DSD nomenclature

In 2005, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) convened a conference to review clinical management practices in intersex and data from long-term health-related and gender-related outcomes research and to identify key areas for future research. Invited conference participants included 48 clinicians and scientists specializing in this field and 2 participants serving as patient advocates. The Consensus Statement on Management of Intersex Disorders , published in 2006, recommended elimination of confusing and potentially stigmatizing terms such as intersex, pseudohermaphroditism, hermaphroditism, and sex reversal to refer to these conditions. Further, the conference summary (hereafter referred to as the Consensus Statement) incorporated all variations in sex development under 1 umbrella term, disorders of sex development (DSD), defined as “congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical.” This move allowed for the shedding of the simplifying notion that gonads are the only parameter defining sex.

As noted by Romao and colleagues elsewhere in this issue DSD are subcategorized based on sex chromosomes: sex chromosome DSD, XY, DSD and XX, DSD. There remains some uncertainty regarding the boundaries for these categories. Perhaps most contentious is the inclusion of Klinefelter syndrome (47,XXY) and Turner syndrome (45,X), and their variants, within the category of sex chromosome DSD. In 2007, ESPE published its own classification of pediatric endocrine diagnoses. The category of DSD appeared and with the same subcategories first introduced in the Consensus Statement. However, this classification scheme excluded from sex chromosome DSD “disorders of gonadal differentiation that do not result in sex reversal/virilised female infant/undervirilised male.” Specific examples of conditions excluded were Klinefelter syndrome and Turner syndrome, both of which were instead classified under the general category of syndromes with endocrine features (subcategory of chromosomal abnormalities).

The principle guiding exclusion from sex chromosome DSD (ie, “disorders of gonadal differentiation that do not result in sex reversal/virilised female infant/undervirilised male”) implies that atypical genital appearance is the sine qua non of DSD. If we follow the argument that Turner and Klinefelter syndromes should not be classified as DSD because the external genitalia are typical, then we should also exclude from DSD women with XY pure gonadal dysgenesis (who have typical external genitalia), males who are XX caused by a translocation of SRY, who often have typical male genitals, and even individuals with complete androgen insensitivity syndrome (CAIS), who appear at birth with typical female genitalia.

In addition, the nomenclature adopted in the Consensus Statement was designed to overturn the practice of classifying DSD exclusively based on the characteristics of the gonads, which did not reflect the various parameters influencing sex development. The definition of DSD now includes not only the gonads and the genitals but also the sex chromosomes as a parameter. Excluding Klinefelter syndrome from the subcategory of sex chromosome DSD because it does not result in undervirilized males is questionable and depends on one’s definition of undervirilized. Suggesting that small, dysgenetic testes, which do not support spermatogenesis (a major male function) are not undervirilized seems to be a subjective interpretation.

The classification of hypospadias as a DSD is also not without debate. Despite the inclusive definition of DSD as “congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical,” the Consensus Statement itself seems to waver when it comes to hypospadias: “Criteria that suggest [italics added] DSD include … isolated perineal hypospadias, or mild hypospadias with undescended testis. Although Romao and colleagues report moving away from evaluating such cases as DSD, recent reports suggest that hypospadias (mild and severe) can be associated with endocrine dysfunction in a few cases and that those with severe hypospadias and an undescended testis may be at higher risk for impaired spermatogenesis.

Romao and colleagues suggest that labeling hypospadias as DSD may evoke needless distress for parents. Although there may be truth to this claim, a recent systematic review of sexual adaptation in adult men who underwent hypospadias repair in childhood suggests they are less satisfied with sexual functioning and less likely to experience intimate relationships compared with control groups, despite positive, objectively assessed, cosmetic results. The Consensus Statement calls for persons with DSD to be cared for by multidisciplinary teams that include mental health providers with qualifying expertise in DSD. If patients with hypospadias are not seen in such clinics, then folding endocrine surveillance and behavioral health services into the treatment plan should be considered.

Genetic diagnosis

In contrast to the views of Romao and colleagues, there is good reason to be more optimistic regarding the promise of genetic diagnosis in DSD. As new genomic technologies have rapidly become an integral part of the diagnostic tools at the disposal of the clinician, and as the cost of DNA sequencing has plummeted, the diagnostic approach to many congenital disorders has shifted dramatically, and DSD is no exception. Ordering a regular karyotype may not any longer be a first-tier test, because sex chromosomes can be rapidly and routinely detected by interphase fluorescent in situ hybridization. A follow-up test, comparative genomic hybridization microarray, detecting copy number variants (microdeletions and microduplications) is now proposed to replace regular cytogenetics approaches for the diagnosis of DSD. Next-generation sequencing is poised to tackle additional diagnostic challenges of DSD, with the already increasing clinical use of whole exome sequencing. It could be argued that the long diagnostic process of DSD, involving a combination of karyotype, endocrine testing, genital imaging, and molecular sequencing, could be drastically reduced by the use of these novel genomic technologies.

Genetic diagnosis

In contrast to the views of Romao and colleagues, there is good reason to be more optimistic regarding the promise of genetic diagnosis in DSD. As new genomic technologies have rapidly become an integral part of the diagnostic tools at the disposal of the clinician, and as the cost of DNA sequencing has plummeted, the diagnostic approach to many congenital disorders has shifted dramatically, and DSD is no exception. Ordering a regular karyotype may not any longer be a first-tier test, because sex chromosomes can be rapidly and routinely detected by interphase fluorescent in situ hybridization. A follow-up test, comparative genomic hybridization microarray, detecting copy number variants (microdeletions and microduplications) is now proposed to replace regular cytogenetics approaches for the diagnosis of DSD. Next-generation sequencing is poised to tackle additional diagnostic challenges of DSD, with the already increasing clinical use of whole exome sequencing. It could be argued that the long diagnostic process of DSD, involving a combination of karyotype, endocrine testing, genital imaging, and molecular sequencing, could be drastically reduced by the use of these novel genomic technologies.

Prenatal ascertainment of DSD

Romao and colleagues accurately report that most cases of DSD are detected in the newborn period; however, these conditions are increasingly identified prenatally. Expectations of the family and health care providers regarding the somatic sex of the child are increasingly driven by advances in technology; for example, remarkably clear ultrasonographic images and genetic testing that can noninvasively and reliably ascertain fetal chromosomal sex between 7 and 12 weeks are widely available in industrialized countries. Discordance between prenatal test findings (eg, genital appearance by ultrasonography and karyotype) can initiate the DSD counseling process even at this early stage. Evidence from studies of prenatal diagnostic counseling suggests that termination of a pregnancy is dependent on the professional background of the health care provider delivering postdiagnostic counseling. There is substantial variation in health care providers’ knowledge regarding DSD. Because these conditions are rare and, historically, understudied and misunderstood, parents are at risk of receiving outdated or incomplete information unless major efforts are made in the context of interdisciplinary care teams.

Beyond diagnosis, the prenatal period has seen efforts at medical intervention to avert phenotypic changes associated with DSD; a case in point, described by Romao and colleagues, is prenatal suppression of adrenal androgens that masculinize the genitalia in 46,XX congenital adrenal hyperplasia (CAH). CAH comprises a family of autosomal-recessive disorders involving impaired synthesis of cortisol. If a woman has previously had a child with CAH and again becomes pregnant with the same partner, the fetus has a 1 in 4 chance of acquiring the genotype associated with CAH. Suppression of fetal adrenal androgens in CAH is achievable by administering glucocorticoids (dexamethasone [DEX]) during the pregnancy. The goal is to reduce genital masculinization of female offspring and obviate reconstructive surgery and presumed distress associated with the birth of a child with atypical genitalia.

Beyond the facts provided in the target article, this topic is worthy of additional discussion to better inform the reader about the nature of the controversy. Criticism of this intervention centers around several issues: first, as noted, the treatment is experimental and, yet, not characteristically delivered in the context of a clinical trial with necessary human subject oversight as called for in CAH practice guidelines ; second, to be effective, DEX treatment must be initiated between gestational weeks 6 and 7 and before it can be determined whether the fetus carries the CAH gene mutation. Treatment continues until chorionic villi sampling can be used for genotyping. If the fetus is 46,XY or 46,XX without the CAH genotype, then treatment is discontinued. Accordingly, 7 of 8 fetuses (all 46,XY and 3 of 4 46,XX) gain no benefit from the treatment but are exposed to potential risks; third, the safety of prenatal DEX for outcomes such as metabolism, cognitive function, and behavioral-emotional adaptation is in question based on animal experimental and human clinical research ; fourth, prenatal treatment does not change the need for lifelong glucocorticoid replacement therapy, the need for careful medical monitoring, or the risk of life-threatening salt-losing crises if treatment adherence is poor. Concern over prenatal DEX treatment has been expressed by bioethicists, who have questioned whether treatment introduced to normalize genital anatomy is confounded with the goal of making gender-role behavior and sexual orientation more typical.

Opportunities for systematic research and theory development that examine the influence of timing of diagnosis (prenatal vs later) on treatment choices (eg, gender assignment, genital surgery, and so forth) and health-related quality of life (HRQoL) outcomes for patients and families are as yet untapped.

Gender assignment

For the previous half-century, much of the medical literature on the treatment of children with DSD has focused on gender, including patient gender identity, gender role, and sexual orientation. (Gender identity refers to a sense of oneself as boy/man or girl/woman; gender role refers to behaviors or traits that show sex-related variation in a culture at one point in time; sexual orientation refers to sexual arousal to individuals of the same sex [homosexual], opposite sex [heterosexual], or both sexes [bisexual]). Beginning in the 1950s, the standard of care as it emerged primarily out of Johns Hopkins University assumed that making a child’s body look gender-typical would facilitate consistent rearing of the child in the assigned gender. As this system spread beyond Hopkins to become a standard of care, some advocated withholding personal medical histories and other important medical information from patients so as not to potentially challenge the sense of gendered self.

The heavy clinical focus on gender identity, gender role, and sexual orientation (ie, psychosexual differentiation) reflected the weight of interest coming from researchers examining the effects of early sex hormone exposure on sex-dimorphic brain development and sexual differentiation of behavior in a variety of animal species as well as sexologically oriented clinical researchers. This clinical work represented a natural extension of animal experimental research showing that early sex hormone exposure during sensitive periods of brain development has permanent (ie, organizational) effects of brain structure and physiology. Persons with DSD were accordingly seen by some researchers as experiments of nature, natural models for the study of the roles of sex chromosomes and hormones on sexual differentiation of human brain and behavior. What few longitudinal studies existed therefore tended to focus on gender-related outcomes to the exclusion of patients’ quality of life. Thus, psychological outcome studies considered whether patients identified as girls/women or boys/men, and whether they were attracted to males or females (or both), but not whether they experienced emotional equanimity, satisfying peer and romantic relations, or how they functioned in various roles across the life span. A recent systematic review of behavioral outcomes in CAH quantifies this bias.

An important guidance in the Consensus Statement directs health care providers to view outcomes in DSD more broadly. For example, it states that “Quality of life encompasses falling in love, dating, attraction, ability to develop intimate relationships, sexual functioning, and the opportunity to marry and raise children, regardless of biologic indicators of sex.” Similarly, providers are encouraged to recognize that “The focus should be on interpersonal relationships and not solely on sexual function and activity. ^(pe493)