Disorders of Sex Development with Testicular Differentiation in SRY-Negative 46,XX Individuals: Clinical and Genetic Aspects

Abstract

Virilisation of the XX foetus is the result of androgen excess, resulting most frequently from congenital adrenal hyperplasia in individuals with typical ovarian differentiation. In rare cases, 46,XX gonads may differentiate into testes, a condition known as 46,XX testicular disorders of sex development (DSD), or give rise to the coexistence of ovarian and testicular tissue, a condition known as 46,XX ovotesticular DSD. Testicular tissue differentiation may be due to the translocation of SRY to the X chromosome or an autosome. In the absence of SRY, overexpression of other pro-testis genes, e.g. SOX family genes, or failure of pro-ovarian/anti-testis genes, such as WNT4 and RSPO1, may underlie the development of testicular tissue. Recent experimental and clinical evidence giving insight into SRY-negative 46,XX testicular or ovotesticular DSD is discussed.

A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor‐1 (WT1) pathogenic variant

“…In 46,XX individuals, there is a subset of patients born with male external genitalia or atypical genitalia because of the presence of testes or ovotestes, named as 46,XX testicular (T) and ovotesticular (OT) disorder of sex development (DSD), respectively. Most 46,XX T‐DSD are caused by a gain‐of‐function in key testicular pathway genes . Approximately, 90% of cases are caused by translocation of SRY onto the X chromosome, particularly in patients with male external genitalia.…”

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

“…When testicular tissue develops in an SRY ‐negative XX foetus, two different mechanisms can be foreseen: the increased expression of pro‐testicular genes, like SOX9 , or the insufficient expression of pro‐ovarian/antitesticular genes, like WNT4 or RSPO1 , whose expression is pivotal in early embryonic gonadogenesis to stabilize β‐catenin and counteract SOX family genes, thus preventing the formation of the coelomic vessels, an essential step that engages the hitherto undifferentiated gonadal ridge into the testicular differentiation pathway. Here, we report the first case of an SRY ‐negative patient with a 46,XX ovotesticular DSD associated with a duplication of a 502‐kb fragment of the long arm of the X chromosome encompassing SOX3 and its regulatory sequences.…”

The Role of Number of Copies, Structure, Behavior and Copy Number Variations (CNV) of the Y Chromosome in Male Infertility

“…SRY-negative, infertile men have been reported as well [55][56][57]. In these patients, the virilization is not directly due to the Y chromosome behavior, but to a mutation that either causes the over-expression of X-linked or autosomal genes promoting masculinization (such as SOX3, SOX9, SOX10) or the down-regulation of autosomal genes blocking it (such as WNT4 and RSPO1) [58,59]. On the X chromosome, a similar habitus is caused by loss-of-function mutations in the Androgen Receptor (AR) coding gene [17,50].…”