Congenital Disorders of Sexual Development

The term “disorders of sexual development” refers to a group of conditions characterized by atypical sexual development in an individual, which may involve abnormalities in the structure and/or function of the internal reproductive organs and/or external genitalia. Typical sex development starts with the chromosomal sex (e.g., 46,XY or 46,XX), which determines the sexual differentiation of the gonads (e.g., testes or ovaries), which secrete hormones that determine the phenotype (e.g., male or female). Most disorders of sexual development are due to abnormalities in specific chromosomes, enzymes, or receptors. Diagnosis typically involves analyzing the karyotype and specific hormone levels. Management can be complex, and often includes psychotherapy, hormone replacement therapy, and/or surgery.

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Overview of Sex Development


Disorders of sexual development are a group of conditions characterized by atypical sexual development in an individual, involving abnormalities in the structure and/or function of both the internal reproductive organs and/or external genitalia.

Overview of typical sex development

  • Chromosomal sex → determines gonadal sex → determines phenotypic sex
  • Up until 6 weeks of gestation, sex development is identical and nonbinary. The developing structures include:
    • Nonbinary, bipotent, undifferentiated gonads
    • Wolffian and Müllerian ducts (both are present in both sexes initially)
    • Urogenital sinus
    • The genital tubercle, genital swellings, and genital folds 
  • The genes present at fertilization will determine how the developing bipotent gonads differentiate (e.g., into a testis or an ovary).
  • The developing gonads will then secrete hormones:
    • The presence and/or absence of specific hormones will determine how the remaining structures differentiate.
    • In general, female organs and structures are the “default” phenotype if specific genes and hormones are not present to stimulate male differentiation.

Sex organs and characteristics

  • Gonads develop based on the karyotype/genes that are present.
    • Testes: 
      • Develop when sex-determining region of the Y chromosome (SRY gene) is present
      • Secrete testosterone and anti-Müllerian hormone (AMH)
    • Ovaries develop when the X chromosome is present and/or the SRY is absent. 
    • Ovotestis: a gonad containing both ovarian and testicular tissue found in patients with true hermaphroditism
  • Wolffian structures differentiate from the Wolffian (mesonephric) ducts in the presence of testosterone:
    • Epididymis
    • Vas deferens
    • Seminal vesicles
    • Ejaculatory ducts
  • Müllerian structures differentiate from the Müllerian (paramesonephric) ducts when AMH is absent:
    • Uterus
    • Fallopian tubes
    • Upper ⅓ of the vagina
  • External genitalia develop from the undifferentiated genital tubercle, genital swelling, and genital folds based on the presence or absence of testosterone.
    • Male: testosterone → penis and scrotum
    • Female: lack of testosterone → clitoris, labia majora, labia minora
  • Secondary sexual characteristics develop based on the hormonal milieu at puberty.
    • Androgenic characteristics: due to the presence of testosterone and/or dihydrotestosterone (DHT)
      • Pubic and axillary hair
      • Facial and body hair in an androgenic distribution and quality (dark and coarse)
      • Deepening of the voice
      • ↑ Muscle mass
    • Estrogenic characteristics result from the presence of estrogen:
      • Breast development
      • Wider hips

Typical male development

Male development begins due to the presence of the sex-determining region of the Y chromosome gene (SRY gene).

  • SRY gene → produces SRY protein (also known as testis-determining factor):
    • Stimulates the differentiation of the bipotent gonad into testes 
    • Stimulates development of:
      • Seminiferous tubules
      • Leydig cells
      • Sertoli cells
    • Suppresses the differentiation of ovaries
  • Testes secrete:
    • AMH
    • Testosterone
    • DHT
  • The above hormones cause:
    • Stimulation of the Wolffian ducts (around the 8th week) to differentiate into the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts
    • Regression of the Müllerian ducts
    • Differentiation of the prostate and external genitalia 
  • The process of differentiation is largely completed by 12 weeks of gestation.
Male development

Male development

DHT: dihydrotestosterone
Image by Lecturio.

Typical female development

  • Development of the ovary from the bipotent gonad requires:
    • Absence of the SRY (preventing differentiation into testes)
    • Presence of several genes found on chromosome 1, including:
      • WNT4 
      • R spondin 1 (Rspo1)
    • Begins around 10 weeks of development
  • Differentiation and development of the Müllerian ducts and external genitalia occur when testicular androgens and AMH are absent.
  • Embryos develop in the “female hormonal environment” within their mother; thus, it is unclear whether hormones produced by the fetus are required for their development.

Summary of Common Disorders of Sexual Development

Table: Common disorders of sexual development
DisorderPathophysiologyKey points
Androgen insensitivity syndrome (AIS)
  • Decreased or no response to androgens
  • Due to mutations affecting the quantity or function of androgen receptors
  • ↑↑ Serum testosterone levels
  • Affected individuals are 46,XY.
  • Phenotypic female genitalia
  • Testes present (undescended)
  • No Müllerian structures
  • Typically present in adolescence as primary amenorrhea, well-developed breasts, and sparse pubic hair
5-α-reductase deficiency
  • Loss-of-function mutation in 5-α-reductase gene impairs conversion of testosterone to dihydrotestosterone (DHT).
  • Normal or ↑ testosterone with ↓ DHT
  • Affected individuals are 46,XY.
  • Impaired virilization in utero → ambiguous genitalia at birth
  • Testes present
  • No Müllerian structures
Aromatase deficiency
  • ↓ Aromatase → ↓ conversion of testosterone into estrogen
  • Individuals will have:
    • ↓ Estrogen
    • ↑ Testosterone
  • 46,XX individuals:
    • Müllerian structures present
    • Virilized/ambiguous genitalia
    • Primary amenorrhea, no breast development, normal pubic hair
  • 46,XY individuals:
    • Normal Wolffian structures and phenotypic male genitalia
    • May have undescended testes, low libido, and/or fertility issues
  • All are prone to effects of ↑ testosterone (e.g., fertility issues, dyslipidemia, glucose intolerance).
Congenital adrenal hyperplasia
  • Due to deficiencies in 1 of the enzymes involved in the steroidogenesis pathway
  • 21-Hydroxylase deficiency by far the most common
  • Intermediate substrates are shunted toward testosterone production (see diagram below).
  • Leads to ↓ cortisol, ↓ aldosterone, ↑ ACTH, and ↑ testosterone
  • 46,XX individuals:
    • Müllerian structures present
    • Virilized/ambiguous genitalia
  • 46,XY individuals:
    • Normal Wolffian structures and phenotypic male genitalia
    • Salt-wasting crisis (1-2 weeks of life)
    • Early virilization
  • All are prone to effects of ↑ testosterone and adrenal tumors.
Kallmann syndrome
  • Decreased secretion or lack of gonadotropin-releasing hormone (GnRH)
  • Leads to a lack of all sex hormones
  • Affects both sexes
  • Can be due to mutations in a variety of genes
  • Presents with absence of sexual development at puberty due to lack of sex hormones
  • Key finding: associated with anosmia (absent sense of smell)
  • Other anomalies may be present, including cleft lip/palate, hearing loss, syndactyly, and renal agenesis.
46,XX gonadal dysgenesis
  • Non-functional ovarian tissue → ↓↓ estrogen
  • Due to various mutations affecting ovarian development
  • Affected individuals are 46,XX.
  • Phenotypic female genitalia
  • Müllerian structures present
  • Presents in adolescence with primary amenorrhea and lack of all secondary sex characteristics
Swyer syndrome
  • 46,XY individuals with non-functional gonadal tissue → ↓ testosterone and ↓ estrogen
  • AMH and testosterone are not secreted in developing embryo → development of uterus, vagina, and female genitalia
  • Mutations may be on an X, Y (SRY region), or autosomal chromosome.
  • Phenotypic female genitalia
  • Müllerian structures present
  • Undeveloped testes are called “streak gonads” → ↑ risk for tumors:
    • Gonadoblastoma
    • Dysgerminoma
  • Presents in adolescence with primary amenorrhea and lack of all secondary sex characteristics
True hermaphroditism
  • Patients have at least 1 ovotestis gonad that contains both ovarian and testicular elements.
  • May have a normal ovary or testis on the contralateral side
  • Karyotype may be either 46,XX (approximately 80%), 46,XY, or 46,XX/XY mosaic (rare).
  • Ambiguous or normal external genitalia at birth
  • Internal structures depend on adjacent gonads:
    • Fallopian tubes may develop beside an ovary or ovotestis (60%‒70% of the time).
    • Vas deferens and epididymis develop beside a testicle.
    • Uterus may develop if an ovary is present.
Turner syndrome
  • Chromosomal anomaly with a partially or completely missing X chromosome
  • Occurs due to nondisjunction during meiosis or mitosis
  • Affected individuals are 45,X0.
  • Phenotypic female genitalia
  • Müllerian structures present
  • Characteristic appearance including short stature, webbed neck, shield chest, and low hairline
  • Multiple medical anomalies involving the cardiac, renal, reproductive, skeletal, and lymphatic systems
  • Most common cause of primary amenorrhea
Klinefelter syndrome
  • Chromosomal anomaly characterized by 1 or more X chromosomes in a male karyotype
  • Most commonly 47,XXY
  • Other possible karyotypes: 48,XXXY and 48,XXYY
  • ↓ Testosterone and ↑ estrogen compared to typical levels in men
  • Phenotypic male genitalia
  • Wolffian structures present; Müllerian structures absent
  • Presents in adolescence with small testes, ↓ body hair, gynecomastia, and infertility
  • Most common cause of hypogonadism in men
21-hydroxylase deficiency

21-hydroxylase deficiency:
Diagram of the pathophysiology of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Image by Lecturio.

Principles of Diagnosis

The differential diagnosis for disorders of sexual development typically includes many of the conditions listed above. The general diagnostic approach to help determine the appropriate diagnosis is listed below.


  • Genital examination:
    • Ambiguous genitalia is likely due to ↑ testosterone/DHT in individuals without SRY (e.g., 46,XX) or ↓ testosterone in individuals with SRY (e.g., 46,XY)
    • Assess the size and descent of testes.
  • Internal pelvic examination on phenotypic females:
    • Is a cervix visible?
    • Is the uterus palpable?
  • Assessment of secondary sex characteristics in adolescents/adults:
    • Breast development = estrogen present
    • Pubic and axillary hair = testosterone present
    • Facial/body hair, deepening of the voice = testosterone present
  • Look for findings associated with specific syndromes (e.g., webbed neck in Turner syndrome).


  • Karyotype with FISH to assess the presence or absences of the SRY gene
  • Testosterone: 
    • Decreases in Kallman, Swyer, and Klinefelter syndromes
    • Increases or is normal in androgen insensitivity syndrome (AIS), 5α-reductase deficiency, aromatase deficiency, and congenital adrenal hyperplasia
  • DHT: 
    • Decreases with 5α-reductase deficiency 
    • Increases in AIS
  • Follicle stimulating hormone (FSH) and luteinizing hormone (LH): 
    • Decrease in Kallman syndrome (due to ↓ gonadotropin-releasing hormone (GnRH))
    • Increase in 46,XX gonadal dysgenesis and Swyer syndrome (normal GnRH function with non-responsive gonads)
  • 17-Hydroxyprogesterone: ↑ in congenital adrenal hyperplasia


Abdominal pelvic ultrasound to assess the internal organs:

  • Presence or absence of a uterus
  • Assessment of the gonads

Consider imaging of the kidneys and urinary tract, as abnormalities in the reproductive organs are frequently associated with renal/urinary anomalies.

Principles of Management

  • Factors affecting management:
    • Age of presentation (infant, adolescent, versus adult)
    • Gender identity and preferences of the patient
    • Hormone status
  • Psychotherapy/counseling: All patients (and potentially family members) should be referred for therapy.
  • Hormone replacement therapy (HRT) may be indicated in patients with hormonal deficiencies (e.g., testosterone and/or estrogen).
  • Surgery:
    • Abnormal gonads, especially gonadoblastomas and dysgerminomas, pose a high risk for malignancy → surgical excision recommended
    • Reconstructive or reassignment surgery


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