DiGeorge Research Articles

Exploring 17q12 Deletion Syndrome: A Case Report of Neurodevelopmental, Endocrine, and Genital Anomalies

Objective − 17q12 deletion syndrome is a rare genetic disease characterized by neurodevelopmental disorders, genital and renal abnormalities, and maturity-onset diabetes of the young type 5 (MODY5).Case Report − This case report details the case of a 13-year-old female with moderate intellectual disability, Mayer-Rokitansky-Küster-Hauser syndrome, multicystic dysplastic kidneys, and MODY5. Genetic testing revealed a 1.52-megabase heterozygous deletion on chromosome 17q12, encompassing the HNF1B and LHX1 genes, which was found to be inherited from the mother. Conclusion − This case underscores the importance of early genetic testing and multidisciplinary approach in managing the multisystemic manifestations of 17q12 deletion syndrome. Early diagnosis and appropriate management are crucial for improving the outcomes and quality of life for affected individuals.

Clinical and genetic characteristics of hypoparathyroidism in children: a multicenter experience in China.

This study was aimed to analyze the clinical and genetic characteristics of hypoparathyroidism in children. We performed a retrospective analysis of 74 patients diagnosed with pediatric hypoparathyroidism from 2014 to 2023, recruited in five medical centers across China. Data of basic information and clinical tests were extracted from patients' records. Whole-exome sequencing (WES), multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray analysis (CMA) were utilized to identify the genetic causes. The results indicated a median onset age of 6.07 ± 4.82 years and a median diagnosis age of 6.91 ± 4.88 years. Of the 46 patients who underwent genetic tests, 35 were found to carry pathogenic variants related to hypoparathyroidism. Specifically, 19 cases (19/46, 41.30%) had 22q11.2 microdeletion, while other variations included AIRE (8/46, 17.39%), GATA3 (3/46, 6.52%), CaSR (2/46, 4.34%), and the rest 3 patients with mutations of TBCE, PTH and mitochondrial gene deletion respectively. Convulsions were the most common initial presentation, observed in 43 cases. The non-DGS group exhibited the lowest serum PTH levels compared to DiGeorge syndrome and gene-negative group. Among the 66 patients who underwent cranial CT or MR, 26 (26/66, 39.99%) presented with intracranial calcification. We reported the largest cohort of childhood hypoparathyroidism with genetic diagnoses, reinforcing the view that genetic disorders account for the majority of pediatric hypoparathyroidism, with the 22q11.2 microdeletion being the most prevalent. Identifying the genetic causes of hypoparathyroidism is crucial for predicting patient outcomes, managing comorbidities, and, importantly, informing decisions regarding the potential use of emerging recombinant human PTH therapy.

Most common congenital syndromes with facial asymmetry: A narrative review.

Symmetry is present in various aspects of everyday life. A symmetrical face is considered attractive, whereas a lack of facial symmetry is regarded as a source of functional and aesthetic problems. Most of the people exhibit slight asymmetries, but some of them reveal severe asymmetries. Among patients presenting with severe facial asymmetries, there may be those with congenital defects. Congenital defects may manifest at the time of birth or be a result of birth trauma.One of the most prevalent asymmetrical birth defects is cleft lip and/or cleft palate. Other congenital defects include craniofacial syndromes, such as Treacher Collins syndrome (TCS) and Goldenhar syndrome. Among the rare syndromes with facial asymmetries, Klippel-Feil syndrome (KFS), PHACE (posterior fossa brain malformation, hemangiomas, arterial anomalies, cardiac anomalies, and eye abnormalities) syndrome, plagiocephaly, and Parry-Romberg syndrome are worth noticing. The majority of craniofacial asymmetries require surgery to improve the patient's facial appearance. The treatment is multidisciplinary and long, and the most common procedures involve reparative and regenerative surgeries. The aim of this review was to present the most common congenital defects with facial asymmetry.

T-cells are significantly reduced in the luminal gastrointestinal tract of patients with “complete” 22q11.2 deletion syndrome (DiGeorge syndrome): Utilization of chromogenic multiplex immunohistochemistry to define cellular populations

Patients with 22q11.2 deletion syndrome or DiGeorge syndrome commonly report gastrointestinal symptoms in addition to more widely understood cardiac and immunodeficiency abnormalities. However, the morphologic features of gastrointestinal tract pathology in these patients are poorly understood. We previously reported that plasma cells are essentially absent from the luminal gastrointestinal tract of patients with “complete” DiGeorge syndrome. Herein, we add to the current understanding of the luminal gastrointestinal tract changes in patients with DiGeorge syndrome. Patients with cytogenetically confirmed DiGeorge syndrome were identified after approval from our institutional review board. Gastrointestinal tract biopsies from patients with DiGeorge syndrome that were severely immunosuppressed (complete DiGeorge syndrome, DGS-I), partially immunocompromised (partial DiGeorge syndrome, DGS), and from control patients were reviewed. Two panels of chromogenic multiplex immunohistochemistry (IHC) were performed to evaluate the immune cell infiltrate in the lamina propria of the duodenum and colon. “Panel #1” was composed of antibodies targeting CD3, CD20, and CD68. “Panel #2” was composed of antibodies targeting CD4, CD8, CD56, and TCRϒδ. Assessment of cell types identified by these antibody targets demonstrated a significant reduction of duodenal and colonic T-cells in patients with complete DiGeorge syndrome. In addition to establishing the morphologic phenotype of the luminal gastrointestinal tract of patients with DiGeorge syndrome, we also highlight our chosen technology of chromogenic multiplex IHC as a relatively accessible research and diagnostic tool with wide potential to be utilized across various disease processes.

Expanded phenotypic spectrum in MODY 5 patients with 17q12 deletion syndrome: experience from an Indian tertiary care hospital.

To study the clinical and genotypic spectrum of patients with HNF-1ß deletions (MODY 5) at a tertiary care hospital. This study included four patients from the Department of Endocrinology at Sher-i-Kashmir Institute of Medical Sciences Srinagar with a strong clinical suspicion of MODY 5. Genetic analysis, including a monogenic gene panel comprising 78 genes associated with MODY and other similar forms of monogenic diabetes, was done. Dosage analysis of HNF 1B by Multiplex Ligand-dependent Probe Amplification (MLPA) was performed. The mean age of patients was 22.25 years with a male-to-female ratio of 3:1. Associated phenotypic features included neurodevelopmental disorder in all four patients, insulin resistance in two patients (2/4) and alopecia in three patients (3/4). One patient had clinical and biochemical hyperandrogenism. All patients had renal malformations, and one patient had a Mullerian anomaly. Family history was present in 1 patient. All patients had pancreatic abnormalities, the most common type being dorsal agenesis of the pancreas (3/4), followed by annular pancreas (1/4). All patients had a genetic deletion of the gene HNF1B on chromosome 17 with a deletion interval of (?_37686431)_(37745059_?), (?_37687281)-(37744884_?), comprising exons 1 to 9. It is imperative to maintain a high index of suspicion for MODY 5 in patients presenting with renal anomalies and diabetes, even in the absence of a family history. Early identification allows for screening family members and ensures a comprehensive approach to identifying and managing other abnormalities in these patients.

Event-free survival in neuroblastoma with MYCN amplification and deletion of 1p or 11q may be associated with altered immune status

BackgroundNeuroblastoma exhibits substantial heterogeneity, which is intricately linked to various genetic alterations. We aimed to explore immune status in the peripheral blood and prognosis of patients with neuroblastoma with different genetic characteristics.MethodsWe enrolled 31 patients with neuroblastoma and collected samples to detect three genetic characteristics. Peripheral blood samples were tested for immune cells and cytokines by fluorescent microspheres conjugated with antibodies and flow cytometry. Event-free survival (EFS) was analyzed using the Kaplan‒Meier method.ResultsTwenty-two patients had genetic aberrations, including MYCN amplification in 6 patients, chromosome 1p deletion in 9 patients, and chromosome 11q deletion in 14 patients. Two genetic alterations were present in seven patients. The EFS was worse in patients with MYCN amplification or 1p deletion than in the corresponding group, whereas 11q deletion was a prognostic factor only in patients with unamplified MYCN. Changes in immune status revealed a decrease in the proportion of T cells in blood, and an increase in regulatory T cells and immunosuppression-related cytokines such as interleukin (IL)-10. The EFS of the IL-10 high-level group was lower than that of the low-level group. Patients with concomitant genetic alterations and a high level of IL-10 had worse EFS than other patients.ConclusionsPatients with neuroblastoma characterized by these genetic characteristics often have suppressed T cell response and an overabundance of immunosuppressive cells and cytokines in the peripheral blood. This imbalance is significantly associated with poor EFS. Moreover, if these patients show an elevated levels of immunosuppressive cytokines such as IL-10, the prognosis will be worse.

Genetic analysis of a child with 18q terminal deletion and aortic regurgitation and a literature review

To explore the genetic characteristics of a child with 18q terminal deletion syndrome. Clinical data of a child presented at the Lianyungang Maternal and Child Health Care Hospital on July 20, 2023 was collected. Peripheral blood sample from the child was subjected to G-banded chromosomal karyotyping and chromosomal microarray analysis (CMA). Relevant literature was searched from CNKI, WanFang and PubMed databases over the past decade (from November 1, 2013 to November 1, 2023) using keywords including "18q-syndrome", "18q deletion syndrome" and "18q terminal deletion". This study was approved by the Lianyungang Maternal and Child Health Care Hospital (Ethics No. LYG-MER2021017). The child, a 4-year-and-6-month-old female, had manifested short stature, intellectual disability, distinctive facial features, aortic regurgitation, auditory canal atresia, and white matter lesions. She was found to have a karyotype of 46,XX,del(18)(q21), whilst the result of CMA was arr[GRCh37]18q21.33q23(60065821_77317445)×1. Both of her parents were found to have a normal karyotype. Literature review has retrieved 7 reports which involved 11 cases with a terminal 18q23 deletion. The phenotypes of cardiac abnormalities have been diverse, with pulmonary stenosis, atrial septal defect and ventricular septal defect being most common. The 18q terminal deletion probably underlay the multiple congenital anomalies and mental retardation in this child.

2q31 microdeletion syndrome with the velocardiofacial phenotype and review of the literature: a case report

BackgroundThe 2q31 deletion results in a distinct phenotype characterized by varying degrees of developmental delay, short stature, facial dysmorphism, and variable limb defects. Dysmorphic features include microcephaly, downslanting palpebral fissures, a long and flat philtrum, micrognathia, and dysplastic, low-set ears. To date, comparative genomic hybridization has identified this deletion in 38 patients. Consequently, additional patients with comprehensive clinical data are required to fully understand the spectrum of clinical manifestation associated with a deletion in the 2q31 cytoband.Case presentationWe present the case of an 8-year-old female patient with clinical features of velocardiofacial syndrome, which include facial dysmorphism, congenital heart disease (persistent truncus arteriosus and ostium secundum-type atrial septal defect), and a seizure syndrome. Array comparative genomic hybridization revealed a non-continous deletion spanning cytobands 2q31.1-to 2q31.3, confirming a diagnosis of 2q31 microdeletion syndrome. The patient has undergone supportive therapies for swallowing and speech. Additionally, we provide a review of the literature on previous cases to give context.ConclusionIn this report, we present the first documented case of a complex, discontinuous deletion spanning in the 2q31-2q32 regions. This case contributes to our understanding of the phenotypic and mutational spectrum observed in individuals with deletions in these cytobands. It underscores the significance of employing high-resolution techniques and comprenhensive analysis in diagnosing patients with complex phenotypes. Such approaches are crucial for differentiating this condition from more common microdeletion syndromes, such as the 22q11 deletion syndrome.

Beyond IQ: executive function deficits and their relation to functional, clinical, and neuroimaging outcomes in 3q29 deletion syndrome.

3q29 deletion syndrome (3q29del) is a rare (~1:30 000) genomic disorder associated with a wide array of neurodevelopmental and psychiatric phenotypes. Prior work by our team identified clinically significant executive function (EF) deficits in 47% of individuals with 3q29del; however, the nuances of EF in this population have not been described. We used the Behavior Rating Inventory of Executive Function (BRIEF) to perform the first in-depth assessment of real-world EF in a cohort of 32 individuals with 3q29del (62.5% male, mean age = 14.5 ± 8.3 years). All participants were also evaluated with gold-standard neuropsychiatric and cognitive assessments. High-resolution structural magnetic resonance imaging was performed on a subset of participants (n = 24). We found global deficits in EF; individuals with 3q29del scored higher than the population mean on the BRIEF global executive composite (GEC) and all subscales. In total, 81.3% of study subjects (n = 26) scored in the clinical range on at least one BRIEF subscale. BRIEF GEC T scores were higher among 3q29del participants with a diagnosis of attention deficit/hyperactivity disorder (ADHD), and BRIEF GEC T scores were associated with schizophrenia spectrum symptoms as measured by the Structured Interview for Psychosis-Risk Syndromes. BRIEF GEC T scores were not associated with cognitive ability. The BRIEF-2 ADHD form accurately (sensitivity = 86.7%) classified individuals with 3q29del based on ADHD diagnosis status. BRIEF GEC T scores were correlated with cerebellar white matter and subregional cerebellar cortex volumes. Together, these data expand our understanding of the phenotypic spectrum of 3q29del and identify EF as a core feature linked to both psychiatric and neuroanatomical features of the syndrome.

Clinical, developmental and serotonemia phenotyping of a sample of 70 Italian patients with Phelan-McDermid Syndrome

BackgroundPhelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD).ObjectivesTo assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels.Methods70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC.ResultsOur sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p < 0.001); (b) serotonin blood levels are significantly lower in 21 PMS patients compared to their 21 unaffected siblings (P < 0.05), and to 432 idiopathic ASD cases (p < 0.001).ConclusionsWe replicate and extend the description of many phenotypic characteristics present in PMS, and report two novel features: (1) growth trajectories are variable and head growth appears to slow down during childhood in some PMS patients; (2) serotonin blood levels are decreased in PMS, and not increased as frequently occurs in ASD. Further investigations of these novel features are under way.

Metataxonomic and Immunological Analysis of Feces from Children with or without Phelan-McDermid Syndrome.

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by a developmental delay and autism spectrum disorder (ASD)-like behaviors. Emerging research suggests a link between gut microbiota and neuropsychiatric conditions, including PMS. This study aimed to investigate the fecal microbiota and immune profiles of children with PMS compared to healthy controls. Fecal samples were collected from children diagnosed with PMS and age-matched healthy controls. The bacterial composition was analyzed using 16S rRNA gene sequencing, while short-chain fatty acids (SCFAs) were quantified through gas chromatography. Immunological profiling was conducted using a multiplex cytokine assay. Significant differences were observed in the gut microbiota composition between PMS patients and controls, including a lower abundance of key bacterial genera such as Faecalibacterium and Agathobacter in PMS patients. SCFA levels were also reduced in PMS patients. Immunological analysis revealed higher levels of several pro-inflammatory cytokines in the PMS group, although these differences were not statistically significant. The findings indicate that children with PMS have distinct gut microbiota and SCFA profiles, which may contribute to the gastrointestinal and neurodevelopmental symptoms observed in this syndrome. These results suggest potential avenues for microbiota-targeted therapies in PMS.

From diagnosis to postoperative challenges: a comprehensive case report on 2q37 deletion syndrome with CHD.

Chromosomal 2q37 deletion syndrome, marked by developmental delays, distinctive facial features, and a spectrum of congenital anomalies, presents significant challenges in the cardiac management of affected individuals. This paper details the case of an 8-month-old male with 2q37 deletion syndrome, manifesting atrial and ventricular septal defects, patent ductus arteriosus, and right ventricular outflow tract stenosis, leading to a demanding postoperative course. Despite an initially stable post-surgery phase, the onset of junctional ectopic tachycardia necessitated prolonged veno-arterial extracorporeal membrane oxygenation support, highlighting the syndrome's potential for intricate postoperative courses. The complexities encountered in this case, including extended renal replacement therapy and delayed thoracic closure, underscore the syndrome's multisystem impact and the critical need for tailored, multidisciplinary care approaches. This report contributes to the growing body of knowledge on the cardiac implications of 2q37 deletion syndrome, emphasising the importance of individualised surgical strategies and the ongoing exploration of genotype-phenotype correlations in this rare genetic disorder.

Diagnosis and Screening of Velocardiofacial Syndrome by Evaluating Facial Photographs Using a Deep Learning-Based Algorithm.

Early detection of rare genetic diseases, including velocardiofacial syndrome (VCFS), is essential for patient well-being. However, their rarity and limited clinical experience of physicians make diagnosis challenging. Deep learning algorithms have emerged as promising tools for efficient and accurate diagnosis. This study investigates the use of a deep learning algorithm to develop a face recognition model for diagnosing VCFS. The study employed publicly available labeled face datasets to train the multitask cascaded convolutional neural networks (MTCNN) model. Subsequently, we examined the binary classification performance for diagnosing VCFS using the most efficient face recognition model. A total of 98 VCFS patients (920 facial photographs) and 91 non-VCFS controls (463 facial photographs) were randomly divided into training and test sets. Additionally, we analyzed whether the classification results matched the known facial phenotype of VCFS. The face recognition model demonstrated high accuracy, ranging from 94% to 99%, depending on the training dataset. The accuracy of the binary classification diagnostic model varied from 81% to 88% when evaluating with photographs taken at various angles, but reached 95% evaluating with frontal photographs only. Gradient-weighted class activation mapping heatmap revealed the high importance level of perinasal and periorbital areas, exhibiting consistency with the conventional facial phenotypes of VCFS. This study shows the feasibility and effectiveness of MTCNN-based model for detecting VCFS solely from facial photographs. The high accuracy underscores the potential of deep learning in aiding early diagnosis of rare genetic diseases, facilitating timely interventions for patient care.

NEUROCOGNITIVE EVALUATION OF PATIENTS WITH DIGEORGE SYNDROME

BackgroundDiGeorge syndrome (DGS), the most common microdeletion syndrome, affects multiple organs, including the heart, the nervous system, and the immune system. In this study, we aimed to evaluate the clinical, laboratory, brain MRI, and neurocognitive findings of our patients with DGS. MethodsClinical and laboratory data of fifty-two patients with DGS between June 2000- March 2022 were evaluated retrospectively. Brain MRI and neuropsychological tests were performed to assess the neurocognitive status of the patients. ResultsFifty-two patients (28 males and 24 females) were included in our study. Fifteen of them died during the follow-up. All 37 patients who are alive had partial DGS. The median age of patients was ten years and seven months, and the median age at diagnosis was five years and four months. Bilateral conduction deceleration in the anterior visual pathways in 6 (20%) of 30 patients was determined by the VEP (Visual Evoked Potentials). The auditory brainstem evoked potential test (BAEP) showed sensorineural hearing loss in 11 out of 30 (36.6%) patients. Brain MRI disclosed brain parenchymal abnormalities in 18 out of 25 (72%) patients. Impairments in executive functions, expressive language, and verbal memory were noted in 18 patients who were neuropsychologically assessed. ConclusionIt is important to keep in mind that patients with DiGeorge syndrome may be accompanied by neurocognitive findings. Awareness of the potential for underlying psychiatric and neurodevelopment disorders is key to anticipatory guidance, optimization of therapies, and maximizing life quality.

Tetralogy of Fallot With Absent Pulmonary Valve Syndrome: The Experience of a Tertiary Care Center in a Developing Country.

Tetralogy of Fallot with an absent pulmonary valve is a very rare variant of tetralogy. It is characterized by absent valve tissue, severe pulmonary regurgitation, and secondary aneurysmal dilatation of the pulmonary arteries. In this study, we aim to investigate the clinical presentations, management strategies, and outcomes of patients with tetralogy of Fallot and absent pulmonary valve. We retrospectively reviewed the charts of all patients who presented to the American University of Beirut Medical Center between January 2010 and December 2020 and who were diagnosed with this anomaly. A total of 300 cases of tetralogy of Fallot were identified, of which 18 patients had absent pulmonary valves. They were followed up for an average of 8.2 years. Prenatal diagnoses were made in four patients, while 13 patients were identified in the neonatal period, with an average age of 4.5 days. Genetic testing confirmed DiGeorge syndrome in one patient. Five patients underwent surgical intervention in the neonatal period, while the remaining patients were operated on during their early childhood. While overall there were no surgical mortalities nor any need for reinterventions, a variety of morbidities were encountered. This study provides an overview of this rare anomaly and its management in a developing country.

Phenome-wide profiling identifies genotype-phenotype associations in Phelan-McDermid syndrome using family-sourced data from an international registry

BackgroundPhelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by 22q13 deletions that include the SHANK3 gene or pathogenic sequence variants in SHANK3. It is characterized by global developmental delay, intellectual disability, speech impairment, autism spectrum disorder, and hypotonia; other variable features include epilepsy, brain and renal malformations, and mild dysmorphic features. Here, we conducted genotype-phenotype correlation analyses using the PMS International Registry, a family-driven registry that compiles clinical data in the form of family-reported outcomes and family-sourced genetic test results.MethodsData from the registry were harmonized and integrated into the i2b2/tranSMART clinical and genomics data warehouse. We gathered information from 401 individuals with 22q13 deletions including SHANK3 (n = 350, ranging in size from 10 kb to 9.1 Mb) or pathogenic or likely pathogenic SHANK3 sequence variants (n = 51), and used regression models with deletion size as a potential predictor of clinical outcomes for 328 phenotypes.ResultsOur results showed that increased deletion size was significantly associated with delay in gross and fine motor acquisitions, a spectrum of conditions related to poor muscle tone, renal malformations, mild dysmorphic features (e.g., large fleshy hands, sacral dimple, dysplastic toenails, supernumerary teeth), lymphedema, congenital heart defects, and more frequent neuroimaging abnormalities and infections. These findings indicate that genes upstream of SHANK3 also contribute to some of the manifestations of PMS in individuals with larger deletions. We also showed that self-help skills, verbal ability and a range of psychiatric diagnoses (e.g., autism, ADHD, anxiety disorder) were more common among individuals with smaller deletions and SHANK3 variants.LimitationsSome participants were tested with targeted 22q microarrays rather than genome-wide arrays, and karyotypes were unavailable in many cases, thus precluding the analysis of the effect of other copy number variants or chromosomal rearrangements on the phenotype.ConclusionsThis is the largest reported case series of individuals with PMS. Overall, we demonstrate the feasibility of using data from a family-sourced registry to conduct genotype-phenotype analyses in rare genetic disorders. We replicate and strengthen previous findings, and reveal novel associations between larger 22q13 deletions and congenital heart defects, neuroimaging abnormalities and recurrent infections.

MicroRNA and Rare Human Diseases

Background: The role of microRNAs (miRNAs) in the pathogenesis of rare genetic disorders has been gradually discovered. MiRNAs, a class of small non-coding RNAs, regulate gene expression by silencing target messenger RNAs (mRNAs). Their biogenesis involves transcription into primary miRNA (pri-miRNA), processing by the DROSHA–DGCR8 (DiGeorge syndrome critical region 8) complex, exportation to the cytoplasm, and further processing by DICER to generate mature miRNAs. These mature miRNAs are incorporated into the RNA-induced silencing complex (RISC), where they modulate gene expression. Methods/Results: The dysregulation of miRNAs is implicated in various Mendelian disorders and familial diseases, including DICER1 syndrome, neurodevelopmental disorders (NDDs), and conditions linked to mutations in miRNA-binding sites. We summarized a few mechanisms how miRNA processing and regulation abnormalities lead to rare genetic disorders. Examples of such genetic diseases include hearing loss associated with MIR96 mutations, eye disorders linked to MIR184 mutations, and skeletal dysplasia involving MIR140 mutations. Conclusions: Understanding these molecular mechanisms is crucial, as miRNA dysregulation is a key factor in the pathogenesis of these conditions, offering significant potential for the diagnosis and potential therapeutic intervention.

Regulatory role and molecular mechanism of METTL14 in vascular endothelial cell injury in preeclampsia.

Preeclampsia (PE) is a pregnancy-related disease characterized by vascular endothelial cell injury. This study aimed to investigate the role of methyltransferase-like protein 14 (METTL14) in vascular endothelial cell injury in PE. The PE cell model was established by treating human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-alpha (TNF-α) in vitro. METTL14 and forkhead box protein 1 (FOXP1) were silenced, and miR-34a-5p was overexpressed in HUVECs to evaluate their effects. HUVEC viability, apoptosis, and the levels of intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and endothelin-1 were measured. The N6-methyladenosine (m6A) modification of pri-miR-34a-5p was quantified. The interactions between miR-34a-5p, DiGeorge syndrome critical region 8, and m6A enrichment in miR-34a-5p were analyzed. The relationship between miR-34a-5p and FOXP1 was also verified. The results showed that the expressions of METTL14, FOXP1, and miR-34a-5p were determined. METTL14 expression was elevated in the TNF-α-induced HUVEC injury model. Silencing METTL14 improved HUVEC viability, inhibited apoptosis, and reduced endothelial inflammation. METTL14 promoted miR-34a-5p expression through m6A modification. Overexpression of miR-34a-5p or silencing of FOXP1 reversed the protective effects of METTL14 silencing on cell injury in the PE model. In conclusion, METTL14 mediated m6A modification to promote miR-34a-5p expression, leading to the inhibition of FOXP1 expression, which aggravated endothelial cell damage in the PE cell model.

Prevalence of concha bullosa in a pediatric population

ObjectiveExisting literature on the prevalence of middle turbinate pneumatization, or concha bullosa (CB), in the pediatric population is limited. CB is an anatomic variant important to identify prior to sinonasal surgery and is often associated with congenital nasal septal deviation (SD). This paper aims to describe the prevalence of CB in the pediatric population on head imaging. MethodsA retrospective chart review was performed for 695 children undergoing CT head for trauma from 2021 to 2022. Nearly equal numbers of males and females were evaluated, with at least 19–20 per year from 0.5 to 18 years. Patients with significant facial fractures, sinusitis, craniofacial syndromes, prior sinus surgery, and sinonasal masses were excluded. Two pediatric neuroradiologists evaluated the CTs. CB was defined as aeration >50 % of the vertical height of the middle turbinate. ResultsIn this study, 384 patients were included. The prevalence of CB was 153 (39.8 %), which was significantly higher in children >4 years (p < 0.0001). Lamellar type CB was the most common, present in 160 out of 768 middle turbinates assessed (20.8 %). SD occurred in 60 (39.2 %) patients with CB and was more commonly contralateral to the CB. ConclusionsThe prevalence of CB in the pediatric population is at the lower range of what is reported in the adult literature. The most common type of CB in patients is lamellar. Similar to previous studies, there is an association between CB and contralateral SD. Finally, there is a positive correlation between the severity of CB and the severity of SD.

Aortic Root Dilation and Genotype Associations in Phelan-McDermid Syndrome.

Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder that results from the loss of one functional copy of the SHANK3 gene. While many clinical features of PMS are well-understood, there is currently limited literature on cardiovascular abnormalities in PMS. This report aims to evaluate the prevalence of aortic root dilation (ARD) among individuals with PMS and to understand if underlying genetic variation relates to risk for ARD. We present findings from 59 participants collected from a multisite observational study evaluating the phenotype and natural history of PMS. Individual echocardiographic and genetic reports were analyzed for aortic root measurements and genetic variant data, respectively. Our a priori hypothesis was that participants with chromosome 22 deletions with hg19 start coordinates on or before 49,900,000 (larger deletions) would have more instances of ARD than participants with deletion start coordinates after 49,900,000 (smaller deletions). Eight participants (14%) had ARD, and its presence was statistically significantly associated with large deletions (p = 0.047). Relatedly, participants with ARD had significantly more genes deleted on chromosome 22 than participants without ARD (p = 0.013). These results could aid in the identification of individuals with PMS who are at higher risk for ARD.