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Congenital, Hereditary, and Neonatal Diseases and Abnormalities - Top 30 Publications

Risk of major congenital malformations in relation to maternal overweight and obesity severity: cohort study of 1.2 million singletons.

Objective To estimate the risks of major congenital malformations in the offspring of mothers who are underweight (body mass index (BMI) <18.5), overweight (BMI 25 to <30), or in obesity classes I (BMI 30 to <35), II (35 to <40), or III (≥40) compared with offspring of normal weight mothers (BMI 18.5 to <25) in early pregnancy.Design Population based cohort study.Setting Nationwide Swedish registries.Participants 1 243 957 liveborn singleton infants from 2001 to 2014 in Sweden. Data on maternal and pregnancy characteristics were obtained by individual record linkages.Exposure Maternal BMI at the first prenatal visit.Main outcome measures Offspring with any major congenital malformation, and subgroups of organ specific malformations diagnosed during the first year of life. Risk ratios were estimated using generalised linear models adjusted for maternal factors, sex of offspring, and birth year.Results A total of 43 550 (3.5%) offspring had any major congenital malformation, and the most common subgroup was for congenital heart defects (n=20 074; 1.6%). Compared with offspring of normal weight mothers (risk of malformations 3.4%), the proportions and adjusted risk ratios of any major congenital malformation among the offspring of mothers with higher BMI were: overweight, 3.5% and 1.05 (95% confidence interval 1.02 to 1.07); obesity class I, 3.8% and 1.12 (1.08 to 1.15), obesity class II, 4.2% and 1.23 (1.17 to 1.30), and obesity class III, 4.7% and 1.37 (1.26 to 1.49). The risks of congenital heart defects, malformations of the nervous system, and limb defects also progressively increased with BMI from overweight to obesity class III. The largest organ specific relative risks related to maternal overweight and increasing obesity were observed for malformations of the nervous system. Malformations of the genital and digestive systems were also increased in offspring of obese mothers.Conclusions Risks of any major congenital malformation and several subgroups of organ specific malformations progressively increased with maternal overweight and increasing severity of obesity. For women who are planning pregnancy, efforts should be encouraged to reduce adiposity in those with a BMI above the normal range.

Cyanotic Congenital Heart Disease: Essential Primer for the Practicing Radiologist.

The cyanotic congenital heart diseases are a rare and heterogeneous group of disorders, often requiring urgent neonatal management. Although echocardiography is the mainstay for imaging, continued technological advances have expanded the role for computed tomography and magnetic resonance imaging, helping to limit invasive cardiac catheterization. In this article, the authors review the broad spectrum of cyanotic congenital heart disease, focusing on the utility of advanced noninvasive imaging modalities while highlighting key clinical features and management considerations.

Respiratory Distress in Neonates: Underlying Causes and Current Imaging Assessment.

The imaging evaluation of the neonate in respiratory distress has been described since the most early days of pediatric radiology but advances in diagnosis and treatment have changed the patient population presenting with these conditions and altered the imaging findings. In this article, the range of conditions that cause neonatal respiratory distress is depicted, including congenital lung malformations and lung disease in both preterm and full-term infants. An updated approach to the imaging of these conditions is reviewed, with a focus on changes that have resulted from advances in treatment and diagnosis.

A Practical Approach to Supratentorial Brain Malformations: What Radiologists Should Know.

For general radiologists, congenital brain malformations pose substantial challenges in terms of recognition, description, and classification. This review describes a practical approach to imaging and classifying the most common supratentorial brain malformations. It begins with a discussion of embryology and optimal imaging technique and then summarizes distinguishing imaging features for several major categories of cerebral malformation, including holoprosencephaly, gray matter heterotopia, lissencephaly/pachygyria, focal cortical dysplasia, polymicrogyria, and cobblestone malformation. The importance of identifying abnormalities in the corpus callosum and basal ganglia is also discussed, both for detection and characterization of cerebral malformations.

Mendel,MD: A user-friendly open-source web tool for analyzing WES and WGS in the diagnosis of patients with Mendelian disorders.

Whole exome and whole genome sequencing have both become widely adopted methods for investigating and diagnosing human Mendelian disorders. As pangenomic agnostic tests, they are capable of more accurate and agile diagnosis compared to traditional sequencing methods. This article describes new software called Mendel,MD, which combines multiple types of filter options and makes use of regularly updated databases to facilitate exome and genome annotation, the filtering process and the selection of candidate genes and variants for experimental validation and possible diagnosis. This tool offers a user-friendly interface, and leads clinicians through simple steps by limiting the number of candidates to achieve a final diagnosis of a medical genetics case. A useful innovation is the "1-click" method, which enables listing all the relevant variants in genes present at OMIM for perusal by clinicians. Mendel,MD was experimentally validated using clinical cases from the literature and was tested by students at the Universidade Federal de Minas Gerais, at GENE-Núcleo de Genética Médica in Brazil and at the Children's University Hospital in Dublin, Ireland. We show in this article how it can simplify and increase the speed of identifying the culprit mutation in each of the clinical cases that were received for further investigation. Mendel,MD proved to be a reliable web-based tool, being open-source and time efficient for identifying the culprit mutation in different clinical cases of patients with Mendelian Disorders. It is also freely accessible for academic users on the following URL:

Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies.

Objective To map the diverse health outcomes associated with serum uric acid (SUA) levels.Design Umbrella review.Data sources Medline, Embase, Cochrane Database of Systematic Reviews, and screening of citations and references.Eligibility criteria Systematic reviews and meta-analyses of observational studies that examined associations between SUA level and health outcomes, meta-analyses of randomised controlled trials that investigated health outcomes related to SUA lowering treatment, and Mendelian randomisation studies that explored the causal associations of SUA level with health outcomes.Results 57 articles reporting 15 systematic reviews and144 meta-analyses of observational studies (76 unique outcomes), 8 articles reporting 31 meta-analyses of randomised controlled trials (20 unique outcomes), and 36 articles reporting 107 Mendelian randomisation studies (56 unique outcomes) met the eligibility criteria. Across all three study types, 136 unique health outcomes were reported. 16 unique outcomes in meta-analyses of observational studies had P<10(-6), 8 unique outcomes in meta-analyses of randomised controlled trials had P<0.001, and 4 unique outcomes in Mendelian randomisation studies had P<0.01. Large between study heterogeneity was common (80% and 45% in meta-analyses of observational studies and of randomised controlled trials, respectively). 42 (55%) meta-analyses of observational studies and 7 (35%) meta-analyses of randomised controlled trials showed evidence of small study effects or excess significance bias. No associations from meta-analyses of observational studies were classified as convincing; five associations were classified as highly suggestive (increased risk of heart failure, hypertension, impaired fasting glucose or diabetes, chronic kidney disease, coronary heart disease mortality with high SUA levels). Only one outcome from randomised controlled trials (decreased risk of nephrolithiasis recurrence with SUA lowering treatment) had P<0.001, a 95% prediction interval excluding the null, and no large heterogeneity or bias. Only one outcome from Mendelian randomisation studies (increased risk of gout with high SUA levels) presented convincing evidence. Hypertension and chronic kidney disease showed concordant evidence in meta-analyses of observational studies, and in some (but not all) meta-analyses of randomised controlled trials with respective intermediate or surrogate outcomes, but they were not statistically significant in Mendelian randomisation studies.Conclusion Despite a few hundred systematic reviews, meta-analyses, and Mendelian randomisation studies exploring 136 unique health outcomes, convincing evidence of a clear role of SUA level only exists for gout and nephrolithiasis.

Lithium Use in Pregnancy and the Risk of Cardiac Malformations.

There has been concern that exposure to lithium early in pregnancy may be associated with a marked increase in the risk of Ebstein's anomaly (a right ventricular outflow tract obstruction defect) in infants and overall congenital cardiac defects, but data are conflicting and limited.

Large Arachnoid Cyst.

Case 17-2017. A 14-Year-Old Boy with Acute Fear of Choking while Swallowing.

Measurement of Hemoglobin A1c in Patients With Sickle Cell Trait-Reply.

Measurement of Hemoglobin A1c in Patients With Sickle Cell Trait.

Inner ear anomalies in children with isolated unilateral congenital aural atresia.

We aim to define the frequencies of anomalies of the inner ear, oval window, and round window ipsilateral to isolated non-syndromic unilateral aural atresia.

The clinical efficacy of early intervention for infected preauricular sinus.

The study was designed to evaluate the outcomes of early surgical intervention, and to suggest the accurate operation time and surgical strategies.

Neonatal Discontinuation Syndrome in Serotonergic Antidepressant-Exposed Neonates.

To determine whether infants exposed in utero to serotonin reuptake inhibitor (SRI) antidepressants or a DSM-IV-TR-defined mood disorder have significantly more neonatal discontinuation signs compared to an unexposed group of infants at 2-4 weeks after birth.

Histologic Remission following Neoadjuvant Immunotherapy in a Patient with Lynch-Syndrome and Primarily Unresectable Relapse of Rectum Carcinoma.

Clinical History A 43-year-old male patient was diagnosed to have rectum carcinoma cT4N2M0 with underlying Lynch-Syndrome. After initializing neoadjuvant radio-chemotherapy followed by operation, the patient presents with an extensive locoregional relapse within a short time. In order to achieve resectability, a second line treatment with FOLFOXIRI protocol in addition to Bevacizumab was conducted. However, after completing six cycles of this intensiv treatment protocol, the tumour showed further progression. Clinical Course Having no evidence of distance metastasis, we decided to initiate off-label use of Pembrolizumab, a PD-1-receptor inhibitor. Clinical symptoms decreased rapidly and after receiving six cycles, PET/CT imaging showed regression. The side effects were limited to subclinical autoimmune thyroiditis. After re-operation no evidence of malignancy were found in the resectates of exenteration of the pelvis. Currently the patient is capable of working with only limited symptoms. Conclusion Pembrolizumab offers new treatment options for patients with DNA-repair-deficiency mismatch, e. g. Lynch-Syndrome. A phase II study already showed effectiveness in this particular group of patients. The striking and unexpected histo-pathologic results showing full remission should draw attention to the use of Pembrolizumab in neoadjuvant settings.

Etiology and clinical presentation of birth defects: population based study.

Objective To assess causation and clinical presentation of major birth defects.Design Population based case cohort.Setting Cases of birth defects in children born 2005-09 to resident women, ascertained through Utah's population based surveillance system. All records underwent clinical re-review.Participants 5504 cases among 270 878 births (prevalence 2.03%), excluding mild isolated conditions (such as muscular ventricular septal defects, distal hypospadias).Main outcome measures The primary outcomes were the proportion of birth defects with a known etiology (chromosomal, genetic, human teratogen, twinning) or unknown etiology, by morphology (isolated, multiple, minors only), and by pathogenesis (sequence, developmental field defect, or known pattern of birth defects).Results Definite cause was assigned in 20.2% (n=1114) of cases: chromosomal or genetic conditions accounted for 94.4% (n=1052), teratogens for 4.1% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.4% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified as unknown etiology; of these 88.2% (n=3874) were isolated birth defects. Family history (similarly affected first degree relative) was documented in 4.8% (n=266). In this cohort, 92.1% (5067/5504) were live born infants (isolated and non-isolated birth defects): 75.3% (4147/5504) were classified as having an isolated birth defect (unknown or known etiology).Conclusions These findings underscore the gaps in our knowledge regarding the causes of birth defects. For the causes that are known, such as smoking or diabetes, assigning causation in individual cases remains challenging. Nevertheless, the ongoing impact of these exposures on fetal development highlights the urgency and benefits of population based preventive interventions. For the causes that are still unknown, better strategies are needed. These can include greater integration of the key elements of etiology, morphology, and pathogenesis into epidemiologic studies; greater collaboration between researchers (such as developmental biologists), clinicians (such as medical geneticists), and epidemiologists; and better ways to objectively measure fetal exposures (beyond maternal self reports) and closer (prenatally) to the critical period of organogenesis.

Gene Therapy in a Patient with Sickle Cell Disease.

Anti-Interleukin-31 Receptor A Antibody for Atopic Dermatitis.

Surgical outcomes of different approaches to esophageal replacement in long-gap esophageal atresia: A systematic review.

Esophageal replacement (ER) surgery has been widely used in long-gap esophageal atresia (LGEA) over the past few decades. The most commonly used surgical approaches in many pediatric surgical centers include colon interposition (CI), gastric pull-up (GPU), jejunal interposition (JI), and gastric tube reconstruction (GTR). However, there is no systematic evidence on which is the optimal conduit for the native esophagus. The aim of this systematic review was to evaluate the short- and long-term outcomes among these 4 replacement approaches in LGEA cases based on current evidence.

Gene Therapy in a Patient with Sickle Cell Disease.

Anti-Interleukin-31 Receptor A Antibody for Atopic Dermatitis.

Anti-Interleukin-31 Receptor A Antibody for Atopic Dermatitis.

Cardiac pseudotumor revealing Behçet's disease.

Intracardiac thrombosis is a rare complication of Behçet's disease (BD), which may manifest as intracardiac tumor. In half of cases, its detection precedes the diagnosis of MB. High mortality rates may be related to post-surgical complications and/or pulmonary arteries involvement. We report the case of a 29-year old young patient, with a previous history of bipolar aphthosis, who underwent surgery after the detection of right atrium and ventricle tumor. Anatomo-pathological examination showed thrombus and MB was diagnosed in the postoperative period. Patient's evolution was favorable under medical treatment based on corticosteroids, colchicine and vitamin K antagonists (AVK). The detection of intracardiac mass in a young subject should suggest the diagnosis of cardiac thrombus and Behçet's disease, even in the absence of ethnic or geographical risk factors.

A rare cause of spinal cord compression: spinal epidural arachnoid cyst (about 3 cases).

Spinal epidural arachnoid cyst (SEAC) is a benign condition whose pathophysiology is still uncertain. It is most commonly asymptomatic but it can cause severe neurological sequelae especially when treatment is not received in time. We conducted a retrospective study of three patients treated for SEAC conducted in the Neurosurgery Department, Hassan II University Hospital, Fez. We report the case of two male patients and a woman, with an average age of 35 years (range: 16-56 years), admitted with slow progressive spinal cord compression. All patients underwent spinal cord MRI showing epidural fluid collection, having the same signal as that of cerebrospinal fluid, compressing the opposite marrow. The collection was located in the chest in all cases. All patients underwent surgery via posterior approach for cyst resection and cyst neck ligation in two cases and dural plasty in a single case. Anatomo-pathologic examination showed arachnoid cysts. Postoperative outcome was simple in all cases. This study aims to update the current understanding of this pathology while insisting on the need for early management given its tendency toward gradual worsening in the absence of adapt therapy. It also aims to review the clinical, paraclinical and therapeutic features of this condition.

Collodion baby: clinical aspects and role of prenatal diagnosis.

Collodion baby is a severe form of congenital ichthyosis detected in neonatal period. It often has a characteristic clinical picture. When evolution is not fatal; it often causes dry Ichthyosis. Thanks to molecular biology techniques, prenatal diagnosis can be made since the 10-12 weeks of amenorrhea, allowing genetic counselling. Prognosis depends on several parameters, namely the degree of the initial manifestation, the duration of desquamation, as well as underlying Ichthyosis This rewiew of the literature which aims to clarify the diagnostic aspects and therapeutic treatment as well as the role of the antenatal diagnosis is based on a new observation of a collodion baby born at 34 weeks, of a parturient woman having an index case and of infant deaths occurring in the first day of life.

Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity.

Lynch syndrome (LS) is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR) genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS) must be defined. We present an oligonucleotide-directed mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, the MSH6 variant of interest is introduced into mouse embryonic stem cells by site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the DNA damaging agent 6-thioguanine (6TG) allows the identification of MMR abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We demonstrate the efficacy of the genetic screen, investigate the phenotype of 26 MSH6 VUS and compare our screening results to clinical data from suspected-LS patients carrying these variant alleles.

Tuberous Sclerosis Complex.

Exome sequencing identifies a de novo mutation of CTNNB1 gene in a patient mainly presented with retinal detachment, lens and vitreous opacities, microcephaly, and developmental delay: Case report and literature review.

The CTNNB1 (β-catenin) gene is well known for its crucial role in cell adhesion and the Wnt-signaling pathway. Previous studies have shown that gain-of-function mutations in the CTNNB1 gene contribute to the occurrence and development of a variety of carcinomas in humans. Recently, de novo, heterozygous, loss-of-function mutations of the CTNNB1 gene were found that partially explain intellectual disability in some patients. Other major clinical symptoms in these patients included microcephaly, abnormal facial features, motor delays, speech impairments, and deformities of the hands and feet. In addition, approximately 75% of these patients had mild visual defects, such as astigmatism, hyperopia, or strabismus PATIENT CONCERNS:: A 15-month-old Chinese boy, presenting with retinal detachment, lens and vitreous opacities, hypertonia of the extremities, mild thumb adduction, microcephaly, and developmental delay, is described. Targeted gene sequencing using an ophthalmic gene panel was performed to test for familial exudative vitreoretinopathy; however, the pathogenic gene was not found.

Isolated olecranon fractures in children affected by osteogenesis imperfecta type I treated with single screw or tension band wiring system: Outcomes and pitfalls in relation to bone mineral density.

The purpose of this study is to compare the results of 2 techniques, tension band wiring (TBW) and fixation with screws, in olecranon fractures in children affected with osteogenesis imperfecta (OI) type I. Between 2010 and 2014, 21 olecranon fractures in 18 children with OI (average age: 12 years old) were treated surgically. Ten patients were treated with the screw fixation and 11 with TBW. A total of 65% of olecranon fractures occurred as a result of a spontaneous avulsion of the olecranon during the contraction of the triceps muscle. The average follow-up was 36 months. Among the children treated with 1 screw, 5 patients needed a surgical revision with TBW due to a mobilization of the screw. In this group, the satisfactory results were 50%. In patients treated with TBW, the satisfactory results were 100% of the cases. The average Z-score, the last one recorded in the patients before the trauma, was -2.53 in patients treated with screw fixation and -2.04 in those treated with TBW. TBW represents the safest surgical treatment for patients suffering from OI type I, as it helps to prevent the rigidity of the elbow through an earlier recovery of the range of motion, and there was no loosening of the implant. In analyzing the average Z-score before any fracture, the fixation with screws has an increased risk of failure in combination with low bone mineral density.

Limb-Girdle Muscular Dystrophy 2B and Miyoshi Presentations of Dysferlinopathy.

We report the following 2 subtypes of progressive limb-girdle dystrophy type 2B: limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi. The first patient described had weakness in the anterior thigh muscles (LGMD2B) and the second patient had calf muscle weakness and atrophy (Miyoshi). Literature review was performed and LGMD2B was compared and distinguished from other myopathies of similar nature. Genetic testing with polymerase chain reaction analysis of the DYSF gene confirmed the diagnosis in both patients. Additional findings of histopathology, specific stain for sarcolemmal membrane protein, Western blot analysis and clinical presentation clinched the diagnosis further of dysferlinopathy (LGMD2B) in both our patients. Currently, there is no definitive treatment on the horizon and immunosuppressive therapy is not recommended for this condition. Gene therapy may have a future role, but at present, muscle-strengthening exercises and patient awareness are the mainstays.