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Definition

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  • Congenital conditions in which there is discordance between anatomic sex, hormonal sex, and the sex chromosomes.

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Virilization of Females

(Female Pseudohermaphroditism)

  • Most commonly: enzymatic deficiencies in cortisol pathway → excessive ACTH, leading to congenital adrenal hyperplasia and excess androgen production
  • Most common is 21-hydroxylase deficiency
  • Other causes include virilizing tumors and maternal use of androgens (systemic or topical)

Inadequate Male Virilization

(Male Pseudohermaphroditism)

Three possible etiologies:

  • Decreased androgen production (nonvirilizing adrenal hyperplasia, inadequate Müllerian inhibiting substance)
  • Decreased end-organ response to androgen (testicular feminization—due to abnormal receptor)
  • 5α-reductase deficiency

Abnormal Gonadal Differentiation

  • True hermaphroditism (both testicular and ovarian tissue present in one individual)
  • Gonadal dysgenesis: partial (with one functional gonad, one streak) or total (two streak gonads; chance of neoplastic transformation high in Y-chromosome form)

Chromosomal Abnormalities or Associations

  • Trisomies 13 and 18
  • Triploidies
  • Smith–Lemli–Opitz syndrome
  • Rieger's syndrome
  • CHARGE association
  • VACTERL association
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Clinical Presentations

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  • Overt genital ambiguity
  • Apparent female genitalia with an enlarged clitoris, posterior labial fusion, or an inguinal/ labial mass
  • Apparent male genitalia with bilateral descended testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended testes
  • Family history of DSD, such as CAIS (Complete Androgen Insensitivity Syndrome)
  • Discordance between genital appearance and a prenatal karyotype

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Diagnostic Evaluation

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  • Karyotyping with X- and Y-specific probe
  • Abdominal US
  • Measurement of the following hormones:
    • 17-hydroxyprogesterone
    • Testosterone
    • Gonadotropin
    • Anti-Müllerian hormone
  • Serum electrolytes
  • Urinalysis

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Inherited CausesAcquired Causes

Adrenocortical Dysgenesis

Impaired Steroid Responsiveness

Disorders of Steroid Biosynthesis

  • Caused by mutations in DAX1 and SF1 genes
  • These genes encode a nuclear transcription factor expressed in both gonads and the adrenal cortex
  • Results in deficiency of all adrenal steroids

Pseudohypoaldosteronism:

  • Mutation of aldosterone receptor gene or of epithelial sodium channel genes
  • Clinical presentation with salt wasting, hyperkalemia, shock, dehydration

Familial unresponsiveness to ACTH:

  • Results in normal mineralocorticoid activity, with diminished glucocorticoid activity
  • Clinical presentation with profound hypoglycemia and hypotension

StAR (acute steroid regulatory protein) deficiency:

  • Mediates transfer of cholesterol across mitochondrial membrane
  • Adrenals are large and lipid laden
  • Decreased levels of all adrenal steroids
  • 46 XY males appear female or only minimally virilized

3-β-Hydroxysteroid dehydrogenase deficiency:

  • Catalyzes the conversion of pregnenolone, 17-OH-pregnenolone, DHEA, and androstenedione
  • Clinical manifestations:
    • Salt-wasting adrenal crisis
    • 46, XX female may be mildly virilized
    • 46, XY male is undervirilized
    • Elevated substrates: DHEA and 17-OH-pregnenolone
    • Elevated 17-OH-progesterone

21-Hydroxylase deficiency:

  • Most common cause of CAH
  • Classic salt-wasting CAH:
    • Adrenal crisis with shock, hyperkalemia, and hyponatremia
    • Polyuria
    • Presentation at 1–4 wk of life
    • 46, XX infants are virilized

Exogenous glucocorticoid administration:

  • Infants receiving high-dose glucocorticoids for >10–14 d are at high risk
  • May require hydrocortisone for unexplained hypotension or hypoglycemia or in preparation for surgery

Bilateral adrenal hemorrhage:

  • Can be seen in LGA infants with difficult delivery/coagulopathy
  • Asymptomatic infants can have suprarenal calcifications on plain film of abdomen
  • ...

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