General Medical Information

XX Gonadal Dysgenesis due to Follicle

Joe Leigh Simpson

In Finland, Aittomaki and Aittomaki searched hospitals and cytogenetic laboratories to identify 75 patients country-wide having XX gonadal dysgenesis, defined as 46,XX women with primary or secondary amenorrhea and serum FSH greater than 40 mIU/mL. These 75 patients included 57 sporadic cases and 18 cases having affected relatives (seven different families). Most cases were found in north central Finland, a sparsely populated part of the country. The overall frequency of the disorder in Finland was one per 8,300 liveborn females, a relatively high incidence attributed to a founder effect. Segregation ratio of 0.23 for female siblings was consistent with autosomal recessive inheritance, as was the high consanguinity rate (12%). Sib-pair analysis using polymorphic DNA markers localized the gene to chromosome 2p, a region that was known to contain genes for both the FSHR and the luteinizing hormone receptor (LHR). One specific mutation in exon 7 (C566T: yielding alanine rather than valine) was observed in six families.

C566T was not found in all Finnish XX gonadal dysgenesis cases. The C566T-negative cases in Finland could represent the same disorder discussed previously (XX gonadal dysgenesis with no somatic anomalies). This would be consistent with the C566T mutation only rarely being detected in women with 46,XX ovarian failure who reside outside Finland. Layman found no mutations in the FSHR gene in 35 46,XX women having hypergonadotropic hypogonadism (15 with primary amenorrhea and 20 with secondary amenorrhea). Liu found no sequence abnormalities in one multigeneration POF family, four sporadic POF cases, and two cases of hypergonadotropic hypogonadism cases.

When Aittomaki contrasted the phenotype of C566T XX gonadal dysgenesis with non-C566T XX gonadal dysgenesis, the former was more likely to have ovarian follicles on ultrasound. C566T XX gonadal dysgenesis thus showed some features expected for gonadotropin resistance (Savage syndrome); however, FSH level clearly was elevated, and the phenotype was far more reminiscent of the bilateral streak gonads and prototypal XX gonadal dysgenesis.