Congenital Anomalies最新文献

Heterozygous loss-of-function variants in heterogeneous nuclear ribonucleoprotein U (HNRNPU) cause early-onset developmental and epileptic encephalopathy with multiple congenital anomalies. Limited clinical information is currently available on HNRNPU-related neurodevelopmental disorder. The patient was a 1-year-old Japanese girl with developmental delay, hypotonia, early-onset epilepsy, respiratory distress, and distinctive facial features, including ptosis, epicanthus, a prominent nasal bridge, a wide nasal floor, a cleft soft palate, and micrognathia. Respiratory distress was caused by pharyngeal stenosis and laryngomalacia, which gradually worsened, necessitating a scheduled tracheostomy at 1 year and 7 months of age. We performed whole-exome sequencing and identified a novel de novo nonsense variant in HNRNPU. We herein describe the first case of HNRNPU-related neurodevelopmental disorder with severe airway anomalies and a novel nonsense variant, thereby expanding the phenotypic spectrum

Pregnancy loss is a significant concern worldwide, encompassing miscarriage and stillbirth. Miscarriage, defined as the loss of a baby before 28 weeks of gestation, accounts for approximately 15% of pregnancies. Stillbirth, occurring at or after 28 weeks of gestation, affects nearly 2.0 million pregnancies annually, predominantly in low- and middle-income regions. This study aims to investigate the potential of Anemarrhena rhizome (AR) herbal medicine in mitigating pregnancy loss and reducing the incidence of cleft palate in A/J mice models. A total of 390 6-week-old A/J mice were used for the study. Three different dosages of dried AR (6, 12, and 18 g) were boiled to prepare water extracts. The mice were divided into experimental groups receiving these extracts and a control group. Pregnancy outcomes, including fetal mortality rates and incidence of cleft palate, were assessed. The experimental groups receiving AR herbal medicine demonstrated significantly lower fetal mortality rates compared to the control group. Additionally, the incidence of cleft palate was notably reduced in the experimental groups, with the AR 6 g and AR 12 g groups showing significant reductions compared to the control group. AR herbal medicine shows promise in mitigating pregnancy loss and reducing the incidence of cleft palate in A/J mice models. These findings suggest the potential of AR as a therapeutic agent for improving fetal health outcomes. Further research is warranted to elucidate the underlying mechanisms and optimize dosage strategies for maximizing its therapeutic benefits in pregnancy-related complications.

The current case report presents the postmortem examination findings of a 17-week-old female fetus displaying thanatophoric dysplasia type 1 (TD-1) due to a known fibroblast growth factor receptor 3 (FGFR3) gene mutation. Gross and X-ray examination revealed significant abnormalities, including skeletal malformations with prominent TD-1 femur curvature. Microscopical evaluation indicated inadequate histological growth for the gestational age, with specific organ immaturity noted in multiple hematoxylin and eosin sections from internal organs, bone from epiphyses and diaphyses levels. Immunohistochemical analysis was conducted using specific markers, such as S100, CD34, CD117, glycophorin-C, and myeloperoxidase, to identify various hematopoietic and mesenchymal cell types. Furthermore, this report underscores the often-overlooked aspect of fetal hematopoiesis in cases diagnosed with TD-1, shedding light on the development of hematopoietic cells and their markers in various tissues, with a particular emphasis on the investigation of bone marrow foci in areas with incipient or no apparent ossification. Immunohistochemical identification of hematopoiesis also served as an indirect way to identify areas of incipient or abnormal ossification.

Turner syndrome is a chromosomal disorder, characterized by the partial or total deletion of one X chromosome, resulting in various karyotypes that presumably lead to different phenotypes. However, most studies find it difficult to predict phenotypes from karyotypes due to the presence of mosaicism. The purpose of this study is to clarify the relationship between karyotype and phenotype in Turner syndrome with non-mosaic X chromosome structural rearrangements. A systematic literature search was conducted using Medline and Embase classics plus Embase between 1947 and September 2023. A total of 487 Turner women with non-mosaic X chromosome structural rearrangements were included from the 69 studies. The prevalence of short stature was 72.4% in Turner syndrome with non-mosaic X chromosome structural rearrangements, 80.1% in the short arm deletion group (del (Xp)), 75% in the del(X)(p22.3) group, 65.8% in the del(X)(p21) and del(X)(p22) group, and 37.5% (20%–66.7%) in the long arm deletion group (del(Xq)). The prevalence of ovarian dysfunction was 78.8% in Turner syndrome with non-mosaic X chromosome structural rearrangements, 72.5% in the del (Xp) group, 27.6% in the del (X)(p22.3) group, 33.3% in the del (X)(p21) and del(X)(p22) group, and 94.6% in the del (Xq) group. The recognition of X chromosome breakpoints is useful in the management of Turner syndrome complications, since some phenotypes are unique depending on the deletion region. Ovarian dysfunction is significantly related to karyotype, so the identification of karyotypes in Turner syndrome is important for managing ovarian dysfunction and predicting future fertility.

Congenital heart defects (CHDs) are caused by a complex interaction between numerous genetic and environmental risk factors, some of which may differ between different populations. A case–control study was conducted among 1232 newborns, including 308 patients with isolated CHDs (cases) and 924 infants without birth defects (controls), born all during the period 2009–2023 at the Hospital Civil de Guadalajara “Dr. Juan I. Menchaca” (Guadalajara, Mexico). Potential parental risk factors for CHDs were compared using multivariate logistic regression analysis to evaluate the deviance explained by different variables of interest. Consanguinity [adjusted odds ratio (aOR) = 3.3; 95% confidence interval (CI) 1.3–8.5], relatives with CHD (aOR = 8.5; 95% CI 5.3–13.8), maternal first-trimester exposure to diabetes (aOR = 3.5; 95% CI 2.4–5.1), hypertension (aOR = 2.6; 95% CI 1.5–4.4), alcohol consumption (aOR = 1.5; 95% CI 1.0–2.1), and illicit drug use (aOR = 2.4; 95% CI 1.2–5.3), as well as for the paternal history of alcohol consumption (aOR = 1.4; 95% CI 1.0–1.8) and illicit drug use (aOR = 2.7; 95% CI 1.7–4.1), were associated with CHDs. Contrarily, aOR for maternal age ≤19 years (aOR = 0.6; 95% CI 0.4–0.8) and maternal first-trimester coffee consumption (aOR = 0.7; 95% CI 0.5–0.9) have protective odds. Our results suggest that genetic factors, maternal diseases, environmental exposures, and reproductive factors can increase the occurrence of isolated CHDs in our sample, and they are discussed as clues in its pathogenesis.

Sonic hedgehog (Shh) is expressed in the oropharyngeal epithelium, including the frontonasal ectodermal zone (FEZ), which is defined as the boundary between Shh and Fgf8 expression domains in the frontonasal epithelium. To investigate the role of SHH signaling from the oropharyngeal epithelium, we generated mice in which Shh expression is specifically deleted in the oropharyngeal epithelium (Isl1-Cre; Shh^f/f). In the mutant mouse, Shh expression was excised in the oropharyngeal epithelium as well as FEZ and ventral forebrain, consistent with the expression pattern of Isl1. Isl1-Cre; Shh^f/f mice exhibited a complete loss of lower jaw components and a malformed upper jaw with defects in the cranial base and secondary palate. Massive cell death was observed in the mandibular process at embryonic day (E) 9.5 and E10.5, while mild cell death was observed in the lambdoidal region (the fusion area in the maxillary, lateral nasal, and medial nasal processes) at E10.5. An RNA-seq analysis revealed that Satb2, a gene involved in cell survival during jaw formation, was downregulated in the lambdoidal region in Isl1-Cre; Shh^f/f mice. These results suggest that Shh expression in the FEZ is required for cell survival and skeletogenesis in the lambdoidal region during the development of the upper jaw and that the developmental control governed by SHH signaling is different between upper and lower jaws.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive leukodystrophy characterized by ichthyosis, intellectual disability, and progressive spastic paralysis caused by biallelic pathogenic variants in the ALDH3A2 gene that encodes the fatty aldehyde dehydrogenase, fatty aldehyde dehydrogenase (FALDH); FALDH catalyzes several metabolic reactions involved in fatty aldehyde oxidation. Only a few studies have been performed to determine the lipid profile of patients with SLS. In a previous postmortem study of the brain of a 65-year-old patient with SLS, lipidomic analysis revealed an accumulation of long-chain unsaturated ether lipid species in the white matter and gray matter. In the present study, we established a disease model using patient-derived neuronal and oligodendrocyte lineage cells to analyze the lipid metabolism and gene expression profiles in SLS. To achieve this, we generated induced pluripotent stem cells (iPSCs) from two patients with the SLS phenotype carrying previously known ALDH3A2 pathogenic variants: One was a compound heterozygote (c.1339A>G:p.(Lys447Glu) and c.57_132dup:p.(Ile45Serfs*34)) and the other was a homozygote (c.1339A>G: p.(Lys447Glu)). The FALDH activity was almost zero in the SLS-iPSC lines established from both patients. Phospholipid analysis of neurospheres, and oligospheres (spheres enriched with oligodendrocyte-lineage cells) derived from the iPSCs by liquid chromatography-mass spectrometry showed accumulation of ether phospholipids in the Sjögren-Larsson patient-derived neurospheres and oligospheres. The results are consistent with the previously reported accumulation of ether lipids in the postmortem brain tissue of an SLS patient. Therefore, iPSCs and iPSC-derived neurospheres and oligospheres established from SLS patients can be useful tools for future pathological analysis of the central nervous system pathophysiology in SLS.

We evaluated the teratogenic risk associated with exposure to cefditoren pivoxil during the first trimester of pregnancy using the integrated databases of the Toranomon Hospital and the National Center for Child Health and Development. Among 13 599 registered individuals, the analysis included 285 subjects who had taken cefditoren pivoxil during the first trimester of pregnancy. The rates of stillbirth, miscarriage, and elective terminations were 0.4%, 5.6%, and 2.1%, respectively. Among 262 live births, the rates of preterm birth, low birth weight, and major congenital malformations were 4.6%, 5.7%, and 1.2%, respectively. Our results suggest that exposure to cefditoren pivoxil during the first trimester of pregnancy does not significantly increase the risk of adverse pregnancy outcomes and infant outcomes.