neonates or infants. Testicular JGCT carries a good prognosis and lacks any type of hormonal activity, a common feature observed in ovarian JGCT. It has been described in dysgenetic testes of few patients with mixed gonadal dysgenesis; differently from partial gonadal dysgenesis, these patients have a 45X0/46XY mosaic karyotype, and two distinct gonadal phenotypes (a dysgenetic testis in one side and a streak gonad on the other). Only two cases of JGCT arising in DDS patients, similar to the present case, have been published.
JGCT has never been described on streak gonads, suggesting that minimal differentiation of sex cords is needed for its development. It is also noteworthy that neoplastic tubules and cysts appear to be continuous with normal seminiferous cords, supporting an origin for the tumor cells on immature sex cord cells/Sertoli cell precursors. In addition, it could be also speculated whether neoplastic transformation of sex cord cells indicate a potential for ovarian differentiation on these maldeveloped gonads.
Morphologically, the differential diagnosis of JGCT arising on dysgenetic testis must be made with gonadoblastoma, in which a component of sex cord/somatic cells is also present, as well as Call-Exner bodies; however, gonadoblastomas also display a germ cell component, and the use of special stains (Oct 3/4, PLAP and c-kit) to highlight the latter may be necessary.
In summary, the possibility of gonadal dysgenesis should be always suspected on cases of JGCT arising in testicular tissue. By the other hand, JGCT must be included in the spectrum of neoplasms arising in dysgenetic testes. It is important to distinguish JGCT from other gonadal neoplasms, since it carries a better prognosis than germ cell tumors.
Contributed by Mariana Cajaiba, MD