Dioxins and furans maternal transfer: A study of breast milk and cord serum levels among Lebanese mothers and associations with newborn anthropometric measurements.

Dioxins and furans (PCDD/Fs) are anthropogenic pollutants that persist in the environment for long years, bioaccumulating in food & contaminating humans. In pregnancy, they can transfer through the placenta and reach the fetus, which negatively affects fetal growth. They can also reach newborns through breastfeeding. In this study, we focused on this critical subpopulation and identified the presence of PCDD/Fs among pregnant women in breast milk (n = 41) and cord serum (n = 49); we assessed the correlation between different matrices, evaluated the predictors and associations with newborn anthropometric measurements. Over 70.7 % of PCDD/Fs were detected in breast milk and 46.9-55.1 % in cord serum. Cord/maternal serum and breast milk to maternal serum ratios were > 1 with a significant positive Spearman correlation (0.669-0.729). Breast milk & maternal serum PCDD/Fs were associated inversely with age and positively with red meat intake. Cord serum PCDD/Fs were inversely associated with pre-pregnancy weight loss and passive smoking. Parity and gestational weight gain showed positive associations with Z-scores at birth. Z-score differences showed negative and positive associations with passive smoking and pre-pregnancy BMI respectively.

The Environmental Exposures in Lebanese Infants (EELI) birth cohort: an investigation into the Developmental Origins of Health and Diseases (DOHaD).

The EELI Study is a longitudinal birth cohort launched in 2021 in Lebanon to examine the long-term impact of environmental exposures on the health of prospective Lebanese mothers and infants and disease outcomes. This article delineates the adopted study design and protocols, current progress, and contextual considerations for the planning and launching of a birth cohort in a resource-limited setting. A sample of n = 135 pregnant women expecting to give birth at the Hôtel-Dieu de France University Hospital has been recruited since the study launch. Over 500 variables have been recorded for each participant, and over 1000 biological specimens have been processed and stored in a biobank for further analysis. The EELI study establishes methodological and logistic basis to explore the concept of the exposome and its implementation and to establish a toolkit of the SOPs and questionnaires that can be employed by the other countries in the Eastern Mediterranean region.

Maternal Serum, Cord and Human Milk Levels of Per- and Polyfluoroalkyl Substances (PFAS), Association with Predictors and Effect on Newborn Anthropometry.

BACKGROUND: The understanding of per- and polyfluoroalkyl substances (PFAS) health effects is rapidly advancing among critical populations. Therefore, the objective of this study was to assess PFAS serum levels among Lebanese pregnant women, cord serum and human milk levels, their determinants, and effects on newborn anthropometry. METHODS: We measured concentrations of six PFAS (PFHpA, PFOA, PFHxS, PFOS, PFNA and PFDA) using liquid chromatography MS/MS for 419 participants, of which 269 had sociodemographic, anthropometric, environmental and dietary information. RESULTS: The percentage of detection for PFHpA, PFOA, PFHxS and PFOS was 36.3-37.7%. PFOA and PFOS levels (95th percentile) were higher than HBM-I and HBM-II values. While PFAS were not detected in cord serum, five compounds were detected in human milk. Multivariate regression showed that fish/shellfish consumption, vicinity to illegal incineration and higher educational level were associated with an almost twice higher risk of elevated PFHpA, PFOA, PFHxS and PFOS serum levels. Higher PFAS levels in human milk were observed with higher eggs and dairy products consumption, in addition to tap water (preliminary findings). Higher PFHpA was significantly associated with lower newborn weight-for-length Z-score at birth. CONCLUSIONS: Findings establish the need for further studies, and urgent action to reduce exposure among subgroups with higher PFAS levels.

Contraception knowledge and practices among students in Lebanese universities.

This study aimed to evaluate the proportion of contraception users among Lebanese youth, and the extent of knowledge and perception on birth control; and to raise awareness and sensitise young adults to sexual health, which remains taboo in Lebanon. The 30-item questionnaire was broadcasted to students in private and public universities in Lebanon, through social media and it collected information on contraception use and student knowledge. Over 30% of responders were medical students, and 41% have ever used contraceptives (mostly women); among which, 52.1% for contraception versus 47.9% for medical reasons. According to responders, the pill ranked high in terms of effectiveness (72.4% of responders perceive the pill as effective), followed by the male condom (69.1%) and the hormonal intrauterine device (29.6%). Some would not use contraception in the future, for religious reasons (30.8%) or for fear of complications (46.2%); indeed, around a third of contraceptive users (all female) have experienced adverse effects. Finally, students expressed concern about long-term complications of contraceptive use (pulmonary embolism/phlebitis, breast/endometrial/ovarian cancer, stroke, depression and myocardial infarction). Though less frequent than in the Western world, contraception use in Lebanon is non-negligible and gaps in university students' knowledge on contraception were identified; which should prompt sexual education and family planning initiatives in Lebanon.

The rate of cesarean delivery changes after internal audit based on the Robson Ten Group Classification System in Lebanon.

OBJECTIVE: To evaluate the efficiency of the Robson classification as an internal clinical audit and feedback of the high rate of cesarean delivery at Hotel Dieu de France, a tertiary referral hospital. METHODS: A pre-post study was conducted, with a retrospective approach in 2018 and 2019, identified as the pre-period (before the implementation of the Robson classification), and with a prospective approach in 2020 and 2021, labeled the post-period. RESULTS: The total number of deliveries during the study period was 2560; 1305 patients were included in the pre-period and 1255 patients delivered in the post-period. No significant differences between the two groups were found. No significant difference was found in the overall rate of cesarean delivery between the first and second periods (57.86% vs 56.72%; P = 0.2). However, a significant decrease in the absolute contribution of groups 3 and 4 (multiparous women without a previous uterine scar with a single cephalic pregnancy, ≥37 weeks of gestation, with spontaneous labor or induced labor) in the overall rate of cesarean delivery was remarked (P = 0.02 and 0.01, respectively). CONCLUSION: The Robson classification seems to be appropriate to monitor and audit the rate of cesarean delivery, but not sufficient to decrease the rate and change the practice.

Serum levels of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in a sample of Lebanese pregnant women: The role of dietary, anthropometric, and environmental factors.

Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are unintentionally produced, toxic environmental chemicals that persist for long years and bioaccumulate along the food chain, contaminating humans through diet. A particularly critical population subgroup is pregnant women given the adverse health effects on fetuses and newborns. Several anthropogenic sources of exposure to PCDD/Fs exist in Lebanon. Therefore, the aim of the present cross-sectional study is to measure the levels of PCDD/Fs in a sample of pregnant women in Lebanon and to explore potential associated factors. In this study, we measured serum concentrations of seven dioxins and ten furans, among 423 pregnant women recruited at delivery, using gas chromatography MS/MS. Among 269 participants, maternal sociodemographic information was collected including vicinity to landfills, incineration, pesticide use, industrial activity, and smoking. Anthropometric data were registered regarding pre-pregnancy body mass index (BMI), pre-pregnancy weight loss from restrictive diet, and gestational weight gain. Intake of major food groups generally related to PCDD/Fs was reported (fish, red meat, poultry, and dairy). Bivariate and multivariate analyses were performed to identify associations. PCDD/Fs were detected in 0 to 56.1% of the sample. Geometric mean concentrations were 75.5 (2.35) pg/g lipid and 2.25 (1.39) TEQ2005 pg/g lipid for total dioxins, and 2.66 (1.76) pg/g lipid and 0.34 (1.78) TEQ2005 pg/g lipid for total furans. Levels were relatively lower than levels previously observed in France, Germany, Mexico, Ghana, and Japan. Red meat consumption was the most consistently associated factor with a 2.38-2.57 fold increase in PCDD/F levels. Pre-pregnancy weight loss showed inverse associations with PCDD/F congeners. Vicinity to illegal incineration was also associated with a 2.32-2.43 fold increase in PCDD/F levels. In conclusion, results showed the importance of dietary, anthropometric, and environmental factors in the present sample's exposure to PCDD/Fs, in a region that contains anthropogenic sources of contamination.

Dietary patterns and birth outcomes of healthy Lebanese pregnant women.

Background: The aim of this study was to define the dietary patterns (DPs) of a sample of Lebanese pregnant women and to establish their correlation with maternal and neonatal outcomes. Methods: A cross-sectional study was conducted among 358 Lebanese pregnant women. Maternal socio-demographic variables, anthropometric measurements, gestational weight gain and neonatal outcomes such as weight, length, head circumference and Apgar score were collected by qualified dietitians. Dietary intake was assessed by a validated food frequency questionnaire and three 24-h dietary recalls. DPs were determined, a posteriori, by a factor analysis to distinguish the inter-correlations between the food groups and a cluster analysis method to assemble the participants into groupings based on similarities in food consumption. Results: The identified DPs were not exclusively composed of specific food groups, since some components were overlapping in the DPs. The first one was characterized by a high consumption of starchy vegetables, unsaturated fats and unhealthy foods, the second was rich in fruits and vegetables, seeds, rice and pasta, and in fried local meals and the third was mainly based on protein-rich foods like poultry, fish, eggs and dairy products. They were named respectively as "Westernized," "Mixed" and "Neo-Mediterranean" by the research team. Women having the lowest pre-gestational body mass index (BMI) and higher gestational age followed mainly the "Neo-Mediterranean" eating pattern. Conclusion: The three identified DPs among Lebanese pregnant women were correlated with the pre-gestational BMI, and some maternal variables. However, neither the maternal nor the neonatal outcomes were correlated with the DP adopted by the mothers.

Pure Laparoscopic Donor Nephrectomy: A Single Institution Experience From a Middle Eastern Country.

BACKGROUND: Laparoscopic live donor nephrectomy (LLDN) is the most adopted technique for kidney transplantation. Several obstacles preclude brain-dead organ transplantation in the Middle East, going from social and cultural barriers to economical and structural difficulties. To our knowledge, this is the first study to report Lebanese experience with pure LLDN, and kidney transplantation. METHODS: We included 120 cases of pure LLDN performed at our center. Demographic, perioperative, and immediate postoperative data were analyzed. Surgical particularities of the technique are described. RESULTS: The reported laparoscopic technique allowed for minimal perioperative morbidity, with an overall complication rate of 3%. Operative time averaged 146 minutes and warm ischemia time averaged 4 minutes. Mean hospital stay was 3 ± 1 days. Postoperative hemoglobin and creatinine showed a mean absolute variation of 0.09 ± 0.06 g/dL for hemoglobin and 0.51 ± 015 µmoles/L increase for creatinine. No Clavien-Dindo III-V complications were recorded. CONCLUSIONS: Strict adherence to the reproducible pure LLDN technique allowed for the performance of almost 45 cases per year with minimal morbidity and results comparable to similar series.

Cesarean section rates in a tertiary referral hospital in Beirut from 2018 to 2020: Our experience using the Robson Classification.

OBJECTIVE: To evaluate the cesarean section rate using the Robson Classification for the first time in Lebanon, at Hôtel-Dieu de France University Hospital, a tertiary referral center in Beirut. METHODS: Routine medical record data that included all live births from January 1, 2018 to September 30, 2020 was investigated. The overall cesarean section rate was recorded, and the size, cesarean section rate, and absolute and relative contributions were calculated within each group. RESULTS: The overall cesarean section rate was 56.8%. The highest relative contribution to this rate came from Robson groups 5, 2 and 10, respectively. A decrease in cesarean section rate was noted in 2020 among women admitted for induction of labor (groups 2 and 4) following the implementation of new department policies and the restrictions caused by the coronavirus disease 2019 pandemic. CONCLUSION: More than 50% of the deliveries in our department were by cesarean sections (CS). Strategies to reduce this rate should include stricter departmental policies for avoidance of unindicated primary CS and raising practitioners' and patients' awareness about trial of labor after cesarean section.

Determinants of pyelonephritis onset in patients with obstructive urolithiasis.

BACKGROUND: Acute obstructive pyelonephritis due to urolithiasis represents a medico-surgical emergency that can lead to life-threatening complications. There are still no established factors that reliably predict progression toward acute pyelonephritis in patients presenting with a simple renal colic. OBJECTIVE: To investigate clinical and paraclinical factors that are associated with the onset of acute obstructive pyelonephritis. METHODS: Patients presenting to the emergency department for renal colic with obstructive urolithiasis on imaging were enrolled in the study. Demographic data, vital signs, medical comorbidities, blood test results, urinalysis, and radiological findings were recorded. Obstructive pyelonephritis was defined by the presence of two or more of the following criteria: fever, flank pain or costovertebral angle tenderness, and a positive urine culture. RESULTS: Seventeen patients out of 120 presenting with renal colic, were diagnosed with acute obstructive pyelonephritis (14%). Parameters that were associated with the onset of obstructive pyelonephritis were: diabetes (p = 0.03), elevated CRP (p = 0.01), stone size (>5 mm) (p = 0.03), dilatation of renal pelvis (p = 0.01), peri-renal fat stranding (p = 0.02), and positive nitrites on urinalysis (p < 0.01). Hyperleukocytosis, acute kidney injury, multiple stones, pyuria (>10/mm3), hypertension, and were not associated with the onset of obstructive pyelonephritis. CONCLUSION: This study showed that known diabetic status, elevated CRP, positive urine nitrites, stone size (>5 mm), pyelic dilatation, and peri-renal fat stranding were associated with the onset of pyelonephritis in patients presenting to the emergency department with obstructive urolithiasis.

Prognostic role of neutrophil-to-lymphocyte ratio (NLR) in urological tumors: an umbrella review of evidence from systematic reviews and meta-analyses.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been studied as a biomarker for cancer prognosis, predicting survival in many tumors. The aim of this umbrella review was to combine the results from all systematic reviews and meta-analyses related to the prognostic role of the NLR in patients with urological tumors. METHODS: A PubMed, Scopus, Embase and Cochrane search was undergone from inception through September 2020 for systematic reviews and meta-analyses investigating the prognostic value of NLR in urological tumors, subdivided into prostate cancer, renal cell carcinoma, urothelial bladder and upper tract carcinomas PROSPERO (CRD42020216310). RESULTS: The results have shown, with a high level of evidence, that an elevated NLR predicts worse overall survival (OS), progression-free survival (PFS) and relapse-free survival (RFS) in prostate cancer, worse OS, PFS and RFS in renal cell carcinoma, worse OS, PFS, RFS and cancer-specific survival (CSS) in muscle invasive bladder cancer, worse PFS and RFS in non-muscle invasive bladder cancer, and worse OS, PFS, RFS and CSS in urothelial upper tract carcinoma. CONCLUSION: NLR has a significant prognostic value in urological tumors and should be included in prognostic scores of these cancers.

Maternal and cord serum levels of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) among Lebanese pregnant women and predictors of exposure.

In this study, the six indicator non-dioxin-like polychlorinated biphenyls NDL-PCBs (PCB28, PCB52, PCB101, PCB138, PCB153, PCB180), as well as four organochlorine pesticides (OCPs), hexachlorobenzene (HCB), ß-hexachlorocyclohexane (ß-HCH), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichlorethylene (DDE) were measured in 98 maternal and 49 cord sera samples of a group of Lebanese women who gave birth in three hospitals in Greater Beirut, between March and July 2018. Results showed that the levels of these persistent organic pollutants (POPs) in maternal serum were below critical limits as well as those in other countries (Tunisia, France, Portugal, Spain, Poland, Greenland, Canada, Brazil, and China). The ratios of cord serum concentrations to maternal serum concentrations of analyzed POPs were higher than 1. PCB maternal serum concentrations were found to be linked to illegal incineration (OR = 5.78; p = 0.004) as well as eggs (OR = 4.68; p = 0.027) and fruits and vegetables consumption (OR = 3.92; p = 0.016). OCP concentrations were linked to red meat and cold cuts intake (OR = 3.67-4.59; p = 0.001-0.004). While PCB levels were not correlated to newborns anthropometric measurements, OCP levels in cord serum were found to be positively linked to the birth length of newborns (p = 0.014-0.027).

Pregnancy physical activity questionnaire (PPAQ): Translation and cross cultural adaption of an Arabic version.

INTRODUCTION: Physical activity level during pregnancy is unknown in Middle Eastern and North African countries, since no valid tools assessing it exist in Arabic. The aim of this study is to culturally adapt and translate to Arabic an internationally validated instrument, the Pregnancy Physical Activity Questionnaire (PPAQ), and to measure the physical activity of pregnant women using the adapted PPAQ, Arabic version. This tool is time-sparing, self-administered and is the only one taking into account childcare and household chores. METHODS: After following the guidelines for translation and back-translation by certified translators, a committee composed of professionals in the field reviewed each item of the PPAQ, for its comprehensibility. This Arabic version of the PPAQ was tested on a sample of 179 pregnant Lebanese women, from different educational backgrounds, socioeconomic status and gestational ages. RESULTS: Cross-cultural adaptations were applied on the newly translated PPAQ in Arabic version, thus questions referring to some types of outdoor activities were excluded from the final format. Our results reported that 51% and 1.7% of women engage respectively in light and high intensity physical activity, while 18% had a sedentary lifestyle. Occupational type of activities were significantly more performed by women having a higher education (p value 0.001), as opposed to those who attended only high school, who were physically more active in household activities (p value 0.038). Second trimester was a period where pregnant women were active for household, caregiving (p value 0.031), whereas women in their third trimester were physically more active in occupational activities (p value 0.001). Sport-oriented activities were performed by women reporting a good physical status (p value 0.03). Age and crowding index were significantly correlated with occupational, household and caregiving activities (p values 0.004, 0.008 respectively). No significant correlations were observed with pre-gestational body mass index and the physical activity levels. CONCLUSION: A valid tool will help researchers in Arab countries identify physical activity levels of pregnant women and consequently emit specific guidelines relative to the importance and the benefits of a daily active lifestyle throughout gestation.

Minimally invasive simple prostatectomy in the era of laser enucleation for high-volume prostates: A systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis of available prospective and retrospective studies comparing the minimally invasive (laparoscopic or robot-assisted) simple prostatectomy (MISP) and laser enucleation of the prostate for treating male lower urinary tract symptoms in high-volume prostates, as laser enucleation of the prostate is the new trend for treating high-volume prostates (>80 mL) but many urologists now prefer MISP. METHODS: A systematic search was done using the Medical Literature Analysis and Retrieval System Online (MEDLINE) and Cochrane databases in June 2019, with research terms including: 'laser', 'laparoscopy', 'enucleation', 'BPH', 'simple prostatectomy', 'Millins', and 'adenomectomy'. The meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Of 38 screened articles, six were analysed and a total of 975 men were included. The average operative time, length of stay and catheterisation time were significantly shorter in the laser enucleation group (P = 0.006, P < 0.001 and P < 0.001, respectively). The amount of prostatic tissue removed during surgery was comparable between both the laser enucleation and MISP groups (P = 0.39). The International Prostate Symptom Score, prostate-specific antigen level, maximum urinary flow rate and post-void residual urine volume were also comparable at 3 months. Finally, similar transfusion rates and Clavien-Dindo complication rates were observed (P = 0.08 and P = 0.41, respectively). CONCLUSION: This systematic review of the literature and meta-analysis provide a further demonstration of the safety and effectiveness of both laser enucleation and MISP. While laser enucleation had a shorter catheterisation time and hospital stay than MISP, the latter still had unique and specific indications.Abbreviations: ELEP: eraser laser enucleation of the prostate; HoLEP: holmium laser enucleation of the prostate; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PVR: post-void residual urine volume; Qmax: maximum urinary flow rate; (L)(MI)(RA)SP: (laparoscopic) (minimally-invasive) (robot-assisted) simple prostatectomy.

The use of mirabegron in neurogenic bladder: a systematic review.

PURPOSE: To evaluate the use of mirabegron in patients with neurogenic bladder. METHODS: A systematic review of the literature was conducted using four databases (Medline via PubMed, Scopus, Cochrane, and EMBASE). Articles evaluating mirabegron in neurogenic bladder patients were collected, and assessment of the drug's efficacy was reviewed according to clinical and urodynamic parameters. RESULTS: Seven studies were selected and a total of 302 patients with NB were evaluated, ranging from 15 to 66 patients per study. All of the patients had received antimuscarinics as a previous treatment modality. Mirabegron was used as a second-line treatment after antimuscarinics lacked efficacy or caused adverse effects. The duration of the treatments ranged from 4 to 12 weeks. Reported in two studies each, bladder compliance and maximal cystometric capacity were the most commonly improved urodynamic parameters. In the majority of the studies, positive outcomes were reported for clinical scores. Additionally, analysis of the IPSS subscores revealed an improvement of storage symptoms as opposed to voiding symptoms. In all of the studies, mirabegron was well tolerated. CONCLUSION: Mirabegron appears to be an effective treatment in the management of neurogenic bladder unresponsive to antimuscarinics, particularly in patients presenting with storage symptoms. There is still no evidence concerning the use of mirabegron as a first-line therapy for neurogenic bladder.

Complexity of consenting for medical termination of pregnancy: prospective and longitudinal study in Paris.

BACKGROUND: We analyzed the patients' perception of prenatal diagnosis of fetal cardiac pathology, and the reasons for choosing to continue with pregnancy despite being eligible to receive a medical termination of pregnancy. We also identified the challenges, the motives interfering in decision-making, and the consequences of the decisions on pregnancy, child and mother. METHODS: This descriptive, prospective and longitudinal study was conducted in France, amongst pregnant women who wished to continue their pregnancy despite an unfavorable medical advice (incurable fetal cardiac pathologies). Socio-demographic data were collected through a questionnaire. Such questionnaire covered information assessing the parents/mother's perception of prenatal diagnosis, and medical termination of pregnancy, their interpretation of the established diagnosis and their motives for not considering pregnancy termination. RESULTS: 72 eligible patients were analyzed over one year: mean age 33 ± 6.89 years, 47 patients had already given birth to ≥1 healthy child. Mean gestational age at the detection of fetal cardiac pathologies was 30 ± 4.37 weeks of amenorrhea. Patients decided to keep the child after 3 ± 1.25 consultations. 56 (77.78%) patients made their decision with their husbands and 16 made their decision alone. Reasons for declining the medical termination were culpability and responsibility (n = 36), ideologies and convictions (n = 24), mistrust and hope (n = 12). Newborns of 67 patients died with a mean survival duration of 38 days. CONCLUSIONS: Patient informed consent should be sought before any decision in neonatology, even if conflicting with the medical team's knowledge and the pregnant mother's benefits. Decisions to accept or decline pregnancy termination depend on the patients' psychological character, ideologies, convictions, and mistrust in the diagnosis/prognosis, or hope in the fetus survival.

Impact of maternal body mass index and gestational weight gain on neonatal outcomes among healthy Middle-Eastern females.

BACKGROUND: Studies on the relative impact of body mass index in women in childbearing age and gestational weight gain on neonatal outcomes are scarce in the Middle East. OBJECTIVES: The primary objective of this research was to assess the impact of maternal body mass index (BMI) and gestational weight gain (GWG) on neonatal outcomes. The effect of maternal age and folic acid supplementation before and during pregnancy was also examined. SUBJECTS AND METHODS: This is a retrospective cross sectional observational study of 1000 full term deliveries of women enrolled thru the National Collaborative Perinatal Neonatal Network, in Lebanon. Maternal characteristics such as age, BMI and GWG and neonatal outcomes such as weight, height, head circumference and Apgar score were the primary studied variables in this study. Total maternal weight gain were compared to the guidelines depicted by the Institute of Medicine (IOM). RESULTS: The negative outcomes of newborns such as lean body weight and macrosomia were significantly present in women who gained respectively below or above the IOM's cut-off points. Pregestational body mass index influenced significantly the infants' birth weight, in both the underweight and obese categories. Birth height, head circumference and Apgar score were not influenced by pregestational body mass index or gestational weight gain. No significant associations were found between maternal age and pregestational body mass index and gestational weight gain. CONCLUSION: Studies evaluating the impact of weight before and during pregnancy on neonatal outcomes and anthropometrics measurements are lacking in the Middle East. Our results highlight the importance of nutritional counseling in order to shed the extra weights before conceiving and monitor weight gain to avoid the negative impact on feto-maternal health.

Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome.

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.