BRCA carriers after risk-reducing bilateral salpingo-oophorectomy: menopausal hormone therapy knowledge gaps, and the impact of physicians' recommendations.

OBJECTIVE: Female carriers of BRCA1/2 gene mutations are at an increased lifetime risk for breast and ovarian cancers. They are recommended to undergo risk-reducing surgery, including bilateral salpingo-oophorectomy (RR-BSO), upon completion of childbearing. RR-BSO surgery decreases morbidity and mortality but results in early menopause. Menopausal hormone therapy (MHT) is under-utilized despite being shown as safe for carriers. We aim to evaluate the factors associated with decision-making regarding MHT use following RR-BSO in healthy BRCA mutation carriers. METHODS: Female carriers aged <50 years who underwent RR-BSO and were followed in a multidisciplinary clinic completed online multiple-choice and free-text questionnaires. RESULTS: A total of 142 women met the inclusion criteria and filled the questionnaire: 83 were MHT users and 59 were non-users. MHT users underwent RR-BSO earlier than non-users (40.82 ± 3.91 vs. 42.88 ± 4.34; p < 0.0001). MHT usage was positively associated with MHT explanation (odds ratio 4.318, 95% confidence interval [CI] [1.341-13.902], p = 0.014), and knowledge regarding the safety of MHT and its effects on general health (odds ratio 2.001, 95% CI [1.443-2.774], p < 0.0001). MHT users and non-users retrospectively evaluated their comprehension of RR-BSO consequences as significantly lower than before surgery (p < 0.001). CONCLUSION: Post-RR-BSO outcomes, including the effects on women's quality of life and its possible mitigation through MHT use, need to be addressed pre surgery by healthcare providers.

Novel WWOX deleterious variants cause early infantile epileptic encephalopathy, severe developmental delay and dysmorphism among Yemenite Jews.

The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.

Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation - c.109C>T (p.R37X).

Alpha-thalassemia intellectual disability, one of the recognizable X-linked disability syndromes, is characterized by short stature, microcephaly, distinctive facies, hypotonic appearance, cardiac and genital anomalies, and marked skewing of X-inactivation in female carriers. With the advent of next generation sequencing, mutations have been identified that result in less severe phenotypes lacking one or more of these phenotypic manifestations. Here we report five unrelated kindreds in which a c.109C>T (p.R37X) mutation segregates with a variable but overall milder phenotype. The distinctive facial appearance of alpha-thalassemia intellectual disability was present in only one of the 18 affected males evaluated beyond the age of puberty, although suggestive facial appearance was present in several during infancy or early childhood. Although the responsible genetic alteration is a nonsense mutation in exon 2 of ATRX, the phenotype appears to be partially rescued by the production of alternative transcripts and/or other molecular mechanisms.

Severe heart disease complicating pregnancy does not preclude a favourable pregnancy outcome: 15 years' experience in a single centre.

Heart disease (HD) in pregnancy remains a major cause of non-obstetric maternal and neonatal mortality and morbidity. This study describes the outcome in 164 pregnant women with HD (158 deliveries in women in New York Heart Association (NYHA) Classes 1 and 2; 17 in NYHA Classes 3 and 4) who received good antenatal care and benefitted from a specific protocol and experience of a dedicated staff. There were no maternal or neonatal deaths; 46 women were diagnosed peripartum. Based on a sub-division into NYHA categories, and when sub-divided by HD, there were no statistically significant differences between groups with regard to maternal age, gestational age at admission or at delivery, birth weight, 5 min Apgar scores, mode of delivery (caesarean delivery), senior obstetric/anaesthesiology staff in attendance or delivery during day/working hours. There was a higher incidence of pre-term deliveries in women with rheumatic heart disease and Marfan syndrome (p = 0.06) relative to others. Babies of women with coronary heart disease had prolonged postpartum course in the NICU (p = 0.0001) and longer total hospital stays for the mother. In conclusion, well-managed, motivated mothers with HD who benefit from comprehensive antenatal care, and are managed primarily by their obstetric and anaesthesia teams, can aspire to a good outcome for themselves and their babies.

Lidocaine-prilocaine (EMLA) cream as analgesia for hysterosalpingography: a prospective, randomized, controlled, double blinded study.

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 = 0.02). CONCLUSIONS: Topical application of EMLA 5% cream on the uterine cervix before performing HSG significantly reduced the pain during this procedure.