Congenital Cytomegalovirus-Related Hearing Loss.

Congenital hearing loss is a significant global health concern that affects millions of newborns and infants worldwide, posing substantial challenges for affected individuals, their families, and healthcare systems. This condition, present at birth, can stem from genetic factors, in utero exposures, infections, or complications during pregnancy or childbirth. The spectrum of congenital hearing loss ranges from mild to profound, impacting the development of speech, language, and cognitive skills, thereby influencing educational achievements, social integration, and future employment opportunities. Early detection and intervention strategies, such as newborn hearing screenings, genetic counseling, and the use of hearing aids or cochlear implants, are crucial for mitigating these impacts. This review article aims to explore the diagnostic approaches and management strategies for congenital cytomegalovirus-related hearing loss, emphasizing the importance of interdisciplinary care and the potential for technological advances to improve outcomes for affected individuals.

Beyond Weight Loss: A Comprehensive Review of Pregnancy Management following Bariatric Procedures.

The increasing prevalence of bariatric surgery among women of childbearing age raises critical questions about the correct management of pregnancy following these procedures. This literature review delves into the multifaceted considerations surrounding pregnancy after bariatric surgery, with a particular focus on the importance of preconception counselling, appropriate nutrition assessment, and the necessity of correct folic acid supplementation. Key areas of investigation include nutrient absorption challenges, weight gain during pregnancy, and potential micronutrient deficiencies. Examining the relationship between bariatric surgery and birth defects, particularly heart and musculoskeletal issues, uncovers a twofold increase in risk for women who underwent surgery before pregnancy, with the risk emphasized before folic acid fortification. In contrast, a nationwide study suggests that infants born to mothers with bariatric surgery exhibit a reduced risk of major birth defects, potentially associated with improved glucose metabolism. In addition, this review outlines strategies for managing gestational diabetes and other pregnancy-related complications in individuals with a history of bariatric surgery. By synthesizing existing literature, this paper aims to provide healthcare providers with a comprehensive framework for the correct management of pregnancy in this unique patient population, promoting the health and well-being of both mother and child.

Prenatal Features of MIRAGE Syndrome-Case Report and Review of the Literature.

MIRAGE syndrome is a recently described congenital condition characterized genetically by heterozygous gain-of-function missense mutations in the growth repressor sterile alpha domain containing 9 (SAMD9) located on the arm of chromosome 7 (7q21.2). The syndrome is rare and is usually diagnosed in newborns and children with myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy, hence the acronym MIRAGE. The aims of this paper are (1) to present fetal ultrasound features in a case where MIRAGE syndrome was diagnosed prenatally and (2) to review the existing literature records on prenatal manifestations of MIRAGE syndrome. In our case, the fetus had severe early fetal growth restriction (FGR) with normal Doppler studies, atypical genitalia, oligohydramnios, and hyperechogenic bowel at the routine mid-gestation anomaly scan. Amniocentesis excluded infections and numeric or structural chromosomal abnormalities while whole exome sequencing (WES) of the fetal genetic material identified the specific mutation. Targeted testing in parents was negative, suggesting the "de novo" mutation in the fetus. We could not identify other specific case reports in the literature on the prenatal diagnosis of MIRAGE syndrome. In cases reported in the literature where the diagnosis of MIRAGE syndrome was achieved postnatally, there are mentions related to the marked FGR on prenatal ultrasound. Severe early-onset FGR with no other apparent cause seems to be a central prenatal feature in these babies, and WES should be offered, especially if there are other structural abnormalities. Prenatal diagnosis of MIRAGE syndrome is possible, allowing for reproductive choices, improved counseling of parents, and better preparation of neonatal care.

Exome sequencing in a Romanian Bardet-Biedl syndrome cohort revealed an overabundance of causal BBS12 variants.

Bardet-Biedl syndrome (BBS), is an emblematic ciliopathy hallmarked by pleiotropy, phenotype variability, and extensive genetic heterogeneity. BBS is a rare (~1/140,000 to ~1/160,000 in Europe) autosomal recessive pediatric disorder characterized by retinal degeneration, truncal obesity, polydactyly, cognitive impairment, renal dysfunction, and hypogonadism. Twenty-eight genes involved in ciliary structure or function have been implicated in BBS, and explain the molecular basis for ~75%-80% of individuals. To investigate the mutational spectrum of BBS in Romania, we ascertained a cohort of 24 individuals in 23 families. Following informed consent, we performed proband exome sequencing (ES). We detected 17 different putative disease-causing single nucleotide variants or small insertion-deletions and two pathogenic exon disruptive copy number variants in known BBS genes in 17 pedigrees. The most frequently impacted genes were BBS12 (35%), followed by BBS4, BBS7, and BBS10 (9% each) and BBS1, BBS2, and BBS5 (4% each). Homozygous BBS12 p.Arg355* variants were present in seven pedigrees of both Eastern European and Romani origin. Our data show that although the diagnostic rate of BBS in Romania is likely consistent with other worldwide cohorts (74%), we observed a unique distribution of causal BBS genes, including overrepresentation of BBS12 due to a recurrent nonsense variant, that has implications for regional diagnostics.

Microduplication 3p26.3p24.3 and 4q34.3q35.2 Microdeletion Identified in a Patient with Developmental Delay Associated with Brain Malformation.

Microdeletions and microduplications are involved in many of prenatal and postnatal cases of multiple congenital malformations (MCM), developmental delay/intellectual disability (DD/ID), and autism spectrum disorders (ASD). Molecular karyotyping analysis (MCA), performed by DNA microarray technology, is a valuable method used to elucidate the ethology of these clinical expressions, essentially contributing to the diagnosis of rare genetic diseases produced by DNA copy number variations (CNVs). MCA is frequently used as the first-tier cytogenetic diagnostic test for patients with MCM, DD/ID, or ASD due to its much higher resolution (≥10×) for detecting microdeletions and microduplications than classic cytogenetic analysis by G-banded karyotyping. Therefore, MCA can detect about 10% pathogenic genomic imbalances more than G-banded karyotyping alone. In addition, MCA using the Single Nucleotide Polymorphism-array (SNP-array) method also allows highlighting the regions of loss of heterozygosity and uniparental disomy, which are the basis of some genetic syndromes. We presented a case of a five-year-old patient, with global development delay, bilateral fronto-parietal lysencephaly, and pachygyria, for which MCA through SNP-Array led to the detection of the genetic changes, such as 3p26.3p24.3 microduplication and 4q34.3q35.2 microdeletion, which were the basis of the patient's phenotype and to the precise establishment of the diagnosis.

Menke-Hennekam Syndrome: A Literature Review and a New Case Report.

BACKGROUND: Menke-Hennekam syndrome (MHS) is a rare and recently described syndrome consecutive to the variants in exon 30 or 31 in CREBBP (CREB-binding protein gene). The CREB-binding protein (CREBBP) and EP300 genes are two commonly expressed genes whose products possess acetyltransferase activity for histones and various other proteins. Mutations that affect these two genes are known to cause Rubinstein-Taybi syndrome (RTS); however, with the application of whole exome sequencing (WES) there were reports of variants that affect specific regions of exon 30 or 31 of these two genes but without the specific phenotype of RTS. MATERIAL AND METHODS: A review of the available literature was conducted, aimed at underscoring the difficulties in diagnosing MHS based on phenotype particularities. RESULTS: Five applicable studies were identified by searching PubMed, Web of Science, and Scopus databases for publications up to November 2021 using the key terms "Menke-Hennekam syndrome" and "CREBBP". CONCLUSIONS: In this paper, we present a new case and highlight the importance of exome sequencing to identify different mutations of exons 30 and 31 of the CREBBP gene involved in MHS, and we make formal recommendations based on our literature review.

A Rare Case of Allantoic Cyst with Patent Urachus in Fetus with a Microdeletion in 1q21.1q21.2 Region.

An allantoic cyst is a rare malformation with a frequency of 3 in 1,000,000 that may be seen antenatally by ultrasound assessment when the connection between the cloaca (future bladder) and the allantois fails to regress. A patent urachus that presents as a cyst (allantoic) is usually considered not to be associated with chromosomal abnormalities, but if it is not repaired after birth this leads to complications such as urinary tract infections and stone formation. We present a case of a fetus diagnosed with allantoic cyst at the first trimester ultrasound assessment at 12 weeks gestation. The follow up scans showed a decrease in size of the allantoic cyst with no other obvious major defects and, when invasive testing (amniocentesis with microarray analysis) was performed, a rare microdeletion, 1q21.1q21.2 was identified (1.82 Mb deletion).

A Broader Perspective on the Prenatal Diagnosis of Cornelia de Lange Syndrome: Review of the Literature and Case Presentation.

Cornelia de Lange syndrome (CDLS) is caused by pathogenic variants in genes which are structural or regulatory components of the cohesin complex. The classical Cornelia de Lange (CDLS) phenotype is characterized by distinctive facial features, growth retardation, upper limb reduction defects, hirsutism, and developmental delay. Non-classical phenotypes make this condition heterogeneous. Although CDLS is a heterogeneous clinical and genetic condition, clear diagnostic criteria have been described by specialist consensus. Many of these criteria refer to features that can be seen on prenatal ultrasound. The aim of this paper is twofold: to present the ultrasound findings in fetuses affected by CDLS syndrome; to discuss the recent advances and the limitations in the ultrasound and genetic prenatal diagnosis of CDLS. Our review aims to offer, apart from the data needed to understand the genetics and the prenatal presentation of the disease, a joint perspective of the two specialists involved in the prenatal management of this pathology: the fetal medicine specialist and the geneticist. To better illustrate the data presented, we also include a representative clinical case.

The outcome of structural heart defects diagnosed in the first trimester of pregnancy.

PURPOSE: We present the results of a detailed protocol of fetal heart examination in the first trimester, in a fetal medicine unit in Romania. METHODS: Since October 2009, in Filantropia Hospital in Bucharest, we have systematically assessed pregnancies at 11-14 weeks to screen for aneuploidies and for major fetal structural defects. The fetal anatomy examination protocol included the detailed assessment of the fetal heart. This was performed using the same principles as for the second trimester examination, in the entire cohort. RESULTS: Our population consisted of 7693 patients and 7816 embryos. The protocol for the ultrasound evaluation of the fetal heart was completed for 7597 embryos (97.2%). The outcome is known for 6912 cases (90.9%). We diagnosed 39 heart defects - 30 in the first trimester, seven in the second trimester, two postnatally. Twenty of the 39 heart defects were isolated cardiac malformations. Twelve of the isolated heart defects were diagnosed in the first trimester. The sensitivity of the first trimester ultrasound in identifying major heart defects was 76.92%. The overall survival in cases of isolated congenital heart disease diagnosed in the first trimester was significantly lower than the survival in the cases diagnosed in the second trimester. CONCLUSIONS: Many (76.92%) of the significant heart defects can be diagnosed by ultrasound examination, in the first trimester. Our study is an argument for developing the multidisciplinary approach needed for the management of early detected structural heart disease.

Prenatal features of mandibulofacial dysostosis Guion-Almeida Type.

Facial dysostoses are clinically and genetically heterogeneous conditions characterized by congenital craniofacial anomalies which result from abnormal development of the first two pharyngeal arches and their derivatives during embryogenesis. Mandibulofacial dysostosis Guion-Almeida type (MFDGA) is a rare and relatively new syndrome described in the literature, first identified by Guion-Almeida et al. in 2000 and 2006. Another 108 cases have been documented after that. Prenatal diagnosis of this syndrome has not been described yet. Here we present the prenatal ultrasound findings in a case where MFDGA was confirmed after delivery. We suggest that MFDGA should be included in the prenatal differential diagnosis of syndromes with micrognathia and craniofacial anomalies.

Case report of a novel phenotype in 18q deletion syndrome.

The latest decades are characterized by an enormous progression in the field of human genetics. In consequences, for various phenotypic manifestations, genetic testing could identify a specific underlying cause. An estimated incidence for all types of 18q deletions is one in 55 000 births predominant on females. About 94% of cases with 18q deletion syndrome appearance are de novo, and the remaining 6% are the inherited from a parent carrying a balanced chromosomal translocation. We present the case of a 35-year-old female who was admitted in our Unit for a second ultrasound opinion after being diagnosed at the second trimester scan at gestational age of 21 weeks of pregnancy with multiple brain and heart malformations, having the recommendation for fetal magnetic resonance imaging (MRI). Further investigations included genetic analysis and pathological examination. Major malformations diagnosed and confirmed were agenesis of the corpus callosum, ventriculomegaly with dilated fourth ventricle, partial agenesis of vermis, bilateral anophthalmia with wide nasal base and left cleft lip. Additional, cardiac malformation, with an important ventricular septal defect and overriding aorta were noted. The results of the microarray analysis showed an abnormal fetal karyotype with a loss of 30.5 basis identified in the long arm of chromosome 18. Although most of the cases of 18q deletion are sporadically or de novo, could be cases where the possible existing syndromes can be inherited from a healthy or mild affected parent. Therefore, in order to establish the recurrence risk, parental karyotypes are recommended.

First Prenatal Diagnosis of a Niemann-Pick Disease Type C2 Revealed by a Cystic Hygroma: A Case Report and Review of the Literature.

BACKGROUND: The importance of fetal nuchal translucency was highlighted in the early 1990s as a useful first-trimester marker to identify fetal chromosomal abnormalities. Here, we report the prenatal diagnosis of a fetus with Niemann-Pick disease type C initially identified by first-trimester ultrasonographic markers and eventually confirmed by extensive genetic evaluation. CASE PRESENTATION: The fetus of a 30-year-old woman exhibited a cystic hygroma in the first trimester of pregnancy. The woman underwent chorionic villus sampling with extensive genetic investigations to identify the genetic cause of the ultrasonographic findings. Owing to normal karyotype results, further evaluation of 1,024 genes underlying structural abnormalities was performed. This test identified a homozygous mutation of the NPC2 gene (OMIM 601015), which has been reported to be pathogenic and responsible for Niemann-Pick disease type C2 (NPD-C2). Genetic evaluation of the parents found them to be carriers. Considering the poor prognosis, the parents decided to terminate the pregnancy. Ultrasonographic screening during the subsequent pregnancy showed normal findings; however, molecular testing for the previous familial mutation c.441 + 1G>A identified the fetus as homozygous for this mutation. Therefore, the parent chose to terminate the subsequent pregnancy as well. CONCLUSION: We report the first prenatal diagnosis of NPD-C2 based on a cystic hygroma found during the first trimester of pregnancy as the sole indicator.

Diagnosis of Fetal Structural Anomalies at 11 to 14 Weeks.

OBJECTIVES: To assess the performance of first-trimester ultrasound (US) in identifying major fetal structural abnormalities in an unselected population. METHODS: We conducted a retrospective analysis of all pregnancies that underwent the 11- to 14-week scan in the Fetal Medicine Department of Filantropia Hospital in Bucharest, which were prospectively examined within our screening program. The purpose of the first-trimester US was to evaluate the risk for chromosomal abnormalities and to conduct fetal anatomic examination using a detailed protocol. RESULTS: Our population consisted of 7480 pregnant patients (7576 fetuses). The follow-up was completed for 6045 patients (6114 fetuses). The prevalence of major structural anomalies was 1.89%. In the first trimester, we identified 79% of all major structural anomalies. The highest detection rates were achieved for abdominal wall defects (100%), major central nervous system anomalies (88%), cardiac defects (74%), and skeletal anomalies (71%). The nuchal translucency was increased in 35% of the cases with structural anomalies, and 95% of these were diagnosed in the first trimester. Seventy percent of the patients who presented with structural anomalies and a normal nuchal translucency were diagnosed in the first trimester. CONCLUSIONS: Our results emphasize the importance of performing a detailed US examination at 11 to 14 weeks' gestation in identification of fetal structural defects.

Prenatal Genetic Testing for Dopa-Responsive Dystonia - Clinical Judgment in the Context of Next Generation Sequencing.

We present a family in which the first child was diagnosed with dopa-responsive dystonia based on biochemical findings only. Dopa-responsive dystonia is a severe heterogeneous genetic disease. The possibly involved genes are GCH1 and TH. In their second pregnancy, the parents came for genetic counseling and prenatal diagnosis late, at 12 weeks of gestation. Genetic testing in the affected child was performed, but the results were difficult to interpret. The identified mutations were classified as VOUS - variants of unknown clinical significance. Although possibly causative, a homozygous variant in the TH gene was not reported before in children with dopa-responsive dystonia. Due to limited time, establishing the fetal prognosis was challenging. Our report emphasizes the importance of a multidisciplinary approach in the context of new diagnostic techniques, such as Next Generation Sequencing. We illustrate the fact that behind any laboratory result remains sophisticated clinical judgment. We also describe a previously not reported variant of the TH gene in a child with severe, early-onset dystonia.

The first trimester combined test for aneuploidies - a single center experience.

PURPOSE: We present the results of the systematic application of the first trimester combined test for aneuploidies, in a Romanian center. METHODS: Since October 2009, in Filantropia Hospital in Bucharest, we have systematically been using the FMF (Fetal Medicine Foundation) combined first trimester test to screen for common aneuploidies at 11 to 13 + 6 weeks of gestation. We assessed the crown to rump length (CRL), nuchal translucency, fetal heart rate as well as PAPP-A, and free ß-hCG in maternal serum. We evaluated additional first trimester ultrasound markers in most of the cases. The individual risk for aneuploidies was calculated using the FMF algorithm. RESULTS: Pregnancy outcome is known for 6030 euploid fetuses and 42 aneuploid fetuses from our screening population. The detection rate for trisomy 21 of the combined test was 87.5% for a screen positive rate of 1.96%. All of the trisomy 18 and trisomy 13 cases were detected prenatally. Some of the trisomy 18 cases proved not to be symptomatic in the first trimester. CONCLUSIONS: Our results are similar to those of the main studies on the FMF method of first trimester screening for aneuploidies. Our numbers are small because of limited availability of the very specialized resources involved.

Managing Crohn's Disease during Pregnancy.

Crohn's disease (CD) is a chronic infl ammatory bowel disease with onset during reproductive age. Advancement in medical therapies and treatment strategies have made pregnancy following a diagnosis of CD a viable and safe option for more women with this disease. In this review we discuss the evidence based management of Crohn's disease during pregnancy.

Utilization of gene mapping and candidate gene mutation screening for diagnosing clinically equivocal conditions: a Norrie disease case study.

Prenatal diagnosis was requested for an undiagnosed eye disease showing X-linked inheritance in a family. No medical records existed for the affected family members. Mapping of the X chromosome and candidate gene mutation screening identified a c.C267A[p.F89L] mutation in NPD previously described as possibly causing Norrie disease. The detection of the c.C267A[p.F89L] variant in another unrelated family confirms the pathogenic nature of the mutation for the Norrie disease phenotype. Gene mapping, haplotype analysis, and candidate gene screening have been previously utilized in research applications but were applied here in a diagnostic setting due to the scarcity of available clinical information. The clinical diagnosis and mutation identification were critical for providing proper genetic counseling and prenatal diagnosis for this family.