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Disorders of Sex Development

DSD Definitions

• Disorders of sex development (DSD) are congenital conditions affecting the reproductive system with atypical development of chromosomal, gonadal, or phenotypic sex. DSD is a new medical term replacing intersexuality or intersex disorders. DSD may lead to a complex clinical picture between male and female. The term DSD also includes disorders of the genitalia associated with a distinct sex role, see the following section for classification.
• Variations or differences in sex development: are substitutes for disorders of sex development, which aim to avoid the pathologization of altered sex development (Cools et al., 2018).
• Transsexuality: is, according to ICD-10 (F64.0), a form of gender identity disorder: a person's desire to live and be accepted as a member of the opposite sex, usually accompanied by a sense of discomfort with, or inappropriateness of, one's anatomic sex, and a wish to have surgery and hormonal treatment to make one's body as congruent as possible with one's preferred sex. DSD excludes the diagnosis of transsexuality.
• Obsolete terms: the following nomenclature should no longer be used, as
  • the terms were clinically unhelpful and caused confusion,
  • The modern understanding of gender development was not taken into account,
  • The traditional view of bisexuality and thus the mandatory assignment of people to either woman or man is considered outdated,
  • Disorders of sex development with clear gender roles were excluded.
  • Hermaphroditism: obsolete term for ovotesticular DSD, an individual with ovarian and testicular tissue.
  • Male pseudohermaphroditism: obsolete term for 46,XY DSD: male sex chromosomes and presence of testis, but indeterminate or female sex phenotype.
  • Female pseudohermaphroditism: obsolete term for 46,XY DSD: female sex chromosomes and presence of ovaries, but indeterminate or male sex phenotype.
  • Intersex disorders or intersexuality: obsolete medical terms for disorders of sex development (DSD). However, some people with DSD use the term for self-description.

Classification of Disorders of Sex Development

The current classification of DSD (disorders in sex development) by pediatric endocrinologists (Chicago Consensus Statement) emphasizes the sex chromosome constellation (Hughes et al., 2006):

• Sex chromosome DSD: with aneuploidy or mosaic sex chromosomes: 45,X (Turner syndrome and variants), 47XXY (Klinefelter syndrome), 45,X/46,XY (mixed gonadal dysgenesis, ovotesticular DSD).
• 46,XY DSD: male sex chromosomes and presence of testis, but indeterminate or female sex phenotype.
  • Impaired gonadal development: gonadal dysgenesis (Swyer syndrome), ovotesticular DSD, anorchidia (vanishing testis syndrome).
  • Disorders or androgen synthesis: congenital adrenal hyperplasia, LH receptor mutations, 5α-reductase deficiency.
  • Androgen receptor defects: androgen insensitivity syndromes like PAIS or CAIS.
  • Disorders of anti-Müllerian hormone: persistent mullerian duct syndrome.
  • Not classified: micropenis, severe hypospadias, epispadias, or bladder exstrophy with epispadias.
• 46,XX DSD: female sex chromosomes and presence of ovaries, but indeterminate or male sex phenotype.
  • Impaired gonadal development: gonadal dysgenesis, ovotesticular DSD, 46,XX men.
  • Increased androgens: congenital adrenal hyperplasia, aromatase deficiency, exposure to maternal androgens.
  • Not classified: severe bladder exstrophy, vaginal atresia, Mayer-Rokitansky-Küster-Hauser syndrome.

Epidemiology of Disorders of Sex Development

The estimated prevalence is 0.1–0.2%. That corresponds to a difficult gender assignment of 1 in 5000 births. However, many patients are diagnosed later in life. Prevalence figures vary widely and depend on the disorders that are added to DSD.

Signs and Symptoms

Leading symptoms are ambiguous genitalia with either female phenotype (enlarged clitoris, fusion of labia, urogenital sinus, virilization from puberty) or male phenotype (bilateral undescended testis, hypoplastic scrotum, scrotal anomalies, micropenis, proximal hypospadias, hypovirilization from puberty).

Neonatal emergency: apparent male newborns with 46,XX DSD (proximal hypospadias, bilateral undescended testes, clitoral hypertrophy without palpable gonads) may present with salt loss due to congenital adrenal hyperplasia; prompt diagnosis is critical to ensure adequate treatment.

Diagnosis of Disorders of Sex Development

Physical examination:

Palpable gonads? Urethral meatus location? Stretched penile length?

Laboratory tests:

Urine and blood tests are used, among others: sodium, potassium, blood gases, cortisol (without and with ACTH stimulation), estradiol, androstenedione, 17-hydroxyprogesterone, testosterone (without and with GnRH stimulation), LH, FSH, and dihydrotestosterone.

Imaging:

Abdominal ultrasonography of the adrenal glands and urinary tract, pelvic ultrasound with search for Müllerian structures (uterus? gonads?). MRI in patients with doubtful findings or unclear diagnosis. Regular imaging of the gonads is necessary in patients with increased tumor risk.

Genetic testing:

Genetic testing includes Karyotyping, molecular karyotyping, or next generation sequencing, depending on the suspected disorder.

Invasive examinations:

Helpful might be cystoscopy, vaginoscopy, diagnostic laparoscopy, or gonadal biopsy.

General Principles of Treatment

Gender binarism and, thus, the mandatory assignment of people to either female or male is considered outdated. Ambiguous external genitalia are initially not a disease, but a social problem of an erroneous assignment into a binary gender system, which does not allow for further options or intermediate stages. Gender binarism is detrimental to the care of DSD-affected patients and families.

Sex assignment after birth:

The biological sex manifests itself at several levels: sex chromosomes, gonads, external genitals, and hormones. Usually, the biological sex (male or female) is determined after birth based on the external genitalia. However, in children with DSD, determining sex on this basis may be difficult or may later prove to be incorrect. In difficult cases, sex determination should be avoided after birth and the family should be referred to an experienced center for further diagnosis and treatment. Since 2018 in Germany, the gender entry is not mandatory in difficult cases, and the affected person can choose later: male, female, or diverse. Incorrect past assignments can also be corrected in adults.

Tumor risk of the gonads:

Depending on the underlying disease, there is an increased risk for the development of germ cell tumors (seminoma, nonseminoma, gonadoblastoma or dysgerminoma). There is a high tumor risk in DSD patients with absent descensus testis and male sex chromosomes (XY) or mosaics with a Y chromosome: PAIS, 46,XY gonadal dysgenesis (Swyer syndrome), 45,X/46,XY mixed gonadal dysgenesis, or Turner syndrome with mosaic of the Y chromosome. Only moderately increased tumor risk is present in CAIS and ovotesticular DSD. No increased tumor risk exists in 5α-reductase deficiency, Klinefelter syndrome (46,XXY), 46,XX DSD such as congenital adrenal hyperplasia (Kathrins et al., 2016).

Irreversible medical procedures:

Irreversible medical procedures such as sex-assigning surgery, removal of the gonads, or initiation of hormone therapy are generally to be refrained from prior to puberty (Ethikrat, 2012) (Cools et al., 2018). The wish of parents for early gender assignment is not a sufficient indication for above mentioned interventions; the child's right to self-determination is paramount.

Exceptions are interventions to avert a concrete danger to the child's health: examples are resection of the gonad in case of concrete suspicion of tumor, orchidopexy in case of cryptorchidism or hypospadias surgery in case of a male gender role, hormone therapy of congenital adrenal hyperplasia or closure of urinary bladder exstrophy. The timing of reconstructive surgery is overall in flux and controversial even within professionals (Mouriquand et al., 2014). In case of doubt, the consent of a family court must be obtained. From puberty onward, the patient is considered to have the beginning capacity to consent regarding future gender roles and aligning medical interventions.

References

M. Cools and Nordenstr&ouml, “Caring for individuals with a difference of sex development (DSD): a Consensus Statement.,” Nature reviews. Endocrinology, vol. 14, no. 7, pp. 415–429, 2018.

Deutscher Ethikrat, “Intersexualität. Stellungnahme.,” 2012. [Online]. Available: https://www.ethikrat.org/fileadmin/Publikationen/....

M. Kathrins and T. F. Kolon, “Malignancy in disorders of sex development.,” Translational andrology and urology, vol. 5, no. 5, pp. 794–798, 2016.

P. Mouriquand, A. Caldamone, P. Malone, J. D. Frank, and P. Hoebeke, “The ESPU/SPU standpoint on the surgical management of Disorders of Sex Development (DSD).,” Journal of pediatric urology, vol. 10, no. 1, pp. 8–10, 2014.

C. Radmayr, G. Bogaert, H. S. Dogan, and Tekg&uuml, “EAU Guidelines: Paediatric Urology,” 2022. [Online]. Available: https://uroweb.org/guidelines/paediatric-urology/.

  Deutsche Version: Störungen der Geschlechtsentwicklung oder Intersexualität