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pure gonadal dysgenesis

Thursday 22 December 2005

Definition: bilateral streak gonads that fail to differenciate.

Pure gonadal dysgenesis (PGD) manifests as bilateral dysgenetic gonads with underdeveloped müllerian derivatives.

There is usually no genital ambiguity, and the phenotype is female from birth.

Pure gonadal dysgenesis is often confused with complete androgen insensitivity syndrome (CAI syndrome), since patients present at puberty with failure of menarche and a female phenotype.

In pure gonadal dysgenesis, there are usually normal or hypoplastic müllerian derivatives because the dysgenetic gonads often do not produce mullerian inhibiting factor (MIF), whereas in complete androgen insensitivity syndrome (CAI syndrome) there are no müllerian derivatives.

Nosology

Pure gonadal dysgenesis, and its eponym, Swyers syndrome, are terms that historically have encompassed diverse conditions, including testicular regression syndrome at one end of the spectrum and mixed gonadal dysgenesis (now 46,XY disorder of sex development) at the other.

‘Pure gonadal dysgenesis’ refers to a phenotypic female where the internal genitalia include müllerian structures (uterus and fallopian tubes) and generally streak gonads, the constellation of which probably still encompasses a multitude of diverse conditions.

The patients may appear phenotypically normal or have hypoplastic external genitalia. The pure gonadal dysgenesis syndrome occurs with both 46,XX and 46,XY karyotypes and has both familial and sporadic patterns of inheritance.

- 46,XX type pure gonadal dysgenesis

The 46,XX type pure gonadal dysgenesis is usually an autosomal recessive disorder, but, less frequently, may be due to an abnormality of the X chromosome, possibly as a mosaic 45,X cell line confi ned to the gonad.

Deletions of the short or long arm of an X chromosome have been identified in some cases. Such patients have greater ovarian development than those with 46,XY pure gonadal dysgenesis or Turner syndrome and present more often with signs of ovarian dysfunction (secondary amenorrhea or infertility) rather than primary gonadal failure (primary amenorrhea).

Some patients may also have mosaic cell lines with the SRY gene absent in some tissues (peripheral leukocytes), but present in others (testicular tissue).

- 46,XY type pure gonadal dysgenesis

The 46,XY type pure gonadal dysgenesis is more common than the 46,XX form of the disorder. The syndrome of pure gonadal dysgenesis may be sporadic or familial with either X-linked recessive or autosomal recessive patterns of inheritance.

- mosaic 45,X/46,XY

Some patients have a mosaic 45,X/46,XY karyotype.

- SRY deletion

The 46,XY type may also involve deletion of the SRY gene, a mutated inactive SRY gene or a defective promoter cofactor.

- DAX1-associated DSD

One gene believed crucial for regulating the SRY gene is DAX1 located on the X chromosomal short arm. The gene is unusual in that only one copy, which
is normal, is insufficient to negate the effects of the SRY gene. A double dosage, i.e., the presence of two active copies in tandem, results in sex reversal from male to female.

It seems that the DAX locus is normally subject to X inactivation as patients with Klinefelters syndrome have two copies of the affected X chromosome locus.

In one series of 14 XY females with pure gonadal dysgenesis, patients who had normal SRY had gonads composed of undifferentiated stroma in which were tubules or a rete structure suggesting some differentiation towards testis. In those cases where there were mutations in SRY-ORF (SRY-opening reading frames), no tubules were observed; the gonads were composed exclusively of ovarian-like stroma with sclerohyaline nodules in some areas.

These data also suggested that SRY may play a role in rete testis formation.

- 46,XX pure gonadal dysgenesis

Patients with 46,XX pure gonadal dysgenesis, as those with Turner syndrome, only rarely have gonadal tumors. Some have had hilus cell hyperplasia and hilus cell tumors with the usual associated virilizing effects.

Epithelial tumors are extremely rare, but of these mucinous tumors occur more frequently than serous. Rare examples of germ cell tumors have been reported, and even though no identifiable Y chromosome component could be detected in some, the possibility of a cryptic Y fragment cannot be excluded.

- Tumoral risk

Patients with 46,XY pure gonadal dysgenesis are at high risk for gonadoblastoma
and other germ cell tumors, as is true of all patients with streak gonads and a Y chromosome.

In one series, 11 of 20 patients had gonadal neoplasms; eight were gonadoblastomas, half of which were bilateral, and eight were dysgerminoma, all unilateral.

On this basis, patients with 46,XY pure gonadal dysgenesis might be considered a subset of the broader condition of mixed gonadal dysgenesis.

Nota bene:

- 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)

See also

- intersex
- hermaphrodisms