Disorders of sex development: update on the genetic background, terminology and risk for the development of germ cell tumors

Disorders of sex development (DSD) are defined as a congenital condition in which development of chromosomal, gonadal or anatomical sex is atypical. DSD patients with gonadal dysgenesis or hypovirilization, containing part of the Y chromosome (GBY), have an increased risk for malignant type II germ cell tumors (GCTs: seminomas and nonseminomas). DSD may be diagnosed in newborns (e.g., ambiguous genitalia), or later in life, even at or after puberty. Here we describe three independent male patients with a GCT; two were retrospectively recognized as DSD, based on the histological identification of both carcinomain situand gonadoblastoma in a single gonad as the cancer precursor. Hypospadias and cryptorchidism in their history are consistent with this conclusion. The power of recognition of these parameters is demonstrated by the third patient, in which the precursor lesion was diagnosed before progression to invasiveness. Early recognition based on these clinical parameters could have prevented development of (metastatic) cancer, to be treated by systemic therapy. All three patients showed a normal male 46,XY karyotype, without obvious genetic rearrangements by high-resolution whole-genome copy number analysis. These cases demonstrate overlap between DSD and the so-called testicular dysgenesis syndrome (TDS), of significant relevance for identification of individuals at increased risk for development of a malignant GCT.

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Malignant Germ Cell Tumors and Their Precursor Gonadal Lesions in Patients with XY-DSD: A Case Series and Review of the Literature

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18115648 ◽

2021 ◽

Vol 18 (11) ◽

pp. 5648

Author(s):

Sahra Steinmacher ◽

Sara Y. Brucker ◽

Andrina Kölle ◽

Bernhard Krämer ◽

Dorit Schöller ◽

...

Keyword(s):

Germ Cell ◽

Malignant Transformation ◽

Ideal Point ◽

Germ Cell Tumors ◽

Disorders Of Sex Development ◽

Case Series ◽

Cell Adenoma ◽

Sex Development ◽

Number Of Patients ◽

Malignant Germ Cell Tumors

The risk of gonadal germ cell tumors is increased over the lifetime of patients with XY-disorders of sex development (XY-DSD). The aim of this study was to evaluate clinical features and histopathological outcome after gonadectomy in patients with XY-DSD to assess the risk of malignant transformation to gonadal germ cell tumors. Thirty-five women treated for XY-DSD at our hospital between 2003 and 2020 were enrolled in this study. Twenty-seven (77%) underwent prophylactic gonadectomy, 10 (29%) at our department and 17 (48%) at external hospitals. Eight (23%) patients didn´t receive gonadectomy. Of the patients who underwent a surgical procedure at our hospital, two patients were diagnosed with a unilateral seminoma, one patient with a bilateral and one patient with a unilateral Sertoli cell adenoma. According to these findings, preventive gonadectomy in patients with XY-DSD should be taken into consideration. Guidelines concerning the necessity of gonadectomy to avoid malignant transformation are still lacking. The risk of malignant germ cell tumors from rudimentary gonads has not been investigated sufficiently to date, as it is mostly based on case series due to the rarity of the condition. In our study we retrospectively analyzed patients who partly underwent bilateral gonadectomy, aiming to fill this gap. Concerning the ideal point of time for gonadectomy, further studies with a higher number of patients are needed.

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Malignant Gonadal Germ Cell Tumors (Other Than Pure Germinoma) in Patients With Disorders of Sex Development

The American Journal of Surgical Pathology ◽

10.1097/pas.0000000000001815 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Sheila E. Segura ◽

Robert H. Young ◽

Esther Oliva ◽

Thomas M. Ulbright

Keyword(s):

Germ Cell ◽

Germ Cell Tumors ◽

Disorders Of Sex Development ◽

Sex Development

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WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

Sexual Development ◽

10.1159/000517373 ◽

2021 ◽

pp. 1-9

Author(s):

Maria T.M. Ferrari ◽

Andreia Watanabe ◽

Thatiane E. da Silva ◽

Nathalia L. Gomes ◽

Rafael L. Batista ◽

...

Keyword(s):

Kidney Development ◽

Wilms Tumor ◽

Genetic Diagnosis ◽

Germ Cell Tumors ◽

Disorders Of Sex Development ◽

Medical Attention ◽

Primary Amenorrhea ◽

Normal Female ◽

Sex Development ◽

Pathogenic Variants

Wilms’ tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys–Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms’ tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.

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Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology

International Journal of Molecular Sciences ◽

10.3390/ijms20205017 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5017 ◽

Cited By ~ 4

Author(s):

Leendert H. J. Looijenga ◽

Chia-Sui Kao ◽

Muhammad T. Idrees

Keyword(s):

Germ Cell ◽

Y Chromosome ◽

Association Studies ◽

Cell Cancer ◽

Disorders Of Sex Development ◽

Germ Cell Cancer ◽

Genome Wide Association Studies ◽

Sex Development ◽

Stage Of Development ◽

Increased Risk

The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY region, as well as anatomical localization and degree of testicularization and maturation of the gonad. The latter specifically relates to the germ cells present being at risk when blocked in an embryonic stage of development. GGCC originates from either germ cell neoplasia in situ (testicular environment) or gonadoblastoma (ovarian-like environment). These precursors are characterized by presence of the markers OCT3/4 (POU5F1), SOX17, NANOG, as well as TSPY, and cKIT and its ligand KITLG. One of the aims is to stratify individuals with an increased risk based on other parameters than histological investigation of a gonadal biopsy. These might include evaluation of defined susceptibility alleles, as identified by Genome Wide Association Studies, and detailed evaluation of the molecular mechanism underlying the DSD in the individual patient, combined with DNA, mRNA, and microRNA profiling of liquid biopsies. This review will discuss the current opportunities as well as limitations of available knowledge in the context of predicting the risk of GGCC in individual patients.

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