Genetically, ovarian failure is associated with X chromosomal abnormalities

X chromosomal abnormalities

These abnormalities could include a small defect in chromosomal arrangement such as deletions, isochromosomes and balanced X chromosome-autosomal translocations. However, complete deletion of one X (Turner’s syndrome) has also been recorded (16).

X monosomy (Turner’s syndrome)

Complete or near-complete absence of one X chromosome is the most common chromosomal defect in humans (17). This condition leads to ovarian dysgenesis characterized by prienorrhea, short stature and characteristic phenotypic features. Two functioning X chromosomes are necessary for normal ovarian function (18). In the presence of only one X chromosome, ovarian follicles degenerate from birth onwards. This is most likely caused by lack of diploid dosage of one or more vital genes and accelerated follicular atresia. Histological data indicate that oogenesis proceeds normally in these individuals until diplotene oocytes begin to be incorporated into follicles. There is a subsequent block in the production of complete follicles manifesting as follicular atresia. In 80% of cases, the paternally derived is lost (19).

However, the identification of genes or critical regions responsible for individual Turner’s syndrome features has turned out to be problematic. Cytogenetic data indicate the reduced dosages of genes on the short arms of the X (Xp) and Y (Yp) chromosomes (2. 6Mb Xp-Yp pseudoautosomal region) tends to be associated with short stature and somatic anomalies (20, 21), whereas deletions on the long arm of the X (Xq) chromosome tends to be associated with ovarian failure but no somatic anomalies (22, 23). The degrees of ovarian dysfunction and the extent of the somatic anomalies are variable. While the most affected patients have prienorrhea, streak gonads and absence of pubertal development, some develop normally and occasionally have a successful pregnancy and then secondary amenorrhea, while other patients have no somatic defects.

Association between trisomy X and POF have been reported (24). In one reported series, 3. 8% of patients with POF had the triple X syndrome (25). POF has also been reported in a girl with 48XXXX (26). Individuals with 45X/46XX and 46XX/47XXX carry mixed germ lines, which manifest as phenotypic abnormalities and POF (27). The association of POF and X chromosome deletions or X-autosomal translocations has been extensively reported in literature (15). Deletions of the X chromosome have been suggested in three main critical regions: X q13. 3- q22, Xq26-q28, as well as Xp11. 2 (28, 29). Deletions at Xp11. 2 result in 50% prienorrhea, and deletions at X q13 usually produce prienorrhea (15). Balanced X chromosome and autosomal translocation have been reported in more than 100 POF cases, and the break points of balanced X-autosomal translocations were reported in the region between Xq13 and Xq27 (30).

Adolescent girls with Turner’s syndrome or other chromosomal abnormalities who still have follicles in their ovaries could be candidates for oocyte or/ and ovarian tissue cryopreservation, to save their ovaries for future fertilization by ovarian reimplantation (31, 32).

Fragile X syndrome

Fragile X syndrome is an X-linked dominant condition with incomplete penetration and a prevalence of 1/4000 in males and 1/6000 in females (33). It is the most common hereditary cause of mental retardation and developmental delay (34). It is caused by an expansion of CGG trinucleotide repeats in the 5? untranslated region of the first exon of the fragile X mental retardation 1 (FMR1) gene. This gene is located on the X chromosome at Xq27.3. Fully affected individuals have more than 200 CGG repeats, whereas normally there are between 5 and 54 CGG repeats. Premutation alleles, defined as between 55 and 200 CGG repeats, are at risk of expanding into a full mutation in the next generation (35, 36). A recent study showed that a number of CGG repeats between 30 and 40 might be used to predict premature ovarian aging and POF in infertile patients (37). Expansion to more than 200 repeats leads to methylation-coupled silencing of the FMR1 gene and absence of FMR-protein. This protein has an important role in prenatal and postnatal brain development (38).