Clinical profile, hormonal profile, genetic profile and quality of life assessment in patients with 46XY karyotype with Disorders of sex development

**Research Hypothesis:**Concordance of clinical, biochemical and genetic diagnosis is variable among various subtypes of 46XY Disorder of sex development (DSD)

Research Question: 1. Does genetic diagnosis differ from overall clinical and/or biochemical diagnosis?

2. Do psychosocial outcomes, gender identity and quality of life differ in various subtypes of 46XY DSD?

3. What is the quality of life in parents of patients affected with 46XY DSD and is it poorer?

Summary:

Differences/ Disorders of sex development (DSD) encompass a group of congenital conditions in which there exists a discrepancy in the chromosomal sex, gonadal sex or phenotypic/ anatomic sex; resulting in atypical presentation of the same. It is to be noted that none of these processes absolutely define a person’s sex or gender identity.

Etiology

DSD can arise due to:

1.     Differences in number and structure of sex chromosome

2.     Variations in genes responsible for genitalia and gonadal development

3.     Disorders related to steroidogenesis pathway of adrenals and gonads

4.     Maternal factors (Exogenous and endogenous)

5.     Endocrine disruptors, altering gentalia development

Genetics

Historically, clinical phenotype, in correlation with hormonal tests, anatomical imaging have guided single gene-based testing (Sanger sequencing). This approach had a poor yield, owing to reasons that phenotype-genotype correlation was poor and phenotypes do overlap, which is why, with advances in genomics, the approach was shifted to a multi-gene testing.

 Exome sequences and panel-based testing is currently available for diagnostic evaluation. Exome sequencing has an advantage of identifying known genes, as well as facilitates discovery of novel genes. Even in those who have a negative gene screening, since data regarding the genomics  is constantly evolving, there is data and studies to suggest that reanalysis of data after a certain period of 2-3 years, can increase diagnostic yield to by ~10%.

Phenotype-hormonal profile-genotype correlation

Each of these entities present in  a similar fashion, with degree of masculinisation variable in each of these cases. Hormonal evaluation may help narrow down the diagnosis, with certain ratios being introduced to help guide diagnostic evaluation.

The heterogeneity in presentation of patients with DSD owes to the complex mechanisms governing the development of reproduction systems.  Similarly, there are a number of genes responsible for the DSD pathogenicity. The wide spectrum of phenotypic presentation and a plethora of genes associated with the same clinical phenotype makes it vital to pinpoint the gene involved, with the help of diagnostic algorithms and advancement in genomics. Here came the Next-Generation Sequencing technology, which improved the diagnostic yield.

Need for genetic diagnosis

Reaching the genetic diagnosis is important due to the reasons enumerated below(4–7)

1.     Provides add-on details to management algorithm

2.     Gonad germ-line tumour risk

3.     Achieving long-term optimal outcomes

4.     Contributes to solution to gender identity uncertainty

5.     Genetic counselling to parents and potential risk to consequential fetus recurrence

6.     Predict prognosis

7.     Predicts the risks in family members

8.     Information on associated anomalies/ comorbidities, including adrenal health

9.     Mutation positive 46XY DSD patients have a more varied phenotype compared to mutation negative, which will require a tailored approach to management.

10.  Guide on deciding sex of rearing

11.  Guides timing of genitoplasty surgery or medical therapy

12.  Certain DSD  subtypes do not have a pathognomonic hormonal signature

13.  Detection of other associated organ involvement may be of importance inorder to diagnosis, screening and prevention.

14.  Need for additional behavioural and educational support in patients with sex chromosome DSD

15.  Guidance on long-term fertility and need for fertility preservation options

16.  Counselling couples contemplating future pregnancy

17.  Counselling patients about the likely course of their condition

18.  Contributes to clinical knowledge

19.  Provides reassurance to patients and their families

Psychosocial Impact

Psychosexual development plays an important role in the formation of sexual identity and is the main component of sexual identity, which is influenced by genetic status, pre/postnatal exposure to androgens, sociocultural factors, and family dynamics. Gender assignment is an important problem in DSD patients who have a virilized brain with undervirilised external genitalia.

DSD can impose a high degree of stress on patients and their families and exert a wide range of effects on ‘social and psychosexual adjustment, mental health, quality of life and social participation’. Common problems with 46XY patients with DSD are: psychosocial concerns, with issues involving gender identity, gender dysphoria, social stigmatisation, infertility, body dissatisfaction with their body and sex life , lower self-esteem; resulting in a poorer quality of life. It appears that having a DSD can be accompanied by a wide range of psychologically relevant concerns.

Long-term psychological, physical, and social outcomes in those with DSD are unclear and lack literature. clinical parameters, mutation analysis and surgical outcomes have been studied upon; health-related quality of life assessment are an important  tool to evaluate outcomes, especially in patients with DSD, since it takes into account multiple dimensions. Psychosexual determinants including gender identity/gender dysphoria and gender role behaviour are all very unique issues pertinent to DSD. Each DSD subtype has its own psychosexual signature, which each individual may or my not conform to. Patients with Complete androgen insensitivity syndrome (subtype of DSD) are almost always raised as females (female gender identity), with a small number of them developing gender dysphoria. Patients with Partial androgen insensitivity syndrome on the other hand, are more likely to identify with a gender that is incongruent with their sex of rearing. Similarly, other subtypes of DSD have their own hormonal signatures, influenced by social and behavioural factors, which may or may not lead to a gender dysphoria.

Hence there is a need to screen and assess for quality of life parameters