46,<scp>XX</scp> ovotesticular <scp>DSD</scp> associated with a <scp>SOX</scp>3 gene duplication in a <scp>SRY</scp>‐negative boy

Grinspon, Romina; Nevado, Julián; Alvarez, Maria de los Angeles Mori; Rey, Graciela Monica del; Castéra, Roberto; Venara, Marcela; Chiesa, Ana; Podestá, Miguel Luis; Lapunzina, Pablo; Rey, Rodolfo

doi:10.1111/cen.13126

Cited by 32 publications

(28 citation statements)

References 6 publications

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“…46,XX testicular DSD has also been reported in association with a 774-kb insertion translocation from chromosome 1 into a palindromic sequence 82 kb distal to SOX3 [Haines et al, 2015]. Three further duplications of the SOX3 gene have been reported in XX males [Moalem et al, 2012;Vetro et al, 2015;Grinspon et al, 2016].…”

Section: Sox Gene Mutationsmentioning

confidence: 97%

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

Bashamboo

2016

Sex Dev

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In this review we will consider the gene mutations responsible for the non-syndromic forms of disorders of sex development (DSD) and how recent genetic findings are providing insights into the mechanism of sex determination. High-throughput sequencing technologies are having a major impact on our understanding of the genetic basis of rare human disorders, including DSD. The study of human DSD is progressively revealing subtle differences in the genetics of the sex-determining system between the mouse and the human. This plasticity of the sex-determining pathway is apparent in (a) the difference in phenotypes in human and mouse associated with the same gene, (b) the different gene regulatory mechanisms between human and mouse, and finally (c) the different and unexpected reproductive phenotypes seen in association with mutations in well-studied sex-determining genes.

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Section: Sox Gene Mutationsmentioning

confidence: 97%

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

Bashamboo

2016

Sex Dev

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“…In 46,XX DSD patients with ambiguous external genitalia, AMH levels above the normal female range exclude the diagnosis of congenital adrenal hyperplasia, aromatase defects or virilizing tumors, and are highly suggestive of an Ovotesticular DSD [53, 78, 83]. …”

Section: Serum Amh In the Diagnosis Of Conditions Affecting Testiculamentioning

confidence: 99%

Anti-Müllerian hormone as a marker of steroid and gonadotropin action in the testis of children and adolescents with disorders of the gonadal axis

Edelsztein

Grinspon

Schteingart

et al. 2016

Int J Pediatr Endocrinol

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102

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In pediatric patients, basal testosterone and gonadotropin levels may be uninformative in the assessment of testicular function. Measurement of serum anti-Müllerian hormone (AMH) has become increasingly widespread since it provides information about the activity of the male gonad without the need for dynamic tests, and also reflects the action of FSH and androgens within the testis. AMH is secreted in high amounts by Sertoli cells from fetal life until the onset of puberty. Basal AMH expression is not dependent on gonadotropins or sex steroids; however, FSH further increases and testosterone inhibits AMH production. During puberty, testosterone induces Sertoli cell maturation, and prevails over FSH on AMH regulation. Therefore, AMH production decreases. Serum AMH is undetectable in patients with congenital or acquired anorchidism, or with complete gonadal dysgenesis. Low circulating levels of AMH may reflect primary testicular dysfunction, e.g. in certain patients with cryptorchidism, monorchidism, partial gonadal dysgenesis, or central hypogonadism. AMH is low in boys with precocious puberty, but it increases to prepubertal levels after successful treatment. Conversely, serum AMH remains at high, prepubertal levels in boys with constitutional delay of puberty. Serum AMH measurements are useful, together with testosterone determination, in the diagnosis of patients with ambiguous genitalia: both are low in patients with gonadal dysgenesis, including ovotesticular disorders of sex development, testosterone is low but AMH is in the normal male range or higher in patients with disorders of androgen synthesis, and both hormones are normal or high in patients with androgen insensitivity. Finally, elevation of serum AMH above normal male prepubertal levels may be indicative of rare cases of sex-cord stromal tumors or Sertoli cell-limited disturbance in the McCune Albright syndrome.

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“…Human and mouse studies support this hypothesis. Ectopic expression of Sox3 in mice leads to complete sex reversal [Sutton et al, 2011], and some human XX DSD cases are caused by duplication of the SOX3 coding region and/or its 5 ′ flanking region [Sutton et al, 2011;Moalem et al, 2012;Vetro et al, 2015;Grinspon et al, 2016].…”

Section: Discussionmentioning

confidence: 99%

“…In humans these include mutations of the RSPO1 gene [Parma et al, 2006], duplication or triplication of the upstream regulatory region of SOX9 [Cox et al, 2011;Vetro et al, 2015], and duplication of the SOX3 gene [Sutton et al, 2011;Moalem et al, 2012;Vetro et al, 2015;Grinspon et al, 2016]. It can be anticipated that multiplication of the regulatory sequence of SOX9 is responsible for its expression or overexpression in gonads of XX fetuses, in spite of the lack of the SRY transcription factor.…”

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confidence: 99%

Methylation Patterns of SOX3, SOX9, and WNT4 Genes in Gonads of Dogs with XX (SRY-Negative) Disorder of Sexual Development

Salamon

Flisikowski²,

Świtoński³

2017

Sex Dev

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Ovotesticular or testicular disorder of sexual development in dogs with female karyotype and lack of SRY (XX DSD) is a common sexual anomaly diagnosed in numerous breeds. The molecular background, however, remains unclear, and epigenetic mechanisms, including DNA methylation, have not been studied. The aim of our study was comparative methylation analysis of CpG islands in promoters of candidate genes for XX DSD: SOX9, SOX3, and WNT4. Methylation studies were performed on DNA extracted from formalin-fixed/paraffin-embedded or frozen gonads from 2 dogs with ovotesticular and 2 dogs with testicular XX DSD as well as control females (n = 4) and males (n = 2). Bisulfite-converted DNA was used for CpG methylation analysis using quantitative pyrosequencing. Promoter regions of SOX9 and WNT4 showed similar CpG methylation in each group, ranging from 0 to 5.5% and from 39 to 74%, respectively. The SOX3 promoter showed significantly higher methylation in the ovotesticular XX DSD cases and the testicular XX DSD and control males, suggesting that SOX3 methylation may play a role in canine XX DSD pathogenesis.

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46,XX ovotesticular DSD associated with a SOX3 gene duplication in a SRY‐negative boy

Cited by 32 publications

References 6 publications

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

Anti-Müllerian hormone as a marker of steroid and gonadotropin action in the testis of children and adolescents with disorders of the gonadal axis

Methylation Patterns of <b><i>SOX3, SOX9</i></b>, and <b><i>WNT4</i></b> Genes in Gonads of Dogs with XX (<b><i>SRY</i></b>-Negative) Disorder of Sexual Development

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