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gonadal dysgenesis

Wednesday 15 December 2004

Types

- ovarian dysgenesis (dysgenetic ovary)
- testicular dysgenesis (dysgenetic testis)
- streak gonad

Variants

- mixed gonadal dysgenesis
- pure gonadal dysgenesis
- XX gonadal dysgenesis
- XY gonadal dysgenesis (gonadal dysgenesis, XY female type) (MIM.306100)

Synopsis

- ambiguous genitalia
- persistent mullerian duct structures and wolffian duct derivatives
- abnormally developed gonads

Note: some don’t separate types of gonadal dysgenesis

Tumoral predisposition

Increased risk of tumor development : potential for neoplastic transformation of gonads

  • gonadoblastoma :
    • 30% of patients with mixed gonadal dysgenesis
    • less than 3% of patients with true hermaphrodism
    • 50% of patients with 46XY pure gonadal dysgenesis
    • very high frequency of associated malignant germ cell tumor
  • dysgerminoma :
    • malignant germ cell tumor most commonly associated with gonadoblastoma

Etiology

  • embryonal formation of the urogenital ridge derives from the intermediate mesoderm, as germ cells are migrating
  • mutations in genes for factors influencing urogenital ridge formation produce abnormal gonads in mice :
    • Emx2 (EMX2), GATA-4 (GATA4), Lim1 (LHX1), Lhx9 (LHX9)
  • Frasier syndrome (MIM 136680):
    • gonadal dysgenesis (streak gonads) and renal abnormalities (nephrotic syndrome)
    • mutation of the splice site of WT1, producing WT1 protein without KTS (a series of three amino acids, lysine, threonine and serine, in the DNA-binding domain)
    • gonads lacking KTS exhibit a decreased production of :
      • SRY, a urogenital ridge protein critical in testicular development
      • Müllerian inhibiting substance, a glycoprotein hormone derived from Sertoli cells and an early marker of testicular differenciation
  • Denys-Drash syndrome (MIM 194080):
    • mutations in WT1 outside the KTS region, with resulting more complete differenciation of the gonads
    • low testosterone levels may produce male pseudohermaphrodism, hypospadias and cryptorchidism
    • high incidence of Wilms tumor and nephropathy (focal glomerular and mesangial sclerosis)
  • mixed gonadal dysgenesis :
    • classic form : unilateral streak gonad and unilateral dysgenetic fibrotic testis, retained müllerian ducts and incomplete genital masculanization (testosterone deficiency)
    • most often : 46X0-46XY mosaic karyotype
    • 46XY karyotype in 40% of patients
  • pure gonadal dysgenesis :
    • bilateral streak gonads that fail to differenciate
    • mutations in the SRY gene on the distal short arm of the Y chromosome in 46XY sex-reversed females with pure gonadal dysgenesis
    • translocation in chromosome 9p near the SRY-related SOX9 gene induces campomelic dysplasia (46XY sex-reversal, sreak gonads, severe skeletal malformation)
  • true hermaphrodism :
    • presence of both ovarian and testicular tissue in the same or in a contralateral gonad
    • translocation of the SRY gene to a cryptic site on the X chromosome described in a few cases
  • mullerian agenesis :
    • undifferentiated gonad with both male and female reproductive ducts
    • inactivation of Wnt-4 may be implicated

References

- MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med. 2004 Jan 22;350(4):367-78. PMID: 14736929

- Vaiman D, Pailhoux E. Mammalian sex reversal and intersexuality: deciphering the sex-determination cascade. Trends Genet. 2000 Nov;16(11):488-94. PMID: 11074290