• Clinical science

Disorders of sex development


Disorders of sex development are a group of congenital conditions that affect the development of the chromosomal, gonadal, or phenotypic sex. The underlying genetic mutations affect the number and function of sex chromosomes (e.g., in Turner syndrome), lead to structural changes with altered sensitivity of hormone receptors (e.g., androgen insensitivity syndrome), or alter the function of enzymes responsible for sex hormone synthesis (e.g., congenital adrenal hyperplasia). The most characteristic clinical feature is the development of a sexual phenotype which does not correspond to the sexual genotype. Other common features include reduced fertility or infertility and concomitant organ malformations (e.g., cardiac abnormalities). Disorders of sex development can also present with difficulties in gender identification and cause considerable psychological distress. The diagnosis of these conditions is based on characteristic clinical features, evaluation of hormone levels, and genetic testing. Management includes hormone substitution, possibly sex reassignment surgery, and psychological counseling.

Congenital adrenal hyperplasia

Androgen insensitivity syndrome

  • Etiology: X-linked recessive mutation of the gene locus encoding the androgen receptor → varying degrees of end-organ insensitivity to androgens
  • Karyotype: 46,XY
  • Clinical features
    • Complete androgen insensitivity
      • Female external genitalia (testicular feminization) and physique
      • Blind-ended vaginal pouch, uterine agenesis
      • Scant or missing pubic hair
      • Primary amenorrhea, infertility (no menarche)
    • Partial androgen insensitivity: variations in phenotype, depending on the degree of androgen insensitivity
    • Male internal genitalia
    • Detection of abdominal/inguinal masses in newbornsintra-abdominal localization of undescended testicles
  • Diagnostics
  • Therapy
    • Management depends on receptor status and, especially, on the phenotype and gender identity of the affected patient.
    • Hormone treatment
    • Gonadectomy for intra-abdominal testicles typically performed after puberty (high risk of malignancy)
    • Psychological support


Aromatase deficiency

  • Karyotype: 46 XX or 46 XY (normal sex development)
  • Pathophysiology: : Mutations in the CYP19A1 gene which encodes for the enzyme aromatase ↓ serum estrogen and ↑ serum testosterone
  • Clinical features
  • Treatment
    • Estrogen and progesterone replacement therapy
    • Calcium and vitamin D supplementation
    • Surgical correction of ambiguous genitalia


5-alpha-reductase deficiency

  • Synonym: pseudovaginal perineoscrotal hypospadias (PPSH)
  • Etiology: rare autosomal recessive loss-of-function mutation of chromosome 2
  • Karyotype: 46,XY
  • Pathophysiology
    • Normal testosterone production
    • Defective 5-alpha-reductase: testosterone not converted into dihydrotestosterone (DHT)DHT-dependent virilization of genitalia does not occur
  • Clinical features
    • Female external genitalia at birth, sometimes with pseudovaginal perineoscrotal hypospadias
    • Internal urogenital organs are male
    • In puberty, increasing synthesis of testosterone leads to virilization (phallic growth, testicular descent, development of male gender identity).
  • Diagnostics
  • Therapy
    • Female gender identity: gonadectomy; estrogen substitution therapy upon completion of longitudinal growth
    • Male gender identity: testosterone substitution


Klinefelter syndrome

  • Karyotype: 47 XXY, rarely 48 XXXY and 48 XXYY
  • Incidence: approximately 1:600 children [6][7]
  • Etiology: most commonly due to nondisjunction of sex chromosomes during meiosis of parental germ cells
  • Clinical features
  • Diagnostics: : primarily a clinical diagnosis; karyotyping confirms the diagnosis
  • Complications: Increased risk of breast cancer development due to decreased levels of testosterone and increased levels of estrogen.
  • Therapy: life-long testosterone substitution [6]


Turner syndrome


Ovotesticular disorder of sex development

Pure gonadal dysgenesis


Swyer syndrome


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last updated 08/09/2019
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