DiGeorge Research Articles

Abstract 11589: Late Complications After Interrupted Aortic Arch Repair

Description of Case: A 38-year-old man with known type B interrupted aortic arch (IAA), bicuspid aortic valve, and a complex surgical history (including IAA repair with an ascending-descending aortic conduit, later conduit graft revision, and left pulmonary artery [LPA] stent) presented after many years of loss to follow-up and was found to have hypertensive urgency. Echocardiogram showed turbulent flow in the proximal descending aorta concerning for arch obstruction. Computed tomography angiography (CTA) (Fig. 1 A–C) showed: narrowed proximal graft anastomosis, dilation of the aortic root and ascending aorta, a large pseudoaneurysm arising from the distal graft anastomosis, and LPA stenosis due to compression from the descending aorta. Following improved hypertension, the patient underwent placement of a left carotid-subclavian bypass graft followed by thoracic endovascular aortic repair (TEVAR) with an endograft positioned across the distal aortic jump graft suture line. CTA one month postoperatively (Fig. 1 D–F) confirmed exclusion of the pseudoaneurysm. Discussion: Type B IAA is considered the most common subtype of IAA among cases diagnosed in infancy, though recent data regarding IAA epidemiology are scarce. IAA is associated with other congenital abnormalities, such as ventricular septal defect (VSD), LV outflow tract abnormalities, and 22q11 deletion syndrome. Additional surgical aortic arch procedures in these patients are not uncommon, perhaps especially among patients who required reintervention for LV outflow tract obstruction. While most studies examining long-term outcomes after IAA repair have not commented specifically on late risk of aneurysm or pseudoaneurysm, such findings have been described in the literature. Additionally, use of polytetrafluoroethylene material in arch repair and arch repair by a method other than direct anastomosis—such as were seen in our patient—have been observed to be risk factors for late reintervention.

STAG2 Somatic Mutations Are Associated with Specific Dysplastic Megakaryocytic and Myeloid Cell Features in Myelodysplastic Syndrome

Introduction: Although myelodysplastic neoplasms/myelodysplastic syndromes (MDS) are driven by genetic mutations, their diagnosis relies on morphologic evaluation of abnormal hematopoiesis in the bone marrow. Only a small number of genetic abnormalities define bone marrow morphologic features in MDS, such as those harboring SF3B1 mutations and deletions of chromosome 5q. We hypothesized that there are additional genetic alterations and dysplastic morphologic features in MDS that have not been well-described in the literature. We assessed genetic morphologic associations between 50 commonly mutated genes and 10 morphologic features in a cohort of MDS bone marrows with a high degree of dysplasia. We validated and extended these findings in an independent cohort of myeloid neoplasms. STAG2 mutations were strongly associated with specific dysplastic megakaryocytic and myeloid cell features in both cohorts. Methods: We reviewed bone marrow core biopsies and aspirates from 272 MDS clinical cases (2013-2014) and selected 89 for further study based on the presence of prominent dysplastic features. Each case was independently evaluated by two pathologists for the following dysplastic features: small hypolobated megakaryocytes, widely separated megakaryocyte nuclei; abnormal myeloid nuclear segmentation, myeloid hypogranulation, Auer rods; ring sideroblasts, erythroid binucleation, irregular erythrocyte nuclei, erythroid nuclear cytoplasmic dyssynchrony, and erythroid karyorrhexis. Targeted next generation sequencing was performed using a 50 gene panel comprising the most common somatic myeloid mutations. For each dysplastic feature, univariate risk analysis was used to identify genetic mutations for use in multivariable analysis. Significant associations were validated through blinded morphologic review in an independent cohort of 155 bone marrow biopsies of myeloid neoplasms, comprised of 83 myelodysplastic syndromes, 33 myelodysplastic/myeloproliferative neoplasms and 39 acute myeloid leukemias, diagnosed between 2014 and 2019 and selected for mutations identified in the initial discovery cohort ( STAG2, RUNX1, SRSF2, ASXL1 and SETBP1) . Results: Pairwise analyses demonstrated broad patterns of genetic associations with myeloid/megakaryocytic dysplasia versus erythroid dysplasia (Panel 1). In multivariable analysis, STAG2 and SRSF2 mutations were significantly associated with megakaryocytes with widely separated nuclei ( STAG2, OR = 25.5, 95% CI [4.17, 493.5], P = 0.003; SRSF2, OR = 10.1, 95% CI [2.07, 75.0], P = 0.008). Mutations in STAG2 and SETBP1 were significantly associated with abnormal myeloid nuclear segmentation ( STAG2, OR = 7.08, 95% CI [1.94, 28.0], P = 0.003; SETBP1, OR = 12.2, 95% CI [1.29, 267.4], P = 0.04). Furthermore, STAG2 mutations were significantly associated with myeloid cell hypogranulation (OR = 12.7, 95% CI [3.10, 86.3], P = 0.002). Because this initial cohort was relatively small, which led to wide confidence intervals suggesting estimation instability, we validated and extended these findings in an independent cohort of myeloid neoplasms. In the validation cohort (enriched for mutations in STAG2, SRSF2, and SETBP1), STAG2 mutations were significantly associated with separated megakaryocyte nuclei (univariate OR = 4.18, 95% CI [1.98, 8.80], P = 0.0002), abnormal myeloid nuclear segmentation (univariate OR = 3.47, 95% CI [1.47, 8.22], P = 0.008), and myeloid cell hypogranulation (multivariable OR = 5.28, 95% CI [2.18, 13.4], P = 0.0003) (Panel 2). In contrast, morphologic associations with SRSF2 and SETBP1 mutations were not validated. Conclusion: STAG2 genetic alterations are strongly associated with the presence of separated megakaryocyte nuclei, abnormal myeloid nuclear segmentation and myeloid cell hypogranulation in MDS. Our data suggest that STAG2 may affect pathways involved in nuclear shape control and secondary granule formation. Panel 1: Pairwise associations between gene mutation and bone marrow morphology in MDS. N, number. Panel 2: Multivariable (black) and univariate (white) analysis in two independent cohorts showing significant gene associations with megakaryocytes with separated nuclei, abnormal myeloid nuclear segmentation, and myeloid cell hypogranulation. CI, confidence interval.

The surgical treatment of velopharyngeal insufficiency in patients with velo cardio facial syndrome

The surgical treatment of velopharyngeal insufficiency in patients with velo cardio facial syndrome

Brain Gene Co-Expression Network Analysis Identifies 22q13 Region Genes Associated with Autism, Intellectual Disability, Seizures, Language Impairment, and Hypotonia.

Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder caused by 22q13 region deletions or SHANK3 gene variants. Deletions vary in size and can affect other genes in addition to SHANK3. PMS is characterized by autism spectrum disorder (ASD), intellectual disability (ID), developmental delays, seizures, speech delay, hypotonia, and minor dysmorphic features. It is challenging to determine individual gene contributions due to variability in deletion sizes and clinical features. We implemented a genomic data mining approach for identifying and prioritizing the candidate genes in the 22q13 region for five phenotypes: ASD, ID, seizures, language impairment, and hypotonia. Weighted gene co-expression networks were constructed using the BrainSpan transcriptome dataset of a human brain. Bioinformatic analyses of the co-expression modules allowed us to select specific candidate genes, including EP300, TCF20, RBX1, XPNPEP3, PMM1, SCO2, BRD1, and SHANK3, for the common neurological phenotypes of PMS. The findings help understand the disease mechanisms and may provide novel therapeutic targets for the precise treatment of PMS.

Living with and managing seizures among parents of children diagnosed with Phelan-McDermid syndrome: a qualitative study using in-depth interviews.

To describe the experience of parents of children diagnosed with Phelan-McDermid syndrome (PMS) in relation to epileptic seizures and/or convulsions, their daily management and impact on family life. A qualitative descriptive study was conducted. The study included parents of children diagnosed with PMS by a medical specialist. Purposive sampling was used, and data were collected via in-depth interviews. A thematic analysis was performed on the data. This study was conducted according to the Standards for Reporting Qualitative Research. Thirty-two parents were recruited. Four themes were identified: (a) the first epileptic seizure, where the first seizure appears abruptly and unexpectedly; (b) living with seizures, seizures generate high concern about the evolution of the disease and the future of children with PMS; (c) treatment of epileptic seizures, obtaining an adequate treatment is a long process that involves decision making by parents; (d) the impact of epilepsy on the family, where there is a change in the functioning and relationships among family members. Conclusions: It is necessary to develop programs where parents can discuss treatment decisions with professionals and provide coping strategies for the management of epilepsy and seizures. What is Known: • Children with Phelan-McDermid syndrome may develop epilepsy. Parents receive insufficient information for the management and control of seizures. • Parents describe concerns about the evolution of epilepsy in their children's adulthood, along with the impact of seizures and/or convulsions on their children. What is New: • Epilepsy and seizures force the entire family to adapt their lifestyle and give up activities that can trigger seizures. • Parents pointed out the need to create programs to inform about the benefits and disadvantages of pharmacological treatments in order to improve decision making.

Gait Abnormalities in Children with Phelan-McDermid Syndrome.

Background: Phelan-McDermid syndrome is a genetic disorder caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 and is characterized by autism spectrum disorder, intellectual disability, speech and language abnormalities, hypotonia, and mild dysmorphic features. Early literature in Phelan-McDermid syndrome did not include gait abnormalities as part of the syndrome although recent prospective studies report that the prevalence of gait abnormalities ranges from 55% to 94%. We compared gait abnormalities in individuals with Phelan-McDermid syndrome, idiopathic autism spectrum disorder, and typically developing controls, and explored associations between gait abnormalities, autism spectrum disorder, and intellectual functioning. Method: The study cohort consists of 67 participants between the ages of 3 and 18 years, divided into 3 groups: Phelan-McDermid syndrome (n = 46), idiopathic autism spectrum disorder (n = 11), and typically developing controls (n = 10). Gait was recorded using a video camera and scored across 26 gait features using a "Gait Clinical Observations scale" designed specifically for this study. Results: Gait abnormalities were significantly higher in the Phelan-McDermid syndrome group as compared to idiopathic autism spectrum disorder or typically developing controls. The number of gait abnormalities across groups was also significantly correlated with Intellectual Quotient/Developmental Quotient (IQ/DQ). In analysis of covariance including IQ/DQ, the effect of group was not significant, but the effect of IQ/DQ was significant. Conclusions: Overall differences in gait abnormalities were determined by the degree of intellectual disability, which was significantly higher in Phelan-McDermid syndrome.

Hematological aberrations in patient with Jacobsen syndrome

Hematological aberrations in patient with Jacobsen syndrome

SETting up the genome: KMT2D and KDM6A genomic function in the Kabuki syndrome craniofacial developmental disorder.

Kabuki syndrome is a congenital developmental disorder that is characterized by distinctive facial gestalt and skeletal abnormalities. Although rare, the disorder shares clinical features with several related craniofacial syndromes that manifest from mutations in chromatin-modifying enzymes. Collectively, these clinical studies underscore the crucial, concerted functions of chromatin factors in shaping developmental genome structure and driving cellular transcriptional states. Kabuki syndrome predominantly results from mutations in KMT2D, a histone H3 lysine 4 methylase, or KDM6A, a histone H3 lysine 27 demethylase. In this review, we summarize the research efforts to model Kabuki syndrome in vivo to understand the cellular and molecular mechanisms that lead to the craniofacial and skeletal pathogenesis that defines the disorder. As several studies have indicated the importance of KMT2D and KDM6A function through catalytic-independent mechanisms, we highlight noncanonical roles for these enzymes as recruitment centers for alternative chromatin and transcriptional machinery.

Incidental finding at methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA): how to proceed?

Introduction: Since the advent of new generation sequencing, professionals are aware of the possibility of obtaining findings unrelated to the pathology under study. However, this possibility is usually forgotten in the case of studies aimed at a single gene or region. We report a case of a 16-month-old girl with clinical suspicion of Silver-Russell syndrome (SRS). Methods: Following the international SRS consensus, methylation alterations and copy number variations (CNVs) at 11p15 region and maternal uniparental disomy of chromosome 7 were analysed and discarded by MS-MLPA. Results: Unexpectedly, the 11p15 region MS-MLPA showed a decrease in the signal of a copy number reference probe. Deletions affecting a single probe are inconclusive. So, we faced the ethical dilemma of whether it was appropriate to confirm this alteration with independent techniques and to offer a diagnostic possibility that was in no way related to clinical suspicion. Fortunately, in this particular case, the informed consent had not been specific to a particular pathology but to any disorder associated with growth failure. Performed alternative studies allowed the final diagnosis of 22q deletion syndrome. Conclusion: We demonstrate the importance of informing patients about the possibility of obtaining incidental findings in genetic techniques (not only in next generation sequencing) during pre-test genetic counselling consultations. In addition, we highlight the relevance of including in the informed consent the option of knowing these unexpected incidental findings as in some cases, this will help to elucidate the definitive diagnosis and provide the correct follow-up and treatment.

5.25 Psychiatric Comorbidities Among Adolescents With DiGeorge Syndrome: Prevalence and Healthcare Utilization Analysis

5.25 Psychiatric Comorbidities Among Adolescents With DiGeorge Syndrome: Prevalence and Healthcare Utilization Analysis

Assessing Complication Risk of Pressure Equalizing Tube Placement in Children With Velocardiofacial Syndrome (22q11.2 Deletion Syndrome/DiGeorge Syndrome).

Persistent tympanic membrane perforation is a known complication of pressure-equalizing (PE) tube insertion. Conductive hearing loss and otorrhea can necessitate surgical repair of these perforations. Long-term tympanostomy tube placement can increase the risk of these complications. Patients with velocardiofacial syndrome (VCFS) typically require prolonged PE tube placement and are thought to have higher risk of requiring additional otologic interventions after PE tube placement. To date, no work has established rates of post-PE tube complications requiring myringoplasty or tympanoplasty in patients with VCFS. A retrospective case review including all patients with VCFS at a single large children's hospital between the years 2000 and 2020 was performed. Number of PE tube insertions required and additional otologic interventions performed were the primary endpoints assessed. Of 212 total patients with VCFS, 66 (31%) underwent PE tube placement. Of these children, 46 (70%) required 2 or more sets of PE tubes. A total of 53 patients (80.3%) required no otologic interventions apart from PE tube insertions. Of the 13 patients (19.7%) requiring additional otologic surgery, 6 (9.5%) underwent myringoplasty, and 9 patients (13.6%) required tympanoplasty. There was no significant difference in tympanoplasty (P > 1), myringoplasty (P > 1), or other surgical intervention rates (P = .7464) between VCFS patients with any type of cleft palate versus those with anatomically normal palates. This work suggests that most VCFS patients that require tubes, require at least 2 sets of PE tubes, and that the rate of post-PE tube complications requiring further otologic surgery is an order of magnitude higher than the rate established at this institution. Counseling for PE tube placement in VCFS patients may require specific dialogue regarding the substantially increased risk of complications and effort to build appropriate expectations for surgical outcomes regardless of palatal status.

Sella Turcica Bridging and its Association with Dental Anomalies - An Update

: The Sella turcica is an anatomical structure shaped explicitly like a saddle, located within the middle cranial fossa on the intracranial surface of the sphenoid bone. This structure is commonly observed on lateral cephalograms, frequently employed for orthodontic diagnosis. The Cephalometric radiographs utilize various landmarks as reference points to examine craniofacial structures and Sella Turcica (ST) is the most significant and reliable cranial landmark. The Sella point, located at the midpoint of the ST structure, is a cranial base point that accommodates the pituitary gland. The cephalometric analysis relies on this factor to identify pituitary gland-related pathologies, making it a valuable source of information for craniofacial syndromes. Facial structure development exhibits comparable characteristics to the Sella turcica. Glandular abnormalities possess the potential to be linked to functional disorders, which can result in altered hormonal levels affecting dental growth. Comprehensive understanding of the radiological anatomy and variations help assess growth and identify changes in various anomalies or pathological conditions. Additionally, it can assist in predicting the potential outcome of orthodontic treatment. The objective of this review is to determine and update whether a correlation exists between the bridging of Sella turcica and various dental anomalies related to the shape, size, structure, number, and eruption of teeth. In conclusion, it was noted that Sella turcica bridging is frequently observed in orthodontic patients measuring a clear correlation between dental anomalies and Sella bridging. Key words: Sella Turcica Bridging; Dental Anomalies; Genetics; Lateral Cephalogram; Orthodontist.

Судомний синдром у підлітка як прояв синдрому делеції 22q11.2

22q11.2 deletion syndrome (DiGeorge syndrome) is one of the most common chromosomal abnormalities, which is characterized by multiplicity and variability of damage to various organs and systems: cardiovascular, immune, nervous, endocrine, skeletal. Purpose - to increase doctors' awareness regarding the diagnosis of 22q11.2 deletion syndrome in patients with seizure disorder based on a clinical case analysis. Here we report a clinical case of DiGeorge syndrome (22q11.2 deletion syndrome) in a boy with seizures diagnosed at the age of 14 years by genetic testing because of suspected epileptic encephalopathy. Diagnosed hypofunction of the parathyroid gland and hypocalcemia are obviously the cause of seizures and required a change in treatment. Despite the presence of T- and B-lymphopenia, the boy did not have a frequent infectious syndrome. The absence of defining signs of the 22q11.2 deletion syndrome at an early age, namely the absence of data for a congenital heart defect, pronounced facial dysmorphias, frequent infections, did not give an opportunity to suspect this syndrome at an early age. Taking into account the prevalence, multiplicity and variability of the lesion and the varying degree of severity of clinical manifestations in 22q11.2 deletion syndrome, patients with this syndrome can be found in the practice of every doctor. With seizures in combination with developmental disorders, it is necessary to rule out 22q11.2 deletion syndrome at any age. Wider awareness of the dysmorphic and clinical manifestations of this syndrome will allow better diagnosis of this disease, which requires a multidisciplinary approach to management. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors.

Finnish children who needed long-term home respiratory support had severe sleep-disordered breathing and complex medical backgrounds.

No studies have described long-term paediatric home respiratory support in Nordic countries. We examined the clinical characteristics and long-term outcomes of paediatric patients who received continuous positive airway pressure, non-invasive-positive-pressure ventilation and invasive ventilation from a multidisciplinary home respiratory support team. Retrospective tertiary-level data were collected between 1 January 2010 and 31 December 2020 in Tampere University Hospital. These comprised patient demographics, treatment course and polysomnography-confirmed sleep-disordered breathing (SDB). There were 93 patients (63.4% boys). The median age at treatment initiation was 8.4 (range 0.11-16.9) years. The patients had: neuromuscular disease (16.1%), central nervous system disease (14.0%), developmental disabilities and congenital syndrome (29.0%), lung-airway conditions (11.8%), craniofacial syndrome (15.1%) and severe obesity (14.0%). More than two-thirds had severe SDB (66.7%) and the most common one was obstructive sleep apnoea in 66.7%. We found that 92.5% received long-term therapy for more than 3 months and the mean treatment duration was 3.3 ± 2.7 years. A non-invasive mask interface was used in 94.7% of cases and 5.3% needed tracheostomy ventilation. More than a quarter (26.7%) achieved disease resolution during the study period. Most children who needed long-term home respiratory support had complex conditions and severe, persistent SDB.

Drugs prescribed for Phelan-McDermid syndrome differentially impact sensory behaviors in shank3 zebrafish models.

Background: Altered sensory processing is a pervasive symptom in individuals with Autism Spectrum Disorders (ASD); people with Phelan McDermid syndrome (PMS), in particular, show reduced responses to sensory stimuli. PMS is caused by deletions of the terminal end of chromosome 22 or point mutations in Shank3. People with PMS can present with an array of symptoms including ASD, epilepsy, gastrointestinal distress, and reduced responses to sensory stimuli. People with PMS are often medicated to manage behaviors like aggression and/or self-harm and/or epilepsy, and it remains unclear how these medications might impact perception/sensory processing. Here we test this using zebrafish mutant shank3ab PMS models that likewise show reduced sensory responses in a visual motor response (VMR) assay, in which increased locomotion is triggered by light to dark transitions. Methods: We screened three medications, risperidone, lithium chloride (LiCl), and carbamazepine (CBZ), prescribed to people with PMS and one drug, 2-methyl-6-(phenylethynyl) pyridine (MPEP) tested in rodent models of PMS, for their effects on a sensory-induced behavior in two zebrafish PMS models with frameshift mutations in either the N- or C- termini. To test how pharmacological treatments affect the VMR, we exposed larvae to selected drugs for 24 hours and then quantified their locomotion during four ten-minute cycles of lights on-to-off stimuli. Results: We found that risperidone normalized the VMR in shank3 models. LiCl and CBZ had no effect on the VMR in any of the three genotypes. MPEP reduced the VMR in wildtype (WT) to levels seen in shank3 models but caused no changes in either shank3 model. Finally, shank3 mutants showed resistance to the seizure-inducing drug pentylenetetrazol (PTZ), at a dosage that results in hyperactive swimming in WT zebrafish. Conclusions: Our work shows that the effects of drugs on sensory processing are varied in ways that can be highly genotype- and drug-dependent.

Синдром Ди Джорджи: ранняя диагностика в практике педиатра

Введение. Синдром Ди Джорджи объединен в группу под термином «синдром делеции хромосомы 22q11.2». Он относится к комбинированным первичным иммунодефицитам с синдромальными проявлениями. Фенотип синдрома Ди Джорджи необычайно вариабелен даже среди родственников. Симптомы синдрома Ди Джорджи могут различаться как по степени тяжести, так и по типам. Некоторые признаки могут быть выявлены при рождении, например, расщелина нёба или врожденный порок сердца, в то время как другие диагностируются у детей в старшем возрасте. В статье представлены данные современной литературы, собственные данные, в качестве клинического примера приведено описание наблюдения ребенка 8 лет с синдромом Ди Джорджи. Цель работы. Проведение анализа клинических особенностей детей с синдромом Ди Джорджи на основе базы данных родителей. Материалы и методы. Нами проанализирована база данных о 135 детях с синдромом Ди Джорджи, которая ведется родителями пациентов, проживающих на территории Российской Федерации. Математическая обработка данных производилась в таблицах Microsoft Office Excel. Результаты. В ходе анализа клинических особенностей синдрома Ди Джорджи у детей нами выявлено, что наиболее часто встречались врожденные пороки и аномалии развития сердца (81%), из которых большую часть составляли конотрункальные пороки (57%), а также врожденные пороки других органов и систем (33%), нарушение походки (21%), гипо-/аплазия тимуса (18%), грыжи (17%), офтальмологическая патология (14%), тугоухость (6%), гипоплазия зубной эмали (3,7%). Среди других врожденных пороков и аномалий чаще всего встречались пороки костной ткани (37%) и мочеполовой системы (24%), пороки желудочно-кишечного тракта (17%). Отмечена высокая частота встречаемости расщелин нёба (74%) среди пороков костной ткани. У детей с синдромом Ди Джорджи выявлена высокая частота встречаемости офтальмологической патологии, а именно: астигматизм (50%), ангиопатия сетчатки (20%), колобома радужки (5%), косоглазие (15%). Заключение. Анализ базы данных анкет позволил выделить основные и дополнительные диагностически значимые симптомы синдрома Ди Джорджи, на которые необходимо обращать внимание при первичном осмотре любого пациента с подозрением на иммунодефицит. Особое внимание в диагностическом плане следует уделять детям с иммунодефицитами, которые родились до 2023 г. В связи с тем что все большее число пациентов с синдромом Ди Джорджи доживает до взрослого возраста, важна разработка алгоритмов прогноза данного заболевания. Background. Di Giorgi syndrome is grouped under the term chromosome 22q11.2 deletion syndrome (22q11.2DS). It refers to combined primary immunodeficiencies with syndromal manifestations. The phenotype of 22q11.2DS is unusually variable, even among relatives. The symptoms of 22q11.2DS can vary in both severity and type. Some features may be identified at birth, such as cleft palate or congenital heart defect, while others are diagnosed in older children. The article presents data from the current literature, our own data, and a description of our clinical observation of an 8-year-old child with 22q11.2DS. Objective. The aim of the study is to analyze the clinical features of children with 22q11.2DS on the basis of the parents' database. Materials and methods. We analyzed a database of 135 children with 22q11.2DS maintained by parents of patients living in the Russian Federation. Mathematical processing of the data was performed in Microsoft Office Excel tables. Results. In analyzing the clinical features in children with 22q11.2DS, we found that congenital heart malformations and anomalies were the most common (81%), of which conotruncal malformations accounted for the majority (57%), as well as congenital malformations of other organs and systems (33%), gait disorders (21%), thymus hypo-/aplasia (18%), hernias (17%), ophthalmologic pathology (14%), hearing loss (6%), and dental enamel hypoplasia (3.7%). Among other congenital malformations and anomalies, bone (37%), genitourinary (24%), and gastrointestinal (17%) malformations were the most common. There was a high incidence of cleft palate (74%) among bone malformations. Children with 22q11.2DS have a high incidence of ophthalmologic pathology: astigmatism (50%), retinal angiopathy (20%), iris coloboma (5%), and strabismus (15%). Conclusion. The analysis of the questionnaire database allowed us to identify the main and additional diagnostically significant symptoms of 22q11.2DS, which should be paid attention to during the initial examination of any patient with suspected immunodeficiency. Special diagnostic attention should be paid to immunodeficient children born before 2023. Due to the fact that an increasing number of patients with 22q11.2DS survive to adulthood, the development of algorithms for the prognosis of this disease is important.

External genitalia phenotypes of a Mab21l1-null mouse model for cerebellar, ocular, craniofacial, and genital (COFG) syndrome.

The cerebellar, ocular, craniofacial, and genital (COFG) syndrome is a human genetic disease that is caused by MAB21L1 mutations. A COFG mouse model with Mab21l1-null mutation causes severe microphthalmia and fontanelle dysosteogenesis, similar to the symptoms in human patients. One of the typical symptoms is scrotal agenesis in male infants, while male Mab21l1-null mice show hypoplastic preputial glands, a rodent-specific derivative of the cranial scrotal fold. However, it is still unclear where and how MAB21Ll acts in the external genitalia in both mice and humans. Here we show that, at the neonatal stage, MAB21L1 expression in the external genitalia was restricted to two mesenchymal cell populations-underneath the scrotal and labial skin and around the preputial and clitoral glands (PG/CG). Morphometric analyses of the Mab21l1-/- pups revealed a significant reduction in the external size of the scrotum, vulva, and CG, as well as PG. In the periglandular region around PG and CG, the periglandular mesenchymal cells showed a drastic reduction in both cell density and immunoreactive signals for several extracellular matrix proteins (e.g., collagen I, fibronectin, and proteoglycans), together with their reduced Ki67-positive cell proliferation index. In the Mab21l1-/- PG/CG, together with reduced vascularization, the glandular epithelia displayed atrophy with discontinuous basal lamina along the basal surface and defective glycogen accumulation in their cytoplasm. Under a 5-day organ culture of the isolated PG, the Mab21l1-/- explants showed poor outgrowth and retention of the glandular structure in vitro. However, the addition of exogenous Matrigel could partially rescue such tissue-autonomous phenotypes, showing glandular morphology similar to that of the wild-type explants. These findings suggest that MAB21L1+ mesenchymal cells play a crucial role in providing nutrient ECM support for glandular outgrowth and morphogenesis in the peripheral external genitalia.

C6 (Clinical Case) A 5-Year-Old with Headbanging and Hemiparesis

Abstract Introduction/Background A 5-year-old boy had a medical history of Phelan-McDermid syndrome; and with that associated autism spectrum disorder; severe, medication-resistant headbanging; and type 1 diabetes. He presented to community hospital with acute onset inability to walk, irritability, and vomiting. Case Description On examination he had left arm weakness and truncal ataxia. CT head identified a left cerebellar infarction. He was transferred to the local children’s hospital, and CT angiogram showed left PICA proximal occlusion. Due to diagnostic delay, the infarct was not amenable to endovascular intervention. Initial management was neuroprotective care, and given his history of headbanging and the risk of further trauma, only ASA monotherapy. MR brain visualized a left vertebral artery dissection, the stroke’s likely cause. Other causes were ruled out with normal echocardiogram and thrombophilia work-up, including antiphospholipid panel. Genetic analysis was negative for connective tissue diseases, bleeding or clotting disorders. On day 5 of admission, he acutely developed worsened left arm weakness and inability to bear weight. Repeat brain imaging showed new bilateral medial thalamic infarcts and diffusion restriction within the right putamen. Given this progression, despite the risk of bleeding, heparin was initiated. On day 9, repeat CT head identified a new lacunar infarct. On day 14, repeat MRI confirmed clinical stability, and he was switched from heparin to enoxaparin. After 27 days, he was discharged for home-based rehabilitation. His three-month follow-up MRI was stable, and anticoagulation was discontinued, while he remained on ASA only. Discussion There is no known association between Phelan-McDermid syndrome and cerebrovascular diseases. However, self-injurious behaviour, such as head banging, is not uncommon in the paediatric population, particularly among neurodiverse patients. These behaviours, in and of themselves, can cause significant injury and morbidity. The case shows how severe headbanging may have caused vertebral artery dissection with thromboembolic consequences. As such, for patients who demonstrate self-injurious behaviour, it is important to counsel these patients and families on potential harms, and inform efforts to mitigate risk, where possible. In cases of acute change to neurological status, stroke should remain on the differential diagnosis, and brain imaging should be considered. Time to central imaging affects therapeutic opportunities, as exemplified in this case where, due to delays in obtaining imaging, endovascular therapy was not an option for the patient. Conclusion Many children engage in self-injurious behaviour that can, as in this case, cause devastating consequences. Clinicians should remain wary of change in neurologic status and have low thresholds for central nervous system imaging, especially for patients with non-verbal communication.

Abnormal developmental trajectory and vulnerability to cardiac arrhythmias in tetralogy of Fallot with DiGeorge syndrome

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Ventricular dysfunction and cardiac arrhythmias are well-documented complications in patients with repaired TOF. Whether intrinsic abnormalities exist in TOF cardiomyocytes is unknown. We establish human induced pluripotent stem cells (hiPSCs) from TOF patients with and without DiGeorge (DG) syndrome, the latter being the most commonly associated syndromal association of TOF. TOF-DG hiPSC-derived cardiomyocytes (hiPSC-CMs) show impaired ventricular specification, downregulated cardiac gene expression and upregulated neural gene expression. Transcriptomic profiling of the in vitro cardiac progenitors reveals early bifurcation, as marked by ectopic RGS13 expression, in the trajectory of TOF-DG-hiPSC cardiac differentiation. Functional assessments further reveal increased arrhythmogenicity in TOF-DG-hiPSC-CMs. These findings are found only in the TOF-DG but not TOF-with no DG (ND) patient-derived hiPSC-CMs and cardiac progenitors (CPs), which have implications on the worse clinical outcomes of TOF-DG patients.

Adaptive behaviour deficits in individuals with 3q29 deletion syndrome.

3q29 deletion syndrome (3q29del) is associated with a significantly increased risk for neurodevelopmental and neuropsychiatric phenotypes. Mild to moderate intellectual disability (ID) is common in this population, and previous work by our team identified substantial deficits in adaptive behaviour. However, the full profile of adaptive function in 3q29del has not been described nor has it been compared with other genomic syndromes associated with elevated risk for neurodevelopmental and neuropsychiatric phenotypes. Individuals with 3q29del (n=32, 62.5% male) were evaluated using the Vineland Adaptive Behaviour Scales, Third Edition, Comprehensive Parent/Caregiver Form (Vineland-3). We explored the relationship between adaptive behaviour and cognitive function, executive function, and neurodevelopmental and neuropsychiatric comorbidities in our 3q29del study sample, and we compared subjects with 3q29del with published data on fragile X syndrome, 22q11.2 deletion syndrome and 16p11.2 deletion and duplication syndromes. Individuals with 3q29del had global deficits in adaptive behaviour that were not driven by specific weaknesses in any given domain. Individual neurodevelopmental and neuropsychiatric diagnoses had a small effect on adaptive behaviour, and the cumulative number of comorbid diagnoses was significantly negatively associated with Vineland-3 performance. Both cognitive ability and executive function were significantly associated with adaptive behaviour, and executive function was a better predictor of Vineland-3 performance than cognitive ability. Finally, the severity of adaptive behaviour deficits in 3q29del was distinct from previously published data on comparable genomic disorders. Individuals with 3q29del have significant deficits in adaptive behaviour, affecting all domains assessed by the Vineland-3. Executive function is a better predictor of adaptive behaviour than cognitive ability in this population and suggests that interventions targeting executive function may be an effective therapeutic strategy.