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Classification of Differences of Sex Development (DSD)

Primary Cause

Secondary Root

Tertiary Root

46,XY,DSD

Disorders of gonadal development
  • Monogenic forms of complete gonadal dysgenesis or partial gonadal dysgenesis (e.g., SRY, NRSA1, and WT1)
  • Testes regression
  • Ovotesticular DSD
  • Syndromic forms

Disorders of androgen synthesis
  • Associated exclusively with androgen biosynthesis defects (e.g., mutations in SRD5A2 and HSD17B3)
  • Associated with congenital adrenal hyperplasia and early androgen biosynthesis defects
  • Associated with placental insufficiency or endocrine disruption
  • Syndromic forms (e.g., Smith-Lemli-Opitz)

Disorders of androgen action
  • Complete androgen insensitivity syndrome
  • Partial androgen insensitivity syndrome

Persistent Müllerian Duct Syndrome
  • Result of mutations in AMH and AMHR2 genes
  • Result of deficiencies in AMH and AMHR2 genes

Unclassified disorders
  • Hypospadias of unknown origin
  • Epispadias
  • Complex syndromic disorders

46,XX DSD

Disorders of androgen excess
  • Congenital adrenal hyperplasia (most common)
  • Aromatase deficiency
  • Luteoma (maternal virilizing tumors)
  • Iatrogenic forms (androgenic drugs)

Disorders of gonadal development
  • (Ovo) testicular DSD
  • Monogenic forms of primary ovarian insufficiency (e.g., NR5A1 and WT1)
  • Syndromic forms

Unclassified disorders
  • Mayer-Rokitansky-Küster-Hauser syndrome types 1 and 2
  • Complex syndromic disorders

Sex Chromosomal DSD

45,X
  • Turner syndrome and variants

47,XXY
  • Klinefelter syndrome and variants

45,X/46,XY and 46,XX/46,XY
  • Mixed gonadal dysgenesis
  • Chimerism

Adapted from:

Cools, M., Nordenström, A., Robeva, R., Hall, J., Westerveld, P., Flück, C., Köhler, B., Berra, M., Springer, A., Schweizer, K., Pasterski, V., & the European Cooperation in Science and Technology (COST) Action BM1303 Working Group 1. (2018). Caring for individuals with a difference of sex development (DSD): A consensus statement. Nature Reviews. Endocrinology, 14(7), 415-429. https://doi.org/10.1038/s41574-018-0010-8

León, N. Y., Reyes, A. P., & Harley, V. R. (2019). A clinical algorithm to diagnose differences of sex development. The Lancet Diabetes & Endocrinology, 7(7), 560-574. https://dx.doi.org/10.1016/S2213-8587(18)30339-5

These pathways do not establish a standard of care to be followed in every case. It is recognized that each case is different, and those individuals involved in providing health care are expected to use their judgment in determining what is in the best interests of the patient based on the circumstances existing at the time. It is impossible to anticipate all possible situations that may exist and to prepare a pathway for each. Accordingly, these pathways should guide care with the understanding that departures from them may be required at times.

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Differences of Sex Development (DSD)
Classification of Differences of Sex Development (DSD)