DiGeorge Research Articles

Phelan-McDermid syndrome and seizures provoked by fever — clinical and electroencephalographic comparisons of two patients

Phelan-McDermid syndrome and seizures provoked by fever — clinical and electroencephalographic comparisons of two patients

Evaluation of the effect of palatoplasty on the quality of life and speech outcomes in patients with velocardiofacial syndrome.

Children diagnosed with velocardiofacial syndrome (VCFS) suffer from various disabilities. Palatal abnormalities, as well as speech and language impairment, adversely affect a child's quality of life (QoL) and are some of the most distressing aspects for the parents of these children. The present study aimed to explore the effect of palatoplasty on the health-related quality of life (HRQoL) and speech outcomes in children with VCFS. The study recruited 20 patients (N = 20) with VCFS and connected speech, aged 3 years or older, having either undiagnosed submucous cleft palate (SMCP) or velopharyngeal insufficiency (VPI), and requiring primary cleft palate surgery or revision surgery. Speech assessment was conducted prior to palatoplasty and 6 months after the surgery. Intelligibility and hypernasality were evaluated using the Cleft Audit Protocol for Speech - Augmented (CAPS-A). The parent proxy-report form of the Pediatric Quality of Life Inventory (PedsQL™) was used to evaluate and compare the HRQoL of the VCFS patients before and after palatoplasty. Significant improvement in the HRQoL scores was achieved after the surgery across all domains (physical, emotional, social, and school functioning), especially in the emotional and social dimensions (p < 0.000). The post-operative speech assessment based on CAPS-A demonstrated improvement in speech intelligibility and hypernasality in the majority of patients. Given that children with VCFS face various medical and social problems, suitable palatal interventions are beneficial, improving both the speech ability and QoL of these children.

Long-term Outcomes After Interrupted Aortic Arch Repair

BackgroundInterrupted aortic arch (IAA) is associated with left ventricular outflow tract obstruction (LVOTO) and DiGeorge syndrome. High-risk infantile surgery is required to address IAA, with limited data available on long-term outcomes. We used the Pediatric Cardiac Care Consortium, a multicenter US-based registry for pediatric cardiac interventions, to assess long-term outcomes after IAA repair by patient characteristics and surgical approach. MethodsThis is a retrospective cohort study of patients undergoing IAA repair between 1982 and 2003. Kaplan-Meier plots and Cox proportional hazards regression were used to examine associations with postdischarge deaths tracked by matching with the US National Death Index. ResultsOf 390 patients meeting inclusion criteria, 309 (79.2%) survived to discharge. During a median follow-up of 23.6 years, 30-year survival reached 80.7% for patients surviving hospital discharge after initial IAA repair. Adjusted analysis revealed higher risk of death for type B vs type A (adjusted hazard ratio [aHR], 3.32; 95% CI, 1.48-7.44), staged repair (aHR, 2.50; 95% CI, 1.14-5.50), and LVOTO interventions during initial hospitalization (aHR, 4.12; 95% CI, 1.83-9.27) but not for LVOTO without need for interventions or presence of DiGeorge syndrome. There was a trend toward improved in-hospital and long-term survival over time during the study period. ConclusionsStaged repair, type B IAA, and need for LVOTO intervention during initial hospitalization for repair are associated with high risk of death out to 30 years. Survival outcomes are improving, but further efforts need to minimize staged approach and risks associated with LVOTO relief procedures.

The role of long noncoding RNA DGCR5 in cancers: Focus on molecular targets.

Long noncoding RNAs (lncRNAs) are major components of cellular transcripts that are emerging as important players in various biological pathways. Due to their specific expression and functional diversity in a variety of cancers, lncRNAs have promising applications in cancer diagnosis, prognosis, and therapy. Studies have shown that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) with high specificity and accuracy has the potential to become biomarkers in cancers. LncRNA DGCR5 can be noninvasively extracted from body fluids, tissues, and cells, and can be used as independent or auxiliary biomarkers to improve the accuracy of diagnosis or prognosis. Now, the underlying mechanisms of lncRNAs such as DGCR5 were explored as therapeutic targets, which have been investigated in clinical trials of several cancers. The DGCR5 lacks an appropriate animal model, which is necessary to gain greater knowledge of their functions. While some studies on the uses of DGCR5 have been carried out, the small sample size makes them unreliable. In this review, we presented a compilation of recent publications addressing the potential of lncRNA DGCR5 that could be considered as biomarkers or therapeutic targets, with the hopes of providing promised implications for future cancer therapy.

Commentary on "Craniofacial Syndromes and class III phenotype: common genotype fingerprints? A scoping review and meta-analysis".

Commentary on "Craniofacial Syndromes and class III phenotype: common genotype fingerprints? A scoping review and meta-analysis".

Maximal Mouth Opening in Infants: A Single-Group Prospective Cohort Study

BackgroundDetection of mandibular range of motion variations in infants may allow for early diagnosis of pathologic conditions to the temporomandibular joint. PurposeThe purpose of this study was to determine the normal ranges for maximal mouth opening (MMO) in healthy infants under 12 months of age. Study design, setting, sampleA single-group prospective cohort study of consecutive patients below 12 months of age was conducted in an outpatient setting at the Florida Craniofacial Institute in Tampa, Florida. Patients were excluded if they had trismus, presented with signs of obstructive sleep apnea, suffered a facial fracture, or were diagnosed with a craniofacial syndrome. Predictor/exposure/independent variableAge (in months) at the time of presentation, measured as a continuous variable. Main outcome variable(s)The main outcome variable was MMO. This was measured by placing a thumb and forefinger in the infant’s mouth and apply slight pressure to encourage maximal mouth opening. In older infants with erupted central incisors, MMO was measured from the gingival margins. CovariatesThe covariates were sex, race, and gestational age. AnalysesFindings were presented as means with 95% confidence intervals. A multivariate linear regression analysis was conducted to evaluate changes in MMO with increasing age. ResultsThe sample was composed of 151 infants with a mean age of 5.2 months (95% CI 4.8 to 5.6), and 33% were female. The mean MMO was 32.1 mm (95% CI 31.5 to 32.7). Results of the linear regression analysis showed MMO to significantly increase with increasing age, increasing at a mean rate of approximately 1 mm per month (coefficient 1.06, 95% CI 0.88 to 1.23, p<0.001). In neonates <1 month of age, the mean MMO was 22.0 mm (95% CI 20.4-23.6), compared to a mean of 36.7 mm (95% CI 34.8-38.6) in infants 11 months of age. Conclusions and RelevanceThe results of this study provide normative data of the association of age with MMO, which may be of value in assessing for infants with jaw mobility disorders.

Risk Factors for Hardware Removal Following Bimaxillary Surgery: A National Database Analysis.

Orthognathic surgery typically relies on the rigid fixation of fracture fragments using metal hardware. Though hardware is usually intended to be implanted permanently, the removal of hardware (ROH) is sometimes indicated for a variety of reasons. The authors sought to identify risk factors for ROH following orthognathic surgery. The authors conducted a retrospective analysis of the Merative MarketScan Research Databases, 2007-2021 using Current Procedural Terminology (CPT) and International Classification of Disease (ICD-9 and ICD-10) codes to identify patients who underwent an index Le Fort 1 osteotomy and bilateral sagittal split osteotomy operation on the same day. Statistical analysis involved χ2, Shapiro-Wilk, Wilcoxon-Mann-Whitney, Poisson regression, and multivariable logistic regression tests. 4698 patients met the inclusion criteria. The mean age at surgery was 25 years, and 57% were female. ROH occurred in 5.9% of patients. The mean time to hardware removal was 190.5±172.4 days. In a multivariate logistic regression, increased odds of ROH were associated with older patient age [OR: 1.02 (1.01-1.03), P=0.046], sleep apnea [OR: 1.62 (1.13-2.32), P=0.018], and craniofacial syndrome and/or cleft diagnoses [OR: 1.88 (1.14-2.55), P<0.001]. In the same model, postoperative oral antibiotic prophylaxis was not associated with ROH (P=0.494). The incidence of all-cause complications [IRR: 1.03 (1.01-1.05), P<0.001] rose over the study period, while the incidence of ROH did not change significantly (P=0.281). Patients at elevated risk should be counseled on the increased possibility of a second operation for ROH before having orthognathic surgery to ensure expectations and health care utilization decisions align with the evidence.

Clinical and Treatment History of Patients with Partial DiGeorge Syndrome and Autoimmune Cytopenia at Multiple Centers.

Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation. Objectives of this study were to characterize the natural history, immune phenotype, and biomarkers in pDGS with AIC. Data on clinical presentation, disease severity, immunological phenotype, treatment selection, and response for patients with pDGS with AIC were collected via retrospective chart review. Flow cytometric analysis was done to assess T and B cell subsets, including biomarkers of immune dysregulation. Twenty-nine patients with the diagnosis of pDGS and AIC were identified from 5 international institutions. Nineteen (62%) patients developed Evan's syndrome (ES) during their clinical course and twenty (69%) had antibody deficiency syndrome. These patients demonstrated expansion in T follicular helper cells, CD19hiCD21lo B cells, and double negative cells and reduction in CD4 naïve T cells and regulatory T cells. First-line treatment for 17/29 (59%) included corticosteroids and/or high-dose immunoglobulin replacement therapy. Other overlapping therapies included eltrombopag, rituximab, and T cell immunomodulators. AIC in pDGS is often refractory to conventional AIC treatment paradigms. Biomarkers may have utility for correlation with disease state and potentially even response to therapy. Immunomodulating therapies could be initiated early based on early immune phenotyping and biomarkers before the disease develops or significantly worsens.

Behavioral Phenotypes and Comorbidity in 3q29 Deletion Syndrome: Results from the 3q29 Registry.

3q29 deletion syndrome (3q29del) is associated with a significantly increased risk for neurodevelopmental and neuropsychiatric disorders. However, the full spectrum of behavioral phenotypes associated with 3q29del is still evolving. Individuals with 3q29del (n = 96, 60.42% male) or their guardian completed the Achenbach Child or Adult Behavior Checklist (CBCL/ABCL) via the online 3q29 registry (3q29deletion.org). Typically developing controls (n = 57, 49.12% male) were ascertained as a comparison group. We analyzed mean performance on the CBCL/ABCL for individuals with 3q29del and controls across composite, DSM-keyed, and developmental scales; and the relationship between CBCL/ABCL performance and clinical and developmental phenotypes for individuals with 3q29del. Individuals with 3q29del showed significantly elevated behavioral and developmental impairment relative to controls across CBCL/ABCL domains. A substantial proportion of study participants with 3q29del scored in the Borderline or Clinical range for composite and DSM-keyed scales, indicating significant behavioral problems that may require clinical evaluation. We found that the preschool CBCL DSM-keyed autism spectrum problems scale is a potential screening tool for autism spectrum disorder (ASD) for individuals with 3q29del; CBCL/ABCL DSM-keyed scales were not accurate screeners for anxiety disorders or attention-deficit/hyperactivity disorder (ADHD) in our study sample. We identified a high degree of psychiatric comorbidity in individuals with 3q29del, with 60.42% (n = 58) of individuals with 3q29del scoring in the Borderline or Clinical range on two or more DSM-keyed CBCL/ABCL scales. Finally, we found that the degree of developmental delay in participants with 3q29del does not explain the increased behavioral problems observed on the CBCL/ABCL. The CBCL/ABCL can be used as screening tools in populations such as 3q29del, even in the presence of substantial psychiatric comorbidity. These results expand our understanding of the phenotypic spectrum of 3q29del and demonstrate an effective method for recruiting and phenotyping a large sample of individuals with a rare genetic disorder.

The first clinical validation of whole-genome screening on standard trophectoderm biopsies of preimplantation embryos

The first clinical validation of whole-genome screening on standard trophectoderm biopsies of preimplantation embryos

N6-methyladenosine-induced miR-182-5p promotes multiple myeloma tumorigenesis by regulating CAMK2N1.

Methyltransferase like 3 (METTL3) has been reported to promote tumorigenesis of multiple myeloma (MM), however, the molecular mechanism still needs further research. The N6-methyladenosine (m6A) level in tissues or cells was measured by m6A kit and dot blot assay. The mRNA and protein expression were detected by quantitative real-time PCR (RT-qPCR) and Western blot, respectively. The cell counting kit-8 and colony formation assay were used to detect the cell proliferation. Coimmunoprecipitation (Co-IP) experiment verified the binding of two proteins. The luciferase reporter experiment demonstrated the targeted binding of miR-182-5p and CaMKII inhibitor 1 (CAMK2N1). More importantly, tumor growth was measured in xenograft mice. Our data showed that the expression of METTL3 was significantly increased in MM patients' samples and MM cells. METTL3 overexpression promoted MM cells proliferation, and METTL3 knockdown inhibited MM cells proliferation. Mechanically, METTL3-dependent m6A participated in DiGeorge syndrome critical region 8 (DGCR8)-mediated maturation of pri-miR-182. Upregulation of miR-182-5p further enhanced the promoting proliferation effect of METTL3 overexpression on MM cells. Moreover, the luciferase reporter gene experiment proved that miR-182-5p targetedly regulated CAMK2N1 expression. Xenograft tumor in nude mice further verified that METTL3 promoted MM tumor growth through miR-182/CAMK2N1 signal axis. In summary, the METTL3/miR-182-5p/CAMK2N1 axis plays an important role in MM tumorigenesis, which may provide a new target for MM therapy.

Thrombospondin-1 is an endogenous substrate of cereblon responsible for immunomodulatory drug–induced thromboembolism

AbstractImmunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography–mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

Oral health knowledge, attitude and practice among parents of children with craniofacial syndromes.

Parents play an important role in caring for their children's oral health, especially for those with craniofacial deformities. In this study, we analyzed the oral health knowledge, attitude and practice (KAP) among parents of children of 1 to 16 years-of-age with craniofacial syndromes (CS) at Universiti Malaya Medical Center (UMMC), Malaysia. This was a case-controlled study conducted between March and December 2021 involving 30 parents of children with CS and 30 parents of normal children as controls. A modified validated KAP questionnaire was distributed to all parents. Statistical analysis was carried out using SPSS 26.0 and descriptive analysis was performed, with data expressed as mean, standard deviation, frequency and percentage (%). Most respondents from both groups were mothers (73.3%) between 31 to 40 years-of-age. Both groups of parents had similar levels of oral health knowledge; there was no significant difference between the two groups for 10 of the KAP questions (p > 0.05). However, there was a significant different between the two groups with regards to two 2 relating to the definition of plaque and its relationship to dental caries (p = 0.035 and p = 0.032, respectively). Some parents of CS children believed that primary teeth were not important (23.33%) and were not concerned if their children showed changes in tooth color (26.67%). Despite parental acknowledgement of ideal practice, both groups of children showed irregular dental attendance and reduced toothbrushing frequency. Parents of children with CS had a similar depth of oral health knowledge and a slightly reduced positive attitude when compared to parents in the control group. However, both groups of parents had poor knowledge relating to the transmission and causes of dental caries. Healthcare providers should increase their awareness strategies for parents to be more aware of the ways to improve their children's oral health.

Phelan-Mcdermid syndrome: Three Case Reports and a Literature Review

Phelan-McDermid syndrome (PMS) [OMIM: 606232], is a neurodevelopmental disorder commonly due to a deletion of chromosome 22q13.3. It is characterized by a neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. The CGH array was performed in three patients referred to our genetics department for an autism spectrum disorder and a facial dysmorphia with a normal constitutional karyotype. The results showed a deletion of chromosome 22. The aim of the present case reports is to address these observations in the literature and to establish the genotype-phenotype correlation underlying this syndrome.

Neurological involvement in patients with primary immunodeficiency.

Primary immunodeficiency diseases (PID) are defined by recurrent infections, allergies, autoimmunity, and malignancies. Neurologic symptoms are one of the major components of some immunodeficiency syndromes, such as Ataxia-Telangiectasia (AT), Nijmegen breakage syndrome (NBS), and Purine Nucleoside Phosphorylase (PNP) deficiency, which are considered as the primary involvement. Various pathological mechanisms, DNA repair disorders, metabolic abnormalities, and autoimmune phenomena have also been linked with neurological conditions. We retrospectively assessed the neurological involvement in 108 patients out of 6000 with PID in this study. The female/male ratio of the cases was 49/59, and the median age was 13 years (min = 1; max = 60). Neurological problems were detected at a median age of 7 years (min = 0.5; max = 30). Di George Syndrome (DGS) and CVID (common variable immunodeficiency) were the most common diseases in our cohort (n = 31, 30% and n = 30, 27%, respectively). The most frequent outcomes were cognitive delay (n = 63, 58%), epilepsy (n = 25, 23%), and ataxia (n = 20, 18%). Central nervous system involvement was found in 99% of the patients (n = 107), and peripheral nervous system complication was found in only one patient with CVID and chronic inflammatory demyelinating polyneuropathy (CDIP). Cranial MRI was found to be abnormal in 74% (n = 80) of the patients. MRI findings included cerebellar atrophy (n = 33, 34%), white matter lesion (n = 27, 28.4%), cerebral atrophy (n = 21, 22.3%), gray matter lesion (n = 6, 6.3%), hydrocephalus (n = 5, 5,3%), and pituitary gland lesion (n = 3, 3.2%), intracranial hemorrhage (n = 3, 3%), intracranial vasculitis (n = 3, 2.7%), and arterio-venous malformation (n = 1, 0,9%). Primary involvement (a component of the disease) was 60% (n = 65), and secondary (infection or autoimmunity) and tertiary involvements (structural or incidental lesions) contributed 20% (n = 20) each in the patients. In this study, we describe the various neurologic findings of patients with PID. The neurologic presentation may represent the initial manifestation of certain types of PID. Early diagnosis and treatment are essential to prevent or reduce further neurologic damages.

Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle.

Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes. Their etiology is multifactorial and characterized by overlapping genetic causes. In this chapter, we present the different genetic alterations underlying the two diseases, which range from chromosomal abnormalities like aneuploidies and structural mutations to rare singlenucleotide variations affecting distinct genes. For example, mutations in the cardiac transcription factors NKX2-5, GATA4, and HAND2 have been identified in isolated TOF cases, while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of TBX1, cause Holt-Oram and DiGeorge syndrome, respectively. Moreover, genes involved in signaling pathways, laterality determination, and epigenetic mechanisms have also been found mutated in TOF and/or DORV patients. Finally, genome-wide association studies identified common singlenucleotide polymorphisms associated with the risk for TOF.

Human Genetics of Ventricular Septal Defect.

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copynumber variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.

Endoscopic Microvascular Decompression.

Microvascular decompression is a widely accepted surgical treatment for compressive cranial nerve pathologies such as trigeminal neuralgia, hemifacial spasm, glossopharyngeal neuralgia, and other craniofacial pain syndromes. Endoscopy has risen as a safe and effective minimally invasive tool to optimize microvascular decompression. Endoscopy offers improved visualization, minimizes retraction, and allows for smaller surgical openings compared to traditional microscopic approaches. There are several reports of improved neuralgia outcomes and reduced post-operative complications after endoscopic microvascular decompression. In skilled surgical hands, endoscopy is an excellent option for microvascular decompression as stand-alone tool or adjunct to the microscope. An overview of the history, operative considerations, and techniques is provided in this chapter.

Congenital continuous retrograde basilar flow suggests type B interrupted aortic arch in a neonate: A case report

Reversed flow in the basilar artery can be acquired or congenital. Acquired reversed flow in the basilar artery can result from acute thrombosis of the basilar artery or retrograde vertebral artery flow. Congenital continuous retrograde basilar artery flow has not been described. We report a 2-day-old male presenting with hypocalcemic seizures which led us to obtain a Duplex echoencephalogram. An echocardiogram was subsequently ordered. In the coronal plane through the anterior fontanelle, retrograde flow was seen in the basilar artery and the right vertebral artery. In the axial plane through the temporal window, the flow was anteroposterior in both posterior communicating arteries. In the posterior cerebral arteries, the flow was retrograde in the P1 segment and anterograde in the P2 and P3 segments. An interrupted aortic arch was suspected. The echocardiogram showed a large perimembranous ventricular septal defect with bidirectional shunting, a hypoplastic and bicuspid aortic valve, an aortic arch interrupted between the left common carotid artery and the left subclavian artery (type B interrupted aortic arch), and a 5 mm patent ductus arteriosus with predominant right to left flow. Because of the patency of the large patent ductus arteriosus, our patient showed no sign of posterior circulation insufficiency. Prostaglandin E1 therapy was initiated immediately. Diagnosis of DiGeorge syndrome was proven. The infant underwent interrupted aortic arch repair and anterograde flow was established in the basilar artery. We conclude that congenital asymptomatic continuous retrograde flow in the basilar artery and left vertebral artery is a medical emergency as it implies the presence of type B interrupted aortic arch with large patent ductus arteriosus in a neonate.

A DiGeorge Syndrome Case Report&amp;#8212;Challenges of Diagnosis and Management

A DiGeorge Syndrome Case Report&amp;#8212;Challenges of Diagnosis and Management