Idiopathic (80%–90% of cases) amenorrhea with absence of secondary sexual characteristics, breast development may occur if ovarian function is initially present. Mosaicism of an XO or XY cell line may cause ovarian insufficiency. Individuals with a 47,XXX karyotype may develop ovarian failure (87). The most common physical features of 47,XXX are tall stature, epicanthal folds, hypotonia, and clinodactyly.
A deletion of a portion of the X chromosome may be present in patients with POI. The Xq21-28 region is critical (7,88). Several genes in this region are identified as the cause of early ovarian insufficiency in humans. Examples include the POF1B gene located at Xq21, the DIAPH2 gene located at distal Xq21, and the XPNPEP2 gene located at Xq25 (89,90). The specific functions of these genes require further investigation. In addition, a mutation of the BMP15 gene located at Xp11.2 is identified in patients with premature ovarian failure (91).
An autosomal recessive form of premature ovarian failure is associated with hearing loss in Perrault syndrome (92). Mutations in FOXL2 causes ovarian failure and ptosis (93). Familial ovarian failure is inherited by dominant Mendelian inheritance in rare cases (94). Numerous genetic mutations leading to ovarian insufficiency are identified and many more are likely to be discovered (95,96). Other than the FMR1 premutation described next, no one mutation is particularly common.
Fragile X Carriers Fragile X syndrome, the most common cause of inherited (X-linked) intellectual disability, is caused by inactivation of the FMR1 (fragile X mental retardation 1) gene located on Xq27.3. This inactivation occurs as a result of expansion of a cytosine-guanine-guanine (CGG) triplet repeat of more than 200 copies (97). FMR1 premutation carriers (typically defined as greater than 55 but under 200 CGG repeats) may have primary ovarian insufficiency and impaired fertility. The prevalence of POI in women who carry the FMR1 premutation is estimated to be between 13% and 26%. The risk of having POI appears to increase with increasing premutation repeat size between 59 and 99. It is possible that there is an increased risk of POI among women who carry intermediate-size allele (approximately 41 to 58 repeats), but this is not conclusively proven. The risk plateaus or decreases for women with repeat sizes of 100. Interestingly, women with full mutations (200 or more CGG repeats) are not at higher risk for POI. It is hypothesized that expression of abnormal FMR1 mRNA produced by patients with the premutation causes dysfunction in the ovary, which does not occur when the FMR1 gene is inactivated and not transcribed. The incidence of having a premutation is 0.8% to 7.5% of women with sporadic POI and up to 13% of women with familial POI.
FMR1 premutations carried by women are unstable and can expand in the next generation to transmit fragile X syndrome to male offspring, especially if women have more than 100 repeats. The smallest repeat to expand to the full mutation in one generation is approximately 59. In contrast to potential expansion in women, the repeat sequence is transmitted from fathers to daughters in a relatively stable manner.