The genetic causes of premature ovarian failure (POF) are highly heterogeneous, and causative mutations have been identified in more than ten genes so far. In two families affected by POF accompanied by hearing loss (together, these symptoms compose Perrault syndrome), exome sequencing revealed mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase: homozygous c.1565C>A (p.Thr522Asn) in a consanguineous Palestinian family and compound heterozygous c.1077delT and c.1886C>T (p.Thr629Met) in a nonconsanguineous Slovenian family. LARS2 c.1077delT leads to a frameshift at codon 360 of the 901 residue protein. LARS2 p.Thr522Asn occurs in the LARS2 catalytic domain at a site conserved from bacteria through mammals. LARS2 p.Thr629Met occurs in the LARS2 leucine-specific domain, which is adjacent to a catalytic loop critical in all species but for which primary sequence is not well conserved. A recently developed method of detecting remote homologies revealed threonine at this site in consensus sequences derived from multiple-species alignments seeded by human and E. coli residues at this region. Yeast complementation indicated that LARS2 c.1077delT is nonfunctional and that LARS2 p.Thr522Asn is partially functional. LARS2 p.Thr629Met was functional in this assay but might be insufficient as a heterozygote with the fully nonfunctional LARS2 c.1077delT allele. A known C. elegans strain with the protein-truncating alteration LARS-2 p.Trp247Ter was confirmed to be sterile. After HARS2, LARS2 is the second gene encoding mitochondrial tRNA synthetase to be found to harbor mutations leading to Perrault syndrome, further supporting a critical role for mitochondria in the maintenance of ovarian function and hearing.

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.

BACKGROUND: The aim of our study is to evaluate the efficacy of applying lidocaine 25 mg-prilocaine-25 mg/G cream (EMLA 5%) on the uterine cervix for pain relief when performing hysterosalpingography (HSG). METHODS: Eighty-two patients undergoing HSG as part of infertility evaluation were randomized into groups receiving EMLA (42) or placebo cream (40) in a double-blinded prospective study from which four women were later excluded. The cream was applied to the uterine cervix by means of a cervical cup 30 min before the HSG. Pain perception related to the HSG procedure was scored by visual analogue scale (VAS) at five predefined steps: after speculum application, after cervical instrumentation of the tenaculum and cannula, at the end of uterine filling, at completion of tubal spillage, and immediately following instrument removal. In addition, the patients were asked to retrospectively rate the pain during the entire procedure in a telephone interview the following day. RESULTS: Cervical instrumentation was found to be the most painful step of HSG (P < 0.001). When comparing the VAS pain scores, cervical instrumentation in the EMLA-treated patients was associated with significantly less pain than the control group: 3.3+ + + + + 2.9 versus 4.9 + + + + + 2.7, respectively (P 5 0.02). CONCLUSION: Topical application of EMLA 5% cream on the uterine cervix before performing HSG significantly reduced the pain during this procedure.

for the Israeli Consortium of Hereditary Breast Cancer BACKGROUND: BRCA1/2 mutation carriers have an increased risk of developing ovarian cancer, leading to the recommendation of risk-reducing salpingo-oophorectomy (RRSO) at 35-40 years of age. The role, if any, that BRCA mutations play in conferring uterine cancer risk, is unresolved. METHOD: Jewish Israeli women, carriers of one of the predominant Jewish mutations in BRCA1/2 from 1998 to 2016, were recruited. Cancer diagnoses were determined through the Israeli National Cancer Registry. Uterine cancer risk was assessed by computing the standardized incidence ratio of observed-to-expected number of cases, using the exact 2-sided P value of Poisson count. RESULTS: Overall, 2627 eligible mutation carriers were recruited from 1998 to 2016, 2312 (88%) of whom were Ashkenazi Jews (1463 BRCA1, 1154 BRCA2 mutation carriers, 10 double mutation carriers). Among these participants, 1310 underwent RRSO without hysterectomy at a mean (± standard deviation) age of 43.6 years (± 4.4 years). During 32,774 women-years of follow up, 14 women developed uterine cancer, and the observed-to-expected rate of all histological subtypes was 3.98 (95% confidence interval [CI], 2.17-6.67; P < .001). For serous papillary (n = 5), the observed-to-expected ratio was 14.29 (95% CI, 4.64-33.34; P < .001), and for sarcoma (n = 4) it was 37.74 (95% CI, 10.28-96.62). These rates were also higher than those detected in a group of 1844 age-and ethnicity-matched women (53% with breast cancer). CONCLUSION: Israeli BRCA1 or BRCA2 mutation carriers are at an increased risk for developing uterine cancer, especially serous papillary and sarcoma. These elevated risks of uterine cancer should be discussed with BRCA carriers. Cancer 2019;125:698-703.

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.

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BackgroundRepeat cesarean delivery (CD) accounts for approximately 15% of all annual deliveries in the US with an estimated 656,250 operations per year. We aimed to study whether prolonged operative time (OT; skin incision to closure) is a risk marker for post-operative maternal complications among women undergoing repeat CD.MethodsWe conducted a cross-sectional retrospective study in a single tertiary center including all women who underwent repeat CD but excluding those with cesarean hysterectomy. Prolonged OT was defined as duration of CD longer than the 90th percentile duration on record for each specific surgeon in order to correct for technique differences between surgeons. Bi-variate analysis was used to study the association of prolonged OT with each one of the following maternal complications: post-operative blood transfusion, prolonged maternal hospitalization (defined as hospitalization duration longer than 1 week post-CD), infection necessitating antibiotics, re-laparotomy within 7 days post-CD, and re-admission within 42 days post-CD. A multivariate regression analysis was performed controlling for maternal age, ethnicity, parity, number of fetus, gestational age at delivery, trial of labor after cesarean, anesthesia, and number of previous CDs. The adjusted odd ratio was calculated for each complication independently and for a composite adverse maternal outcome defined as any one of the above.ResultsA total of 6507 repeat CDs were included; prolonged OT was highly associated (P value < 0.000) with: post-operative blood transfusion (4.4% vs. 1.5%), prolonged hospitalization (8.4% vs. 4.0%), infection necessitating antibiotics (2% vs. 1%), and readmission (1.8% vs. 0.8%) when compared to control. The composite adverse maternal outcome was also associated with prolonged OT (20.2% vs. 11.2%, p < 0.000). These correlations remained statistically significant in the multivariate regression analysis when controlling for confounders.ConclusionsAmong women undergoing repeat CD, prolonged OT (reflecting CD duration greater than 90th percentile for the specific surgeon) is a risk marker for post-operative maternal complications.

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