Congenital Anomalies最新文献

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by excessive and frequent epistaxis, telangiectasia, and visceral involvement, with a strong positive family history. The genes responsible for HHT are endoglin (ENG), activin A receptor-like kinase 1 (ACVRL1 or ALK-1), and SMAD4 are known. As opposed to epistaxis and telangiectasia, whether or not the disease is prone to any visceral lesions depends on the causative gene. Arteriovenous malformations (AVMs) of the brain and lung are common in ENG, hepatic AVMs and cutaneous telangiectasia are common in ACVRL1, and juvenile polyposis (JP-HHT) is characteristic in SMAD4. Therefore, the diagnosis of HHT and its subclasses in patients with recurrent epistaxis is clinically important for predicting cerebral and visceral complications and for prophylactic medical or surgical treatment. Genomic techniques for the molecular diagnosis of HHT have advanced remarkably in recent years. Long-read sequencing using nanopore technology is now recognized as a new and effective approach for the detection of structural aberrations, such as large deletions, that cannot be detected by conventional short-read analysis. In particular, a new technique called adaptive long-read sequencing can selectively sequence only pre-defined target regions. Here we report two patients with HHT in whom no variants were found by short-read targeted sequencing, but structural variants were detected by adaptive nanopore sequencing. These molecular diagnostic results were used in their clinical management.

Congenital chylous ascites (CCA) is a rare condition caused by maldevelopment of the intra-abdominal lymphatic system, resulting in chyle accumulation in the peritoneal cavity. Diagnosis involves analyzing milky-white ascitic fluid with elevated triglycerides and T-lymphocyte predominance, with lymphangiography or lymphoscintigraphy as the gold standard. Initial treatment focuses on nutrition and medical therapies like medium-chain triglycerides (MCT) and total parenteral nutrition (TPN). Surgery is considered if conservative measures fail. A neonate with CCA required TPN, MCT formula, octreotide, and paracentesis. Lymphoscintigraphy showed bilateral lymphatic leakage. Despite medical management, the condition remained refractory, and exploratory surgery was performed, revealing a mesothelial cyst and peritoneal defect, which was treated with fibrin glue. Post-surgery, the infant's ascites resolved, highlighting the need for surgery in refractory cases.

This study examined the impact of blood glucose-regulated gestational diabetes (GDM) on fetal pulmonary artery Doppler parameters. This prospective case–control study was performed at a tertiary university hospital. The study cohort comprised GDM patients with controlled blood glucose levels and a healthy control group. Acceleration time/ejection time (At/Et) of the main pulmonary artery, right pulmonary artery, and left pulmonary artery Doppler parameters were assessed and contrasted between the two groups. The study comprised 90 patients, with 30 in the gestational diabetes mellitus group focused on blood sugar regulation and 60 in the healthy control group. No statistically significant difference was observed between the two groups regarding the common main pulmonary artery At/Et (p = 0.465), right pulmonary artery At/Et (p = 0.237), and left pulmonary artery At/Et (p = 0.283). No statistically significant difference was noted between the two groups regarding APGAR scores and blood gas parameters of the newborns (p < 0.05). No statistically significant difference was observed in fetal pulmonary artery Doppler parameters (p < 0.05) when gestational diabetes mellitus cases were classified based on the utilization of diet and insulin for blood sugar regulation. The pulmonary artery Doppler parameters in fetuses of pregnant women with gestational diabetes mellitus and controlled blood sugar levels are comparable to those of healthy controls. Moreover, dietary habits and insulin administration for glycemic control did not alter pulmonary artery Doppler metrics. The findings suggest that well-managed gestational diabetes mellitus, irrespective of the treatment modality, do not substantially influence the fetal pulmonary artery dynamics.

The cranial base (CB) and facial skeleton, despite differing in function and origin, are developmentally related. However, the mechanisms underlying the structural connection remain poorly understood. This article reviews CB malformations in congenital facial anomalies to identify the morphological basis for the relationship between these regions. Various types of CB deformities were identified in each facial anomaly; however, even anomalies with similar facial features did not necessarily share the same CB deformity, indicating that the underlying mechanisms exhibit complex interactions. To elucidate the biological processes related to these morphological interactions, detailed craniofacial geometry should be analyzed while retaining as much quantitative shape information as possible. Geometric morphometrics (GM) is an effective method for craniofacial studies because it analyzes shapes using landmark coordinates to retain relative geometric information, and it can be applied to complex shapes, such as curvatures or processes. Therefore, the application of GM in previous craniofacial studies is also reviewed. Quantitative data on normal and abnormal craniofacial development, encompassing both the prenatal and postnatal periods from GM studies, may provide valuable insight into the pathogenesis of congenital craniofacial anomalies.

Proper vertebral column development requires precise segmentation and regulated chondrogenesis during embryogenesis. Mutations affecting fibroblast growth factor 9 (FGF9) signaling disrupt these processes, resulting in abnormal vertebral column development. A missense mutation in FGF9 (p.Asn143Thr) produces elbow knee synostosis (Eks)-mutant mice, which display skeletal fusions, including those in the vertebral column, underscoring the essential role of FGF9 in vertebral segmentation and vertebral joint development. However, the mechanisms regulating joint formation in vertebrae remain elusive. Here, we report that the homozygous Eks mutant mice exhibit neural arch lamina fusion along the rostrocaudal axis at the dorsolateral position in neonates. We investigated the cellular and molecular mechanisms underlying the cervical vertebral fusion in Fgf9^Eks/Eks embryos. Fgf9^Eks/Eks embryos showed multiple fusions and thickened cartilage of cervical lamina on embryonic day (E) 14.5 and E13.5. Additionally, Fgf9^Eks/Eks embryos exhibited COL2A1 expression domain expansion accompanied by ectopic chondrocyte accumulation in the presumptive interlaminar space on E12.5 and E11.5. These anomalies persisted through endochondral ossification, leading to postnatal cervical vertebral bone fusion. Ectopic expression of COL2A1, Cyclin D1, and fibroblast growth factor (FGF) signaling target ETV4 was observed in the presumptive interlaminar space, indicating altered cell proliferation and cell fate specification. These findings demonstrate that FGF9^Eks protein interferes with vertebral column segmentation by impairing chondrogenic boundary regulation through ectopic cell proliferation and transcriptional activity. In conclusion, ectopic FGF9 signaling leads to cervical vertebral fusion, highlighting its contributing role in maintaining vertebral segmentation and chondrogenesis during embryogenesis.

ZNF335 plays an essential role in the neurogenesis of the human brain, and pathogenic variants of ZNF335 are associated with primary or secondary (postnatal) microcephaly. We performed exome sequencing in a patient with secondary microcephaly, epilepsy, global developmental delay, and dysmorphic craniofacial features, and identified compound heterozygous missense and intronic variants in ZNF335 (NM_022095.4:c.1504T>G, p.(Tyr502Asp) and c.1665 + 6T>A). Using a minigene assay, we demonstrated that the intronic variant causes aberrant splicing, resulting in significantly reduced ZNF335 protein levels. In addition, a review of the clinical findings of previously reported 10 patients with ZNF335 variants revealed that microcephaly was present in all patients, about half of them were secondary, and epilepsy and severe developmental delay were also quite recurrent findings.

Non-syndromic cleft lip and/or palate (NCL/P) is a congenital craniofacial anomaly with significant psychosocial and economic impacts. In Ethiopia, the prevalence of NCL/P and access to specialized care are not well documented. This study aimed to evaluate the knowledge and awareness of NCL/P among families of affected children and dental school students in Ethiopia and explore their perceptions and attitudes toward NCL/P. From 2009 to 2018, we conducted questionnaire surveys involving 86 patients with NCL/P and their families in the towns of Addis Ababa and Butajira, including 161 students from the School of Dentistry, Addis Ababa University. The surveys assessed the knowledge, perceptions, and attitudes toward NCL/P and their social implications. The majority of patients with NCL/P were born at home and in low-income families. Concerns about the future social life of patients were prominent, with stigma and discrimination reported by 32% of the patients' families. Among the dental school students, 66% had some knowledge of NCL/P, primarily from media sources. Students perceived higher levels of societal blame towards mothers of patients with NCL/P than reported by the patients' families. This study revealed significant gaps in the knowledge and awareness regarding NCL/P among dental school students. It also revealed the substantial social stigma that the patients affected by NCL/P and their families faced in Ethiopia. Enhancing public education and providing comprehensive multidisciplinary care is crucial for improving the quality of life of patients with NCL/P in Ethiopia.

The Fukushima Daiichi Nuclear Disaster (FDND) occurred in 2011, which occurred after the Great East Japan Earthquake. However, how the incidence of radiation-induced malformations in Fukushima has been affected by FDND remains to be elucidated. To address this, we analyzed birth data from Fukushima and other areas in Japan from the International Clearinghouse for Birth Defects Surveillance and Research Japan Center, including information on birth defects between January 2010 and December 2022. Among the registered birth defects, microcephaly, microphthalmia, and neural tube defects were classified as radiation-induced malformations. Our study included 90 433 births in Fukushima, accounting for 52.6% of all births. Among these, birth defects were observed in 1376 (1.52%) births, of which 28 (0.031%) were diagnosed with radiation-induced malformations. With regard to other areas in Japan, 1 323 391 births, which accounted for 10.9% of all births, were registered; births with birth defects and radiation-induced malformations were observed in 37 490 (3.67%) and 889 (0.067%), respectively. Because sampling bias was suspected, we compared the rates of radiation-induced malformations in Fukushima and other areas in Japan by adjusting the incidence in Fukushima with the incidences of ventricular septal defects in both areas. However, there was no statistically significant difference between them. Our results, which covered the largest number of births in Fukushima, did not find a significant increase in the incidence of radiation-induced malformations in Fukushima since FDND.

This study aimed to assess the prevalence of soft markers on second-trimester sonography in low-risk and screening naïve Indian antenatal women and determine their association with aneuploidy. Soft markers were evaluated through ultrasound, and likelihood ratios (LRs) and modified risk (MR) for aneuploidy were calculated. Pregnant women with a MR >1:250 underwent genetic counseling and invasive testing, whereas those with a lower risk received follow-up. Associations were estimated via Fisher's exact test. A total of 4051 anomaly scans were reviewed, among which 207 (5.1%) women were found to have soft markers (SMs). These included 153 (3.7%) isolated SMs, 43 (1.06%) multiple SMs, and 11 (0.2%) SMs with structural abnormalities. The most common SM was renal pyelectasis. Invasive test uptake increased by 25% among pregnancies with isolated markers and by 55% for those with multiple SMs. A significant association was found between isolated short femur and aneuploidy (p = 0.026), and between multiple SMs and aneuploidy (p = 0.039). Soft markers in low-risk couples can lead to unnecessary invasive testing and anxiety. Genetic counseling is important for discussing relevant factors. Invasive testing for aneuploidies should be based on the modified risk, the presence of multiple SMs, or structural anomalies on ultrasonography.

Children with Down syndrome often experience obstructive sleep apnea (OSA), which can be severe and, if untreated, leads to serious complications. Polysomnography, the gold standard for diagnosing OSA, has long waiting lists and poses challenges for these children. The modified OSA-18 questionnaire may help determine the severity of OSA in this population, facilitating the study of its prevalence and risk factors. A cohort of 180 children with Down syndrome, aged 2–12 years, was enrolled from August 2020 to January 2022. Participants completed the modified OSA-18 questionnaire, where a score of 21+ indicated a high risk of severe OSA. Demographic data, prevalence, and associated risk variables were analyzed. A total of 180 participants were included. Their mean age was 8.9 ± 2.8 years, and a slight majority were male (52.2%). Most had normal weight (44.4%); 33.9% were overweight, and 21.7% had obesity. The prevalence of those at high risk for severe OSA was 19.4%. The only significant risk factor for severe OSA was obesity (p < 0.001; OR = 6.96; 95% CI = 2.65–18.28). The study found a lower prevalence of high-risk severe OSA in children than reported by polysomnography-based studies, with obesity as the sole risk factor. The research confirmed that the modified OSA-18 questionnaire is a more convenient and quicker assessment tool. Prompt assessment of obese children with Down syndrome for severe OSA is crucial to prevent sequelae.