**Abstract**

The birth of a baby with atypical external and/or internal genitalia is a family crisis that requires the interaction between multidisciplinary group physicians including pediatric urologists, pediatric endocrinologists, medical geneticists, genetic counsellors, gynecologists, psychologists/psychiatrists and social workers with expertise in this field. Following each of the specialists' assessment the findings, plan for investigations, the psychosocial situation and gender assignment and treatment should be reviewed among the group members prior to meeting the family. Following the group discussion the information should be presented to the parents using easy to understand language with visual aids and their questions should be answered so that they can make an informed decision regarding gender assignment, surgical options, where medically indicated, and hormone treatment. Potential for sexual relationships and fertility preservation should be discussed. The birth of a baby with abnormalities may be associated with mother/parental guilt feeling and the point that there is nothing that they did or did not do that caused the newborn's condition. Disorder of sex development (DSD) can be divided into isolated and non-isolated according to the finding on physical examination and should be further classified into abnormalities of chromosomal abnormalities, gonadal defect, internal and external genital abnormalities. Investigations should be directed by the physical examination findings and the results of the radiological, endocrine and genetic investigation including FISH analysis, microarray analysis, DNA analysis using a variety of DSD panels and, when required, whole exome/ genome sequencing.

**Keywords:** sex development, sex differentiation, gonadal differentiation, genital abnormalities, congenital adrenal hyperplasia, androgen secretion, androgen action, androgen insensitivity, gender assignment, psychosocial status

### **1. Introduction**

Sex development involves many autosomal and X-linked genes acting and interacting along a short duration in a precise synergy. The process of sex determination includes 4 layers:


### 3.Development of the internal genitalia

#### 4.Determination of the external genitalia

DSD is a heterogeneous group of congenital abnormalities associated with atypical development of the external and internal genitalia with an estimated incidence of 1:200–1:4500 [1]. Some of the abnormalities seem to have increased in incidence along the years with hypospadias reported to reach an incidence of 1:125 newborn males and cryptorchidism reaching an incidence as high as 3% of fullterm male newborns.

The nomenclature used to describe the genital abnormalities was initially descriptive, and on many occasions offensive. The advances in genetics and genomics knowledge substantially improved our understanding of the etiology of these conditions and resulted in a need to change the nomenclature. Thus, a new concept was introduced at the Chicago Consensus Conference 2005 [2] which defined the DSD as a congenital condition in which the development of chromosomal, gonadal or anatomical sex is atypical (instead of abnormal or ambiguous).

DSD can be divided into isolated or non-isolated/associated with other major abnormalities (**Figure 1**). When non-isolated they are usually associated with a variety of chromosome abnormalities, single gene or developmental field disorders which involve different body organ and systems (**Figure 2**). This review will mainly highlight the isolated/non-syndromic group of disorders of sex development.

In humans, the gonads are populated by primordial germ cells, deriving from the yolk sac wall early in week five post conception. Normally, it is the presence or absence of the of the SRY gene in the Y chromosome in the germ cells that starts the chain of events which cause the gonadal determination as testis in males. The secretion of testicular hormones in males and their attachment to their action through receptors results in normal development of the male internal and external genitalia (**Figures 3** and **4**). The absence of the SRY gene or function and the expression of genes induced by them will result in the development of ovaries. The lack of hormones produced by the testis will determine the normal formation of female internal and external genitalia (**Figures 3** and **4**).

It was previously thought that the absence of SRY gene in the gonadal ridge will result in ovarian differentiation while the existence of the SRY gene will result in

**63**

(**Figure 3**):

**Figure 3.**

**Figure 2.**

only from puberty

*Gonadal differentiation and function.*

*Approach to the Newborn with Disorders of Sex Development*

testicular development. However it is currently clear that gonadal sex is determined by antagonistic actions of ovarian and testicular cascades [5, 6] around week six post conception. In the female embryo, high levels of retinoic acid around the germ cells induces the STRA8 gene expression, resulting in germ cell meiosis and formation of oocytes. The absence of retinoic acid in the developing testis, results in formation of gonocytes which differentiate into spermatogonia and proliferate

There are three main differences between ovarian and testicular activities

1.The testes produce testosterone early in embryogenesis which induce the formation of the male external genital while the ovaries produce hormones

through mitosis with the meiosis happening after puberty [7].

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

*Differential diagnosis in isolated disorders of sex development.*

**Figure 1.**

*Disorders of sex development—initial assessment.*

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

#### **Figure 2.**

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

DSD is a heterogeneous group of congenital abnormalities associated with atypical development of the external and internal genitalia with an estimated incidence of 1:200–1:4500 [1]. Some of the abnormalities seem to have increased in incidence along the years with hypospadias reported to reach an incidence of 1:125 newborn males and cryptorchidism reaching an incidence as high as 3% of full-

The nomenclature used to describe the genital abnormalities was initially descriptive, and on many occasions offensive. The advances in genetics and genomics knowledge substantially improved our understanding of the etiology of these conditions and resulted in a need to change the nomenclature. Thus, a new concept was introduced at the Chicago Consensus Conference 2005 [2] which defined the DSD as a congenital condition in which the development of chromosomal, gonadal

DSD can be divided into isolated or non-isolated/associated with other major abnormalities (**Figure 1**). When non-isolated they are usually associated with a variety of chromosome abnormalities, single gene or developmental field disorders which involve different body organ and systems (**Figure 2**). This review will mainly highlight the isolated/non-syndromic group of disorders of sex development. In humans, the gonads are populated by primordial germ cells, deriving from the yolk sac wall early in week five post conception. Normally, it is the presence or absence of the of the SRY gene in the Y chromosome in the germ cells that starts the chain of events which cause the gonadal determination as testis in males. The secretion of testicular hormones in males and their attachment to their action through receptors results in normal development of the male internal and external genitalia (**Figures 3** and **4**). The absence of the SRY gene or function and the expression of genes induced by them will result in the development of ovaries. The lack of hormones produced by the testis will determine the normal formation of female

It was previously thought that the absence of SRY gene in the gonadal ridge will result in ovarian differentiation while the existence of the SRY gene will result in

or anatomical sex is atypical (instead of abnormal or ambiguous).

internal and external genitalia (**Figures 3** and **4**).

3.Development of the internal genitalia

4.Determination of the external genitalia

term male newborns.

**62**

**Figure 1.**

*Disorders of sex development—initial assessment.*

*Differential diagnosis in isolated disorders of sex development.*

#### **Figure 3.** *Gonadal differentiation and function.*

testicular development. However it is currently clear that gonadal sex is determined by antagonistic actions of ovarian and testicular cascades [5, 6] around week six post conception. In the female embryo, high levels of retinoic acid around the germ cells induces the STRA8 gene expression, resulting in germ cell meiosis and formation of oocytes. The absence of retinoic acid in the developing testis, results in formation of gonocytes which differentiate into spermatogonia and proliferate through mitosis with the meiosis happening after puberty [7].

There are three main differences between ovarian and testicular activities (**Figure 3**):

1.The testes produce testosterone early in embryogenesis which induce the formation of the male external genital while the ovaries produce hormones only from puberty

**Figure 4.**

*Diagram of the known major genes involved in testicular and ovarian differentiation and function (adapted from [3, 4]).*


The management of a newborn with abnormal genitalia has to be individualized taking into account the specific genital abnormalities as well as the parental and family as a whole. The decision regarding the sex of rearing should take into account the, surgical and non-surgical treatment, future pubertal development and fertility. This should be considered an urgent clinical situation and requires immediate assessment and counselling, and if possible, involvement of the DSD multidisciplinary core team including endocrinology, clinical genetics, genetic counselling, urology, obstetrics and gynecology, social work and psychology/ psychiatry among others.
