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Background Congenital insensitivity to pain (CIP) is a rare autosomal recessive syndrome characterized by lack of pain perception with a wide spectrum of clinical signs such as anosmia and hyposmia. SCN9A gene variants were found to be associated with CIP. We here report on a family with three CIP affected patients referred for genetic investigations. Methods and Results Whole exome sequencing analysis revealed the presence of a novel nonsense, homozygous SCN9A pathogenic variant: SCN9A (NM_001365536.1): c.4633G > T, p.(Glu1545*) in exon 26. Conclusion Our three Lebanese patients had CIP, urinary incontinence and normal olfactory function while two of them also presented with osteoporosis and osteoarthritis; this association of features has not been previously reported in the literature. We hope that this report would contribute to a better delineation of the spectrum caused by SCN9A pathogenic variants.

Cystic fibrosis is the most common life-limiting autosomal recessive disease in western countries with an incidence of 1:2500 in United States and 1:1000 in some European countries. Similar incidences were noted for the Middle East with variations from 1 in 2560 to 1 in 15,876 according to the degree of consanguinity. This is a preliminary systematic study that aims to assess the incidence and carrier rate of cystic fibrosis in the Middle Eastern Lebanese population; known for a high frequency of consanguinity. One hundred thirteen DNA samples were collected from neonatal blood cards obtained from newborns to healthy unrelated families with no previous history of Cystic fibrosis. Screening for Cystic Fibrosis-causing pathogenic variants was performed using next generation sequencing, and 17 different single nucleotide variants were detected, including six pathogenic and likely pathogenic. 5.5%-7% newborns were found to be carriers of a variant strongly suggestive of pathogenicity and comparable to published literature worldwide. This pilot analysis highlights the challenging interpretation of CFTR variants in a country underrepresented by large ethnic population analyses, and stresses the importance of premarital screening programs for Cystic fibrosis.

17p13.3 microduplication syndrome has been associated with a clinical spectrum of phenotypes, and depending on the genes involved in the microduplication, it is categorized into two classes (Class I and Class II). We herein, describe two patients diagnosed with Class I 17p13.3 microduplication by BACs-on-Beads (BoBs) assay and further confirmed by fluorescence in situ hybridization (FISH). Our patients (Patient 1: 4-year-old male; Patient 2: 2-year-old male) presented with developmental delay, intellectual disability, and dysmorphic facial features. When compared with the literature, our patients manifested distinctive features (Patient 1: primary hypothyroidism; Patient 2: bilateral cryptorchidism) that were not previously described in the duplication 17p13.3 spectrum.

Background The literature has always been controversial on the use of gonadotropin-releasing hormone agonists in preserving fertility in women of childbearing age after chemotherapy; thereby, in this article, we will be discussing its use in preserving fertility. Main body of abstract When it comes to preserving fertility, it is crucial to consider all available options in this topic due to its very sensitive nature, thereby we have found that while a lot of trials favor the use of gonadotropin-releasing hormone agonists, the lack of proper follow-up and long-term trials renders its use highly debatable, and since the longest follow-up trial showed non-significant results, it also opens the floor for debate on whether this short-term benefit is worth adding another drug to the regimen or not. Short conclusion As described in this review, while the use of gonadotropin-releasing hormone agonists is beneficial in a lot of studies, the lack of long-term reports still makes its use debatable, thereby more trials should be done.

BACs-on-Beads (BoBs™) assay is a rapid aneuploidy test (RAT) that detects numerical chromosomal aneuploidies and multiple microdeletion/microduplication syndromes. This study was conducted to appraise the usefulness of the BoB™ assay as a complementary diagnostic tool to conventional karyotyping for the rapid detection of chromosomal aneuploidies. A total of 485 prenatal (amniotic fluid and chorionic villi) and blood/products of conception samples were collected between July 2013 and August 2018, and analyzed by the BoBs™ assay and cytogenetic karyotyping and further validated by fluorescence in situ hybridization (FISH). Forty-three of 484 qualifying samples (8.9%) were identified as abnormal by the BoBs™ assay. The assay was comparable to karyotyping in the detection of common structural abnormalities (trisomy 21, trisomy 18, X, and Y), with a sensitivity of 96.0% and a specificity of 100%. BoBs™ assay detected 20 microdeletion and microduplication syndromes that were missed by karyotyping. BoBs™, however, missed 10 cases of polyploidies and chromosomal rearrangements which were identified by conventional karyotyping. Our findings suggest that BoBs™ is a reliable RAT which is suitable in combination with conventional karyotyping for the detection of common aneuploidies. The assay also improves the diagnostic yield by recognizing clinically relevant submicroscopic copy number gains and losses.

Background Previous studies have suggested that the prevalence of BRCA1 and 2 mutations in the Lebanese population is low despite the observation that the median age of breast cancer diagnosis is significantly lower than European and North American populations. We aimed at reviewing the rates and patterns of BRCA1/2 mutations found in individuals referred to the medical genetics unit at the American University of Beirut. We also evaluated the performance of clinical prediction tools. Methods We retrospectively reviewed the cases of all individuals undergoing BRCA mutation testing from April 2011 to May 2016. To put our findings in to context, we conducted a literature review of the most recently published data from the region. Results Two-hundred eighty one individuals were referred for testing. The prevalence of mutated BRCA1 or 2 genes were 6 and 1.4% respectively. Three mutations accounted for 54% of the pathogenic mutations found. The BRCA1 c.131G > T mutation was found among 5/17 (29%) unrelated subjects with BRCA1 mutation and is unique to the Lebanese and Palestinian populations. For patients tested between 2014 and 2016, all patients positive for mutations fit the NCCN guidelines for BRCA mutation screening. The Manchester Score failed to predict pathogenic mutations. Conclusion The BRCA1 c.131G > T mutation can be considered a founder mutation in the Lebanese population detected among 5/17 (29%) of individuals diagnosed with a mutation in BRCA1 and among 7/269 families in this cohort. On review of recently published data regarding the landscape of BRCA mutations in the Middle East and North Africa, each region appears to have a unique spectrum of mutations.

β-Thalassemia (β-thal) is highly prevalent among the Mediterranean populations. In Lebanon, the carrier rate of the disease is estimated to be around 2.0-3.0%. In this retrospective study, we determined the spectrum of β-thal mutations in a total of 170 individuals from a sample of 140 Lebanese, Iraqi and Syrian refugee families in Lebanon, over a period from 2012 to 2018. Twenty-eight different β-globin gene mutations were identified. The most prevalent mutations were IVS-I-110 (G>A) (HBB: c.93-21G>A), IVS-II-1 (G>A) (HBB: c.315+1G>A), IVS-I-6 (T>C) (HBB: c.92+6T>C) and IVS-I-1 (G>A) (HBB: c.92+1G>A), accounting for the majority of mutations found in HBB mutations analysed in 250 alleles. Ten different β-globin gene mutations that were not previously described in Lebanon were identified in our study. These mutations include the IVS-II-848 (C>A) (HBB: c.316-3C>A), codons 9/10 (+T) (HBB: c.30_31insT), codon 15 (-T) (HBB: c.46delT), -86 (C>G) (HBB: c.-136C>G), Cap +22 (G>A) (HBB: c.-29G>A), -28 (A>C) (HBB: c.-78A>C), codon 7 (GAG>TAG) (HBB: c.22G>T), codon 26 (GAG>TAG) (HBB: c.79G>T), codons 41/42 (-TTCT) (HBB: c.126_129delCTTT), and codons 82/83 (-G) (HBB: c.250delG). Of these, six mutations [codons 9/10, codon 15 (-T), -86, codon 7, codon 26, codons 82/83) were identified in Lebanese samples only; one mutation (IVS-II-848) was identified in both Lebanese and Iraqis; and three mutations (Cap +22, -28, codons 41/42) were identified in Iraqi samples only. Further studies will help better delineate the spectrum of β-thal mutations among different ethnic groups, and provide crucial prevention strategies.

Although the adverse effects of non-essential heavy metals on semen quality have been demonstrated in experimental animal models and occupational human exposure studies, little is known about the reproductive efficiency of exposed sperm during the process of intracytoplasmic sperm injection (ICSI). Our study aims to evaluate the effect of paternal exposure to non-essential heavy metals on embryo efficiency outcomes (embryo cleavage, fragmentation, implantation, and live birth) in ICSI cycle. Ninety-five heterosexual couples who underwent 95 ICSI cycles and 78 fresh embryo transfers between January 2003 and December 2009 were evaluated. Men whose female partner was undergoing ICSI were asked to provide semen and blood samples. Heavy metal levels (Pb, Cd, As, Hg, Ba, and U) were analyzed using an ion-coupled plasma-mass spectrometry (ICP-MS; Agilent 7500 ce, Agilent Technologies, Germany) equipped with a cell dynamic range (CDR). Paternal exposure to trace heavy metals was found to influence intermediate reproductive endpoints in ICSI cycles. After adjusting for paternal and maternal confounders, paternal blood concentrations of Cd [−0.30(−0.11,−0.02)], As [−0.26(−0.16,−0.11)], and U [−0.22(−0.24,−0.02)] were inversely associated with embryo cell cleavage on day 3. Counterintuitively, paternal blood and semen Pb levels [0.26(0.01,0.22); 0.25(0.03,0.14)] as well as semen U levels [0.27(0.01,0.19)] were positively associated with the proportion of implanted embryos. There were no significant associations observed for clinical pregnancy and live birth rates with any paternal heavy metal concentrations in semen and blood. These findings highlight the importance of paternal health for embryo efficiency outcomes in ICSI treatment cycles and the need for more male partner inclusive counseling in fertility practice. They also underline a paradoxical positive association between some heavy metal pollutants at low exposure levels and reproductive outcomes.

Recurrent pregnancy loss (RPL) is a problem affecting up to 5% of women of childbearing age due to many factors. Studies have shown that RPL and cardiovascular disease (CVD) may have shared risk factors. We compared the prevalence of 12 cardiovascular disease related gene mutations in patients with a history of RPL to normal controls in a major tertiary care center in Lebanon. The CVD StripAssay (ViennaLab, Austria) was used to analyze the CVD genes on 70 women with RPL history as part of the initial routine workup for recurrent miscarriage at the American University of Beirut Medical Center. The obtained results were compared with data of controls from the Lebanese population using Fisher's exact test and Chi square analysis. Two genes of the CVD panel demonstrated a strong relationship with RPL, including, MTHFR (C677T homozygosity, A1298C homozygosity, and compound heterozygosity for C677T and A1298C) and Factor II (heterozygosity for G20210A). Moreover, a protective role of positive APO-E3 isoform was observed. This study is the first in the Lebanese population in associating RPL with a large panel of CVD related genes.

BACKGROUND: Human exposure to environmental pollutants is widespread. It was suggested that exposure to non-essential heavy metals may adversely affect semen development in men. PURPOSE: To evaluate associations between non-essential heavy metals in blood and seminal fluid and semen quality parameters in men. METHODS: Male partners of heterosexual couples were included. The following elements were measured in blood and seminal fluid: lead (Pb), cadmium (Cd), arsenic (As), barium (Ba), mercury (Hg), and uranium (U) using ion-coupled plasma-mass spectrometry. SETTING: The fertility clinic at the American University of Beirut Medical Center. MAIN OUTCOME MEASURES: Semen quality parameters (volume, concentration, total count, progressive motility, viability, and normal morphology). RESULTS: We found that participants with low-quality semen had significantly higher Cd and Ba concentrations in the seminal fluid than participants with normal-quality semen. We also observed significant associations between low sperm viability and higher blood Cd and Ba, as well as higher seminal Pb, Cd, Ba, and U. Furthermore, U concentrations in the seminal fluid were associated with increased odds ratios for below-reference progressive sperm motility and normal morphology. CONCLUSIONS: Environmental exposures to Pb, Cd, Ba, and U appear to adversely influence sperm development in men. In non-occupationally exposed men, measurements of heavy metals in the seminal fluid may be more predictive of below-reference sperm quality parameters than in blood.

In recent years, there has been a paralleled increase between male obesity and infertility rates. Obesity is associated with impaired hypothalamic-pituitary-gonadal axis, aberrant semen parameters, and subfertility or infertility. Weight loss is strongly recommended for the management of obesity-associated infertility. Lifestyle modifications that include caloric restriction and increased physical activity have a short-lived impact. Bariatric surgery is a better and more durable weight loss alternative. Comprehensive information about the benefits of weight loss on obesity-associated male infertility following bariatric surgery is still emerging. In this review, we discuss the hormonal, physical and environmental mechanism contributing to obesity-associated infertility. We then assess weight loss approaches, which include lifestyle modification, medical and surgical approaches, that can improve fertility in obese men. This review focuses also on bariatric surgery for the management of obese men seeking fertility treatment. Anecdotal evidence suggesting that bariatric surgery can impair fertility is also discussed.

Background The aim of this retrospective study is to investigate the cumulative live birth rate (CLBR) following one or more completed in vitro fertilization (IVF) cycles (up to 6 cycles) stratified by maternal age and type of infertility. Materials and Methods In this retrospective study, five hundred forty-seven women who received 736 fresh ovarian stimulation/embryo transfer cycles between January 2016 and December 2016 were included in the study at a tertiary care center located in Lebanon. Results In all women, the live birth rate for the first cycle was 33.0% [95% confidence interval (CI): 27.8-38.2]. The CLBR showed an increase with each successive fresh cycle to reach 56.9% (95% CI: 51.2-62.4) after 3 cycles and 67.9% (95% CI: of 62.5-73.0) after 6 cycles. The CLBR following 6 cycles reached 69.9% (95% CI: 63.8-75.6) in women younger than 35 years. In women older than 40 years, however, the live birth rate for the first cycle was signifi- cantly low at 3.1% (95% CI: 0.3-9.5) with a plateau in success rates after 4 cycles reaching 21.9% (95% CI: 9.2-40.0). Couples with different types of infertility had CLBRs ranging from 65% to 72%, with the exception of women with low ovarian reserve, where CLBRs reached 29.4% (95% CI: 10.3-56.0). Conclusion The CLBR at a referral center in a Middle Eastern country reached 67.9 % after 6 cycles, with variations by age and type of infertility treatment. These findings are encouraging for patients insisting to extend their treatment beyond 4 to 5 cycles.

Fertility preservation (FP) aims to help individuals overcome the infertility associated with cancer treatments such as chemotherapy and radiation. The objective of this study was to assess the awareness, attitudes and knowledge of oncologists' and clinical practitioners' (CPs) about fertility preservation and its options in Lebanon. This was a cross-sectional study with surveys carried out between March 2012 and February 2013 on CPs at the American University of Beirut Medical Centre and Saint Jude's Children Cancer Centre as well as all registered oncologists in Lebanon. Ninety percent of CPs (n = 88) and 94% of oncologists (n = 53) agreed that fertility preservation should be discussed with patient before their cancer treatment. Our data showed a gender bias in relation to patients being informed of their FP options, as well as conflicting knowledge of FP options available in Lebanon among oncologists. The CPs were more likely to have accurate knowledge of FP options and treatment than oncologists. A proactive approach is required to: (1) increase the awareness and knowledge of FP; (2) improve attitudes towards FP; and (3) encourage its communication between CPs, oncologists and patients in Lebanon. Increased education programs, awareness campaigns and development of dedicated FP centres are needed.

Transcription Factor AP-2 Beta (TFAP2B) functions in the differentiation of neural crest cell derivatives and contributes to the embryogenesis of the ductus arteriosus. Mutations of TFAP2B produces Char syndrome. Char syndrome is an autosomal dominant disorder comprising facial dysmorphism, hand anomalies, and patent ductus arteriosus (PDA). In this report, we describe a proband with a de novo TFAP2B frameshift mutation c.650delG p.(Gly217Alafs*32) in the basic domain. The proband presented mainly with musculoskeletal features of Char syndrome. No PDA was identified at presentation suggesting that this syndrome may prove to be phenotypically heterogeneous. This report will help illustrate the genotype/phenotype correlation of TAFB2 mutations and better delineate the clinical features in Char syndrome.

Aim The aims of this study is to address the improvement in CRP and adiponectin in obese PCOS and non PCOS after bariatric surgery, and to show that obese PCOS women have a slower rate of improvement when compared to obese non PCOS women. Methods This is a prospective case-control study evaluating the effect of weight loss by sleeve gastrectomy among obese PCOS patients. Results There was a 36.28% of weight loss among obese PCOS and 33.04% among the control group at 12 months. Both groups showed a significant increase in the adiponectin levels at 3, 6 and 12 months’ post-surgery. The rate of increase was higher in the obese non PCOS women (4.93 ± 1.79–9.79 ± 3.9) compared to obese PCOS women (5.05 ± 1.98–7.25 ± 0.21). The CRP levels decreased with weight loss after the surgery to reach statistical significance at 3 months in obese PCOS group (4.18 ± 3.94, p = 0.048). Conclusion The degree of weight loss after surgery was effective in lowering CRP and increasing adiponectin levels in PCOS women. However, this improvement was slower compared to obese non PCOS patients. A genetic predisposition to insulin resistance might explain these findings.

The symptom burden of midlife ovarian senescence and its impact on physical, emotional, and sexual well-being has long been perceived as disruptive to the personal, social, and professional aspirations of postmenopausal women. Low serum estrogen levels prevailing after menopause have also been associated with accelerated aging of tissues and organs, particularly the skeletal and cardiovascular systems [1, 2]. With the triumphant development of the oral contraceptive pill in 1960 [3], hope grew that biological challenges unique to the female post-reproductive years can too be conquered with the use of synthetic sex steroids. This hope was stoked as well by Wilson’s negative portrayal of the menopause as an “estrogen deficiency state” which “must be replaced” to avoid the “tragedy” and “decay” of menopause [4, 5]. Within a decade of Wilson’s influential assertions, the number of menopausal women who had taken up long-term estrogen therapy had soared [6]. Few years later, a significant body of observational data would demonstrate that such menopausal hormone therapy (MHT) is not only effective for control of troublesome symptoms but may also have benefits for the prevention of chronic diseases commonly associated with female aging [7–9]. The promise that a pill may improve life’s quality, and possibly its quantity, by increasing the odds of avoiding a heart attack or a hip fracture captured the attention of tens of millions of menopausal women whose ranks in the USA were growing rapidly as the baby boom generation matured. The promise of MHT also captured the attention of employers and the insurance industry who have a perennial interest in workforce wellness and of the pharmaceutical industry who saw a tremendous opportunity for growth. In 1991, the 102nd US Congress got involved as well, passing the Women’s Health Equity Act of 1991 [10]. While this act failed to become law, significant portions of it were ultimately included in the NIH Revitalization Act of 1993 which did become law, appropriating significant resources for women’s health research [11]. This confluence of public and private interests set the stage for accelerated investigation in menopausal medicine, including federally funded research developed and coordinated by the newly minted Office of Women’s Health at the National Institutes of Health (NIH). With cancer, heart disease, and osteoporosis as the leading causes of death, disability, and impaired quality of life in older women, the NIH launched in 1993 a landmark 15-year effort, the Women’s Health Initiative (WHI), to study these matters with scientific rigor. The role of MHT figured prominently in this effort with the inclusion of two long-term prospective randomized controlled trials (RCTs) – the WHI estrogen and progesterone (WHI-EP) and the WHI estrogen (WHI-E)-alone hormone trials. The publication of results in 2002 and 2004 of these WHI hormone trials formed a watershed event with worldwide changes in clinical practice and social attitudes toward acceptance of MHT. The WHI results inspired not only new and innovative MHT research but also a second look at existing MHT data that had predated WHI. This chapter summarizes five decades of MHT research in chronological order and highlights trends in clinical practice which swayed the research agenda and in turn were influenced by the results.

Study Objective Polycystic ovarian syndrome (PCOS) is a major endocrine disorder afflicting women of reproductive age group. Women with PCOS suffer from depressive and anxiety disorders and they are more likely to be depressed compared to healthy women. However, no studies have assayed the perception of the clinical manifestations of PCOS in the adolescent group. In this study, we aimed at analyzing the anxiety, cognitive, and depressive states of adolescent girls with PCOS. Design A total of 37 adolescents presenting to a tertiary care center in Lebanon and aged 14–18 years participated in the current study. Socio-economic and demographic data were collected and self-reported questionnaires (FSIQ, SDQ, SCARED, and BDI) were presented to the study group and analyzed. Results The FSIQ levels among adolescents with PCOS were significantly lower compared to healthy controls. Surprisingly, there were no differences between the adolescent girls with PCOS and the healthy age-matched girls in the anxiety and depressive states and in psychiatric symptoms. Conclusions This is the first study to assay for cognitive, anxiety, and depressive states in adolescent girls. No major differences were found among both groups except in cognitive levels. However, long-term follow-up for proper management of psychiatric disorders is warranted. Moreover, the latency of androgens and its contribution to psychiatric illnesses in women with PCOS could be a major factor for development of psychiatric symptoms, rather than the hyperandrogenic levels per se .

To create a diagnostic document describing the utilization of pre-implantation genetic testing (PGT) in the absence of monitoring and regulation. Retrospective cohort study of couples undergoing PGT between 2004 and 2007 in Lebanon. The clinical indications for 192 PGT cycles performed during the study period were gender selection (96.3%), chromosomal aneuploidy (3.1%), and balanced translocation (0.5%). When gender selection was sought, the selection of a son was desired in 94.1% of cases. Of couples undergoing PGT for sex selection, 16.2% were childless, 8.6% had one child of the opposite gender, 28.1% had two same-gender children, 29.7% had three same-gender children, and 11.9% had four or more. Our findings demonstrate the morally questionable consequences of self-regulated systems in which physicians are the sole gatekeepers of norms and ethics.

Many cultural and religious beliefs place virginity at a high level of social significance, in that women who lose their virginity before marriage may face humiliation, ostracism, divorce, and extreme violence. This led to an increase in the demand for virginity restoration through surgical hymen reconstruction among these cultures. However, data regarding the acceptance of hymenoplasty in societies that consider sexuality a taboo are scarce. In this cross-sectional study, we investigated the effects of gender and religion on sexual attitudes towards hymenoplasty, premarital sex, and virginity in a sample of 600 Lebanese university students. Our findings showed that approval of hymenoplasty was low among participants regardless of gender (25.7 % men vs. 19.1 % women) and religious affiliations (22.5 % Muslims vs. 22.3 % Christians). Arguments for rejection were rooted in moral ethics and personal convictions: "form of deceiving and cheating" (80.7 %) and "betrayal of honesty in the relationship" (80.4 %). Reasons for acceptance included: personal belief in "women's rights, autonomy, and freedom" (72.2 %) and "physical harm and death" (63.5 %).Male participants were more likely to approve premarital coital sex than females (61.0 vs. 27.3 %). Muslims were also more likely to reject marrying a non-virgin than Christians (39.9 vs. 18.0 %). Female participants expressed more tolerance towards marrying a non-virgin male partner (78.3 vs. 57.3 %). Low acceptance of hymenoplasty among Lebanese university students was found to be related to moral ethics and personal convictions independently from gender and religious affiliation. Differences in sexual attitudes towards premarital coital sex and virginity, however, were more significantly influenced by culture and religion.

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This study aims to evaluate the effects of fever on follicular development in women undergoing controlled ovarian stimulation during in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) cycles.This was a retrospective observational self-controlled study at a tertiary-care fertility centre. Six gonadotropin stimulation cycles characterised by poor ovarian response in which women reported the occurrence of a febrile illness, were considered for evaluation. Fever-exposed cycles were compared to the next stimulation cycle in the same women. Primary outcome measures were final number of pre-ovulatory follicles (≥ 16 mm) and final peak serum estradiol levels (pg/mL). Other outcome measures were final number of medium-sized follicles (12-15 mm), final mean estradiol serum level per follicle ≥ 12 mm (pg/mL), total days of stimulation and total gonadotropin ampoules utilised.Fever-exposed cycles were associated with significantly lower number of pre-ovulatory follicles (0.7 ± 0.8), significantly higher number of medium-size follicles (21.0 ± 4.5), and significantly reduced serum estradiol per follicle ≥12 mm (50.7 ± 11.7 pg/mL). They also required a significantly longer duration of ovarian stimulation (15.7 ± 3.3 days) and a significantly increased number of gonadotropin ampoules (47.2 ± 10.9). Four women had polycystic ovary syndrome and one hypothalamic hypogonadism.This preliminary report suggests a possible negative effect of fever on follicular development and ovarian estradiol production in some women undergoing controlled ovarian stimulation.