Introduction
Differences of sex development (DSDs; also known as disorders of sex development ) is a group of congenital conditions of the urogenital and reproductive tracts that affects human sex determination and/or differentiation. Sex differentiation and development involve a series of events and stages whereby the indifferent gonads, internal reproductive organs, and external genitalia progressively acquire male or female characteristics. In patients with DSDs, the typical development of chromosomal, gonadal, or anatomic sex is altered; karyotype, gonads, and phenotype do not correlate. The evaluation of an individual with DSD includes careful consideration of the medical, surgical, and psychosocial needs of the patient and family. Care is optimally provided in a patient-centered, multidisciplinary approach. Here we discuss the core clinical concepts and highlight discussion on a subset of specific DSD diagnoses.
Background and embryology
Biologic sex is determined by the sex chromosomes complement that provide direction for an undifferentiated embryo to form along a male or female path. Sex determination and differentiation is comprised of (1) chromosomal sex which refers to the sex chromosome complement (eg. XX, XY) and is established at fertilization. This guides the differentiation of (2) gonadal sex, which is the presence of testis or ovaries. The hormones produced from the gonad then determine the (3) phenotypic or anatomic sex, which refers to the appearance of internal and external genitalia. Multiple genes are involved in differentiation of the bipotential gonad, and a mutation or error encoding these genes can lead to resulting altered development ( Fig. 24.1 ).
The gonads and reproductive tract are derived from the urogenital ridges. The paired urogenital ridges appear in the fourth week postfertilization and are composed of intermediate mesoderm covered by coelomic epithelium. In addition to the reproductive tract, the urogenital ridge also develops into the kidneys and adrenal cortices. Initially gonads are considered bipotential, as they are undifferentiated and may develop into testes or ovaries. Although numerous genes are involved in the process, NR5A1 and Wilms tumor 1 have been identified as two genes instrumental to the development of the urogenital ridge into an undifferentiated or bipotential gonad, which will then subsequently form into testes or ovaries.
At the sixth week of embryonic life, the initial stages of sexual differentiation are noted where under the presence of the SRY gene on the short arm of the Y chromosome (this is also known as the testis-determining factor on the Y chromosome ), upregulation of SOX-9 occurs, and the undifferentiated gonad develops into testes, with the appearance of first Sertoli and then Leydig germ cells by week 8. The Sertoli cells begin producing anti-müllerian hormone (AMH) and Leydig cells produce testosterone. The testes start to descend from the abdominal cavity around week 10, and the descent of the testes to the scrotum by the twenty-fifth to thirty-fifth weeks of development. In the absence of SRY, there is a lack of Sertoli and Leydig cells, resulting in an upregulation of ovary-specific transcription factors by week 9. Germ cells then differentiate into oogonia, and under this influence by week 11 to 12, ovarian development subsequently occurs. The paramount importance of testicular differentiation for fetal sex development has prompted the use of the expression “sex determination” to refer to the differentiation of the bipotential or primitive gonads into testes.
Initially, both of the paired Wolffian or mesonephric (male) and müllerian or paramesonephric (female) ducts are present. Under the influence of testosterone, the Wolffian ducts differentiate into male reproductive structures, whereas AMH secretion causes regression of the müllerian ducts, which are completely absent by week 10. In the absence of high concentrations of AMH and testosterone produced by testicular tissue, there is müllerian duct differentiation and Wolffian duct regression. The paired müllerian ducts develop into the fallopian tubes, uterus, cervix, and upper two-thirds of the vagina. The müllerian duct then meets with the urogenital sinus, which forms the lower vagina. , , The Wolffian ducts form the epididymis, vas deferens, seminal vesicles, and common ejaculatory duct. ,
The external genitalia, initially undifferentiated and composed of the genital tubercle, the labioscrotal folds, and the urogenital sinus, similarly undergo hormonally dependent differentiation around weeks 8 to 12 ( Fig. 24.2 ).
Male external genital development requires (1) high levels of circulating testosterone, (2) 5-alpha reductase type 2 enzyme for the conversion of testosterone to dihydrotestosterone (DHT) in target organs, and (3) functional androgen receptors. DHT is a potent androgen that results in enlargement of the genital tubercle to a penis and fusion of the labioscrotal folds to form the scrotum. In the absence of elevated androgens, female external genitalia are formed.
Epidemiology
DSD occur in about 1:4500 to 5000 live births and can be caused by atypical chromosomal, gonadal, or phenotypic sex caused by a variation from the typical sequence of sex development. There are generally three categories of DSD: (1) sex chromosome DSD, (2) 46,XY DSD, and (3) 46,XX DSD. Fig. 24.3 describes the three main groups of DSDs and differential diagnosis for each disorder.
Terminology
Terminology used to describe individuals with DSD should be sensitive to the concerns of the patient and family, be descriptive, reflect the genetic etiology, and accommodate the spectrum of phenotypical variation. Terminology continues to evolve over time, and some historical terminology used to discuss individuals may be outdated, controversial, and/or offensive to some patients and families Table 24.1 outlines new and revised terminology.
| Updated Terminology | Historical Terminology |
|---|---|
| Differences in Sexual Development |
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| 46,XX DSD |
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| 46,XY DSD |
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| Ovotesticular DSD |
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| 46,XX testicular DSD |
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| 46,XY complete gonadal dysgenesis |
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* Intersex: Increasingly this term is no longer used in favor of differences in sexual development, however some providers, patients, families, organizations and advocacy groups continue to use this as a descriptive term.
Sex vs. gender
Although definitions vary, it is important to understand that the concepts of sex and gender are not interchangeable. Gender is not to be thought of in a “male” or “female” context but is a social construct that refers to the roles, behaviors, and expectations attributed to men and women in a given society. , Concepts surrounding sexuality and gender in DSD patients are critically important to address, as issues pertaining to sex assignment and gonadal function may be complex. Gender dysphoria generally affects between 8.5% and 20% of individuals with DSDs. Moreover, studies have shown that sexuality and sexual function may be negatively affected. Fortunately, the literature has supported overall good sexual well-being among patients who have had optimal medical care.
Evaluation
Most individuals with DSD will be diagnosed at birth or in the prenatal setting, whereas others will be diagnosed later, such as in the cases of delayed puberty, amenorrhea, or virilization in a girl. 
For people with DSD, adequate support, quality of life, sexual aspects, physical and psychological well-being, and satisfaction with the treatment (hormonal, surgical, psychological) are predictors of good global development, and insufficient or inadequate medical care might result in adverse patient outcomes. , ,
Approach to evaluation in newborn/infant
Assessment of the newborn with ambiguous genitalia includes careful history, physical examination, and baseline studies, which then inform and guide additional testing. Of particular importance are the assessment of genital anatomy ( Fig 24.4 ) to describe the degree of virilization, karyotype analysis, hormonal evaluation, and imaging to aid with location of gonads. , Table 24.2 outlines aspects to the approach of the newborn.
| Approach to Newborn/Infant | |
| History |
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| Physical exam |
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| Laboratory evaluation |
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| Genetic evaluation |
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| Imaging |
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Essentials of diagnosis and key treatment considerations
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Avoid immediate gender assignment in individuals with ambiguous genitalia before expert evaluation.
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Focus on a multidisciplinary team approach.
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Ensure open communication with patients and families with respect and autonomy for patient and family concerns.
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Support the individual in expressing their gender identity as they grow.
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Address any critical associated medical concerns and treatment as needed.
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Discuss endogenous sex steroid adequacy and indications for hormone replacement therapy.
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Consider indications and counseling for surgical management, including gonadectomy and genital surgery, in a patient-centered approach with a focus on patient well-being.
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Discuss impact on fertility and options for fertility preservation where available.
A patient-centered and multidisciplinary care approach with psychosocial support and education is critical to the care ( Fig. 24.5 ). For example, if a newborn is diagnosed with ambiguous genitalia, an algorithm is followed ( Fig. 24.6 ).
Assessment of genital anatomy and gender assignment
For the newborn with ambiguous genitalia, a variety of methods are used to describe the extent of virilization of the external genitalia, with an aim to communicate the phenotype of an individual. The Quigley scale is a grading system that defines seven classes between “fully masculinized” and “fully feminized” genitalia. The Prader staging is useful to communicate the extent of virilization in 46,XX patients and comprises five stages: 0 (female phenotype, normal clitoris) to V (male phenotype with clitoris appearing as male phallus) ( Figs. 24.7 and 24.8 ). The external masculinization score (EMS) is a scoring system ranging from 0 to 12 used to classify the degree of undervirilization of a 46,XY patient. Modified, nonbinary tools, aimed to be more objective and inclusive are in the process of development and validation.
Gender assignment of a child with ambiguous genitalia can be difficult for families and clinicians. The approach to sex of rearing decisions in DSD patients has changed fundamentally over time and involves many factors. Influencing factors for sex assignment include specific DSD diagnosis, genital appearance or extent of virilization or feminization (i.e., Prader stage and phallus length), fertility potential, therapeutic and surgical options, and familial views or circumstances including cultural factors. , Regardless of the gender assigned, providers should understand that as a child grows, they will express their gender identity and should be provided support and resources to allow for gender expression.
Approach to evaluation in the adolescent
For the adolescent patient, in addition to a detailed history, evaluation for the presence and sequence of secondary sex characteristics, including androgen or estrogen effect, growth patterns, primary amenorrhea, or virilization, is completed. As the adolescent is gaining autonomy in their care, they should be included in discussions surrounding their diagnosis and care, including medical, surgical options, gender identity, sexuality and sexual function, and fertility potential as age and maturity appropriate.
Treatment considerations
Management for individuals with DSD is complex and should focus on fostering the well-being of the child and the future adult.
Hormone replacement.
Some patients with DSD may have impaired sex steroid production because of gonadal failure/variable function or their gonads removed before, during, or after adolescence, thus requiring hormone replacement therapy (HRT). The goals of HRT are to induce puberty and/or maintain secondary sexual characteristics with adequate circulating sex steroids (estradiol or testosterone), optimize bone health, and promote physical and social well-being.
In biologic females with DSD and absence of endogenous estrogen, HRT with exogenous estrogen is offered for those who identify as females. For pubertal induction, formulations of estrogen are typically introduced at a low dose, gradually increasing to an adult replacement dose over 1 to 2 years. In the presence of a uterus, progesterone is added when the adult dose of estrogen is attained, or earlier if menarche occurs. Pubertal induction using the natural estrogen 17-beta-estradiol is preferable to synthetic or equine estrogens, and this can be administered via oral or transdermal routes. ,
In males who require HRT, exogenous treatment with intramuscular testosterone esters is usually used. Alternatively, testosterone gels and patches may also be used. Optimal hormone replacement throughout the age spectrums is still evolving.
Surgical management.
Considerations for surgical management vary and include feminizing genitoplasty with clitoral reduction (clitoroplasty), external genitalia reconstruction, and gonadectomy. , The medical management in early childhood has been criticized from an ethical point of view, and some advocate for a moratorium on any feminizing or masculinizing operations except for medical emergencies. , 
Given the vast heterogeneity of DSD, there is no clear consensus on optimal timing for surgical management. However, our knowledge of the various conditions, outcomes, and quality-of-life measures have improved. DSD care today involves a more patient-centered approach, which has led to a shift from early to later genital surgery, with postponing of surgical management all together in many cases. , ,
Genital surgery.
Table 24.3 highlights arguments for early for delayed genitoplasty.
| EARLY SURGERY | LATE SURGERY | ||
|---|---|---|---|
| Advantages | Disadvantages | Advantages | Disadvantages |
| Reinforcement of sex of rearing | Scarring at the introitus, necessitating repeated surgeries; potential impact on sexual function | Allows individual to participate in informed consent process | Blood loss and infections are more common in adult patients |
| Relieve of parental tension regarding the ambiguity of the genitalia | Necessity of revisions of the clitoris in adolescence because of regrowth of tissue in puberty | Potentially reduces need for further surgery in adulthood | Fewer surgeons have experience with late (delayed?) vaginoplasty |
| Belief that procedure performed early enough in life would be forgotten by the patient | Inability of patient to participate in shared decision making | Allows for vaginal dilation by patient | No consensus regarding the technique used for late vaginoplasties |
| Procedure completed prior to gender self-identification | Larger caliber of the proximal vagina leads to a better end result at the level of anastomosis | ||
| Presence of estrogens allows for easier tissue plane identification and postoperative healing | |||
Any surgical intervention in neonates and infants that leads to irreversible changes should be done with the utmost caution. ,
Goals of early genital surgery should focus on functionality such as to address issues of urinary tract obstruction or infections and not cosmesis. It is now recommended that surgery be considered only in cases of severe virilization (Prader III, IV, and V). There is limited evidence on patient viewpoints; however, a study composed of 459 individuals with 46,XX and 46,XY DSD found that individuals who had early genital surgery were more likely to approve of it. Participant perspectives varied by diagnosis, gender, history of surgery, and contact with support groups. At this time a few medical centers in the United States have stopped offering vaginoplasty and clitoroplasty for patients too young to participate in the decision making (outside of medical necessity) even in complex cases. ,
Gonadectomy.
Gonadectomy is indicated to reduce the risk of developing a malignant germ cell tumor in patients with Y chromatin present. However, the risk of malignancy is based on the underlying etiology. The highest risk is noted in patients with gonadal dysgenesis and partial androgen insensitivity syndrome (PAIS) with intraabdominal gonads. Other conditions confer much lower risk. , Table 24.4 provides a key tool outlining malignancy risk assessment, which can inform surgical timing decisions. As gonadectomy necessitates lifelong HRT and removes fertility potential, risk stratification is important in the discussion of optimal timing of gonadectomy. Whereas early removal is typically recommended for diagnoses carrying a high risk of tumor, delayed removal after pubertal development is complete, and patient consent can be obtained if recommended. An increasing number of adults with a DSD have retained gonads. However, to date there are no clear guidelines for monitoring or screening for malignancy in addition, and often surveillance imaging and gonadal biopsies are considered.
