The use of array-CGH in a cohort of Greek children with developmental delay

<p>Abstract</p> <p>Background</p> <p>The genetic diagnosis of mental retardation (MR) is difficult to establish and at present many cases remain undiagnosed and unexplained. Standard karyotyping has been used as one of the routine techniques for the last decades. The implementation of Array Comparative Genomic Hybridization (array-CGH) has enabled the analysis of copy number variants (CNVs) with high resolution. Major cohort studies attribute 11% of patients with unexplained mental retardation to clinically significant CNVs. Here we report the use of array-CGH for the first time in a Greek cohort. A total of 82 children of Greek origin with mean age 4.9 years were analysed in the present study. Patients with visible cytogenetic abnormalities ascertained by standard karyotyping as well as those with subtelomeric abnormalities determined by Multiplex Ligation-dependent Probe Amplification (MLPA) or subtelomeric FISH had been excluded.</p> <p>Results</p> <p>Fourteen CNVs were detected in the studied patients. In nine patients (11%) the chromosomal aberrations were inherited from one of the parents. One patients showed two duplications, a 550 kb duplication in 3p14.1 inherited from the father and a ~1.1 Mb duplication in (22)(q13.1q13.2) inherited from the mother. Although both parents were phenotypically normal, it cannot be excluded that the dual duplication is causative for the patient's clinical profile including dysmorphic features and severe developmental delay. Furthermore, three <it>de novo </it>clinically significant CNVs were detected (3.7%). There was a ~6 Mb triplication of 18q21.1 in a girl 5 years of age with moderate MR and mild dysmorphic features and a ~4.8 Mb duplication at (10)(q11.1q11.21) in a 2 years old boy with severe MR, multiple congenital anomalies, severe central hypotonia, and ataxia. Finally, in a 3 year-old girl with microcephaly and severe hypotonia a deletion in (2)(q31.2q31.3) of about ~3.9 Mb was discovered. All CNVs were confirmed by Fluorescence <it>in situ </it>hybridization (FISH). For the remaining 9 patients the detected CNVs (inherited duplications or deletions of 80 kb to 800 kb in size) were probably not associated with the clinical findings.</p> <p>Conclusions</p> <p>Genomic microarrays have within the recent years proven to be a highly useful tool in the investigation of unexplained MR. The cohorts reported so far agree on an around 11% diagnostic yield of clinically significant CNVs in patients with unexplained MR. Various publicly available databases have been created for the interpretation of identified CNVs and parents are analyzed in case a rare CNV is identified in the child. We have conducted a study of Greek patients with unexplained MR and confirmed the high diagnostic value of the previous studies. It is important that the technique becomes available also in less developed countries when the cost of consumables will be reduced.</p

Fetal growth restriction and postnatal development

The interaction between genetic constitution and in utero environment determines fetal growth and development and influences the susceptibility to certain disorders in adulthood. Data from both animal and human studies indicate that prenatal and early postnatal malnutrition can program the hypothalamus-pituitary-adrenal axis (HPA axis), altering neuroendocrine response to stressors throughout lifetime. Impaired uteroplacental perfusion results in fetal growth restriction (FGR). In FGR there is evidence of chronic hypoxemia and alterations in metabolic, endocrine, and hematological parameters, compatible with starvation. Furthermore, FGR is associated with increased perinatal mortality and in the survivors there is increased susceptibility to diabetes and cardiovascular disease in adulthood. There is evidence that early postnatal growth acceleration, which would normally be considered desirable, may exacerbate metabolic dysfunction in later life

The impact of Mayer&ndash;Rokitansky&ndash;K&uuml;ster&ndash;Hauser Syndrome on Psychology, Quality of Life, and Sexual Life of Patients: A Systematic Review

Background: Mayer&ndash;Rokitansky&ndash;K&uuml;ster&ndash;Hauser (MRKH) syndrome is a rare congenital syndrome characterized by uterovaginal agenesis. Most patients are diagnosed during adolescence, when body image and sexual identity are shaped. Our main objective was to investigate how MRKH syndrome affects psychology, quality of life (QoL), and the sexual life of patients compared with non-affected individuals. Methods: Original peer-reviewed research papers examining psychological outcomes, QoL, and sexual function of MRKH patients were searched in PubMed. Titles, abstracts, and full text from potentially eligible records were reviewed by two independent reviewers. Case reports and papers published not in English were excluded. Results: Our search identified 63 records, of which 20 were included: 10 examined psychological and psychosocial outcomes, 14 examined sexual function outcomes, and 6 examined QoL outcomes. Results may be affected by selection bias and confounding due to differences between MRKH patients and controls. Conclusions: MRKH could be associated with a higher prevalence of anxiety and depression symptoms and social insecurity compared with women of a similar age without the condition. MRKH could also be associated with greater pain and discomfort during sexual intercourse and limitations in arousal, lubrication, and orgasm. MRKH patients more commonly experience impairment of mental-health-related QoL, but physical-health-related QoL is not affected

The impact of Mayer–Rokitansky–Küster–Hauser Syndrome on Psychology, Quality of Life, and Sexual Life of Patients: A Systematic Review

Background: Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a rare congenital syndrome characterized by uterovaginal agenesis. Most patients are diagnosed during adolescence, when body image and sexual identity are shaped. Our main objective was to investigate how MRKH syndrome affects psychology, quality of life (QoL), and the sexual life of patients compared with non-affected individuals. Methods: Original peer-reviewed research papers examining psychological outcomes, QoL, and sexual function of MRKH patients were searched in PubMed. Titles, abstracts, and full text from potentially eligible records were reviewed by two independent reviewers. Case reports and papers published not in English were excluded. Results: Our search identified 63 records, of which 20 were included: 10 examined psychological and psychosocial outcomes, 14 examined sexual function outcomes, and 6 examined QoL outcomes. Results may be affected by selection bias and confounding due to differences between MRKH patients and controls. Conclusions: MRKH could be associated with a higher prevalence of anxiety and depression symptoms and social insecurity compared with women of a similar age without the condition. MRKH could also be associated with greater pain and discomfort during sexual intercourse and limitations in arousal, lubrication, and orgasm. MRKH patients more commonly experience impairment of mental-health-related QoL, but physical-health-related QoL is not affected

Prediction of Preterm Delivery by Late Cervical Length Measurement after 24 Weeks

Objective: To examine the value of the cervical length (CL) measurement at 24-30 gestational weeks in the prediction of spontaneous preterm delivery (SPD) between 30 and 34 weeks (SPD34) and between 34 and 37 weeks (SPD37). Methods: We performed a prospective cross-sectional study. CL was measured once by transvaginal ultrasound examination between 24 and 30 weeks. Results: The study sample consisted of 1,180 low-risk singleton pregnancies. 10 women (0.85%) had a SPD34 and 60 (5.08%) had a SPD37. CL was shorter (p &lt;0.001) in the women who had a SPD34 (median 11 mm) compared to the women who delivered after 34 weeks (median 31 mm). CL was shorter (p &lt; 0.001) in the women who had a SPD37 (median 22 mm) compared to the women who delivered after 37 weeks (median 31 mm). CL predicted SPD34 (OR = 0.837, R-2 = 0.2768, AUC = 0.9406, p &lt; 0.001) and SPD37 (OR = 0.907, R-2 = 0.1085, AUC = 0.7584, p &lt; 0.001). The model achieved a sensitivity of 70.0 and 38.3% for 10% false-positive rate for SPD34 and SPD37, respectively. Conclusions: CL after 24 weeks is significantly shorter in women destined to have a SPD. In low-risk singleton pregnancies CL performs very well in predicting SPD34 and adequately in predicting SPD37. (C) 2015 S. Karger AG, Base

Familial Aggregation of a Novel Missense Variant of <i>COL2A1</i> Gene Associated with Short Extremities: Case Report and Review of the Literature

We present two cases of family members (first cousins) with short extremities caused by a novel variant of COL2A1 gene (NM_001844.5). Case 1 description: A 29-year-old woman presented in her first pregnancy for a second trimester anomaly scan at 23 weeks of gestation. Fetal long bones were measured below the third centile for gestational age. Follow-up scans revealed fetal long bone growth deceleration. Initial genetic work-up was negative and the rest of the maternal follow-up was unremarkable. A male baby weighing 3180 g was delivered at 39 weeks and 4 days of gestation. Case 2 description: A 33-year-old pregnant woman presented for a routine second trimester anomaly scan at 20 weeks and 4 days of gestation. All fetal measurements were appropriate for the gestational age. The routine growth scan performed at 32 weeks showed fetal long bone measurements below the third centile for gestational age, while the follow-up growth scan at 36 weeks and 4 days of gestation revealed consistent, below the third centile, fetal long bone growth. Given that the fetuses of these two cases were related (first cousins), whole exome sequencing (WES) was performed on Case 2. WES revealed a novel heterozygous missense variant c.1132G>A (p. Gly378Ser) of COL2A1 gene (NM_001844.5). Subsequently, targeted genetic sequencing for the variant was performed on Case 1 and the same novel variant was found. Targeted sequencing revealed the same variant in the mother of Case 1 and the father of Case 2 (siblings). A female baby weighing 3200 g was delivered at 40 weeks and 4 days of gestation

Physical Health, Media Use, Stress, and Mental Health in Pregnant Women during the COVID-19 Pandemic

Background: The COVID-19 pandemic has led to significant changes in the care of pregnant women and their fetuses. Emerging data show elevated depression and anxiety symptoms among pregnant women. Aims: The purpose of this article is to investigate the psychological and behavioral impact of the COVID-19 pandemic on pregnant women in Greece during the first national lockdown. Methods: We used a cross-sectional, anonymous survey to collect data in two fetal medicine clinics in the largest urban centers of Greece during the months of April and May 2020. The questionnaire was largely based on the CoRonavIruS Health Impact Survey (CRISIS), and assessed sociodemographic characteristics, general health and obstetric data and COVID-19-related worries and life changes. Mood symptoms, substance use and lifestyle behaviors were assessed at two time points (3 months prior to the pandemic and the 2 weeks before taking the survey), while perceived stress was measured with the perceived stress scale (PSS-14). Results: A total of 308 pregnant women (Mage = 34.72), with a mean gestation of 21.19 weeks participated in the study. Over one-third of the women found COVID-19 restrictions stressful, and their highest COVID-19-related worry was having to be isolated from their baby. Mean PSS-14 score was 21.94, suggesting moderate stress. The strongest predictors of stress were physical and mental health status before COVID-19 and having experienced a stressful life event during their pregnancy. Compared to 3 months before the pandemic, women reported higher scores on mood symptoms (p &lt; 0.001), TV use (p = 0.01) and social media use (p = 0.031) in the last 2 weeks before taking the survey. Conclusion: Our study provides important preliminary evidence of the negative impact of the COVID-19 pandemic and the lockdown on pregnant women&rsquo;s well-being and functioning

Conjoined Twins Complicating a Dichorionic Triplet Pregnancy after Intracytoplasmic Sperm Injection: A Case Report and Review of the Literature

Conjoined twins represent a rare type of monoamniotic twins. Ultrasound assessment during the first trimester can facilitate the diagnosis, however further assessment by colour Doppler studies, 3D imaging, fetal echocardiography and fetal magnetic resonance imaging (MRI) is usually required in order to determine the specific fetal abnormalities and to guide appropriate pregnancy management. This case report presents a rare case of conjoined twins complicating a dichorionic-diamniotic triplet pregnancy, achieved after intracytoplasmic sperm injection (ICSI) and blastocyst transfer. A 44-year-old woman was referred for chorionicity determination to our Fetal Medicine Centre due to suspicion of conjoined twins in a triplet pregnancy. Ultrasound assessment at 11 weeks demonstrated a dichorionic triplet pregnancy which was also complicated by a rare type of conjoined twins (thoracoomphalopagus) and after a successful embryo reduction a neonate of 2200 g was delivered by caesarean section at term. The accurate diagnosis and early detection of conjoined twins by a fetal medicine specialist is crucial, especially as far as multiple pregnancies with three or more fetuses are concerned

The Effect of Stimulation Protocols (GnRH Agonist vs. Antagonist) on the Activity of mTOR and Hippo Pathways of Ovarian Granulosa Cells and Its Potential Correlation with the Outcomes of In Vitro Fertilization: A Hypothesis

Controlled ovarian hyperstimulation (COH) is essential for the success of in vitro fertilization (IVF). Evidence showing the comparison of different COH protocols remains predominantly of low certainty and derives from unspecified infertile and highly heterogeneous populations. Thus, personalized approaches to examine the response of patients to the various COH protocols need to be investigated. Data from in vitro and animal studies have identified the mechanistic target of rapamycin (mTOR) and Hippo signaling pathways play a key role in follicular homeostasis and oocyte quality. To be specific, current data indicate the controlled activation of mTOR and the controlled inhibition of the Hippo pathway within the ovarian granulosa cells (GC). Both are reported to lead to a nurturing follicular microenvironment, increase oocyte quality, and potentially improve reproductive outcomes. As intracellular markers, phosphorylated/unphosphorylated levels of the pathways&rsquo; main downstream mediators could be included among the candidate &ldquo;personalized&rdquo; predictors of patients&rsquo; response to COH protocols and final IVF outcomes. Based on these hypotheses, we make a preliminary attempt to investigate their validity: We propose a prospective cohort study to compare the levels of certain phosphorylated/unphosphorylated components of the investigated pathways (mTOR, ribosomal protein S6 kinase beta-1 (p70S6K-1), yes-associated protein-1 (YAP-1), and transcriptional coactivator with PDZ-binding motif (TAZ)) within the follicular fluid-isolated GC between women undergoing gonadotropin-releasing hormone (GnRH) antagonist/&ldquo;short&rdquo; protocols and those receiving GnRH agonist/&ldquo;long 21&rdquo; protocols. A case-control design comparing these levels between women achieving pregnancy and those who did not is further planned. Additional analyses addressing the population&rsquo;s expected heterogeneity are planned after the completion of the pilot phase, during which 100 participants undergoing IVF are intended to be recruited. At this stage, these hypotheses are solely based on in vitro/animal data, and thus, similar studies on humans in this respect are necessary for the investigation of their potential validity

Preeclampsia and Cerebral Palsy in Offspring

The aim of this systematic review and meta-analysis is to examine the association between exposure to preeclampsia during pregnancy and the occurrence of cerebral palsy in offspring. For this reason, the authors searched PubMed/Medline, EMBASE, and Google Scholar databases (end-of-search: 22 November 2021) and identified the most relevant studies. Then, a meta-analysis of all the eligible studies was performed. Subgroup and meta-regression analyses by study design, degree of adjustment, and geographical region were also conducted. A total of 10 studies were finally included, and no statistical significance was noted in the association between preeclampsia and cerebral palsy (pooled OR = 1.16, 95% CI: 0.77&ndash;1.74). The subgroup of studies that provided adjusted odds ratios for any variable except for gestational age showed a statistically significant association (pooled OR = 1.62, 95% CI: 1.36&ndash;1.93), whereas the association dissipated in studies also adjusting for gestational age (pooled OR = 1.63, 95% CI: 0.48&ndash;5.50). In conclusion, it seems that preeclampsia is not associated with cerebral palsy independently of gestational age; however, further research is needed to shed light on this topic