Overview Of Disorders Of Sexual Differentiation (DSD): Definition, Care, Diagnosis

What is DSD?

Sexual differentiation is an important and complex process in fetal development requiring specific interaction between genes, proteins, and hormones. Abnormalities in this process characterize Disorders of Sexual Differentiation (DSD). The 2006 Consensus defines DSD by congenital conditions in which development of chromosomal, gonadal or anatomic sex is atypical. Although there are a myriad of DSD conditions ranging in clinical severity and population frequency, there are 3 broad categories recognized: Sex chromosome DSD; 46, XY DSD; 46, XX DSD. The incidence of DSD is estimates at 1/4500-5500, however it is difficult to accurately assess incidence due to variety in terminology, age at presentation and which cases constitute as DSD.

What is standard of care for DSD?

Historically, medical care for DSD focused on early surgical intervention and rapid assignment of binary gender, as it was believed that this was crucial in healthy psychosocial and gender identity development. Long term studies on outcomes of infant cosmetic surgery have proved that infants who received DSD related surgery were generally unsatisfied long term and 98% required further procedures. Since 2006, medical management has shifted to focus more on improving quality of life (QoL) and psychological well-being of patient’s with DSD. Patient’s with DSD can present at birth with ambiguous genitalia or abnormal phenotype-karyotype profile, or later in life with abnormal pubertal onset. The current standard of care in DSD treatment is to take in in depth personal and family history followed by a detailed physical examination and biochemical analysis of steroid hormones. Based on these findings, targeted gene panels are performed to identify the molecular etiology. Although this is the outlined standard of care, professionals agree that DSD management needs to be streamlined in practice and that a strict pathway involving in-depth biochemical and molecular investigations is critical to improving care.

What is the number of non-diagnosed cases DSD?

Many genes involved in sexual differentiation have been identified through studying DSD patients, yet a significant proportion of DSD cases are left without a definitive diagnosis or etiological cause. It is estimated that 90% of 46, XX DSD cases are caused by CAH, but even with advanced genetics, approximately 50% of 46, XY DSD cases have no definitive diagnosis. Studies have shown that early genetic diagnosis of DSD is crucial to guide medical management and to improve health outcomes and QoL. One study by (**) et al compared long term outcomes of patients with a clinical diagnosis of partial androgen insensitivity syndrome (PAIS), a 46, XY DSD condition, to patients with a genetic diagnosis of PAIS. They concluded that the genetically confirmed cohort had significantly poorer prognosis, and that genetic conformation is essential to inform medical management.

A second study investigated the molecular variants in children with clinically diagnosed Androgen insensitivity syndrome (AIS). They found that 66% of children with presumed AIS did not have the expected variants in the AR or SRD5A2 genes. They concluded that although clinically similar, molecular etiology can be variable leaving questions about best future management. Medical benefits associated with having a definitive diagnosis include assessing change of crises, use of HRT, fertility, gender, recurrence risk, cancer risk, patient empowerment, QoL, prognosis and appropriate treatment planning. What are psychological outcomes of DSD? World Health organization defines QoL as “an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns.

Many studies have tried to identify the QoL in DSD patients. One quantitative study used the WHOQoL survey to asses QoL in 4 categories: psychological health, physical health, environment, and social relationships. They found DSD patients ranked poorer in physical health, better in environment and similar in psychological health in comparison to the healthy population, but significantly poorer in social relationships compared to the unhealthy population control. Other studies using the WHOQoL with smaller sample sizes had incongruent and variable findings. One study investigated DSD patients in Italy and found a decreased in QoL in psychological health, increase in physical health and no other significant differences compared to the population. In contrast, similar studies from China and Brazil found no significant differences in QoL between DSD patient’s and the population.

It is important to recognize that directly comparing different studies reporting on psychological outcomes and QoL in DSD patients is difficult due to many serious limitations. There are variations in the standardized measurement tools used, differing opinions of what to include as a DSD condition, geographical limitations, small sample sizes, and biased recruitment strategies resulting in findings that are inconsistent and incomparable.

What are the psychological outcomes of not having a diagnosis?

Patients with DSD often undergo long diagnostic periods, uncoordinated diagnostic approach or receive no diagnosis at all. This is problematic as age at start of treatment is negatively associated with QoL. Literature review identified a lack of research comparing QoL of DSD patients with definitive diagnosis to patients lacking a definitive diagnosis. Other studies on conditions with low diagnostic rates have shown that having a definitive diagnosis positively impacts the patient’s and their families’ QoL, well-being, and understanding of the condition. Like DSD, many cases of intellectual disability go without underlying etiology or definitive diagnosis. One qualitative study assessed acceptance of disease and ability to cope in parents with a newborn with special needs. They found that lack of a definitive diagnosis impacted the parent’s emotional reaction to the disorder as well as their ability to cope due to uncertainty. The findings of this study are limited criteria excluding foreign families and biased due to all participants having achieved at least post-secondary education. A similar quantitative study found that mothers of children with undiagnosed intellectual disabilities had significantly worse psychological health than mothers of children with well diagnosed intellectual disabilities, such as Down’s Syndrome. They concluded that the uncertainty associated with not having a definitive diagnosis produces emotional stress and reduces coping. Further they identified that, due to ample social support and clarity of diagnosis, parents of children with Down’s Syndrome are generally as emotionally stable as parents of children with no intellectual disabilities.

Lastly, a qualitative study investigating parental adaptation to a child being diagnosed with MCA found that absence of diagnosis hinders parents from adapting to their child’s condition and induces stress surrounding accessing appropriate resources. Like DSD conditions, MCA conditions are lacking definitive diagnosis in approximately 60% of cases. All but one family studied were of European decent, creating ethnic bias. Further, although there were clear main findings of this study, variability in responses existed between families.

Future Directions

In conclusion, a large proportion of DSD patient’s remain without definitive diagnosis which negatively impacts their prognosis, treatment planning and knowledge of recurrence risk. Although the medical impacts of not having a definitive DSD diagnosis are relatively well understood, there is currently no information on psychological outcomes and QoL.