Gonadal Development and Tumor Formation at the Crossroads of Male and Female Sex Determination

Cools, Martine; Wolffenbuttel, KP; Drop, S. L. S.; Oosterhuis, J. Wolter; Looijenga, Leendert H. J.

doi:10.1159/000329477

Cited by 75 publications

(49 citation statements)

References 189 publications

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“…The invasive GGCC occurring in AIS, mainly seminoma, belong to the group of the type II malignant germ cell tumours of the testis and dysgenetic gonad [for a review, see 10], and are for many years preceded by the presence of an in situ neoplastic lesion, termed now according to the most recent WHO classification, germ cell neoplasia in situ (GCNIS) [11]. An overview of reported cases in children and adults since 2000 is presented in Table 1; before that time, a molecular genetic diagnosis was most often not available and published series mostly reported on a mix of clinical diagnoses, including also many cases with gonadal dysgenesis, who are known to have a much higher risk [12]. Whereas the risk for GGCC has been estimated at less than 1% in childhood, uncertainty prevails concerning this risk in retained gonads after adolescence [13].…”

Section: Introductionmentioning

confidence: 99%

Management of Gonads in Adults with Androgen Insensitivity: An International Survey

et al. 2018

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Background: Complete and partial androgen insensitivity syndrome (CAIS, PAIS) are associated with an increased risk of gonadal germ cell cancer (GGCC). Recent guidelines recommend gonadectomy in women with CAIS in late adolescence. Nevertheless, many adult women prefer to retain their gonads. Aims: This study aims to explore attitudes towards gonadectomy in AIS in centres around the world, estimate the proportion of adults with retained gonads and/or who developed GGCC, and explore reasons for declining gonadectomy. Methods: A survey was performed among health care professionals who use the International DSD Registry (I-DSD). Results: Data were provided from 22 centres in 16 countries on 166 women (CAIS) and 26 men (PAIS). In CAIS, gonadectomy was recommended in early adulthood in 67% of centres; 19/166 (11.4%) women refused gonadectomy. Among 142 women who had gonadectomy, evidence of germ cell neoplasm in situ (GCNIS), the precursor of GGCC, was reported in 2 (1.4%) out of 8 from whom pathology results were formally provided. Nine out of 26 men with PAIS (34.6%) had retained gonads; 11% of centres recommended routine gonadectomy in PAIS. Conclusion: Although development of GGCC seems rare, gonadectomy after puberty is broadly recommended in CAIS; in PAIS this is more variable. Overall, our data reflect the need for evidence-based guidelines regarding prophylactic gonadectomy in AIS.

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Section: Introductionmentioning

confidence: 99%

Management of Gonads in Adults with Androgen Insensitivity: An International Survey

et al. 2018

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“…8,9 Elucidating the underlying causes of DSD can facilitate sex assignment and lead to improved management, a better prognosis and a more accurate evaluation of gonadal function and gonadal germ cell cancer risk. 10 So far, mutations in genes encoding nuclear receptors, such as NR5A1 (also known as the steroidogenic factor 1 gene, or SF1) 11 and the androgen receptor NR3C4 gene 12 have been implicated in DSD pathogenesis as well as the duplication of the nuclear receptor subfamily 0 group B member 1 gene (NR0B1, DAX1). 13 Here, we identified biallelic and monoallelic estrogen receptor 2 (ESR2) variants in one syndromic and two nonsyndromic 46,XY DSD cases, respectively, putting forward ESR2 as a novel disease gene for 46,XY DSD and expanding the spectrum of nuclear receptors implicated in 46,XY DSD etiology.…”

Section: Introductionmentioning

confidence: 99%

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Baetens

Güran

Mendonça

et al. 2018

Genetics in Medicine

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Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.Methods: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-β (ER-β) was performed in an 8-week-old human male embryo.

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“…A gradual transition toward undifferentiated gonadal tissue, containing both SOX9 and FOXL2-positive cells at the upper and lower poles were identified. Undifferentiated gonadal tissue is a gonadal pattern found specifically in patients with gonadal dysgenesis and is typically characterized by the combined expression of FOXL2 and SOX9 (usually with a preponderance of FOXL2), suggesting limited differentiation of the supportive cell lineage into pre-granulosa and preSertoli cells 9 . Immature OCT3/4-positive germ cells were also found, either dispersed in ovarian-like stroma or organized together with Sertoli/granulosa cells in cord-like structures, reminiscent of sex cords.…”

Section: Resultsmentioning

confidence: 99%

A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development

et al. 2011

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Disorders of sex development (DSD) are congenital conditions where chromosomal, gonad or genital development is atypical. In a significant proportion of 46,XY DSD cases it is not possible to identify a causative mutation, making genetic counseling difficult and potentially hindering optimal treatment. Here, we describe the analysis of a 46,XY DSD patient that presented at birth with ambiguous genitalia. Histological analysis of the surgically removed gonads showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. We screened genomic DNA from this patient for deletions and duplications using an Illumina whole-genome SNP microarray. This analysis revealed a heterozygous deletion within the WWOX gene on chromosome 16, removing exons 6-8. Analysis of parental DNA showed that the deletion was inherited from the mother. cDNA analysis confirmed that the deletion maintained the reading frame, with exon 5 being spliced directly onto exon 9. This deletion is the first description of a germline rearrangement affecting the coding sequence of WWOX in humans. Previously described Wwox knockout mouse models showed gonadal abnormalities, supporting a role for WWOX in human gonad development. Keywords: disorders of sex development; copy number; WWOX; gonad; microarrays INTRODUCTIONIn the early stages of human embryogenesis the developing gonads are bipotent, being capable of forming either testes or ovaries. In males the expression of the Y chromosomal SRY gene initiates testis development, whereas ovarian development in principle occurs only in the absence of SRY (reviewed in Wilhelm et al 1 ). Following the establishment of sex-specific expression of key regulatory genes in the gonad, gonadal differentiation results in development of the external genitalia. As a result there are two main stages in gonad formation, and disruption of either can lead to disorders of sex development (DSD). DSD are surprisingly common, with ambiguous genitalia estimated to occur with an incidence of 1 in 4500 live births. 2 A number of genes important in the regulation of sex determination have been identified, yet in as many as 70% of 46,XY DSD cases no genetic cause has been identified. We have previously demonstrated the power of whole-genome copy number analysis with high-density microarrays to identify causative mutations in DSD. 3,4 Here, we describe the use of this approach to identify a multi-exon heterozygous deletion in the WWOX gene of a 46,XY DSD patient.

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Gonadal Development and Tumor Formation at the Crossroads of Male and Female Sex Determination

Cited by 75 publications

References 189 publications

Management of Gonads in Adults with Androgen Insensitivity: An International Survey

Management of Gonads in Adults with Androgen Insensitivity: An International Survey

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development

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