Search

3-M syndrome (OMIM # 273750 ) is a rare autosomal recessive growth disorder characterized by severe pre- and post-natal growth restriction, associated with minor skeletal abnormalities and dysmorphisms. Although the 3-M syndrome is well known as a primordial dwarfism, descriptions of the prenatal growth are missing. We report a family with variable phenotypic features of 3-M syndrome and we describe the prenatal and postnatal growth pattern of two affected sisters with a novel homozygous CUL7 mutation (c.3173-1G>C), showing a pre- and post-natal growth deficiency and a normal cranial circumference. [ABSTRACT FROM AUTHOR]

Objectives. To demonstrate the feasibility of the prenatal diagnosis of partial androgen insensitivity syndrome by 3D-4D ultrasound. Methods. To report prenatal diagnosis of partial androgen insensitivity syndrome at 32nd week of gestation by 3D-4D ultrasound in a fetus with a 46XY karyotype, testing negative to the mutation analysis of SRY gene and the 5ɑ-reductase 2 gene (SRD5A2). Results. 3D-4D surface rendering allows the detection of external and internal genital malformations and can address the prenatal diagnosis of PAIS and can exclude associated complications. Conclusions. Prenatal diagnosis of PAIS allows an adequate parental counseling and an early optimal management of the condition, not only for the psychological and social reflections but also for the avoidance of complications and postnatal morbidity due to misdiagnosis or delays in the treatment of the genital ambiguity [ABSTRACT FROM AUTHOR]

Arboleda-Tham syndrome (ARTHS, MIM 616268) is a rare genetic disease, due to a pathogenic variant of Lysine (K) Acetyltransferase 6A (KAT6A) with autosomal dominant inheritance. Firstly described in 2015, ARTHS is one of the more common causes of undiagnosed syndromic intellectual disability. Due to extreme phenotypic variability, ARTHS clinical diagnosis is challenging, mostly at early stage of the disease. Moreover, because of the wide and unspecific spectrum of ARTHS, identification of the syndrome during prenatal life rarely occurs. Therefore, reported cases of KAT6A syndrome have been identified primarily through clinical or research exome sequencing in a gene-centric approach. In order to expands the genotypic and phenotypic spectrum of ARTHS, we describe prenatal and postnatal findings in a patient with a novel frameshift KAT6A pathogenic variant, displaying a severe phenotype with previously unreported clinical features. [ABSTRACT FROM AUTHOR]

Neuromuscular junctions (NMJs) are specialized synapses, crucial for the communication between spinal motor neurons (MNs) and skeletal muscle. NMJs become vulnerable in degenerative diseases, such as muscle atrophy, where the crosstalk between the different cell populations fails, and the regenerative ability of the entire tissue is hampered. How skeletal muscle sends retrograde signals to MNs through NMJs represents an intriguing field of research, and the role of oxidative stress and its sources remain poorly understood. Recent works demonstrate the myofiber regeneration potential of stem cells, including amniotic fluid stem cells (AFSC), and secreted extracellular vesicles (EVs) as cell-free therapy. To study NMJ perturbations during muscle atrophy, we generated an MN/myotube co-culture system through XonaTM microfluidic devices, and muscle atrophy was induced in vitro by Dexamethasone (Dexa). After atrophy induction, we treated muscle and MN compartments with AFSC-derived EVs (AFSC-EVs) to investigate their regenerative and anti-oxidative potential in counteracting NMJ alterations. We found that the presence of EVs reduced morphological and functional in vitro defects induced by Dexa. Interestingly, oxidative stress, occurring in atrophic myotubes and thus involving neurites as well, was prevented by EV treatment. Here, we provided and validated a fluidically isolated system represented by microfluidic devices for studying human MN and myotube interactions in healthy and Dexa-induced atrophic conditions—allowing the isolation of subcellular compartments for region-specific analyses—and demonstrated the efficacy of AFSC-EVs in counteracting NMJ perturbations. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the deletion of an integral number of 3.3 kb units of the polymorphic D4Z4 repeat array at 4q35. The prenatal identification of this defect can be carried out on chorionic villi or amniocytes, whereas preimplantation genetic testing for monogenic disorders (PGT‐M) requires molecular markers linked to the D4Z4 allele of reduced size. In this context the reliability of this association is crucial. To test the informativeness of the nearby polymorphic markers we investigated recombination at 4q35 using the polymorphic markers D4S1523, D4S163 and D4S139 positioned at 0.55, 0.5 and 0.21 Mb proximal to the D4Z4 array respectively. We determined the probability of recombination events to occur in the D4Z4‐D4S1523 interval considering 86 subjects belonging to 12 FSHD families and found a recombination frequency of 14% between D4Z4 and D4S1523. Our study also revealed the occurrence of de novo variants and germline mosaicism. These findings highlight the recombinogenic nature of the 4q subtelomere and indicate that caution should be taken when interpreting PGT‐M results. It is advisable that a woman who underwent a PGT‐M cycle undertakes a prenatal DNA analysis to confirm the size of the D4Z4 alleles carried by the fetus. [ABSTRACT FROM AUTHOR]

Autosomal recessive cutis laxa type IIIA is a very rare genetic condition, caused by pathogenic variants in ALDH18A1 , encoding delta-1-pyrroline-5-carboxylate synthase (P5CS). This enzyme catalyzes the reduction of glutamic acid to delta1-pyrroline-5-carboxylate, playing a key role in the de novo biosynthesis of proline, ornithine, and arginine. Autosomal recessive cutis laxa type IIIA is characterized by abundant and wrinkled skin, skeletal anomalies, cataract or corneal clouding and neuro-developmental disorders of variable degree. We report on a patient with autosomal recessive cutis laxa type IIIA, due to a homozygous missense c.1273C > T; p. (Arg425Cys) pathogenic variant in ALDH18A1. The patient presented a severe phenotype with serious urological involvement, peculiar cerebro-vascular abnormalities and neurodevelopmental compromise. This description contributes to better characterize the phenotypic spectrum associated with ALDH18A1 pathogenic variants, confirming the systemic involvement as a typical feature of autosomal recessive cutis laxa type IIIA. [ABSTRACT FROM AUTHOR]

Objective: To assess the performance of fetal magnetic resonance imaging (MRI) in detecting associated anomalies in fetuses diagnosed with isolated corpus callosal (CC) anomaly on multiplanar ultrasound evaluation of the fetal brain (neurosonography).Methods: This was a multicenter, retrospective cohort study involving 14 fetal medicine centers in Italy, UK, Portugal, Canada, Austria and Spain. Inclusion criteria were fetuses with an apparently isolated CC anomaly, defined as an anomaly of the CC and no other additional central nervous system (CNS) or extra-CNS abnormality detected on expert ultrasound, including multiplanar neurosonography; normal karyotype; maternal age ≥ 18 years; and gestational age at diagnosis ≥ 18 weeks. The primary outcome was the rate of additional CNS abnormalities detected exclusively on fetal MRI within 2 weeks following neurosonography. The secondary outcomes were the rate of additional abnormalities according to the type of CC abnormality (complete (cACC) or partial (pACC) agenesis of the CC) and the rate of additional anomalies detected only on postnatal imaging or at postmortem examination.Results: A total of 269 fetuses with a sonographic prenatal diagnosis of apparently isolated CC anomalies (207 with cACC and 62 with pACC) were included in the analysis. Additional structural anomalies of the CNS were detected exclusively on prenatal MRI in 11.2% (30/269) of cases, with malformations of cortical development representing the most common type of anomaly. When stratifying the analysis according to the type of CC anomaly, the rate of associated anomalies detected exclusively on MRI was 11.6% (24/207) in cACC cases and 9.7% (6/62) in pACC cases. On multivariate logistic regression analysis, only maternal body mass index was associated independently with the likelihood of detecting associated anomalies on MRI (odds ratio, 1.07 (95% CI, 1.01-1.14); P = 0.03). Associated anomalies were detected exclusively after delivery and were missed on both types of prenatal imaging in 3.9% (8/205) of fetuses with prenatal diagnosis of isolated anomaly of the CC.Conclusion: In fetuses with isolated anomaly of the CC diagnosed on antenatal neurosonography, MRI can identify a small proportion of additional anomalies, mainly malformations of cortical development, which are not detected on ultrasound. © 2021 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to compare vaginal dinoprostone and mechanical methods for induction of labor (IOL) in pregnancies complicated by late fetal growth restriction. Material and methods: Multicenter, retrospective, cohort study involving six referral centers in Italy and Spain. Inclusion criteria were pregnancies complicated by late fetal growth restriction as defined by Delphi consensus criteria. The primary outcome was the occurrence of uterine tachysystole; secondary outcomes were either cesarean delivery or operative vaginal delivery for non‐reassuring fetal status, a composite score of adverse neonatal outcome and admission to neonatal intensive care unit (NICU). Univariate and multivariate logistic regression analysis was used to analyze the data. Results: A total of 571 pregnancies complicated by late fetal growth restriction undergoing IOL (391 with dinoprostone and 180 with mechanical methods) were included in the analysis. The incidence of uterine tachysystole (19.2% vs. 5.6%; p = 0.001) was higher in women undergoing IOL with dinoprostone than in those undergoing IOL with mechanical methods. Similarly, the incidence of cesarean delivery or operative delivery for non‐reassuring fetal status (25.6% vs. 17.2%; p = 0.027), composite adverse neonatal outcome (26.1% vs. 16.7%; p = 0.013) and NICU admission (16.9% vs. 5.6%; p < 0.001) was higher in women undergoing IOL with dinoprostone than in those undergoing IOL with mechanical methods. At logistic regression analysis, IOL with mechanical methods was associated with a significantly lower risk of uterine tachysystole (odds ratio 0.26, 95% confidence interval 0.13‐0.54; p < 0.001). Conclusions: In pregnancies complicated by late fetal growth restriction, IOL with mechanical methods is associated with a lower risk of uterine tachysystole, cesarean delivery or operative delivery for non‐reassuring fetal status, and adverse neonatal outcome compared with pharmacological methods. [ABSTRACT FROM AUTHOR]

Cartilage hair hypoplasia syndrome (OMIM # 250250) is a rare autosomal recessive metaphyseal dysplasia, characterized by disproportionate short stature, hair hypoplasia and variable extra-skeletal manifestations, including immunodeficiency, anemia, intestinal diseases and predisposition to cancers. Cartilage hair hypoplasia syndrome has a broad phenotype and it is caused by homozygous or compound heterozygous mutation in the mitochondrial RNA-processing endoribonuclease on chromosome 9p13. Although it is well known as a primordial dwarfism, descriptions of the prenatal growth are missing. To add further details to the knowledge of the phenotypic spectrum of the disease, we report on two siblings with cartilage hair hypoplasia syndrome, presenting n.64C > T homozygous mutation in the mitochondrial RNA-processing endoribonuclease gene. We describe the prenatal and postnatal growth pattern of the two affected patients, showing severe pre- and post-natal growth deficiency. [ABSTRACT FROM AUTHOR]

Introduction: Corpus callosum agenesis (ACC) is frequently diagnosed during fetal life; its prognosis depends also on additional anomalies. The additional value of fetal magnetic resonance imaging (MRI) in fetuses with "isolated" complete (cACC) and partial (pACC) agenesis of the corpus callosum on ultrasound is still debated. Material and methods: We performed a systematic literature review and meta‐analysis including fetuses with a prenatal diagnosis of cACC and pACC without associated structural anomalies on ultrasound, undergoing fetal MRI. The primary outcome was the rate of additional anomalies detected at fetal MRI. Further analyses assessed the effect of type of ultrasound assessment (neurosonography vs standard axial assessment), gestational age at fetal MRI and rate of postnatally detected brain anomalies. Random‐effect meta‐analyses of proportions were used to analyze the data. Results: Fourteen studies (798 fetuses) were included. In cases with isolated cACC, 10.9% (95% CI 4.1‐20.6) and 4.3% (95% CI 1.4‐8.8) additional anomalies were detected by fetal MRI and postnatally, respectively. Stratifying according to the type of ultrasound assessment, the rate of associated anomalies detected only on fetal MRI was 5.7% (95% CI 0.5‐16.0) with dedicated neurosonography and 18.5% (95% CI 7.8‐32.4) with a standard axial assessment. In fetuses with isolated pACC, 13.4% (95% CI 4.0‐27.0) and 16.2% (95% CI 5.9‐30.3) additional anomalies were detected by fetal MRI or postnatally, respectively. Stratifying according to the type of ultrasound assessment, the rate of associated anomalies detected only on fetal MRI was 11.4% (95% CI 2.7‐25.0) when dedicated neurosonography was performed. Cortical and posterior fossa anomalies represented the most common anomalies missed at ultrasound with both cACC and pACC. Due to the very small number of included cases, stratification according to early (<24 weeks of gestation) and late (>24 weeks) fetal MRI could not be done for either cACC or pACC. Conclusions: The rate of associated anomalies detected exclusively at fetal MRI in isolated ACC undergoing neurosonography is lower than previously reported. Cortical and posterior fossa anomalies are among the most common anomalies detected exclusively at MRI, thus confirming the crucial role of fetal MRI in determining the prognosis of these fetuses. However, some anomalies still go undetected prenatally and this should be stressed during parental counseling. [ABSTRACT FROM AUTHOR]

Objectives. To assess the risk of very low birth weight (VLBW) and extremely low birth weight (ELBW) attributable to second trimester amniocentesis. Methods. Records of 4,877 consecutive amniocentesis, performed between 1997 and 2003, were analyzed. Only VLBW and ELBW in the study population (exposed) and in the control group (unexposed) were evaluated. Comparisons were made between the amniocentesis group versus nonexposed. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for VLBW and ELBW classes. Results. In the study population, the VLBW were 35 (0.71%) and the ELBW were 20 (0.41%). In the control group, the VLBW were 220 (0.67%) and the ELBW were 112 (0.34%). The Odds ratios of the VLBW between the study and the control group did not show any statistical significant risk (OR = 1.07, 95% CI = 0.72-1.54). Also in ELBW odds ratios between study and control group were not statistically significant (OR = 1.20, 95% CI = 0.7-1.95). Conclusions. No effect of the second trimester amniocentesis was noted on VLBW and ELBW. [ABSTRACT FROM AUTHOR]

Human amniotic fluid stem cells (hAFSCs) are broadly multipotent immature progenitor cells with high self-renewal and no tumorigenic properties. These cells, even amplified, present very variable morphology, density, intracellular composition and stemness potential, and this heterogeneity can hinder their characterization and potential use in regenerative medicine. Celector® (Stem Sel ltd.) is a new technology that exploits the Non-Equilibrium Earth Gravity Assisted Field Flow Fractionation principles to characterize and label-free sort stem cells based on their solely physical characteristics without any manipulation. Viable cells are collected and used for further studies or direct applications. In order to understand the intrapopulation heterogeneity, various fractions of hAFSCs were isolated using the Celector® profile and live imaging feature. The gene expression profile of each fraction was analysed using whole-transcriptome sequencing (RNAseq). Gene Set Enrichment Analysis identified significant differential expression in pathways related to Stemness, DNA repair, E2F targets, G2M checkpoint, hypoxia, EM transition, mTORC1 signalling, Unfold Protein Response and p53 signalling. These differences were validated by RT-PCR, immunofluorescence and differentiation assays. Interestingly, the different fractions showed distinct and unique stemness properties. These results suggest the existence of deep intra-population differences that can influence the stemness profile of hAFSCs. This study represents a proof-of-concept of the importance of selecting certain cellular fractions with the highest potential to use in regenerative medicine. [ABSTRACT FROM AUTHOR]

Background—Osteoporosis is characterized by defects in both quality and quantity of bone tissue, which imply high susceptibility to fractures with limitations of autonomy. Current therapies for osteoporosis are mostly concentrated on how to inhibit bone resorption but give serious adverse effects. Therefore, more effective and safer therapies are needed that even encourage bone formation. Here we examined the effect of extracellular vesicles secreted by human amniotic fluid stem cells (AFSC) (AFSC-EV) on a model of osteoporosis in vitro. Methods—human AFSC-EV were added to the culture medium of a human pre-osteoblast cell line (HOB) induced to differentiate, and then treated with dexamethasone as osteoporosis inducer. Aspects of differentiation and viability were assessed by immunofluorescence, Western blot, mass spectrometry, and histological assays. Since steroids induce oxidative stress, the levels of reactive oxygen species and of redox related proteins were evaluated. Results—AFSC-EV were able to ameliorate the differentiation ability of HOB both in the case of pre-osteoblasts and when the differentiation process was affected by dexamethasone. Moreover, the viability was increased and parallelly apoptotic markers were reduced. The presence of EV positively modulated the redox unbalance due to dexamethasone. Conclusion—these findings demonstrated that EV from hAFSC have the ability to recover precursor cell potential and delay local bone loss in steroid-related osteoporosis. [ABSTRACT FROM AUTHOR]

To assess accuracy and reproducibility of MRI diagnosis of invasive placentation (IP) in high-risk patients and to evaluate reliability of MRI features. Secondary aim was to evaluate impact of interventional radiology (IR) on delivery outcomes in patients with IP at MRI. 26 patients (mean age 36.24 y/o,SD 6.16) with clinical risk-factors and echographic suspicion of IP underwent 1.5 T-MRI. Two readers reviewed images. Gold-standard was histology in hysterectomised patients and obstetric evaluation at delivery for patients with preserved uterus. Accuracy and reproducibility of MRI findings were calculated. Incidence of IP was 50% (13/26) and of PP was 11.54% (3/26). MRI showed 100% sensitivity (95% CI = 75.3–100%) and 92.3% specificity (95% CI = 64.0–100%) in the diagnosis of IP. Gold-standard was histology in 10 cases and obstetric evaluation in 16. MRI findings with higher sensitivity were placental heterogeneity, uterine bulging and black intraplacental bands. Uterine scarring, placental heterogeneity, myometrial interruption and tenting of the bladder showed better specificity. MRI inter-rater agreement with Cohen's K was 1. 11 patients among 14 with MRI diagnosis of IP received IR assistance with positive impact on delivery outcomes in terms of blood loss, red cells count, intense care unit length of stay, days of hospitalisation and risk of being transfused. MRI is an accurate and reproducible technique in prenatal diagnosis of IP. MRI helps planning a safe and appropriate delivery eventually assisted by IR, which positively affects foetal and maternal outcomes. The adoption of MRI evaluation in patients with high risk of invasive placentation allows a more accurate diagnosis in terms of both presence of the disease and its extension to or through or even beyond the myometrium. This led to a better dedicated delivery management with eventual adoption of interventional radiology with a global positive effect on foetal and maternal outcomes. [ABSTRACT FROM AUTHOR]