gonadal dysgeneses
Types
ovarian dysgenesis
testicular dysgenesis
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
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
Syndromes of gonadal dysgenesis :
- 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 :
- 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