Rachel Michaelson-Cohen

BRCA mutation carriers do not have compromised ovarian reserve.

Objective The aim of this study is to evaluate the relation between carrying a BRCA1/2 mutation and fertility using the level of anti-müllerian hormone (AMH), which has been previously shown to be an accurate marker of ovarian reserve and fertility potential. Patients and Methods Forty-one healthy BRCA1/2 mutation carriers, aged 26 to 40 years, attending a multidisciplinary breast and ovarian cancer surveillance clinic, were tested for AMH levels using a 2-site ELISA. Levels were compared with those of our general population and with well-established normograms of the general population. Results The mean age of carriers was 33.2 years (26–39 years; SD, 3.99 years). The mean parity of carriers was 1.97 (0–7; SD, 1.49). All women carried at least 1 Ashkenazi Jewish founder mutation. The AMH levels for most carriers were in the reference range, 2.71 ± 0.59 ng/mL (approximately 50th percentile of normograms). These levels were similar to those in the control group, in which the AMH levels were 2.02 ± 0.12 ng/mL (P = 0.27). Conclusions The AMH levels of healthy BRCA1/2 mutation carriers are similar to those of noncarrier women matched for age; therefore, their ovarian reserve is comparable. This is the only study, to the best of our knowledge, that directly examines ovarian reserve in a relatively large group of carriers with an accurate marker. The results of this study may possibly give reassurance to female carriers concerning fertility potential.

Hereditary non-polyposis colorectal cancer or Lynch syndrome: the gynaecological perspective.

Purpose of review Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome is characterized by a number of other cancers including colorectal, endometrial and ovarian cancer. This review covers the gynaecological aspects of managing women with HNPCC: diagnostic criteria, molecular tests for diagnosis, cancer risks and different strategies for surveillance and prevention. Recent findings Studies correcting for ascertainment bias found slightly lower penetrance estimates than those obtained from high-risk families. HNPCC linked ovarian cancer presents at an earlier age and stage and has similar survival rates as sporadic cancer. In endometrial tumours, microsatellite instability or immunohistochemistry has limited effectiveness in selecting individuals for genetic testing, due to molecular differences. Population-based data indicate that a significant proportion of mismatch repair gene carriers would be missed by current clinical criteria. Effective risk prediction models complement clinical risk assessment. Effectiveness of screening is unproven and prophylactic surgery is the best preventive option for women who have completed their families. Multimodal screening protocols from the age of 30–35 years are being evaluated. Summary Risk of endometrial cancer in women with Lynch syndrome is as high as the risk of colorectal cancer. Further research is needed to identify the appropriate strategy for clinical risk assessment and optimize screening. A multidisciplinary approach is necessary to manage these women.

Managing menopausal symptoms after gynecological cancer.

Purpose of review As the length of survival in patients with gynecological malignancies increases due to advances in early diagnosis and therapy, quality of life becomes a major issue for the survivors. These women frequently suffer symptoms following an iatrogenically induced menopause. Many gynecologists advise these patients against hormonal replacement therapy. This review attempts to provide the clinician with information based on current evidence. Recent findings The most recent two prospective studies did not find an increase in the recurrence rates in endometrial cancer patients who used hormonal replacement therapy. To date, there are few studies on hormonal replacement therapy in patients with ovarian cancer but the available data suggest that there is no detriment to overall or disease-free survival. There are no data showing an association between poorer outcome and hormonal replacement therapy use in patients with cervical or vulvar cancers. Summary There is no evidence showing hormones negatively influence survival after treatment for epithelial ovarian, squamous cervical or vulvar cancer. Their use can be considered in symptomatic patients with endometrial cancer, after weighing the benefits against the risk of recurrence. Gynecologic cancer survivors suffering from menopausal symptoms should be supported by advice about the alternatives to hormonal replacement therapy and by giving them nonbiased information on the present knowledge on the effects of hormonal use in women with a previous cancer. It is reasonable to prescribe hormonal replacement therapy to symptomatic, well informed patients.

Genome-wide de novo methylation in epithelial ovarian cancer.

Background: DNA methylation regulates gene expression during development. The methylation pattern is established at the time of implantation. CpG islands are genome regions usually protected from methylation; however, selected islands are methylated later. Many undergo methylation in cancer, causing epigenetic gene silencing. Aberrant methylation occurs early in tumorigenesis, in a specific pattern, inhibiting differentiation. Although methylation of specific genes in ovarian tumors has been demonstrated in numerous studies, they represent only a fraction of all methylated genes in tumorigenesis. Objectives: To explore the hypermethylation design in ovarian cancer compared with the methylation profile of normal ovaries, on a genome-wide scale, thus shedding light on the role of gene silencing in ovarian carcinogenesis. Identifying genes that undergo de novo methylation in ovarian cancer may assist in creating biomarkers for disease diagnosis, prognosis, and treatment responsiveness. Methods: DNA was collected from human epithelial ovarian cancers and normal ovaries. Methylation was detected by immunoprecipitation using 5-methyl-cytosine-antibodies. DNA was hybridized to a CpG island microarray containing 237,220 gene promoter probes. Results were analyzed by hybridization intensity, validated by bisulfite analysis. Results: A total of 367 CpG islands were specifically methylated in cancer cells. There was enrichment of methylated genes in functional categories related to cell differentiation and proliferation inhibition. It seems that their silencing enables tumor proliferation. Conclusions: This study provides new perspectives on methylation in ovarian carcinoma, genome-wide. It illustrates how methylation of CpG islands causes silencing of genes that have a role in cell differentiation and functioning. It creates potential biomarkers for diagnosis, prognosis, and treatment responsiveness.

Does elevated human chorionic gonadotropin alone trigger spontaneous ovarian hyperstimulation syndrome

OBJECTIVE To test whether elevated hCG alone triggers spontaneous ovarian hyperstimulation syndrome (sOHSS). DESIGN Retrospective analysis. SETTING Departments of obstetrics and gynecology and of medical genetics in an academic medical center. PATIENT(S) A patient with sOHSS and 109 patients with elevated hCG. INTERVENTION(S) Collecting blood samples. MAIN OUTCOME MEASURE(S) Follicle-stimulating hormone receptor gene sequence, levels of TSH and hCG. RESULT(S) We described a case of sporadic, nonfamilial sOHSS. Sequencing of the entire coding region the FSH gene revealed wild-type alleles for all the known mutations, and the A919G and A2039G polymorphisms, previously associated with good response to FSH stimulation and severe iatrogenic OHSS. We ruled out hypothyroidism. The level of hCG reached a peak of 344,350 IU/L (95th percentile). One hundred nine pregnancies with hCG of >150,000 IU/L were identified from 2001-2006. After patients with gestational trophoblastic diseases, multiple pregnancies, and iatrogenic OHSS were excluded, 27 patients remained. None of those patients experienced OHSS. CONCLUSION(S) Elevated hCG cannot be responsible for sOHSS as a single factor. Factors other than the hCG-FSH-receptor interaction additionally are involved in the pathogenesis of this syndrome. A combination of mechanisms may allow understanding of this enigmatic disorder. The pathophysiology of sOHSS, a rare phenomenon, has not yet been elucidated.

The counseling and management of young healthy BRCA mutation carriers.

Abstract Although more than 15 years have elapsed since the discovery of the BRCA1 and BRCA2 genes and the associated increased risk of breast and ovarian cancers in mutation carriers, our understanding of the syndrome is still evolving. With the accumulation of knowledge, more questions arise regarding the proper approach to mutation carriers diagnosed as having cancer. Moreover, the number of questions regarding the recommended management methods for healthy carriers and the potential risk-reducing measures is increasing constantly. In this review, we discuss these issues and summarize contemporary recommendations.

A deleterious founder mutation in the BMPER gene causes diaphanospondylodysostosis (DSD)

Diaphonospondylodysostosis (DSD) is a rare, recessively inherited, lethal skeletal dysplasia, characterized by severe spinal ossification, segmentation defects, and renal cystic dysplasia with nephrogenic rests. We hereby present three affected individuals: two children and a fetus from two unrelated East Jerusalem Arab‐Muslim families. Whereas most fetuses die in utero or perinatally, one of the children survived to 15 months. Homozygosity mapping in the two families demonstrated a single common 3.87 Mb region on chromosome 7, ruling out previously known spondylocostal/spondylothoracic dysostosis loci. The 15 protein coding genes in the region were prioritized, and some were sequenced. A single, novel deleterious mutation, Q104X, was detected in the bone morphogenetic protein‐binding endothelial regulator protein (BMPER) gene, recently reported to be mutated in other DSD patients [Funari et al., 2010 ]. The novel mutation we identified is an ancestral founder allele, as evidenced by a shared 440 SNP haplotype, and its frequency in the general Arab population is estimated to be <1:123. Our findings confirm loss of BMPER function as a cause of axial versus appendicular skeletal defects, and suggest that less deleterious mutations may be involved in milder axial skeleton abnormalities.

Prenatal observation of nystagmus, cataracts, and brain abnormalities in a case of Zellweger spectrum disorder syndrome

Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, Israel Department of Genetics, Shaare Zedek Medical Center, Jerusalem, Israel Pediatric Neurology Unit, Shaare Zedek Medical Center, Jerusalem, Israel Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Hospital, Jerusalem, Israel Department of Obstetrics & Gynecology, Hadassah-Hebrew University Hospital, Jerusalem, Israel *Correspondence to: Ori Shen. E-mail: orishen@netvision.net.il

Intrapartum fetal heart rate patterns of trisomy 21 fetuses: A case–control study

BACKGROUND/AIM To determine whether there are specific characteristic intrapartum heart rate patterns for fetuses with trisomy 21(T21). BACKGROUND STUDY DESIGN/PATIENTS Intrapartum fetal heart rate (FHR) tracings of T21 fetuses were compared to those of euploid fetuses in a retrospective, observational, matched, case-control study. The study group consisted of 42 fetuses with T21 and 42 matched euploid controls. Matching was designed to accommodate possible confounders. The sign test and McNemars test were used for categorical variables. The paired t test was used for comparison between quantitative variables. RESULTS Intrapartum baseline FHR of fetuses with T21 was found to be slightly decreased compared to controls (122.5 vs 129.05 beats per minute, p=0.028). No differences were detected in the presence of periodic changes, or FHR variability between the groups. CONCLUSION When evaluating intrapartum FHR of fetuses with T21, decreased baseline FHR can be expected.