**8. Genetic counseling and DSD**

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

When a newborn presents with ambiguous genitalia, a thorough physical examination, as well as various genetic (e.g. karyotype, microarray) and non-genetic investigations are ordered. From this, the health care team is able to have discussions with parents regarding the gender for sex of rearing. With regards to genital surgery, the current suggestion is that if genital surgery is not medically indicated, then to wait until the patient him/herself is able to make this decision. In cases with substantial ambiguity such as in PAIS, mixed gonadal dysgenesis, ovotesticular DSD and females with CAH and severe masculinization, a multidisciplinary DSD team including pediatric endocrinologists, geneticists, genetic counsellors, urologists, gynecologists, social workers and psychologists/psychiatrists with expertise in this field should be part of the care team. The findings, plan for investigations, gender assignment and treatment should be discussed among the group members prior to meeting the parents. Factors which have to be taken into consideration include type of gonads and potential function of these, present or future treatment with hormones, including for inducing puberty or for fertility if this can be predicted, as well as any medically necessary surgical treatment. When meeting with the parents, the team should present this information at a level that the parents can understand, using visual aids to facilitate the discussion. At the same time, if information is known from the literature about certain conditions that parents should be aware of, e.g. female babies with CAH and exposure to high and early levels of androgen levels prenatally can show more behaviors attributable to the male personality and sexual orientation [61–64], and the challenges in repairing severe hypospadias in patients diagnosed with PAIS [65], then this should be shared with them. In this way, the parents, together with the healthcare team's input can come to an informed decision about sex of rearing.

Dysgenetic gonads with a Y chromosome material are associated with an increased risk for malignancy, mainly gonadoblastoma, dysgerminoma and germ cell tumors, including seminoma, non-seminoma, juvenile granulosa cell and germ cell neoplasia in situ [66, 67]. Gonadoblastoma (GB) presents with a mixture of germ cells and stromal elements as well as immature Sertoli cells and may contain calcifications with pure gonadoblastomas being not metastatic. About 80% of patients with GB are phenotypic females and 20% are phenotypic males, many of them with hypospadias and bilateral or unilateral cryptorchidism. The incidence of GB in dysgenetic gonads varies from 4.7% to as high as 25%. Germ cell neoplasia in-situ cells are found lining the seminiferous tubules in dysgenetic testes and resemble immature germ cells. Thus, they cannot be diagnosed before puberty when they are normally present. However, when found in the testes in late childhood or post puberty they are pathological and are capable of transforming into seminomas in males and dysgerminoma in females and this tumor can metastasize. Removal of the gonad prior to puberty in patients with complete androgen insensitivity is controversial in view of the data indicating low risk for malignancy until early adult years [68, 69]. In these patients, if the testes are located in the labia majora, they are amenable to ultrasound surveillance and biopsies, if needed which makes post-pubertal monitoring simpler. When the testes are undescended, laparoscopic gonadopexy to bring them near the anterior abdominal wall to allow surveillance may be an option for patients who decide to avoid gonadectomy [68, 69]. Delayed surgery can help in involving the patient in the decision making [67, 70, 71].

**6. Gender assignment**

**7. Gonadal cancer risk**

**74**

In 2006, a new definition of genetic counseling was published in the Journal of Genetic Counseling, by a task force that was convened by the National Society of Genetic Counselors (NSGC). The definition is as follows: "Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following:


Genetic counselling has an important role in the management of DSD patients and their families. In most cases, counselling involves the woman/couple, following the birth of a child with DSD and/or in discussing the implications of their future reproductive plans. Genetic counselling can also be extended to other family members and the implications to themselves and their future pregnancies. Discussions with other family members require consent from the parents of the index patient or the index patient himself/herself if of age of maturity. Other indications for genetic counselling include an adolescent or young adult with DSD who wishes to learn more about their own diagnosis and the implications for her/his reproductive plans as well a woman/couple during their pregnancy when discordance between the genotypic and phenotypic sex is identified.

Following the birth of a child with DSD, parents are often overwhelmed and confused by their child's condition. Although gender assignment and naming of the child are pressing issues for the parents, these actions should not be unduly rushed. Parents should be provided with information so as to help them in making informed decisions, together with their healthcare team. Adequate counseling and support for parents includes education regarding sexual development in utero (including brain imprinting of gender identity), genetic counseling, ethical considerations of the child's rights to make decisions regarding gender, and information regarding current guidelines and recommendations.

A three generation family history should be obtained with careful inquiry. Information about family history of infertility, women with no menstrual periods, stillbirth, recurrent miscarriages, neonatal death, congenital abnormalities, intellectual disabilities and consanguinity should be obtained. When drawing the family history, it should be kept in mind that chromosome sex and phenotypic sex may be interpreted differently by the family; for the family, it is the phenotypic sex that identifies the family members as male or female (versus chromosome sex). Furthermore, in X-linked conditions the phenotypic infertile female may be chromosomally male (such as in androgen insensitivity or ATRX).

When a diagnosis is established from genetic investigations, then the family can be provided with information regarding the clinical manifestations and natural history, mode of inheritance, medical management recommendations, if any, recurrence risk for future pregnancies, implications to their other children/other family members, as well as information regarding appropriate patient support groups. Cultural differences need to be respected and taken into consideration during the counselling process [73].

In some cases, a DSD is diagnosed incidentally during pregnancy, with no previous family history. This could be following the finding of fetal abnormal external genitalia or finding of discrepancy between the phenotypic sex as determined by fetal ultrasound and the genotypic sex as determined by chorionic villus sampling, amniocentesis or non-invasive prenatal testing (NIPT) done for other reasons. The differential diagnosis for the cases detected incidentally is broad but it should be kept in mind that in a 46,XX fetus, the most likely diagnosis is congenital adrenal hyperplasia. In a 46,XY fetus, the differential diagnosis includes a variety of conditions including androgen insensitivity syndrome, 46,XY gonadal dysgenesis and testosterone biosynthesis defects, when no other abnormalities are identified. When other abnormalities are detected, such as on ultrasound, more rare conditions such as campomelic dysplasia and Smith-Lemli-Opitz syndrome should be considered [74]. Following prenatal diagnosis of a DSD the family may choose to continue with the pregnancy with no further investigations, they may decide to terminate the pregnancy based on the information provided or they may decide to further investigate the etiology of the abnormalities identified. Prior to this however, the genetics health care team should facilitates a discussion with the family outlining each option with the pros/cons of each, including what to expect from a procedure, if applicable, as well as the impact on puberty and fertility and the potential psychosocial perspective. This information is important to allow an informed decision to be made in keeping with their value and belief system. The family should be made aware that the genetics health care team will support whatever decision they make. In situations where the family decides to terminate the pregnancy and the etiology of the condition is not known, the benefits of a fetal autopsy and molecular analysis should be reviewed with the family.

Genetic counselling should be made available to couples who are planning to have more children, following the birth of a child with DSD. The provision of genetic counselling in these cases, in addition to providing psychosocial support, includes information regarding their recurrence risk and their available reproductive options:


Patients with DSD may be infertile. For these patients, conception using donor gametes and/or surrogate mother may be possible and should be discussed. However, to lower the recurrence risk, when applicable, the donor should not be a genetic relative/carrier of the condition.

**77**

*Approach to the Newborn with Disorders of Sex Development*

fertility in view of the patients gender role and identity [75].

Web-based educational resources for families include: www.aboutkidshealth.ca/En/HowTheBodyWorks/

Normal sex development includes determination of chromosome sex, gonadal sex, development of internal and external genitalia as well as the psychosocial sex. This is a complex process involving genetic and non-genetics components, many of them are yet unknown. Disorder of sex development is an etiologically a heterogenous group of disorders with a major lifelong impact on the patients and their

In view of the complexity of these group of patients they should be seen by a DSD team including but not limited to pediatric endocrinologist, pediatric urologist, medical geneticist, genetic counsellor, psychologist/psychiatrist and social worker and the findings and current knowledge should be presented to the parents so that they can make an informed decision regarding the gender, when appropriate. The child with DSD should continue be followed into puberty and adulthood to achieve optimal treatment, psychosocial well-being, sexual satisfaction, and

This website provides detailed graphically illustrated explanations of sex development and DSDs that health professionals can use when working with families.

Androgen Insensitivity Syndrome: Differences of Sex Development Support

CARES foundation: Congenital Adrenal Hyperplasia Research, Education and

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

**9. Conclusion**

families.

**10. Resources**

**10.1 Web based resources**

SexDevelopmentAnOverview

**10.2 Support groups**

http://aisdsd.org/

http://heainfo.org

http://www.caresfoundation.org

Hypospadias and Epispadias Association.

Group.

Support.
