General Medical Information

XX Gonadal Dysgenesis

Joe Leigh Simpson

Gonadal dysgenesis histologically similar to that occurring in individuals with an abnormal sex chromosomal complement may be present in 46,XX individuals, as shown by Simpson over 25 years ago. Mosaicism has been reasonably excluded in affected individuals. The general term XX gonadal dysgenesis is applied to those individuals.

Many different forms of 46,XX gonadal dysgenesis exist, but the form of XX gonadal dysgenesis not associated with somatic anomalies is clearly inherited in autosomal recessive fashion. Affected individuals are normal in stature (mean height 165 cm), and Turner’s stigmata usually are absent. Frequent reports of consanguinity have long made it clear that autosomal recessive genes are responsible. More recent segregation analysis by the author and colleagues revealed the segregation ratio to be 0.16 for female siblings. Thus, two thirds of gonadal dysgenesis cases in 46,XX individuals are genetic. The one third of cases that are nongenetic (phenocopies) could be due to infection, infarction, or infiltrative or autoimmune phenomena.

Of clinical interest is the variable expressivity. In some families, one sibling has streak gonads, whereas another affected individual had primary amenorrhea and extreme ovarian hypoplasia (presence of a few oocytes). If the mutant gene responsible for XX gonadal dysgenesis is capable of variable expression, the gene may be responsible for some sporadic cases of POF.

The mechanism underlying failure of germ cell persistence in XX gonadal dysgenesis is unknown, but several hypotheses seem reasonable. One is perturbation of meiosis, which would be manifested as ovarian failure and infertility in otherwise normal women. Other possibilities include interference with germ cell migration, abnormal connective tissue milieu, or gonadotropin receptor perturbation.

In the absence of candidate genes, identifying autosomal genes responsible for the various forms of XX gonadal dysgenesis is more difficult. A fortuitous family might arise in which an autosomal translocation cosegregates with XX gonadal dysgenesis. Sporadic cases of gonadal dysgenesis have long been associated with reciprocal autosomal translocations, but for years there seemed to be little consistency in the chromosome involved. An alternate approach is a “brute force” genome-wide search for relevant gene(s), utilizing sib-pair analysis with the polymorphic DNA markers readily available throughout the genome. Using sib-pair analysis, as few as 50 to 100 families should identify chromosomal region(s) worthy of sequencing. This method has been applied successfully in Finland to elucidate the form of XX gonadal dysgenesis due to follicle-stimulating hormone receptor (FSHR) mutation.