**3. 46, XY disorders of sex development**

46, XY DSD can be divided into categories;


Both categories lead to feminization or abnormal genitalia.

#### **3.1 Disorders of testicular (gonadal) development**

Disorders of testicular (gonadal) development are characterized by absent or small testes on palpation and/or ultrasound. Müllerian structures (uterus and fallopian tubes) can be present with the external genitalia feminized to varying degrees along with decreased levels of testosterone, dehydroepiandrosterone and androstenedione [17].

At approximately 6 weeks, the gonads can form ovaries or testis [3]. The process of testicular differentiation involves multiple genes (**Figure 4**). Mutations causing haploinsufficiency with a loss of function and duplication with gain of function are known to be associated with 46, XY gonadal DSD. The *SRY* gene encodes a transcription factor that causes a cascade effect allowing the bipotential gonad to form testis [18]. Pathogenic variants and deletions involving the *SRY* gene lead to complete gonadal dysgenesis or 46, XY pure gonadal dysgenesis. Approximately 15% of individuals with Swyer syndrome have this finding. Swyer Syndrome is also known as 46, XY complete gonadal dysgenesis or 46, XY pure gonadal dysgenesis. Patients with Swyer Syndrome present with female internal and external genitalia.

The *SRY* and *NR5A1* genes activate *SOX9* and the anti-Müllerian hormone (AMH) formation and lead to secretion by the Sertoli cells [19]. Mutations in the *SOX9* gene *[OMIM # 608160]* presents with campomelic dysplasia and sex reversal in 50% of the cases with 46, XY. A heterozygous deletion of approximately 240 kb (between 405 kb – 645 kb upstream of the *SOX9* transcription start site) was reported with 46,XY with a normal external female phenotype and severe ambiguous and asymmetric external genitalia [20]. Another case presenting as 46, XX male resulted from a heterozygous duplication upstream of the *SOX9* gene on chromosome 17 [21].

The ligand *FGF9* and the signaling molecule *WNT4* are expressed in the undifferentiated gonad. Further in development they continue to be expressed in the ovary and the testis providing opposing signals that determine gonadal differentiation. *FGF9* promotes testicular differentiation and the Wnt family member (*WNT*)/R-spondin 1 signaling and forkhead box L2 (*FOXL2*) drive female sex determination in XX gonads and promotes ovarian differentiation. Testicular formation is established when the *SRY* gene initiates a feed-forward loop. *SRY* interacts with *SOX9* and *FGF9* leading to upregulation of *FGF9* and repression of *WNT4*. The receptor for the *FGF9* in the developing testis is *FGFR2* [22]. *NR5A1* gene (also known as *SF-1*) (OMIM 184757) is another important gene for the bipotential gonad. This orphan nuclear receptor is expressed in multiple locations including hypothalamus, pituitary, gonads and adrenal glands [3]. Pathogenic variants in this gene can lead to females with premature ovarian failure. They can also present in 46,XY DSD ranging from ambiguous genitalia to female external genitalia with complete to incomplete regression of the Müllerian duct derivatives [23–25]. Various mutations including p.G35D, p.G35E, p.R92Q and p.R255L have been seen to cause adrenal insufficiency combined with gonadal dysfunction. *DAX1* is another important orphan nuclear receptor with roles in the hypothalamus, pituitary, gonads and adrenal glands [26].

The Wilms tumor factor 1 (*WT1*) pathogenic gene mutations are commonly associated with Denys–Drash and Frasier syndrome along with an increased risk for nephroblastoma. Denys–Drash classically presents with a triad of symptoms including genitourinary abnormalities, renal impairment and Wilms tumor [27]. Frasier syndrome classically presents with focal segmental glomerulonephritis (typically presenting as later onset renal impairment) and an increased risk for Wilms tumor. This risk is not as high compared to other *WT1* related conditions. Other genes of interest include *CBX2* and *DHH*. *CBX2* is involved in both the regulation of

**67**

**Figure 5.**

*Approach to the Newborn with Disorders of Sex Development*

homeotic genes and of the bipotential gonad [3]. Pathogenic variants in the *CBX2* gene have presented as a normal female (internal and external genitalia). These studies suggest that *CBX2* could be responsible for repression of ovarian development [28]. In XY individuals with *MAP3K1* pathogenic variants are associated with suppressing *SOX9* and shifting the signaling pathway to promote ovarian differentiation [29]. At approximately 9 weeks of embryonic development Leydig cell differentiation occurs involving *DHH* [3]. Pathogenic variants in *DHH* can cause complete or partial gonadal dysgenesis. They can also be found in minifascicular neuropathy (OMIM 605423) [30]. Pathogenic variants in *DAX1* can cause congenital adrenal hypoplasia and hypogonadotropic hypogonadism (OMIM 300473) and complete or partial gonadal development with ambiguous external genitalia [4]. Other genes associated with XY gonadal dysgenesis include *DMRT1, DMRT2, SOX3*

Disorders of androgen synthesis are characterized by a lack of Müllerian structures. The testes in 46, XY individuals produce Anti-Müllerian hormone and

Two categories can be used to describe Disorders of Androgen Synthesis:

Seven enzymes involved in the production of testosterone and dihydrotestosterone, responsible for 46, XY disorders of sex differentiation have been identified

*Steroid hormone synthesis pathway and associated biochemical abnormalities in 46, XY DSD. POR: P450 oxidoreductase; StAR: steroid acute regulatory protein; 17*α*-OH: 17*α*-hydroxylase; 3*β*-HSD: 3*β*-hydroxysteroid dehydrogenase; 21-OH: 21-hydroxylase; 18-OH: 18-hydroxylase; 11*β*-OH: 11*β*-hydroxylase; 17*β*-HSD:* 

*17*β*-hydroxysteroid dehydrogenase; 5*α*-R: 5*α*-reductase; CAH: congenital adrenal hyperplasia (adapted from [17]).*

have genital abnormalities including normal female external genitalia.

1.Congenital adrenal hyperplasia (CAH) in patients with female

*DOI: http://dx.doi.org/10.5772/intechopen.94570*

and *SOX8* among others [31].

chromosome sex

(**Figure 5**).

**3.2 Disorders of androgen synthesis**

2.Associated with normal adrenal function.

*Approach to the Newborn with Disorders of Sex Development DOI: http://dx.doi.org/10.5772/intechopen.94570*

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

Disorders of testicular (gonadal) development are characterized by absent or small testes on palpation and/or ultrasound. Müllerian structures (uterus and fallopian tubes) can be present with the external genitalia feminized to varying degrees along with decreased levels of testosterone, dehydroepiandrosterone and

with Swyer Syndrome present with female internal and external genitalia. The *SRY* and *NR5A1* genes activate *SOX9* and the anti-Müllerian hormone (AMH) formation and lead to secretion by the Sertoli cells [19]. Mutations in the *SOX9* gene *[OMIM # 608160]* presents with campomelic dysplasia and sex reversal in 50% of the cases with 46, XY. A heterozygous deletion of approximately 240 kb (between 405 kb – 645 kb upstream of the *SOX9* transcription start site) was reported with 46,XY with a normal external female phenotype and severe ambiguous and asymmetric external genitalia [20]. Another case presenting as 46, XX male resulted from a heterozygous duplication upstream of the *SOX9* gene on

The ligand *FGF9* and the signaling molecule *WNT4* are expressed in the undifferentiated gonad. Further in development they continue to be expressed in the ovary and the testis providing opposing signals that determine gonadal differentiation. *FGF9* promotes testicular differentiation and the Wnt family member (*WNT*)/R-spondin 1 signaling and forkhead box L2 (*FOXL2*) drive female sex determination in XX gonads and promotes ovarian differentiation. Testicular formation is established when the *SRY* gene initiates a feed-forward loop. *SRY* interacts with *SOX9* and *FGF9* leading to upregulation of *FGF9* and repression of *WNT4*. The receptor for the *FGF9* in the developing testis is *FGFR2* [22]. *NR5A1* gene (also known as *SF-1*) (OMIM 184757) is another important gene for the bipotential gonad. This orphan nuclear receptor is expressed in multiple locations including hypothalamus, pituitary, gonads and adrenal glands [3]. Pathogenic variants in this gene can lead to females with premature ovarian failure. They can also present in 46,XY DSD ranging from ambiguous genitalia to female external genitalia with complete to incomplete regression of the Müllerian duct derivatives [23–25]. Various mutations including p.G35D, p.G35E, p.R92Q and p.R255L have been seen to cause adrenal insufficiency combined with gonadal dysfunction. *DAX1* is another important orphan nuclear receptor with roles in the hypothalamus, pituitary,

The Wilms tumor factor 1 (*WT1*) pathogenic gene mutations are commonly associated with Denys–Drash and Frasier syndrome along with an increased risk for nephroblastoma. Denys–Drash classically presents with a triad of symptoms including genitourinary abnormalities, renal impairment and Wilms tumor [27]. Frasier syndrome classically presents with focal segmental glomerulonephritis (typically presenting as later onset renal impairment) and an increased risk for Wilms tumor. This risk is not as high compared to other *WT1* related conditions. Other genes of interest include *CBX2* and *DHH*. *CBX2* is involved in both the regulation of

At approximately 6 weeks, the gonads can form ovaries or testis [3]. The process of testicular differentiation involves multiple genes (**Figure 4**). Mutations causing haploinsufficiency with a loss of function and duplication with gain of function are known to be associated with 46, XY gonadal DSD. The *SRY* gene encodes a transcription factor that causes a cascade effect allowing the bipotential gonad to form testis [18]. Pathogenic variants and deletions involving the *SRY* gene lead to complete gonadal dysgenesis or 46, XY pure gonadal dysgenesis. Approximately 15% of individuals with Swyer syndrome have this finding. Swyer Syndrome is also known as 46, XY complete gonadal dysgenesis or 46, XY pure gonadal dysgenesis. Patients

**3.1 Disorders of testicular (gonadal) development**

androstenedione [17].

chromosome 17 [21].

gonads and adrenal glands [26].

**66**

homeotic genes and of the bipotential gonad [3]. Pathogenic variants in the *CBX2* gene have presented as a normal female (internal and external genitalia). These studies suggest that *CBX2* could be responsible for repression of ovarian development [28]. In XY individuals with *MAP3K1* pathogenic variants are associated with suppressing *SOX9* and shifting the signaling pathway to promote ovarian differentiation [29]. At approximately 9 weeks of embryonic development Leydig cell differentiation occurs involving *DHH* [3]. Pathogenic variants in *DHH* can cause complete or partial gonadal dysgenesis. They can also be found in minifascicular neuropathy (OMIM 605423) [30]. Pathogenic variants in *DAX1* can cause congenital adrenal hypoplasia and hypogonadotropic hypogonadism (OMIM 300473) and complete or partial gonadal development with ambiguous external genitalia [4]. Other genes associated with XY gonadal dysgenesis include *DMRT1, DMRT2, SOX3* and *SOX8* among others [31].
