-
Journal of Postgraduate Medicine 2024We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling....
We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling. Rhizo-mesomelic dwarfism was detected antenatally. Within 24 hours of birth, he developed multiple seizures. Examination revealed severe short stature, dolichocephaly, broad forehead, deep set eyes, low set ears, bulbous nose, small, irregular teeth, pointed chin, and triangular facies. He had rhizomelic shortening, stubby fingers, pes planus, and scanty hair. Neurological evaluation revealed ataxia, hypotonia, and global developmental delay. Skeletal survey radiograph revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals and short cone-shaped phalanges with cupping of phalangeal bases. Clinical exome analysis revealed homozygous mutations involving the POC1A gene and the SLC13A5 gene responsible for SOFT syndrome and Kohlschutter-Tonz syndrome respectively, which were inherited from the parents. Both these syndromes are extremely rare, and their co-occurrence is being reported for the first time.
Topics: Male; Infant, Newborn; Humans; Child, Preschool; Epilepsy; Dementia; Amelogenesis Imperfecta; Abnormalities, Multiple; Osteochondrodysplasias; Dwarfism; Symporters; Cytoskeletal Proteins; Cell Cycle Proteins
PubMed: 37706418
DOI: 10.4103/jpgm.jpgm_1001_22 -
Heart (British Cardiac Society) Jan 2024Although survival has significantly improved in the last four decades, the diagnosis of Ebstein's anomaly is still associated with a 20-fold increased risk of mortality,... (Review)
Review
Although survival has significantly improved in the last four decades, the diagnosis of Ebstein's anomaly is still associated with a 20-fold increased risk of mortality, which generally drops after neonatal period and increases subtly thereafter. With increasing age of presentation, appropriate timing of intervention is challenged by a wide spectrum of disease and paucity of data on patient-tailored interventional strategies. The present review sought to shed light on the wide grey zone of post-neonatal Ebstein's manifestations, highlighting current gaps and achievements in knowledge for adequate risk assessment and appropriate therapeutic strategy.A 'wait-and-see' approach has been adopted in many circumstances, though its efficacy is now questioned by the awareness that Ebstein's anomaly is not a benign disease, even when asymptomatic. Moreover, older age at intervention showed a negative impact on post-surgical outcome.In order to tackle the extreme heterogeneity of Ebstein's anomaly, this review displays the multimodality imaging assessment necessary for a proper anatomical classification and the multidisciplinary approach needed for a comprehensive risk stratification and monitoring strategy. Currently available predictors of clinical outcome are summarised for both operated and unoperated patients, with the aim of supporting the decisional process on the choice of appropriate therapy and optimal timing for intervention.
Topics: Infant, Newborn; Child; Adult; Humans; Ebstein Anomaly; Risk Assessment; Multimodal Imaging
PubMed: 37487694
DOI: 10.1136/heartjnl-2023-322420 -
BMC Medical Genomics Oct 2023Whole-exome sequencing (WES) significantly improves the diagnosis of the etiology of fetal structural anomalies. This study aims to evaluate the diagnostic value of...
BACKGROUND
Whole-exome sequencing (WES) significantly improves the diagnosis of the etiology of fetal structural anomalies. This study aims to evaluate the diagnostic value of prenatal WES and to investigate the pathogenic variants in structurally abnormal fetuses.
METHODS
We recruited 144 fetuses with structural anomalies between 14 and 2020 and 15 December 2021 in the study. Genetic screening was performed by WES combined with karyotyping and chromosomal microarray analysis. The molecular diagnostic yield of prenatal WES for each type of fetal structural anomaly and the identified pathogenic genes and mutations were reported.
RESULTS
In this study, we retrospectively analyzed the clinical and genetic data of 145 structurally anomalous fetuses. These cases were classified into 9 phenotypic classes based on antenatal ultrasound findings. Thirty-eight pathogenic variants in 24 genes were identified in 35 of the 145 cases, including 14 novel variants in 13 genes (EP300, MYH3, TSC2, MMP9, CPLANE1, INVS, COL1A1, EYA1, TTC21B, MKS1, COL11A2, PDHA1 and L1CAM). Five additional pathogenic variants were classified as incidental findings. Our study showed that the overall diagnosis rate of WES was 28.1% (27/96) in the parent-fetus trio cases and 16.3% (8/49) in the proband-only cases. Fetuses with musculoskeletal anomalies had the highest diagnostic yield (51.4%, 19/37). In addition, FGFR3 and COL1A1 were the most common pathogenic genes.
CONCLUSIONS
Our work expands the mutation spectrum of the genes associated with fetal structural anomalies and provides valuable information for future parental genetic counselling and pregnancy management of the structurally anomalous fetuses.
Topics: Female; Humans; Pregnancy; East Asian People; Exome Sequencing; Fetus; Pregnancy Trimester, First; Prenatal Diagnosis; Retrospective Studies; Ultrasonography, Prenatal; Congenital Abnormalities
PubMed: 37880672
DOI: 10.1186/s12920-023-01697-3 -
European Journal of Pediatrics Mar 2024Noonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or... (Review)
Review
Noonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Collectively, all these pathogenic variants lead to increased RAS/MAPK activation. The better understanding of the molecular mechanisms underlying the different manifestations of NS and RASopathies has led to the identification of molecular targets for specific pharmacological interventions. Many specific agents (e.g. SHP2 and MEK inhibitors) have already been developed for the treatment of RAS/MAPK-driven malignancies. In addition, other molecules with the property of modulating RAS/MAPK activation are indicated in non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolemia). Conclusion: Drug repositioning of these molecules represents a challenging approach to treat or prevent medical complications associated with RASopathies. What is Known: • Noonan syndrome and related disorders are caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway, resulting in increased activation of this pathway. • This group of disorders is now known as RASopathies and represents one of the largest groups of multiple congenital anomaly diseases known. What is New: • The identification of pathophysiological mechanisms provides new insights into the development of specific therapeutic strategies, in particular treatment aimed at reducing RAS/MAPK hyperactivation. • Drug repositioning of specific agents already developed for the treatment of malignant (e.g. SHP2 and MEK inhibitors) or non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolaemia) represents a challenging approach to the treatment of RASopathies.
Topics: Humans; Noonan Syndrome; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Natriuretic Peptide, C-Type; Mitogen-Activated Protein Kinases; Abnormalities, Multiple; Achondroplasia; Mitogen-Activated Protein Kinase Kinases
PubMed: 37863846
DOI: 10.1007/s00431-023-05263-y -
Scientific Reports May 2024The main objective of this study was to investigate the incidence and characteristics of electrocardiographic abnormalities in patients with microtia, and to explore...
The main objective of this study was to investigate the incidence and characteristics of electrocardiographic abnormalities in patients with microtia, and to explore cardiac maldevelopment associated with microtia. This retrospective study analyzed a large cohort of microtia patients admitted to Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, from September 2017 to August 2022. The routine electrocardiographic reports of these patients were reviewed to assess the incidence and characteristics of abnormalities. The study included a total of 10,151 patients (5598 in the microtia group and 4553 in the control group) who were admitted to the Plastic Surgery Hospital of Peking Union Medical College. The microtia group had a significantly higher incidence of abnormal electrocardiographies compared to the control group (18.3% vs. 13.6%, P < 0.01), even when excluding sinus irregularity (6.1% vs. 4.4%, P < 0.01). Among the 1025 cases of abnormal electrocardiographies in the microtia group, 686 cases were reported with simple sinus irregularity. After excluding sinus irregularity as abnormal, the most prevalent abnormalities was right bundle branch block (37.5%), followed by sinus bradycardia (17.4%), ST-T wave abnormalities (13.3%), atrial rhythm (9.1%), sinus tachycardia (8.3%), and ventricular high voltage (4.7%). Less common ECG abnormalities included atrial tachycardia (2.1%), ventricular premature contraction (2.4%), and ectopic atrial rhythm (1.8%). atrioventricular block and junctional rhythm were present in 1.2% and 0.9% of the cases, respectively. Wolff Parkinson White syndrome and dextrocardia had a lower prevalence, at 0.6% and 0.9%, respectively. The occurrence of electrocardiographic abnormalities in microtia patients was found to be higher compared to the control group. These findings highlight the potential congenital defect in cardiac electrophysiology beyond the presence of congenital heart defect that coincide with microtia.
Topics: Humans; Congenital Microtia; Male; Female; Electrocardiography; Retrospective Studies; Adolescent; Child; Adult; Young Adult; Incidence; Arrhythmias, Cardiac; China
PubMed: 38702362
DOI: 10.1038/s41598-024-60610-9 -
International Journal of Molecular... Dec 2023Infertility affects around 1 in 5 couples in the world. Congenital absence of the uterus results in absolute infertility in females. Müllerian agenesis is the... (Review)
Review
Infertility affects around 1 in 5 couples in the world. Congenital absence of the uterus results in absolute infertility in females. Müllerian agenesis is the nondevelopment of the uterus. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a condition of uterovaginal agenesis in the presence of normal ovaries and the 46 XX Karyotype. With advancements in reproductive techniques, women with MA having biological offspring is possible. The exact etiology of MA is unknown, although several genes and mechanisms affect the development of Müllerian ducts. Through this systematic review of the available literature, we searched for the genetic basis of MA. The aims included identification of the genes, chromosomal locations, changes responsible for MA, and fertility options, in order to offer proper management and counseling to these women with MA. A total of 85 studies were identified through searches. Most of the studies identified multiple genes at various locations, although the commonest involved chromosomes 1, 17, and 22. There is also conflicting evidence of the involvement of various candidate genes in the studies. The etiology of MA seems to be multifactorial and complex, involving multiple genes and mechanisms including various mutations and mosaicism.
Topics: Humans; Female; Mullerian Ducts; Infertility; 46, XX Disorders of Sex Development; Mosaicism; Congenital Abnormalities
PubMed: 38203291
DOI: 10.3390/ijms25010120 -
Materials Today. Bio Dec 2023The remarkable contractility and force generation ability exhibited by cancer cells empower them to overcome the resistance and steric hindrance presented by a...
The remarkable contractility and force generation ability exhibited by cancer cells empower them to overcome the resistance and steric hindrance presented by a three-dimensional, interconnected matrix. Cancer cells disseminate by actively remodelling and deforming their extracellular matrix (ECM). The process of tumour growth and its ECM remodelling have been extensively studied, but the effect of the cellular tumour microenvironment (TME) has been ignored in most studies that investigated tumour-cell-mediated ECM deformations and realignment. This study reports the integration of stromal cells in spheroid contractility assays that impacts the ECM remodelling and invasion abilities of cancer spheroids. To investigate this, we developed a novel multilayer assay that incorporates stromal cells and quantifies the contractile deformations that tumour spheroids exert on the ECM. We observed a negative correlation between the spheroid invasion potential and the levels of collagen deformation. The presence of stromal cells significantly increased cancer cell invasiveness and altered the cancer cells' ability to deform and realign collagen gel, due to upregulation of proinflammatory cytokines. Interestingly, this was observed consistently in both metastatic and non-metastatic cancer cells. Our findings contribute to a better understanding of the vital role played by the cellular TME in regulating the invasive outgrowth of cancer cells and underscore the potential of utilising matrix deformation measurements as a biophysical marker for evaluating invasiveness and informing targeted therapeutic opportunities.
PubMed: 37868949
DOI: 10.1016/j.mtbio.2023.100821 -
The Journal of Maternal-fetal &... Dec 202315q11.2 microdeletion can lead to syndromes affecting the nervous system. However, 15q11.2 microdeletion has large phenotypic differences and incomplete penetrance,... (Review)
Review Meta-Analysis
OBJECTIVE
15q11.2 microdeletion can lead to syndromes affecting the nervous system. However, 15q11.2 microdeletion has large phenotypic differences and incomplete penetrance, which brings challenges to prenatal diagnosis. We reported 21 cases of 15q11.2 microdeletion fetuses in Eastern China and reviewed literature on the prenatal clinical characteristics related to the deletion variants to provide a basis for prenatal genetic counseling.
METHODS
The clinical data of 21 cases of 15q11.2 microdeletion fetuses collected from June 2018 to September 2021 were retrospectively analyzed, and chromosomal microarray analysis was performed. The reported prenatal clinical features of 15q11.2 microdeletion fetuses were reviewed and summarized. A meta-analysis of 20 studies was performed to test heterogeneity, data integration, and sensitivity on the correlation between 15q11.2 microdeletion and neuropsychiatric diseases.
RESULTS
The median age of the women was 29.5 years. The median gestational age at interventional examination was 24 weeks. All fetuses showed deletion variants of the 15q11.2 fragment, and the median deletion range was approximately 0.48 MB. Ultrasound of five cases showed no abnormalities; however, four of them showed a high risk of Down's syndrome (risk values were 1/184, 1/128, 1/47, and 1/54, respectively). The remaining 16 fetuses showed congenital heart disease (7/16), elevated nuchal translucency (5/16), abnormal brain structure (2/16) and renal disease (2/16). In a literature review of 82 prenatal cases, 44% (36/82) had abnormal ultrasound features, 31% (11/36) showed abnormal nuchal translucency, approximately 28% (10/36) showed abnormal cardiac structure, and 14% (5/36) had brain structural abnormalities. The meta-analysis revealed that the frequency of the 15q11.2 microdeletion mutation in patients with schizophrenia and epilepsy was significantly higher (odds ratio 2.04, 95% confidence interval: 1.78-2.33, < 0.00001; odds ratio 5.23, 95% confidence interval: 2.83-9.67, < 0.00001) than that in normal individuals.
CONCLUSION
More than half of the 15q11.2 microdeletion cases presented no abnormalities in prenatal ultrasound examination. The cases with ultrasound features mainly showed isolated malformations such as elevated nuchal translucency, congenital heart disease, and brain structural abnormalities. Postpartum 15q11.2 microdeletion patients are at an increased risk of suffering from schizophrenia, epilepsy, and other neurological and mental diseases from 15q11.2 microdeletion. Therefore, prenatal diagnosis of 15q11.2 microdeletion not only depends on molecular diagnostic techniques but also requires cautious genetic counseling.
Topics: Adult; Female; Humans; Pregnancy; Fetus; Heart Defects, Congenital; Nuchal Translucency Measurement; Prenatal Diagnosis; Retrospective Studies; Ultrasonography, Prenatal
PubMed: 37770195
DOI: 10.1080/14767058.2023.2262700 -
Journal of Orthopaedic Research :... Sep 2023Progressive collapsing foot deformity (PCFD) is characterized by a progressive subluxation of the peritalar bones and respective joints. Two-dimensional conventional...
Progressive collapsing foot deformity (PCFD) is characterized by a progressive subluxation of the peritalar bones and respective joints. Two-dimensional conventional radiographs are limited in their ability to visualize the peritalar bones and joints with adequate detail to describe the complex three-dimensional deformity. An improved understanding of the relationship between joint coverage and deformity would allow clinicians to use coverage analysis to distinguish among the stages of PCFD. The aim of this study was to analyze the joint coverage of the six articular relationships within the talocrural, subtalar, and Chopart joints using weightbearing computed tomography (WBCT) scans. Ten individuals with a flexible hindfoot and ten individuals with a rigid hindfoot presentation of PCFD were compared to twenty-seven asymptomatic control individuals. The three most relevant findings are: (I) the anterior-medial facet of the subtalar joint contains the greatest reduction in coverage for patients with a rigid deformity, (II) an increase in talonavicular overlap (TNO) moderately correlated with a decreased coverage in the: tibiotalar, anterior-medial subtalar, talonavicular joints, and (III) the calcaneocuboid joint lacks radiographic values to adequately quantify alignment and coverage. To conclude, there were significant differences in coverage area of various articulating regions throughout the hind- and midfoot when comparing PCFD patients to asymptomatic control individuals. Relevant radiographic measures correlating to articular coverage areas of clinical interest were identified, possibly helping to better quantify PCFD in clinical practice.
Topics: Humans; Flatfoot; Foot Deformities; Foot; Subtalar Joint; Tarsal Joints; Weight-Bearing
PubMed: 36891918
DOI: 10.1002/jor.25543 -
Progress in Retinal and Eye Research Jul 2023Congenital PAX6-aniridia, initially characterized by the absence of the iris, has progressively been shown to be associated with other developmental ocular abnormalities... (Review)
Review
Congenital PAX6-aniridia, initially characterized by the absence of the iris, has progressively been shown to be associated with other developmental ocular abnormalities and systemic features making congenital aniridia a complex syndromic disorder rather than a simple isolated disease of the iris. Moreover, foveal hypoplasia is now recognized as a more frequent feature than complete iris hypoplasia and a major visual prognosis determinant, reversing the classical clinical picture of this disease. Conversely, iris malformation is also a feature of various anterior segment dysgenesis disorders caused by PAX6-related developmental genes, adding a level of genetic complexity for accurate molecular diagnosis of aniridia. Therefore, the clinical recognition and differential genetic diagnosis of PAX6-related aniridia has been revealed to be much more challenging than initially thought, and still remains under-investigated. Here, we update specific clinical features of aniridia, with emphasis on their genotype correlations, as well as provide new knowledge regarding the PAX6 gene and its mutational spectrum, and highlight the beneficial utility of clinically implementing targeted Next-Generation Sequencing combined with Whole-Genome Sequencing to increase the genetic diagnostic yield of aniridia. We also present new molecular mechanisms underlying aniridia and aniridia-like phenotypes. Finally, we discuss the appropriate medical and surgical management of aniridic eyes, as well as innovative therapeutic options. Altogether, these combined clinical-genetic approaches will help to accelerate time to diagnosis, provide better determination of the disease prognosis and management, and confirm eligibility for future clinical trials or genetic-specific therapies.
Topics: Humans; PAX6 Transcription Factor; Aniridia; Eye Abnormalities; Mutation; Phenotype; Eye Proteins
PubMed: 36280537
DOI: 10.1016/j.preteyeres.2022.101133