Terminal deletions of the long arm of chromosome X that include the FMR1 gene in female patients: a case series

Terminal deletions on the X chromosome in female patients may be detected as part of a work up for infertility, premature ovarian insufficiency (POI) or in screening for fragile X carrier status. We present the clinical, cytogenetic and molecular features of four patients with terminal deletions of chromosome X that include the FMR1 gene, and discuss biological and genetic implications of this deletion. Providers should be aware of possible identification of Xq27 deletions as a potential outcome of fragile X screening.     

The association of FMR1 gene (CGG)n variation with idiopathic female infertility

IntroductionThe FMR1 gene plays an important role in brain development and in the regulation of ovarian function. The FMR1 gene contains CGG repeat variation and the expansion of the repeats is associated with various phenotypes e.g. fragile X syndrome, premature ovarian failure, etc. Repeats ranging < 55 CGG are considered normal, however recent studies suggest that high-normal (35–54 CGG) and low-normal (< 26 CGG) alleles may also have an impact on female reproductive function.Material and methodsWe have performed a case-control study to assess the impact of FMR1 gene CGG repeats on female infertility. The study comprised 161 women with primary and secondary idiopathic infertility and 12 females with diminished ovarian reserve. The control group consisted of 129 healthy women with children. The FMR1 gene trinucleotide CGG repeat variation was detected using a triplet repeat primed polymerase chain reaction with capillary electrophoresis.ResultsThe analysis of CGG repeats revealed that high-normal alleles are statistically significantly more common in the secondary infertility group than in controls (12% vs. 4.3%, p = 0.03, OR = 3.1, 95% CI: 1.1–8.3). The distribution of high-normal alleles and genotypes did not differ between patients with primary infertility and controls (p > 0.05). In addition, the analysis of low-normal allele and genotype frequencies did not present a difference between primary, secondary infertility and the control group (p > 0.05).ConclusionsIn our study, the FMR1 gene high-normal alleles were associated with secondary infertility. However, to address the controversies related to the role of FMR1 genes in the development of diminished ovarian reserve, further studies on the subject are required.     

Evidence for a cryptic 46,XX cell line in a 45,X/46,X,psu idic(Xq) patient with normal reproduction.

Gonadal dysgenesis resulting in primary infertility is one of the most common features of Turner syndrome. There have been a number of cases described of pregnancy in 45,X subjects, but whether or not the fertility is associated with a 46,XX cell line in the germ cells is not known. We describe a 45,X/46,X,psu idic(Xq) female with normal fertility, in whom a cryptic 46,XX cell line was found in the germ cells.     

Detailed clinical and molecular study of 20 females with Xq deletions with special reference to menstruation and fertility

Integrity of the long arm of the X chromosome is important for maintaining female fertility and several critical regions for normal ovarian function have been proposed. In order to understand further the importance of specific areas of the X chromosome, we describe a series of 20 previously unreported patients missing part of Xq in whom detailed phenotypic information has been gathered as well as precise chromosome mapping using array Comparative Genomic Hybridization.Features often associated with Turner syndrome were not common in our study and excluding puberty, menarche and menstruation, the phenotypes observed were present in only a minority of women and were not specific to the X chromosome. The most frequently occurring phenotypic features in our patients were abnormalities of menstruation and fertility. Larger terminal deletions were associated with a higher incidence of primary ovarian failure, occurring at a younger age; however patients with similar or even identical deletions had discordant menstrual phenotypes, making accurate genetic counselling difficult.Nevertheless, large deletions are likely to be associated with complete skewing of X inactivation so that the resulting phenotypes are relatively benign given the amount of genetic material missing, even in cases with unbalanced X;autosome translocations. Some degree of ovarian dysfunction is highly likely, especially for terminal deletions extending proximal to Xq27. In conjunction with patient data from the literature, our study suggests that loss of Xq26–Xq28 has the most significant effect on ovarian function.     

The autoimmune bases of infertility and pregnancy loss

Several lines of evidence suggest that autoimmune mechanisms may influence the reproductive life and fertility of both sexes, commonly manifesting as infertility or pregnancy loss. Part of the controversy that characterizes this assumption derives from the overlooked suspect of autoimmune conditions in the absence of symptoms or the limited physician awareness in a gynecological setting. Numerous autoimmune diseases, including but not limited to systemic lupus erythematosus and anti-phospholipid syndrome, may be associated with infertility and pregnancy loss through different putative mechanisms. First, serum autoantibodies such as anti-phospholipid, anti-thyroid, or antinuclear antibodies may be directly associated with infertility, regardless of the presence of a clinically overt autoimmune disease. Second, autoimmunity may affect all stages of fertility, via ovarian failure, testicular failure, implantation failure, and pregnancy loss. Third, infertility may also be secondary to vasculitis associated with other conditions such as systemic lupus erythematosus and diabetes mellitus. This review article will illustrate and critically discuss the available data on the link between the breakdown of tolerance that characterizes autoimmune diseases and the changes in reproductive life that affect patients in real clinical setting and that often constitute the iatrotropic stimulus.     

Pregnancy outcome and ovarian antibodies in infertility patients undergoing controlled ovarian hyperstimulation

PROBLEM: Several endocrine markers are well-established, but not absolute, predictors of successful outcomes following controlled ovarian hyperstimulation. Another potential predictor for success may be a marker of ovarian autoimmunity. Ovarian antibodies (OVAB) are detected in women with unexplained infertility. We tested the hypothesis that women with OVAB have a poorer pregnancy outcome in in vitro fertilization (IVF). METHOD OF STUDY: Serum samples (n = 47) were assessed by a previously described immunoassay for OVAB in a cross-sectional, retrospective study design. RESULTS: Women who became pregnant had a lower frequency of OVAB than women who did not become pregnant (25.0% [4/16] vs. 58.1% [18/31], respectively; P = 0.03). There was no significant difference in day 3 estradiol, amount of human menopausal gonadotropin given, peak estradiol, the number of follicles observed, or the number of eggs retrieved between women who achieved pregnancy and those who did not. CONCLUSIONS: Together with other information such as reproductive hormone levels and measures of follicle growth, OVAB may contribute additional information for prediction of successful IVF outcomes.     

FMR1 gene and fragile X syndrome

Taxonomic features of fragile X syndrome (FXS) associated with the fragile X mutation have evolved over several decades. Males are more severely impacted cognitively than females, but both show declines in IQ scores as they age. Although many males with FXS exhibit autistic-like features, autism does not occur more frequently in males with FXS than among males with mental retardation (MR). FXS is caused by inactivation of the FMR1 gene located on Xq27.3. FMRP, the protein produced by FMR1, has been detected in most organs and in brain. In cells, it is located primarily in cytoplasm and contains motifs found in RNA-binding proteins. The FMRP N-terminal contains a functional nuclear localization signal which permits the protein to shuttle between cytoplasm and nucleus. FMR1 knockout mice show subtle behavioral and visual-spatial difficulties. Analysis of their brain tissue suggests absence of FMRP impairs synaptic maturation. Individuals with the fragile premutation produce FMRP, and the phenotype associated with the premutation has been controversial. However, there seems to be a higher incidence of premature ovarian failure in women with the premutation than is found in the general female population. This may be related to unusual increases in mRNA levels in premutation carriers.     

Familial inv(X)(p22q22): ovarian dysgenesis in two sisters with del Xq and fertility in one male carrier

A recombinant chromosome with Xp duplication and Xq deletion was found in two sisters with normal height and gonadal dysgenesis. Their mother and other four relatives, including a fertile male, carried an inv(X)(p22q22); the inverted X was randomly inactivated in one female carrier. The abnormal X chromosome showed inactivation in all the examined cells. This is the tenth report of a recombinant X chromosome. A review of the literature shows that: i) most female carriers of inv(X) are phenotypically normal and fertile; ii) recombinants having short-arm duplication and long-arm deletion are associated with ovarian failure and normal or tall stature, whereas the reciprocal recombinants are compatible with fertility but cause short stature; and (ü) except for one index case, all male carriers have a normal phenotype and 11 of them (from eight families) are of proven fertility. Moreover, no instance of male infertility has been documented.     

Pathogenesis of infertility and recurrent pregnancy loss in thyroid autoimmunity

Thyroid autoimmunity is the most prevalent autoimmune state that affects up to 4% of women during the age of fertility. A growing body of clinical studies links thyroid autoimmunity as a cause of infertility and adverse pregnancy outcomes that includes miscarriage or preterm deliveries. Importantly, these adverse effects are persistent in euthyroid women. In the current review we elaborate on the pathogenesis that underlies infertility and increased pregnancy loss among women with autoimmune thyroid disease. Such mechanisms include thyroid autoantibodies that exert their effect in a TSH-dependent but also in a TSH-independent manner. The later includes quantitative and qualitative changes in the profile of endometrial T cells with reduced secretion of IL-4 and IL-10 along with hypersecretion of interferon-γ. Polyclonal B cells activation is 2-3 time more frequent in thyroid autoimmunity and is associated with increased titers of non-organ specific autoantibodies. Hyperactivity and Increased migration of cytotoxic natural killer cells that alter the immune and hormonal response of the uterus is up to 40% more common in women with thyroid autoimmunity. Lack of vitamin D was suggested as a predisposing factor to autoimmune diseases, and was shown to be reduced in patients with thyroid autoimmunity. In turn, its deficiency is also linked to infertility and pregnancy loss, suggesting a potential interplay with thyroid autoimmunity in the context of infertility. In addition, thyroid autoantibodies were also suggested to alter fertility by targeting zona pellucida, human chorionic gonadotropin receptors and other placental antigens.     

Intrauterine insemination: a systematic review on determinants of success

Intrauterine insemination (IUI) is a frequently indicated therapeutic modality in infertility. Here, a systematic review of the literature was performed to examine the current status of clinical and laboratory methodologies used in IUI and the impact of female and male factors on pregnancy success. Emphasis was centred in questioning the following: (i) the value of IUI against timed intercourse; (ii) IUI application with or without controlled ovarian hyperstimulation; (iii) timing and frequency of IUI; and (iv) impact of various parameters (male/female) on the prediction of pregnancy outcome. The odds of multiple pregnancy occurrence and its risk factors, as well as the cost-effectiveness of IUI treatment compared with more complex assisted reproductive technologies are discussed. A computerized literature search was performed including Medline and the Cochrane library, as well as a crossover search from retrieved papers. It is concluded that although IUI is a successful contemporary treatment for appropriately selected cases of female and/or male infertility, further research is needed through well-designed studies to improve the methodologies currently utilized. Importantly, the clinical management of the infertile couple should be performed in an expedited manner taking into consideration the age of the woman, the presence of multifactorial infertility and cost-effectiveness of the available treatment alternatives.     

Association of BRCA1/2 mutations with FMR1 genotypes: Effects on menarcheal and menopausal age

Objective

Female BRCA (breast cancer gene)-1 and BRCA-2 mutations are significantly associated with risk of developing breast and ovarian cancers, in turn, associated with female infertility. BRCA-1 mutations have also been associated with occult primary ovarian insufficiency (OPOI), as have different mutations of the FMR1 gene. We, therefore, hypothesized that FMR1 genotypes may be associated with menarcheal and menopausal ages of BRCA mutation carriers.

Patients

We compared the FMR1 genotype and sub-genotype distribution in 99 BRCA1/2 positive women and in 182 healthy women without a known history of familial breast and ovarian cancer and searched for associations with age at menarche and menopause. T-test was used to assess differences in menarcheal and menopause ages, with times of menarche and menopause as continuous variables.

Results

Women with BRCA1/2 mutations showed significantly different FMR1 genotype and sub-genotype distributions when compared with the control group (p < 0.001). This result remained stable in a sub-group analysis of Caucasian BRCA1/2 carriers and healthy controls (p < 0.001). In addition, BRCA1/2 carriers indicated a trend toward shorter reproductive lifespan (p = 0.18).

Conclusions

Our data confirm the previously reported highly skewed distribution of FMR1 genotypes and sub-genotypes toward a high preponderance of low FMR1 alleles in BRCA1/2 carriers. We could demonstrate that BRCA-1 mutations are associated with an earlier onset of menopause compared to BRCA-2 carriers, although the distribution of the het-norm/low genotype is similar in both groups. Our findings suggest that there may be other factors beside the genotype that has an influence on menarche and especially menopause age in BRCA mutation carriers.     

甲状腺自身免疫与女性妊娠失败的关系

甲状腺自身免疫是女性最常见的自身免疫紊乱之一，影响5％～20％的育龄妇女，与女性不孕和妊娠丢失存在相关性，其病理生理机制可能包括甲状腺依赖性和非甲状腺依赖性。了解甲状腺自身免疫与女性生殖失败相关性的病理生理机制，可以指导临床对不孕妇女、准备妊娠和妊娠期妇女进行甲状腺功能和甲状腺自身免疫的筛查，为妊娠失败提供新的诊治思路。     

Demographic and medical consequences of the postponement of parenthood

BACKGROUND Across the developed world couples are postponing parenthood. This review assesses the consequences of delayed family formation from a demographic and medical perspective. One main focus is on the quantitative importance of pregnancy postponement. METHODS Medical and social science databases were searched for publications on relevant subjects such as delayed parenthood, female and male age, fertility, infertility, time to pregnancy (TTP), fetal death, outcome of medically assisted reproduction (MAR) and mental well-being. RESULTS Postponement of parenthood is linked to a higher rate of involuntary childlessness and smaller families than desired due to increased infertility and fetal death with higher female and male age. For women, the increased risk of prolonged TTP, infertility, spontaneous abortions, ectopic pregnancies and trisomy 21 starts at around 30 years of age with a more pronounced effects >35 years, whereas the increasing risk of preterm births and stillbirths starts at around 35 years with a more pronounced effect >40 years. Advanced male age has an important but less pronounced effect on infertility and adverse outcomes. MAR treatment cannot overcome the age-related decline in fecundity. CONCLUSIONS In general, women have partners who are several years older than themselves and it is important to focus more on the combined effect of higher female and male age on infertility and reproductive outcome. Increasing public awareness of the impact of advanced female and male age on the reproductive outcome is essential for people to make well-informed decisions on when to start family formation.     

Safety issues in assisted reproductive technology: aetiology of health problems in singleton ART babies

The frequency of health problems in singleton assisted reproductive technologies (ART) babies is higher than in singletons from spontaneous gestations. Any of the following factors may be involved: in-vitro technology, ovarian stimulatory drugs and infertility itself. A literature review on premature birth, low birth weight, perinatal mortality and major birth defects in children conceived from infertility treatments was conducted. Only publications comparing the outcome of pregnancy in an infertile group of patients to a matched control group were selected. The analysis of the outcome of singleton pregnancies resulting from IVF versus artificial insemination, obtained with or without the use of ovarian stimulatory agents and obtained with or without the use of a semen donor, suggests that female infertility is an important risk factor. Criteria for screening at-risk infertile women have not yet been identified. Prospective studies designed to identify precisely the aetiology of health problems in singletons ART babies will have to be conducted. The absence of criteria correlating at-risk infertile women to health problems in their children does not allow a gynaecologist the opportunity to offer infertility treatments to the least susceptible patients.     

卵泡输出率的应用研究

目前卵巢反应性的预测指标包括AMH、抑制素B、年龄、窦卵泡、基础性激素、卵巢敏感性（OSI）、卵泡敏感性（FSI）等,而这些指标在预测卵巢对外源性促性腺激素（Gn）的反应存在一定的局限性。在近年生殖医学预测IVF/ICSI妊娠结局及卵巢反应性的相关研究中,提出卵泡输出率（FORT）是一个客观、较新且热门的指标。控制性超促排卵（COH）个体化治疗方案的制定在治疗各种不孕症的过程中具有重要的意义,可以通过FORT评估每个患者卵巢反应性来制定合适的COH方案,从而改善妊娠结局。本文就FORT在卵巢低反应、多囊卵巢综合征（PCOS）、子宫内膜异位症（EMs）、不明原因不孕症、高龄及肿瘤患者对卵巢反应性及IVF/ICSI妊娠结局的相关性研究进行综述。     

Clinical and molecular cytogenetic characterization of two patients with non-mutational aberrations of the FMR2 gene

We report on two patients; a female having mild mental retardation (MR) with a balanced translocation, 46,XX,t(X;15)(q28;p11.2), and a male diagnosed as having mucopolysaccharidosis type II (MPS II or Hunter syndrome) with atypical early-onset MR and a normal male karyotype. Molecular cytogenetic analyses, including fluorescence in situ hybridization and array-based comparative genomic hybridization using an in-house X-tiling array, revealed that first patient to have a breakpoint at Xq28 lying within the FMR2 gene and the second to have a small deletion at Xq28 including part of FMR2 together with the IDS gene responsible for MPS II. In Patient 1, X-chromosome inactivation predominantly occurred in the normal X in her lymphocytes, suggesting that her MR might be explained by a disruption of the FMR2 gene on der(X) t(X;15) concomitant with the predominant inactivation of the intact FMR2 gene in another allele. We compared phenotypes of Patient 2 with those of MPS II cases with deletion of the IDS gene alone reported previously, suggesting that the early-onset MR might be affected by the additional deletion of FMR2.     

Self-reported difficulty in conceiving as a measure of infertility

BACKGROUND: This study aimed to explore the meaning and potential use of women's self-reported difficulties in conceiving as a measure of infertility in epidemiological studies, and to compare women's stated reasons for infertility with information in their medical records. METHODS: Data were available from a population-based case-control study of ovarian cancer involving 1638 women. The sensitivity and specificity of women's self-reported infertility were calculated against their estimated fertility status based on detailed reproductive histories. Self-reported reasons for infertility were compared with diagnoses documented in women's medical records. RESULTS: The sensitivity of women's self-reported difficulty in conceiving was 66 and 69% respectively when compared with calendar-derived and self-reported times taken trying to conceive; its specificity was 95%. Forty-one (23%) of the 179 women for whom medical records were available had their self-reported fertility problem confirmed. Self-reported infertility causes could be compared with diagnoses in medical records for only 22 of these women. CONCLUSIONS: Self-reported difficulty conceiving is a useful measure of infertility for quantifying the burden of fertility problems experienced in the community. Validation of reasons for infertility is unlikely to be feasible through examination of medical records. Improved education of the public regarding the availability and success rates of infertility treatments is proposed.     

青春期前患腮腺炎对成年不孕女性生殖系统的影响

目的探讨女性青春期前患腮腺炎对成年后生殖系统的不良影响。方法回顾性分析1510例接受体外受精-胚胎移植的不孕女性中，青春期前患腮腺炎的成年不孕女性生殖系统疾病的患病率及试管婴儿技术助孕结局。结果有腮腺炎病史的不孕病人行体外受精的妊娠率为22％（45／205），对照组为29．7％，P=O．024。青春期前患腮腺炎患者中成年后子宫内膜异位症、卵巢囊肿的患病率分别为19．57％、23．90％，有腮腺炎病史未合并此类疾病的分别为13．1％、11．24％，P=O．00。腮腺炎病史合并输卵管手术史、卵巢手术史、子宫手术史者分别占28．31％、41．1％、8．68％，分别高于无腮腺炎病史的患者，P〈O．05。结论女性青春期前患腮腺炎与成年后的生殖系统疾病及手术有相关性，需要对青春期前患腮腺炎女性的生育状况加以重视。     

Third party reproduction and the aging couple

The average age of childbearing has been increasing in industrialized nations, including the United States. As a result, more women in their late 30s to early 40s are seeking their first pregnancy than ever before. Unfortunately, fertility declines with increasing female age. In addition, success of infertility treatments including those using assisted reproductive technologies (ART) decreases as the age of the female partner advances. Third party reproduction involves using gametes or the uterus of a third person to achieve pregnancy. Oocyte donation is a common form of third party reproduction, associated with significant success rates, which gives aging couples an opportunity to bear children. For safety and success, all the participants must be extensively screened medically and psychologically. In addition, a detailed understanding of the process by all parties involved should be achieved. While third party reproduction through oocyte donation is a long and labor intensive process with a significant amount of emotional, financial, and physical involvement from all parties, it is quite often a gratifying experience for everyone involved which include, oocyte donors, recipients, social workers, nurses and physicians.