Differences in sex development (DSD) encompass a range of rare conditions that impact genes, hormones, and reproductive organs, including genitalia. These conditions lead to variations in sex development compared to the typical patterns.
Occasionally, these conditions are referred to as Disorders of Sex Development, Variations in Sex Characteristics (VSC), or Diverse Sex Development. Some individuals also prefer the term intersex.
In utero sexual development
Sexual differentiation is a multifactorial process that involves differentiation at the chromosomal, gonadal, hormonal, phenotypic, and psychological levels.
Chromosomal sex is determined at fertilization, during which the sperm contributes either an X or Y chromosome, whereas the female contributes the X chromosome present in the oocyte. This process, which is otherwise known as sex determination, directs the undifferentiated zygote to further progress into either a male or female fetus.
By about six weeks following fertilization, embryonic structures known as indifferent gonads are induced to form either the male testes or female ovaries1. These newly formed gonads subsequently secrete hormones and other factors that contribute to the development and maturation of both internal and external genitalia. In male sexual development, testosterone secretion by the Leydig cells and anti-mullerian factor by the Sertoli cells support the development of internal sex organs and regression of female sex organs2.
Differences in sex development (DSD)
There are various genes involved in facilitating sexual determination, the most notable of which include the SRY, SRY-box transcription factor 9 (SOX9), nuclear receptor subfamily 5 group A member 1 (NR5A1)/steroidogenic factor 1 (SF-1), Desert hedgehog homolog (DHH), dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (NR0B1/DAX1), Wilms tumor 1 (WT1), Wingless-type MMTV integration site family, member 4 (Wnt4), and Wnt7a genes.
The dosage, expression levels, and function of the protein products of these genes determine gonadal differentiation. Thus, a mutation in any of these genes can contribute to the development of DSD.
Epigenetic changes in these genes may also lead to abnormal gene expression. For example, hypermethylation of the SRY gene can lead to the silencing of DMRT1, SOX8, SOX9, NR5A1, and anti-Mullerian hormone (AMH) genes3. Other epigenetic changes that have been implicated in DSDs include histone modifications, nucleosome repositioning, and chromatin regulation.
DSDs can also arise due to alterations in chromosomal, gonadal, hormonal, and ductal sex, as well as external genitalia characteristics.
Classification of DSDs
The Pediatric Endocrinology Society Lawson Wilkins and European Society of Pediatric Endocrinology classifies DSDs as DSD sex chromosomes, 46,XX DSDs, and 46,XY. DSDs Importantly, various DSDs do not fit into a specific diagnostic category or may belong to more than one category.
DSD sex chromosomes
Gonadal dysgenesis, which refers to a group of conditions in which the gonads are not properly developed, can arise from various genetic anomalies, many of which are associated with chromosomal abnormalities. The most common gonadal dysgenesis conditions include Turner syndrome (45,X), Klinefelter syndrome (47,XXY), and Swyer syndrome (46,XY).5
Turner syndrome
Turner syndrome affects one in every 2,000 girls. Some common phenotypic features of Turner syndrome include winged neck, cleft palate, short stature, sexual infantilism, and shield chest.
Turner syndrome arises due to the absence of the second sex chromosome. Although most fetuses affected by the X0 karyotype die in utero, about 3% will survive, 90% of whom will present with ovarian failure and primary amenorrhea. About 95% of women with TS are infertile; however, some may experience menstruation and even become pregnant5.
Klinefelter syndrome
Klinefelter syndrome, which arises due to the presence of an additional X chromosome in males, affects between one in every 500-1,000 children throughout the world.
Some of the most common phenotypic features of Klinefelter syndrome include infertility, hypogonadism, atrophy and hyalinization of the seminiferous tubules, increased number of Leydig cells, as well as small and hard testes5. Many individuals with Klinefelter syndrome are also at an increased risk of cardiovascular, metabolic, bone, neurocognitive, and psychosocial differences.
Swyer syndrome
Despite having a typical male karyotype of XY, individuals affected with Swyer Syndrome will develop as females due to mutations of the SRY gene. Common phenotypic features of Swyer syndrome include the presence of female external genitalia at birth, as well as the lack of secondary sex features like breast development or pubic hair growth during puberty.
46,XX DSDs
Differences in ovarian development include ovotesticular and testicular DSDs, as well as gonadal dysgenesia. Congenital adrenal hyperplasia, aromatase deficiency, and maternal luteoma can also be considered 46,XX DSDs.
46,XY DSDs
Differences in testicular development, which are otherwise referred to as 46,XY DSDs, comprise complete or partial gonadal dysgenesis, gonadal regression, and ovotesticular DSD. Androgen-related differences can also lead to 46,XY DSDs, some of which include 5α reductase deficiency, AMH differences, cloacal extrophy, leutinizing hormone (LH) receptor defects, as well as defects in androgen synthesis3.
Diagnosis
Diagnostic tests for DSDs may include:
- Chromosome analysis
- Blood tests for hormone and electrolyte levels
- Hormone stimulation tests
- Molecular testing
- Endoscopic exam
- Ultrasound imaging
- Magnetic resonance imaging (MRI)
Treatment
Patients diagnosed with DSD often require care from a multidisciplinary healthcare team to address various medical, psychological, and social needs.
A patient-centered approach to patients with intersex variations would foreground greater valuing of the holistic well-being of the individuals in the long term, their diverse needs and identitiy potentials, their possible fertility and hormone balance, their sexual function, and their many other autonomous conditions only discoverable through placing proper consultation and support processes in place in all clinical settings.6”
There is significant controversy and stigma related to the treatment of DSDs. Historically, a gender was assigned early in the treatment process based on external genitalia, with recommended surgery and hormonal therapy to conform to that gender. However, recent understanding acknowledges the complexity of gender and sexuality.
Non-medically necessary genital surgery is contested for breaching human rights to bodily integrity and self-determination. However, the practice still happens in many countries, whereas in others, such as Malta, Greece, Spain, Iceland, and Portugal, the practice has been banned.
Medical intervention is significant to the experiences of many people with DSDs, as it reinforces traditional gender roles and impacts their sense of self, family function, and social agency. Treatment is becoming more individualized and less standardized, with an emphasis on the autonomy and informed consent of the individual.
Access to adequate support is crucial for intersex individuals to manage any issues related to their condition. Families and friends of affected individuals may also benefit from support groups to help them understand and cope with the challenges associated with this condition.
References
- Mehmood, K. T., & Rentea, R. M. Ambiguous Genitalia and Disorders of Sexual Differentiation. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557435/
- Aatsha, P. A., Arbor, T. C., & Krishan, K. Embryology, Sexual Development. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557601/
- Garcia-Acero, M., Moreno, O., Suarez, F., & Rojas, A. (2020). Disorders of Sexual Development: Current Status and Progress in the Diagnostic Approach. Current Urology 13(4); 169-178. doi:10.1159/000499274.
- Mir Abe Marinus, & Cense, M. (2024). A Life Course Perspective on the Sexual Development of Young Intersex People. Healthcare, 12(2), 239–239. doi:10.3390/healthcare12020239.
- Acien, P., & Acien, M. (2020). Disorders of Sex Development: Classification, Review, and Impact on Fertility. Journal of Clinical Medicine 9(11); 3555. doi:10.3390/jcm9113555.
- Jones, T. (2018). Intersex Studies: a Systematic Review of International Health Literature. SAGE Open. doi:10.1177/215824401774577