Figure 2 - uploaded by Richard Nicholl
Content may be subject to copyright.
(A) Partial karyotype showing the Xpair and trisomy 22. (B) Chromosome paint using a whole chromosome probe for No 22 showing three brightly fluorescent acrocentric chromosomes (top left).
Source publication
Complete trisomy 22, with or without mosaicism, has been reported as a distinct syndrome. In this report an infant is described who was externally male but with female rudimentary internal organs and whose karyotype was 47,XX+22.
Contexts in source publication
Context 1
... postmortem examination revealed a small rudimentary vagina and uterus and both gonads which were located in the abdominal cavity contained testicular tissue ( fig 1). fig 2A) which was confirmed by chromosome painting ( fig 2B). Application of Y specific probes for the centromere and GMGY1 0 did not reveal the presence of Y material either as a translocation to Xp or in a separate cell line in mosaic form. ...
Context 2
... postmortem examination revealed a small rudimentary vagina and uterus and both gonads which were located in the abdominal cavity contained testicular tissue ( fig 1). fig 2A) which was confirmed by chromosome painting ( fig 2B). Application of Y specific probes for the centromere and GMGY1 0 did not reveal the presence of Y material either as a translocation to Xp or in a separate cell line in mosaic form. ...
Citations
... Sox10 overexpression in XX mice leads to female-to-male sex reversal as it was shown that SOX10 can activate some of the downstream targets of Sox9 in the testis, such as Amh [Polanco et al., 2010]. In human, partial or complete duplications of chromosome 22, involving SOX10, were described in several 46,XX DSD patients, leading to an almost complete masculinization of the external genitalia or ambiguous genitalia, along with partial sex reversal of the gonads [Cantu et al., 1981;Nicholl et al., 1994;Aleck et al., 1999;Seeherunvong et al., 2004]. DOI: 10.1159/000524453 Conclusion SRY and the other SOX proteins, which all contain an HMG-box DNA-binding domain, share a high level of similarity and can probably compensate and replace each other in certain situations. ...
SOX genesare master regulatory genes controlling development and are fundamental to the establishment of sex determination in a multitude of organisms. The discovery of the master sex-determining gene SRY in 1990 was pivotal for the understanding of how testis development is initiated in mammals. With this discovery, an entire family of SOX factors were uncovered that play crucial roles in cell fate decisions during development. The importance of SOX genes in human reproductive development is evident from the various disorders of sex development (DSD) upon loss or overexpression of SOX gene function. Here, we review the roles that SOX genes play in gonad development and their involvement in DSD. We start with an overview of sex determination and differentiation, DSDs, and the SOX gene family and function. We then provide detailed information and discussion on SOX genes that have been implicated in DSDs, both at the gene and regulatory level. These include SRY, SOX9, SOX3, SOX8, and SOX10. This review provides insights on the crucial balance of SOX gene expression levels needed for gonad development and maintenance and how changes in these levels can lead to DSDs.
... Nevertheless, SOX10 overexpression in the gonadal ridges of transgenic XX mice drives the gonads through the male pathway [121]. In humans, duplications of chromosome 22 encompassing the SOX10 locus have been found in SRY-negative 46,XX cases with testicular or ovotesticular DSD [114][115][116][117]121] (Table 2). External genitalia were male or ambiguous, and multiple congenital defects were found, like intrauterine growth retardation, cleft palate or heart anomalies. ...
Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies the existence of testicular tissue, which can occur in the presence or absence of SRY. Recent advancement in the knowledge of the opposing gene cascades driving to the differentiation of the gonadal ridge into testes or ovaries during early foetal development has provided insight into the molecular explanation of XX maleness.
... Several patients with partial 22q duplication, including SOX10, have shown a sex reversal phenotype (XX male) (Aleck, Argueso, Erickson, Hackel, & Stone, 1999;Rajender et al., 2006;Nicholl et al., 1994). Those patients were not well defined clinically or cytogenetically, and there is controversy over the precise role of SOX10 in the pathogenesis. ...
... 22q duplication with concomitant disorders of sex development has been previously noted in multiple individuals [Rajender et al., 2006;Nicholl et al., 1994;Aleck et al., 1999], and is supported by studies of Sox10 overexpression in the mouse [Polanco et al., 2010]. SOX10 ...
Diagnosis of genetic syndromes may be difficult when specific components of a disorder manifest at a later age. We present a follow up of a previous report [Seeherunvong et al., (2004); AJMGA 127: 149–151], of an individual with 22q duplication and sex-reversal syndrome. The subject's phenotype evolved to include peripheral and central demyelination, Waardenburg syndrome type IV, and Hirschsprung disease (PCWH; MIM 609136). DNA microarray analysis defined the duplication at 22q11.2q13, including SOX10. Sequencing of the coding region of SOX10 did not reveal any mutations. Our data suggest that SOX10 duplication can cause disorders of sex development and PCWH, supporting the hypothesis that SOX10 toxic gain of function rather than dominant negative activity underlies PCWH.
... It has been hypothesized that in these cases, ectopic expression of SOX3 in the gonads at a critical stage of sex development has led to subsequent activation of the male pathway. Interestingly, 46,XX DSD phenotypes have been associated with partial duplications of human chromosome 22q13, containing SOX10a family member of SOX9in their region of overlap (Nicholl et al., 1994;Aleck et al., 1999;Seeherunvong et al., 2004). Although it cannot be completely ruled out that other genes located in the common interval may contribute to human 22q13-associated 46,XX DSD, mouse studies overexpressing Sox10 strongly support that gain-of-function of SOX10, caused by a duplication, is implicated in 22q13-linked 46,XX DSD (Polanco et al., 2010). ...
... It has been hypothesized that in these cases, ectopic expression of SOX3 in the gonads at a critical stage of sex development has led to subsequent activation of the male pathway. Interestingly, 46,XX DSD phenotypes have been associated with partial duplications of human chromosome 22q13, containing SOX10a family member of SOX9in their region of overlap (Nicholl et al., 1994;Aleck et al., 1999;Seeherunvong et al., 2004). Although it cannot be completely ruled out that other genes located in the common interval may contribute to human 22q13-associated 46,XX DSD, mouse studies overexpressing Sox10 strongly support that gain-of-function of SOX10, caused by a duplication, is implicated in 22q13-linked 46,XX DSD (Polanco et al., 2010). ...
This chapter deals with genetic defects of female sexual differentiation and covers 46,XX disorders of sex development (DSD) and mosaicism or chimerism of the sex chromosomes which lead to gonadal dysgenesis or ovotesticular DSD.
First, ovarian differentiation and typical female sexual development, including brain development, will be discussed. Conditions resulting from sex chromosomal mosaicism and chimerism and 46,XX (ovo)testicular DSD are extensively reviewed, with a focus on both etiology and clinical management. Subsequently, various causes of maternal and fetal androgen excess syndromes are reviewed. The syndromes characterized by aplasia or hypoplasia of the uterus and vagina form a separate entity within the 46,XX DSD category and are discussed thereafter. Finally we will summarize relevant points regarding the independent effects of genetic factors and sex steroids on brain and behavior.
... Complete or partial duplications of chromosome 22 in 46,XX-SRY negative individuals are associated with various degrees of masculinization [Nicholl et al., 1994;Aleck et al., 1999;Seeherunvong et al., 2004]. Further delimitation of the minimal region was demonstrated by a de novo duplication of 22q11.2q13 in a 46,XX SRY -negative male with mild hypospadias, dysmorphic features, and hypotonia [Polanco et al., 2010]. ...
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.
... Interestingly, complete or partial duplications of chromosome 22 have been reported in a number of SRY -negative XX cases with ovarian dysgenesis and/or testicular tissue differentiation [Polanco et al., 2010]. Relevant to the present review are a patient with masculinised external genitalia, dysgenetic testes and Müllerian remnants with a 47,XX,+22 karyotype [Nicholl et al., 1994], a patient with ambiguous genitalia (ovotesticular DSD) associated to an inverted duplication of 22q13.122qter [Aleck et al., 1999], and a patient showing only mild hypospadias and bilaterally palpable testes in whom a duplication of 22q11.222q13 ...
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.
... One such example may be SOX10. Complete or partial duplications of chromosome 22 in 46,XX-SRY negative individuals are associated with various degrees of masculinization [60][61][62]. Nicholl et al. described a 46,XX trisomy 22 male with micropenis, but the internal genitalia consisted of a small vagina and uterus with both testis-like gonads located in the abdominal cavity. An individual with ambiguous genitalia with one gonad consisting of ovarian tissue and the other showing testis-like structures was associated with a 46,XX,rec(22)dup(22q)inv(22)(p13q13.1)mat ...
... Interestingly, the ectopic expression of other members of this family, namely Sox3 or Sox10, in XX genital ridges also leads to female-to-male sex reversal in mice (Polanco et al., 2010;Sutton et al., 2011), suggesting that these proteins can replace SRY and/or SOX9 in the up-regulation of testisspecific target genes. Genomic rearrangements of SOX3 have been identified in human patients with XX male sex reversal (Moalem et al., 2012;Sutton et al., 2011), and SOX10 maps to a region of human chromosome 22q13 that is frequently duplicated in 46,XX DSD (Aleck et al., 1999;Cantu et al., 1981;Nicholl et al., 1994;Seeherunvong et al., 2004), indicating that over-expression of these genes in humans may also cause sex reversal. ...
The determination and coordination of sexual characteristics has always been a source of fascination. In mammals, the male or female fate is genetically decided at conception by the paternal transmission of a Y or an X chromosome. Sexual development then occurs in two sequential steps with the process of sex determination followed by sex differentiation. While early embryos are identical in both sexes, the first visible signs of sexual dimorphism appear during primary sex determination, when the bipotential
gonad differentiates into either a testis or an ovary in XY or XX individuals respectively. Sex differentiation (also referred as secondary sex determination) is then established by the secretion of hormones required for the differentiation of the rest of the embryo either as a male or a female. Embryonic testes secrete three hormones that cause the regression of the Mullerian ducts (anti-Mullerian hormone, AMH), testicular descent (insulin-like 3, INSL3), stabilisation and development of the Wolffian structures into the epididymis, vas deferens and seminal vesicles, and masculinization of the external genitalia (androgens). In XX embryos, the
absence of testicular hormones causes Wolffian duct regression, development of Mullerian structures including the Fallopian tubes, the uterus and the upper part of the vagina, and feminization of the external genitalia.
Wilhelm Dagmar, Chaboissier Marie-Christine and Nef Serge. (2015) Genes and Gene Defects Affecting Gonad Development and Primary Sex Determination. Reference Module in Biomedical Sciences. Elsevier. 08-July-15
... Complete or partial duplications of chromosome 22 in 46,XX-SRY negative individuals are associated with various degrees of masculinization [Nicholl et al., 1994;Aleck et al., 1999;Seeherunvong et al., 2004]. Nicholl et al. [1994] described a 46,XX trisomy 22 male with micropenis, but the internal genitalia consisted of a small vagina and uterus with both testis-like gonads located in the abdominal cavity. ...
... Complete or partial duplications of chromosome 22 in 46,XX-SRY negative individuals are associated with various degrees of masculinization [Nicholl et al., 1994;Aleck et al., 1999;Seeherunvong et al., 2004]. Nicholl et al. [1994] described a 46,XX trisomy 22 male with micropenis, but the internal genitalia consisted of a small vagina and uterus with both testis-like gonads located in the abdominal cavity. The involvement of a gene located on the long arm of chromosome 22 was suggested by an individual with ambiguous genitalia with one gonad containing ovarian tissue and the other showing testis-like structures associated with a 46,XX,rec(22)dup(22q)inv(22) (p13q13.1)mat ...
Here, we discuss recent progress on our understanding of the genetic anomalies that impact directly on the specification and development of the somatic cell compartment of the human gonad. Several new genes and pathways have been identified in the last 5 years associated with human disorders of sex development (DSD). New methods and analytical approaches, including comparative genomic hybridization and next-generation sequencing technologies, are beginning to provide deeper insights into the complexities and alterations of the genetic architecture that are associated with human DSD. The challenges as well as the research opportunities for the future are highlighted as efforts are made to bridge the gap between an increasing quantity of genetic information and the underlying biology.
