Differences of Sexual Development

Descriptive text is not available for this imageBASICS

DESCRIPTION

  • Atypical genitalia (a preferred term) refers to external genitalia that do not have a typical male or female appearance.
  • May result from various differences of sexual development (DSDs), a generic term defined as conditions in which development of chromosomal, gonadal, or phenotypic sex is atypical
    • General DSD categories are 46,XX DSD; 46,XY DSD; and sex chromosome DSD. Within these, other subcategories exist (e.g., ovotesticular DSD, gonadal dysgenesis). When available, specific genetic diagnoses are preferable to these broad categories.
    • Previous terms such as “intersex,” “pseudohermaphroditism,” or “sex reversal” should be avoided.
  • Findings that suggest that a child may have a DSD include the following:
    • Bilateral nonpalpable testes
    • Micropenis (stretched length <2.5 cm at full term)
    • Severe hypospadias or mild hypospadias with unilateral or bilateral undescended testes
    • Clitoromegaly (width >6 mm or length >9 mm), posterior labial fusion
    • Inguinal/labial mass in a phenotypic female
    • Family history of a DSD
    • Discordance between genital appearance and karyotype
  • Genital atypia comprise a spectrum of physical findings; some cases, but not all, may present questions of initial gender assignment.
  • Note: The umbrella term DSD also comprises sex chromosome disorders such as Turner (45,X) and Klinefelter syndromes (47,XXY). However, individuals with these diagnoses typically do not present with atypical genitalia.

EPIDEMIOLOGY

  • Genital anomalies at birth have a prevalence as high as 1 in 300.
  • Genital atypia to the extent that prompts investigation has a prevalence of approximately 1 in 5,000 births.
  • Congenital adrenal hyperplasia (CAH) is the most common cause of DSD and is the cause of 90–95% of 46, XX DSD. CAH is discussed in detail in a separate chapter.
  • 15% of DSDs are chromosomal DSD, including Turner and Klinefelter syndromes.
  • DSDs causing genital atypia are congenital and usually present in the newborn period but may present in adolescents with onset of pubertal disorders.
  • Later presentations of DSDs can occur in older children and young adults, with primary amenorrhea or progressive virilization in phenotypic females or lack of pubertal development in phenotypic males; examples:
    • 46,XY individuals with complete 17α-hydroxylase/17,20-lyase deficiency may present in adolescence with hypertension and delayed puberty.
    • Women with complete androgen insensitivity syndrome (CAIS) may present during adolescence with primary amenorrhea.
    • Children with 5α-reductase deficiency may become virilized during puberty.

RISK FACTORS

  • Numerous single-gene variants causing atypical genitalia have been described. However, outside of CAH and chromosomal DSD, <50% of patients are diagnosed at the molecular level.
  • 46,XY DSD may be associated with pathologic variants in the following genes:
    • Genes involved in testicular development: sex-determining region on Y (SRY), SOX9 deletion, steroidogenic factor 1 (SF-1), Wilms tumor suppressor (WT1) gene, WNT4 duplication, and DAX1 duplication
    • Genes involved in steroid hormone action or synthesis (autosomal recessive, except for the androgen receptor [AR])
      • LH/choriogonadotropin receptor (LHCGR) gene, leading to Leydig cell hypoplasia and decreased testosterone (T) production
      • Genes encoding adrenal steroidogenic enzymes, causing undervirilization: 17α-hydroxylase (CYP17A1), 3β-hydroxysteroid dehydrogenase (HSD3B2), P450 oxidoreductase, and StAR protein (lipoid hyperplasia)
      • 5α-reductase gene (SRD5A2), leading to defective conversion of T to dihydrotestosterone (DHT); DHT is necessary for the in utero development of male external genitalia.
      • AR gene located on the X chromosome (X-linked recessive), leading to impaired androgen action
  • 46,XX DSD may be associated with pathologic variants in the following genes:
    • Genes involved in ovarian development and leading to gonadal dysgenesis: FSH receptor (FSHR), SF-1
    • Genes involved in testicular development: inappropriate presence of SRY, SOX9 duplication
    • Genes encoding adrenal steroidogenic enzymes, leading to virilizing CAH: 21-hydroxylase (CYP21A), the most common form; 11β-hydroxylase (CYP11B1); 3β-hydroxysteroid dehydrogenase (HSD3B2)
    • Aromatase gene (CYP19A1), leading to impaired placental conversion of fetal adrenal androgens to estrogens
  • Sex chromosome DSDs (45,X; 47,XXY; 45,X/46,XY; and 46,XX/46,XY) are caused by meiotic or mitotic nondisjunction.

PATHOPHYSIOLOGY

  • 46,XY DSD
    • Incomplete masculinization of the male fetus can be caused by disorders of T synthesis (e.g., CAH, 5α-reductase deficiency), unresponsiveness to T action (androgen insensitivity syndromes), or defects in testicular development (complete or partial gonadal dysgenesis).
  • 46,XX DSD
    • Masculinization of the female fetus is caused by exposure to androgens, either endogenous or exogenous. The most common cause is CAH in which the fetal adrenal glands overproduce androgens in an attempt to produce cortisol.
  • Sex chromosome DSD
  • Ovotesticular DSD
    • Presence of both ovarian and testicular elements; combinations may include one ovary and one testis, two ovotestes, or one ovotestis with either an ovary or a testis. Differentiation of internal and external genitalia often coincides with the gonad on the ipsilateral side.
    • Karyotypes are 46,XX most commonly; 46,XX/46,XY and 46,XX/47,XXY reported; however, the molecular basis of this disorder may not be known.
  • Gonadal dysgenesis
    • Mixed gonadal dysgenesis (MGD) (classically 45,X/46,XY) involves a streak gonad on one side and a testis, often dysgenetic, on the other side. Phenotype is highly variable and ranges from female external genitalia through all stages of ambiguous genitalia to a normal male.
    • Complete gonadal dysgenesis (46,XX, 46,XY, or a Turner syndrome karyotype) involves replacement of gonads by streak gonads. Neonates have female external genitalia and often present later in life with delayed puberty and primary amenorrhea.

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