Turner’s Syndrome

Classic Turner’s syndrome is characterized by the absence of one X chromosome. Clinical features are variable, and at birth newborns may present with low birth weight, lymphedema of the upper and lower extremities (in 30% of Turner babies), and a webbed neck (pterygium colli). Additional dysmorphic features may include low-set prominent ears, a low posterior hairline, micrognathia, high-arched palate, epicanthal folds, hypoplastic nail beds, and/or hypoplastic fourth and fifth metacarpals. At adolescence, the most common presentation is one of short stature, amenorrhea, and lack of secondary sex characteristics, although the latter is variable and depends upon the extent of gonadal dysgenesis. The diagnosis of Turner’s syndrome should prompt a search for renal anomalies (incidence between 30% and 50%), as well as coarctation of the aorta and hearing loss.

Thirty percent of patients with Turner’s syndrome have the classic 45, X karyotype, and the remaining have a mosaic form where a 45, X cell line is associated with another cell line such as 46, XX or 46, XY. Of note, patients with mosaic forms of Turner’s syndrome can lack the classic phenotypic features, and usually are not diagnosed until presenting with POI later in life.

While one X chromosome in females is inactivated for dosage compensation, several genes escape inactivation and are essential for normal function of the X chromosome. The phenotypic traits of Turner’s syndrome, including POI, have been mapped to a critical region in Xp11.2-p22.1 which escapes X inactivation, and contains the 18 candidate genes that have been reported.

The loss of one X chromosome leads to an accelerated loss of ovarian follicles prior to birth. Many patients with Turner’s syndrome lose all of their follicles prenatally, and some lose their remaining germ cells during childhood. Accordingly, such patients will present with primary amenorrhea. Less than 15% of Turner’s patients will lose their germ cells after puberty and may even have enough germ cells for regular cycles before presenting with secondary amenorrhea. Rarely, some patients with Turner’s syndrome will even achieve pregnancy prior to developing ovarian insufficiency.

Once the germ cells are depleted from the ovaries, the residual gonads consisting only of connective stroma are called “streak gonads.” Patients with a Y cell line Turner’s syndrome have an increased risk of development of gonadoblastoma and malignant germ cell tumors. Consequently, it is recommended that streak gonads be surgically removed.

Trisomy X

Trisomy X affects one in 900 women and is rarely associated with POI. In one series, two of 52 (3.8%) patients with POI had trisomy X. The underlying mechanism is not clear, but may be similar to that observed among patients with Klinefelter’s syndrome.

Deletions

Deletions on an X chromosome leave a portion of the normal X unpaired and can lead to oocyte atresia. Although deletions more often involve the short arm of the X chromosome (Xp), deletions associated with POI more commonly involve the Xq13-25 region. Deletions at Xp11 result in both primary and secondary amenorrhea, whereas deletions at Xq13 usually lead to primary amenorrhea. It has also been noted that more proximal deletions are associated with ovarian failure while distal deletions appear to be innocuous. However, it remains unclear why large deletions that remove the whole critical region for POI, in Xq21, are not associated with ovarian failure.

Translocations

Balanced X/autosomal translocations, while rare, often lead to POI and have been reported in more than 100 postpubertal women. Breakpoints that fall between Xq13 and Xq26 are associated with ovarian failure. Thus, it has been proposed that this is a critical region for normal ovarian function. The most frequent breakpoints involve two specific POI regions: POI1 Xq26-qter, and POI2 Xq13.3-Xq21.1. The chromosome in this region may be particularly sensitive to structural changes that ultimately lead to oocyte apoptosis. Distal deletions involving the POI1 locus are typically associated with POI at age 24–39 years, whereas translocations involving the POI2 locus cause POI at an earlier age of 16–21 years.

Fragile X Metal Retardation ( FMR1 ) Gene

The most common form of inherited mental retardation, the fragile X syndrome, is associated with expansion of a CGG triplet repeat in the 5′ untranslated region of the FMR1 gene located in Xq27.3, outside the Xq POI critical region. Four types of alleles have been identified based on the number of repeats: normal (6–40), gray zone (41–60), premutated (61–200), and fully mutated (>200). The overall prevalence of the fragile X premutation ranges from 1/259 in a nonselected population of over 10,000 French-Canadian women to 1/100 in a population of Israeli women. Women who carry the fragile X premutation (61–200 repeats) are at risk for having a child with fragile X syndrome. In addition, the association between fragile X premutation carrier status and POI has been well documented. The results of an international study examining premature menopause in 760 women from families with fragile X syndrome showed that 16% of the 395 premutation carriers experienced menopause prior to the age of 40, compared with none of the 238 full mutation carriers and one (0.4%) of the 237 controls. Early menopause, however, is only one end of a spectrum of the ovarian dysfunction that occurs, since some women may have elevated serum FSH levels but maintain regular menstrual cycles. Collectively, premutation carriers experience earlier menopause by approximately 5 years.

The mechanism underlying the association between the fragile X premutation and POI, however, remains unclear. The FMR1 gene is expressed in oocytes and encodes an RNA-binding protein involved in translation. Few functional studies of the FMR1 protein have been performed with POI in view. Rather, theories are based on studies using neurons and lymphocytes from patients with a late-onset neurodegenerative disorder also associated with the fragile X premutation, termed fragile X tremor/ataxia syndrome. Premutation carriers are known to produce transcripts with large CGG repeat tracks. In the presence of the full fragile X mutation, however, the FMR1 gene is methylated, and its transcription is blocked. Since ovarian failure has not been demonstrated among women with the full mutation, it cannot be attributed to a lack of the FMR protein. Rather, it has been proposed that the large tracks of rCGGs act in a toxic manner through increased mRNA levels or the unusual structural features of the large repeat tracts in the transcripts. Such structures could bind other important proteins in the cell, rendering them inactive or targeting them for degradation. Alternatively, proteins or transcription factors that bind to the CGG repeats may be unable to perform their normal functions.

Since the fragile X premutation is one of the few genetic causes of premature ovarian failure that can be tested for, it is of particular importance to document the mutation for diagnostic purposes and for assessing the risk of bearing offspring of fragile X mental retardation.

In most people, the CGG segment is repeated in the gene approximately 5–44 times. Increased expression of the CGG segment on the FMR1 gene is associated with impaired cognitive and reproductive function.

Bone Morphogenetic Protein 15 Gene ( BMP15 )

Bone morphogenetic proteins (BMPs) are extracellular signaling proteins belonging to transforming growth factor-β superfamily that also includes growth/differentiation factors (GDFs) encoded by the BMP15 gene. BMP15 is an oocyte-specific GDF that stimulates folliculogenesis and granulosa cell growth and is expressed in oocytes during early folliculogenesis. It is thought that this protein may be involved in oocyte maturation and follicular development as a homodimer or by forming heterodimers with a related protein, Gdf9. The BMP15 gene is located within the POI critical region on Xp11.2.

In 2004, Di Pasquale et al. reported a heterozygous mutation in the BMP15 gene in two sisters with primary amenorrhea. The mutation involved an A to G transition at nucleotide 704 of the BMP15 gene produce Y235C. The father was unaffected as a hemizygous carrier and the mother had only wild-type BMP15 coding sequence. The mutation was not found in 210 alleles from 120 ethnically matched controls.

Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES)

BPES is an autosomal dominant condition characterized by eyelid malformations, low nasal bridge, and ptosis of the eyelids with (type I) or without (type II) POI. Both types map to 3q22-q23 and are associated with a mutation in the FOXL2 gene, which encodes a winged helix/forkhead transcription factor that plays an important role in development, present mostly in the craniofacial region, the pituitary gland, and ovary. Gene mutations leading to a truncated protein tend to produce BPES type I, whereas elongated proteins typically lead to BPES type II. In the human ovary, FOXL2 is expressed initially in cells of the female genital ridge prior to sex determination, and through adulthood is highly expressed in granulosa cells and to a lesser extent in theca and stromal cells. Ovarian failure may be caused by either a decreased number of follicles forming during development or an increased rate of follicle loss. In addition, since FOXL2 is also expressed during pituitary organogenesis, mutations that affect the hypothalamic-pituitary-gonadal axis may also play a role in ovarian failure.

Because the FOXL2 gene is the first human autosomal gene in which dominant mutations have been linked to ovarian function, its potential role in nonsyndromic POI has also been a subject of investigation. However, sequence analysis of the FOXL2 gene in a total of 290 nonsyndromic POI patients from five different studies found only one mutation potentially responsible for the POI. Thus, the role FOXL2 gene mutations in nonsyndromic POI remains unclear.

Inhibin ( INH ) Gene

Inhibin is a gonadal protein that inhibits the synthesis and secretion of FSH from the pituitary, and has been proposed as a strong candidate gene in POI. Low serum inhibin levels have been documented in women with POI. Inhibins have also been implicated in regulating numerous cellular processes including cell proliferation, apoptosis, and tumor suppressor activity. One variation of the INH alpha gene, G769A, has been associated with POI, the prevalence of which may vary in different populations from 0% to 11%.

Galactose-1-Phosphate Uridyltransferase ( GALT ) Gene

Galactosemia is a rare autosomal recessive disorder associated with an impairment in GALT metabolism and consequent excessive galactose levels. GALT deficiency is the most common type of galactosemia. Intracellular accumulation of galactose or its metabolites may cause follicular damage or decrease the number of oogonia formed initially, therefore leading to POI. The GALT gene maps to chromosome 9p13, and female patients with galactosemia have a 60–70% prevalence of POI. Women can present with primary amenorrhea, although the majority develop POI shortly after puberty.

Folliculogenesis Specific Basic Helix–Loop–Helix Gene Mutation ( FIGLA gene)

This gene encodes a protein that functions in postnatal oocyte-specific gene expression that regulates multiple oocyte-specific genes, including genes involved in folliculogenesis and those that encode the zona pellucida. Mutations in this gene cause POI. It seems likely that genetic hierarchies expressed within oocytes complement these somatic signals to maintain appropriate germ cell identity by activating oocyte-associated genes and repressing sperm-associated genes during postnatal oogenesis.

Zhao et al. analyzed the FIGLA gene in 100 Chinese women with POI and identified a 22-bp deletion ( 608697.0001 ) and a 3-bp in-frame deletion (140delN; 608697.0002 ) in two patients, respectively. The mutations were not found in 340 female controls with regular menstrual cycles and no history of infertility.

NOG Gene Mutations Causing Noggin Deficiency

Proximal symphalangism (SYM1) is an autosomal dominant disorder characterized by ankylosis of the proximal interphalangeal joint, fusion of the carpal and tarsal bones, brachydactyly, and conductive deafness. It is caused by haploinsufficiency of the NOG gene on 17q22 encoding Noggin. NOG is also expressed in the ovary and acts as an antagonist for bone morphogenic proteins (BMPs), including BMP 4 and BMP 7, which play an important role in ovarian function. POI has been reported in one female with SYM1 and a documented NOG gene, suggesting increase in the susceptibility to POI by disrupting the function of BMPs.

The Estrogen Receptor (ER)

The estrogen receptor (ER) exists primarily in two isoforms (ERalpha and ERbeta) with specific tissue and cell patterns of expression. The ER gene has been mapped to 6q25.1 and its product is a ligand-activated transcription factor. Variants in the ER have been associated with differences in the clinical expression of risk for breast carcinoma, bone mineral density (primarily in men), and age at menopause. In one large study of 900 postmenopausal women genetic variation in the ESR gene contributed to the variability in the onset of menopause. The ESR genotypes (PP, Pp, and pp) were assessed by polymerase chain reaction using the PvuII endonuclease to detect an anonymous intronic RFLP. Compared with women carrying the pp genotype, homozygous PP women had a 1.1 year ( P < 0.02) earlier onset of menopause. Furthermore, an allele dose effect was observed, corresponding to a 0.5 year ( P < 0.02) earlier onset of menopause per copy of the P allele.