DiGeorge Research Articles

Conductive hearing loss in newborns: Hearing profile, risk factors, and occasions of service.

Infants diagnosed with a conductive hearing loss (CHL) are at increased risk of developmental delays. Using a sample of infants diagnosed with CHL through UNHS, this study aimed to investigate the relationship between specific demographic or clinical characteristics and 1) occasions of service to reach a hearing diagnosis and 2) the profile of CHL. Retrospective analysis was conducted for all infants with CHL born between 01/01/2007 and 31/12/2018 who had received UNHS. Chi squared analysis was conducted on data from 1208 records. Infants with ≥1 risk factor for hearing loss were more likely to attend more than three occasions of service. Infants who were bilateral refer/medical exclusion, Torres Strait Islander, had ≥1 risk factors for hearing loss or were born pre-term had greater proportions of bilateral CHL than unilateral CHL. Mild to moderate was the most frequent degree of CHL, although a unilateral or bilateral CHL did not have an association with the severity of CHL. Compared to other risk factors, infants with a syndrome had greater proportions of bilateral than unilateral CHL. Risk factors of craniofacial abnormality, prolonged ventilation, or syndrome had greater proportions of mild to moderate CHL than moderate or greater. On average, infants were diagnosed with a CHL at 37.29 weeks of age. These findings highlight the relationship between clinical/demographic characteristics and occasions of service to diagnose CHL in children, including the CHL profile. An understanding of this relationship may help clinicians to better plan, assess and manage infants diagnosed with a CHL through UNHS.

DiGeorge syndrome critical region gene 2 (DGCR2), a schizophrenia risk gene, regulates dendritic spine development through cell adhesion

BackgroundDendritic spines are the sites of excitatory synapses on pyramidal neurons, and their development is crucial for neural circuits and brain functions. The spine shape, size, or number alterations are associated with neurological disorders, including schizophrenia. DiGeorge syndrome critical region gene 2 (DGCR2) is one of the deleted genes within the 22q11.2 deletion syndrome (22q11DS), which is a high risk for developing schizophrenia. DGCR2 expression was reduced in schizophrenics. However, the pathophysiological mechanism of DGCR2 in schizophrenia or 22q11DS is still unclear.ResultsHere, we report that DGCR2 expression was increased during the neurodevelopmental period and enriched in the postsynaptic densities (PSDs). DGCR2-deficient hippocampal neurons formed fewer spines. In agreement, glutamatergic transmission and synaptic plasticity were decreased in the hippocampus of DGCR2-deficient mice. Further molecular studies showed that the extracellular domain (ECD) of DGCR2 is responsible for its transcellular interaction with cell adhesion molecule Neurexin1 (NRXN1) and spine development. Consequently, abnormal behaviors, like anxiety, were observed in DGCR2-deficient mice.ConclusionsThese observations indicate that DGCR2 is a novel cell adhesion molecule required for spine development and synaptic plasticity, and its deficiency induces abnormal behaviors in mice. This study provides a potential pathophysiological mechanism of DGCR2 in 22q11DS and related mental disorders.

Comparison of the skeletal, dentoalveolar, and periodontal changes after Ni–Ti leaf spring expander and rapid maxillary expansion: a three-dimensional CBCT based evaluation

BackgroundThe aim of the present study was twofold:(1) three-dimensionally evaluate the quantitative skeletal and dentoalveolar changes after Ni–Ti leaf spring expander (leaf expander) and rapid maxillary expansion (RME) in mixed dentition patients;(2) analyze the modifications of the buccal alveolar bone plate of the maxillary first permanent molars.MethodsPatients who underwent CBCT scans before and after maxillary expansion were randomly selected from the records archived at the Department of Biomedical Surgical and Dental Sciences, University of Milan, Italy.Inclusion criteria were the following: no systemic disease or syndromes; maxillary transverse deficiencies (difference between the upper intermolar width and the lower intermolar width of at least 3 mm and/or clinical need based on radiographic evaluation), early mixed dentition with ages between 7 to 10 years old; cervical vertebra maturation stage (CVMS) 1 or 2; no pathologic periodontal status; skeletal class I or II; maxillary expander cemented on the upper second deciduous molars. Exclusion criteria were the following: patients with pubertal or post-pubertal stage of development (CVMS 3–6); late deciduous or late mixed dentition, impossibility to use the second primary molar as anchorage; skeletal class III malocclusion; craniofacial syndromes; patients unable to be followed during the treatment period. Twenty-three patients treated with Leaf Expander, 11 males (mean age 7.8 ± 0.6 years) and 12 females (mean age 8.1 ± 0.8 years), met the inclusion criteria and constituted the case group. Twenty-four (control group) treated with conventional RME, 12 males (mean age 8.4 ± 0.9 years) and 12 females (mean age 8.1 ± 0.7 years). The paired-sample T test was used for intra-group comparison to evaluate the difference between before (T1) and after (T2) maxillary expansion. Independent sample t-test was computed to perform between groups comparison of the skeletal, dentoalveolar, and periodontal changes.ResultsThe Leaf Expander and RME group showed a significant increase between T1 and T2 for most of the skeletal and dentoalveolar variables. Concerning the skeletal variables only the RME demonstrated a significant increase at the level of the posterior nasal (PNW) and apical base width (PABW) and maxillary mid-alveolar width (MMW). Despite this, when compare with the Leaf Expander, the RME group exhibited a statistically larger width increase for only two skeletal parameters: PNW (p = 0.03) and MMW (p = 0.02). No significant changes at the periodontal level were found in either group.ConclusionsAccording to the current research, the authors confirm the effectiveness of the Leaf Expander and RME to produce similar skeletal and dentoalveolar effects in mixed dentition subjects. Moreover, the devices anchored to deciduous teeth did not reduce the thickness and height of the buccal bone at the level of the maxillary permanent first molars in either of the two groups.

TANGO2 Deficiency Disorder: Two Cases of Developmental Delay Preceding Metabolic Crisis

BackgroundTANGO2 deficiency disorder is a rare genetic disease caused by biallelic defects in TANGO2 gene. MethodsWe report the clinical phenotype of two children with TANGO2 deficiency disorder. ResultsPatient 1 is a female child presenting with developmental delay and microcephaly during the second year of life, who evolved with severe cognitive impairment, facial dysmorphisms, spastic paraparesis, and atonic seizures. At age 13 years, she was hospitalized due to an episode of rhabdomyolysis complicated with cardiac arrhythmia and hypothyroidism. Patient 2 is a female child with dysmorphic facial features, cleft palate, and developmental delay who was diagnosed with DiGeorge syndrome. At age three years, she presented with an acute episode of severe rhabdomyolysis in the context of human herpesvirus 6 infection. After the resolution of this acute episode, she maintained recurrent muscle weakness with axial hypotonia and progressive spasticity of the lower extremities. In both patients, diagnosis of TANGO2 deficiency disorder was only confirmed after an acute metabolic crisis. ConclusionsA high index of suspicion for TANGO2 deficiency disorder is needed in patients with developmental delay or other neurological symptoms and episodic rhabdomyolysis.

Coenzyme Q10, Vitamin E and Polyvitamin B: an exploratory double-blind randomized cross-over study in Phelan-McDermid Syndrome

Aim: Defective mitochondrial function and increased oxidative stress have been documented in Autism Spectrum Disorder (ASD) and Phelan-McDermid syndrome (PMS), one of the best-known monogenic forms of ASD. The purpose of this exploratory, double-blind, randomized cross-over trial (RCT) is to verify the efficacy and safety of a “metabolic support therapy” (MST) in PMS, while defining the experimental methodology most apt at maximizing sensitivity and reliability. Methods: A total of 31 PMS patients completed 4 months of Coenzyme Q10 (50/100 mg b.i.d.) + vitamin E (30/60 mg/d) + polyvitamin B ("active compound") vs. 4 months of only Vitamins E and B ("active comparator"). To explore their sensitivity and reliability, four primary outcome measures were used: VABS, CARS, CGI-I, and VAS. Secondary outcome measures span adaptive behaviors, social cognition, autism, problem behaviors, quality of life (QoL), communication, and comorbidities. Results: CoQ10+vit. E and B yielded significantly greater improvement in several measures of cognition and adaptive functioning, motor skills, and stereotypic behaviors compared to vit. E and B only. Maternal QoL was especially improved in the presence of CoQ10 (P < 0.004). Time x Treatment interactions in CGI-I and VAS "restricted interests" scores support positive contributions also by vitamins E and B. Side effects, including hyperactivity, insomnia, and irritability, were mild, rare, and did not differ between treatment periods. Conclusion: MST may produce small-to-moderate improvement, especially in motor skills, social motivation, adaptive behaviors, responsiveness to environmental stimulation, and stereotypic behaviors in up to approximately 70% of PMS patients. A targeted confirmatory RCT contrasting Q10+vit E and B vs. inactive placebo is now warranted.

An online survey to understand the needs of caregivers of family members with 22q11 deletion syndrome.

Most individuals with 22q11.2 deletion syndrome (22q11DS) have multi-system and lifelong needs requiring substantial support. Their primary caregivers are usually family members who dedicate lifelong time and effort to their role. The pressures of their roles can negatively impact caregivers' psychosocial well-being, suggesting a need for additional support for this community who currently have no specialised interventions available. This online study surveyed 103 caregivers of family members with 22q11DS to determine the barriers to accessing support that they faced, the kind of support they would value and whether an online intervention could meet their needs. The caregivers indicated that a brief online intervention focused on teaching practical skills and connecting them with a peer network of support would be most valuable. Future studies are planned that will build on these results by designing and testing online interventions tailored to this community.

METTL14 mediates m6a modification on osteogenic proliferation and differentiation of bone marrow mesenchymal stem cells by regulating the processing of pri-miR-873.

N6-methyl-adenosine (m6a) is involved in the occurrence and development of various diseases such as autogenic immune disease and tumors. Methyltransferases regulate primary (pri)-microRNA (miRNA/miR) processing by mediating m6a modifications, consequently affecting pathological processes including immune-related diseases by regulating both innate and adaptive immune cells. However, the roles of m6a on the biological functions of bone marrow mesenchymal stem cells (BMSCs) remain to be elucidated. The relative expression levels of methyltransferase-like 14 (METTL14) and other methyltransferases, demethylases, and miR-873 in bone samples from patients with osteoporosis and from normal individuals were measured by reverse transcription-quantitative PCR. Cell Counting Kit-8 assay was used to examine the proliferation of BMSCs. Co-immunoprecipitation (Co-IP) was used to investigate the binding of METTL14 to DiGeorge syndrome critical region 8 (DGCR8). RNA immunoprecipitation (RIP) was used to examine the binding of METTL14 to pri-miR-873. METTL14 and m6a modifications were highly detected in patients with osteoporosis compared with the controls. Co-IP results indicated that silencing of METTL14 reduced METTL14 and m6a modification levels in BMSCs. Downregulation of METTL14 significantly promoted the proliferation of BMSCs. RIP results suggested that METTL14/m6a methylation modification promoted the processing of pri-miR-873 by binding to DGCR8 in BMSCs. Furthermore, overexpression of miR-873 inhibited the proliferation of BMSCs. The results also showed that miR-873 mimics significantly inhibited the proliferation in small interfering (si)-METTL14 transfected BMSCs; however, miR-873 inhibitors markedly promoted the proliferation of si-METTL14 transfected BMSCs. METTL14 and m6a modifications were upregulated in osteoporosis samples. METTL14 promoted the processing of pri-miR-873 into mature miR-873 by regulating m6a modification. Furthermore, overexpression of miR-873 significantly inhibited the proliferation of BMSCs. Therefore, the METTL14/m6a/miR-873 axis may be a potential target for the treatment of osteoporosis.

Severe Hypocalcemia in the Adolescent as the Only Manifestation of <i>22q11</i> Microdeletion Syndrome: Clinical Case

Background. In this article, we would like to describe the atypical clinical picture and course of 22q11 microdeletion syndrome in a patient without specific phenotypic signs and symptoms typical for this disease.Clinical case description. Male patient, 13 years old, was hospitalized for the first time with seizure and multiple spinal fractures caused by hypocalcemia. He was referred to rheumatologist and clinical geneticist after hospital stay. Differential diagnosis included not only various bones metabolic diseases, but also 22q11 deletion syndrome. Later it was confirmed via FISH test.Conclusion. This clinical case proves once again the uniqueness of every single case, as well as the importance of comprehensive approach to the diagnosis and management of such patients.

Updated consensus guidelines on the management of Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.

Tracheostomy experiences in chronic respiratory failure after congenital heart surgery

Introduction
 A small number of children with repaired congenital heart defects may require a tracheostomy for ongoing ventilatory support. Congenital airway anomalies, laryngomalacia, postoperative airway complications and genetic syndromes associated with airway and facial anomalies, such as DiGeorge Syndrome (22q11 deletion), can be counted among the reasons why patients are unable to be weaned from the ventilator. In this study, we aimed to define the outcomes of patients who required a tracheostomy due to chronic respiratory failure after congenital heart surgery, and the existing risk factors for in-hospital and post-discharge mortality.
 Materials and methods
 The files of 1382 patients who underwent surgery due to CHD in the Pediatric Cardiovascular Surgery Clinic in ……………., between February 2019 and February 2023, were retrospectively scanned. Patients’ age, gender, body weight, cardiac diagnosis, surgical intervention, length of stay in the intensive care unit, number of extubation attempts, total length of stay on the ventilator, need for ventilator at discharge, rates of weaning from tracheostomy and time of weaning from tracheostomy and mortality rates, were obtained from patient files and hospital database.
 Results
 Tracheostomy was performed in 15 of 1382 patients who underwent surgery during the four year study period. Mean (SD) duration of ventilation prior to tracheostomy was 35 days (IQR= 19 – 47). The median follow up time in patients was 224 days (IQR=116-538). Three patients were decannulated and six had died. Causes of death in six patients included sepsis (2), cardiac instability (1), neurological complications (2) and pulmonary haemorraghia (1). 
 The median time to discharge after tracheostomy in patients was 51 days (IQR= 33.50 – 147). 
 Eight patients (53.3%) were discharged on home ventilation. Causes of deaths were often multifactorial for children who died during their initial hospital stay. Mortality was seen in six patients, a rate of 40%. 
 Conclusion
 The need for tracheostomy after cardiac surgery plays an important role in early and late mortality in children. Ventilator-dependent chronic respiratory failure is the most common cause of childhood tracheostomies. We believe that determining the optimal timing for tracheostomy in the pediatric population will be effective in reducing prolonged ventilation and tracheostomy-related morbidities.

Description of Neuropsychological Profile in Patients with 22q11 Syndrome

Background: 22q11 deletion syndrome (SD22Q11) is a neurogenetic condition that is associated with a high risk of neurodevelopmental disorders and intellectual disability. People with SD22Q11, both children and adults, often experience significant difficulties in social interactions, as well as neurocognitive deficits, and have elevated rates of autism spectrum disorder (ASD). Despite this, the relationship between basic cognitive processes and cognitive ability in this population has not been well investigated. Methods: the main objective of the present research is to describe the neurocognitive profile of people with SD22Q11 using standardized neuropsychological assessment instruments. For this purpose, a sample of 10 participants aged between 7 and 15 years was administered an assessment battery with the following tests: WISC-V, CELF-5, NEPSY-II, CSAT-R, CARAS-R, TP, MABC-2, BRIEF-2, SENA, DABAS, ABAS-II, SCQ, and ADOS-2. Results: the results showed IQ scores in the borderline normal range, as well as difficulties in language functions, social skills, motor skills, and executive functions. Conclusions: an individualized assessment taking into account the globality of its expression, and a therapeutic approach adapted to the specific needs of children with this syndrome is essential.

Visual-Motor Integration Deficits in 3q29 Deletion Syndrome

3q29 deletion syndrome (3q29del) is associated with neuropsychiatric and neurodevelopmental phenotypes. We previously reported that graphomotor weakness is present in up to 78% of individuals with 3q29del. We have now explored nuances of the graphomotor phenotype and its association with other comorbidities in this population. Participants were recruited from the online 3q29 registry (3q29deletion.org) for two days of deep phenotyping. 32 individuals with 3q29del (62.5% male) were evaluated with the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI) to assess visual-motor integration. Participants were also evaluated with measures of cognitive ability, executive function, adaptive behavior, and school function. Males with 3q29del performed significantly worse than females on the VMI and Motor Coordination subtest. VMI performance was significantly associated with ADHD diagnosis and cognitive ability. Compared to published data from individuals with 22q11.2 deletion syndrome, individuals with 3q29del showed significantly more impairment. The 3q29 deletion is associated with substantial deficits in visual-motor integration, Visual Perception, and Motor Coordination. Our data suggests that 3q29del may qualify as a nonverbal learning disability. Future studies should assess whether individuals with 3q29del would benefit from early interventions, including occupational therapy.

Prospective One-Year Follow-Up of Sensory Processing in Phelan-McDermid Syndrome.

Phelan-McDermid syndrome (PMS) is caused by the loss (deletion) of a small portion of chromosome 22 in a region designated q13.3 (22q13.3 deletion). PMS is one of the most common genetic forms of autism spectrum disorder (ASD) in which sensory reactivity difficulties have been described on limited occasions. The objective of this study is to identify whether changes in sensory reactivity skills occur after one year of follow-up in a group of 44 participants diagnosed with PMS. All participants completed the Short Sensory Profile (SSP). Two-factor ANOVA tests were performed with repeated measures for the study of the evolution of the scores. Participants with PMS showed significant changes after one year of follow-up in sensory reactivity skills associated with tactile hyperreactivity (p = 0.003). The rest of the study variables did not show significant differences compared to the baseline assessment, showing definite differences associated with patterns of hypo-responsiveness and sensory seeking, low/weak energy, and difficulties in auditory filtering. Understanding the evolution of sensory reactivity skills can facilitate the adjustment to behavioral changes in people with PMS and design-targeted interventions to address sensory reactivity challenges.

Ahnak is required to balance calcium ion homeostasis and smooth muscle development in the urinary system

BackgroundVarious renal abnormalities, including hydronephrosis, polycystic kidney disease, and hydroureter, have been reported, and these abnormalities are present in DiGeorge syndrome, renal dysplasia, and acute kidney failure. Previous studies have shown that various genes are associated with renal abnormalities. However, the major target genes of nonobstructive hydronephrosis have not yet been elucidated.ResultsWe examined neuroblast differentiation-associated protein Ahnak localization and analyzed morphogenesis in developing kidney and ureter. To investigated function of Ahnak, RNA-sequencing and calcium imaging were performed in wild type and Ahnak knockout (KO) mice. Ahnak localization was confirmed in the developing mouse kidneys and ureter. An imbalance of calcium homeostasis and hydronephrosis, which involves an expanded renal pelvis and hydroureter, was observed in Ahnak KO mice. Gene Ontology enrichment analysis on RNA-seq results indicated that ‘Channel Activity’, ‘Passive Transmembrane Transporter Activity’ and ‘Cellular Calcium Ion Homeostasis’ were downregulated in Ahnak KO kidney. ‘Muscle Tissue Development’, ‘Muscle Contraction’, and ‘Cellular Calcium Ion Homeostasis’ were downregulated in Ahnak KO ureter. Moreover, peristaltic movement of smooth muscle in the ureter was reduced in Ahnak KO mice.ConclusionsAbnormal calcium homeostasis causes renal disease and is regulated by calcium channels. In this study, we focused on Ahnak, which regulates calcium homeostasis in several organs. Our results indicate that Ahnak plays a pivotal role in kidney and ureter development, and in maintaining the function of the urinary system.

Outcomes of Gastrostomy and Tracheostomy in Infants Undergoing Truncus Arteriosus Repair: Database Study Using the Pediatric Health Information System.

We sought to determine the prevalence of and factors associated with gastrostomy tube placement and tracheostomy in infants undergoing truncus arteriosus repair, and associations between these procedures and outcome. Retrospective cohort study. Pediatric Health Information System database. Infants less than 90 days old who underwent truncus arteriosus repair from 2004 to 2019. None. Multivariable logistic regression models were used to identify factors associated with gastrostomy tube and tracheostomy placement and to identify associations between these procedures and hospital mortality and prolonged postoperative length of stay (LOS; > 30 d). Of 1,645 subjects, gastrostomy tube was performed in 196 (11.9%) and tracheostomy in 56 (3.4%). Factors independently associated with gastrostomy tube placement were DiGeorge syndrome, congenital airway anomaly, admission age less than or equal to 2 days, vocal cord paralysis, cardiac catheterization, infection, and failure to thrive. Factors independently associated with tracheostomy congenital airway anomaly, truncal valve surgery, and cardiac catheterization. Gastrostomy tube was independently associated with prolonged postoperative LOS (odds ratio [OR], 12.10; 95% CI, 7.37-19.86). Hospital mortality occurred in 17 of 56 patients (30.4%) who underwent tracheostomy versus 147 of 1,589 patients (9.3%) who did not ( p < 0.001), and median postoperative LOS was 148 days in patients who underwent tracheostomy versus 18 days in those who did not ( p < 0.001). Tracheostomy was independently associated with mortality (OR, 3.11; 95% CI, 1.43-6.77) and prolonged postoperative LOS (OR, 9.85; 95% CI, 2.16-44.80). In infants undergoing truncus arteriosus repair, tracheostomy is associated with greater odds of mortality; while gastrostomy and tracheostomy are strongly associated with greater odds of prolonged postoperative LOS.

Physiology and Clinical Manifestations of Pathologic Cranial Suture Widening.

Cranial sutures are complex structures integrating mechanical forces with osteogenesis which are often affected in craniofacial syndromes. While premature fusion is frequently described, rare pathological widening of cranial sutures is a comparatively understudied phenomenon. This narrative review aims to bring to light the biologically variable underlying causes of widened sutures and persistent fontanelles leading to a common outcome. The authors herein present four syndromes, selected from a literature review, and their identified biological mechanisms in the context of altered suture physiology, exploring the roles of progenitor cell differentiation, extracellular matrix production, mineralization, and bone resorption. This article illustrates the gaps in understanding of complex craniofacial disorders, and the potential for further unification of genetics, cellular biology, and clinical pillars of health science research to improve treatment outcomes for patients.

Presentation of congenital soft-tissue sarcomas: A single institution experience.

e23551 Background: Pediatric sarcomas make up 10% of pediatric tumors and involve a varied range of histological patterns with different prognosis which creates therapeutic challenges. Neonatal presentation is rare among sarcomas and poses further challenges in therapy. Methods: We present 5 cases of congenital sarcomas reporting pathology, genetics, treatment, and outcomes. We retrospectively identified 5 patients with sarcomas diagnosed in the neonatal period from a single institution in Miami from 2017 – 2022 in order to identify similarities between neonatal sarcomas. Our sarcomas included an embryonal rhabdomyosarcoma (RMS), infantile fibrosarcoma (IFS), rhabdoid tumor, and two undifferentiated sarcomas. Results: The presentation occurred between birth and four days old. Location at presentation was varied. Four of our patients were Nonrhabdomyosarcoma Soft Tissue Sarcomas (NRSTS). Only one patient was diagnosed prenatally, while three were diagnosed at birth, and one at 4 days of life. Three patients presented spindle cell pathology. One of our undifferentiated sarcomas was classified as IFS-like, Archer FusionPlex was negative for mutation. Our other undifferentiated sarcoma showed a COL1A1 gene rearrangement on chromosome 17q.21 with immunostains positive for BCOR, SMARCB1, SMARCA4. Congenital fibrosarcoma showed ETV6 fusion with NTRK and immunostains positive for FLI-1, SMA, CD34, INI-1. The RMS showed focal loss of PTCH1 and FANCC and had immunostains positive for desmin and myogenin. The metastatic rhabdoid tumor showed SMARCB1 whole gene deletion as well as a 570kB deletion in chromosome 22q11.23. Three patients were treated on ARST 0331 with vincristine, doxorubicin, and cyclophosphamide (VAC), with the undifferentiated sarcoma requiring advancement to ARST 0332. The patient with metastatic rhabdoid tumor was treated with AREN 0321. Four patients required surgery. We had 1-year-survival in three patients, all treated on ARST 0331 or ARST 0332. The patient with metastatic rhabdoid tumor died at 4 months of age while on AREN 0321, and our patient with IFS-like sarcoma decompensate and died at ten days old, prior to starting therapy. Conclusions: We show multiple genetic mutations with SMARCB1 alteration in both an undifferentiated sarcoma and a malignant rhabdoid tumor but otherwise found no significant pattern among individual sarcomas. Our cases show good outcomes for patients qualifying for ARST 0331. We highlight the need for improved methods of detection of pediatric tumors in utero.

Di George syndrome revealed by hypocalcemia: A case report

Di George syndrome or (the 22q11.2 deletion syndrome) is due to a chromosomal abnormality namely a genetic abnormality caused by a microdeletion of chromosome 22. The main manifestations are cardiac congenital malformations, thymic hypoplasia, and hypoparathyroidism with hypocalcemia, psychomotor retardation, craniofacial dysmorphies and sometimes immunodeficiency. The diagnosis can be made antenatally, during fetopathological examination or after birth. We report the case of a 49-year-old female patient who was initially followed for iatrogenic hypoparathyroidism under Levothyrox replacement therapy and whose evolution was marked by the discovery of a Di George syndrome during follow-up.

0808 Comparison of Maxillary Transverse Dimension with Pediatric Obstructive Sleep Apnea Presence and Severity

Abstract Introduction Obstructive Sleep Apnea (OSA) in children and adolescents is commonly discussed amongst dental specialists. Physical attributes such as a high and narrow palate, dolichofacial appearance, and retrognathic mandible are reported to increase pediatric risk for OSA. Previous research states rapid maxillary expansion decreases AHI in children with OSA and may be an effective treatment option. Current literature does not report a consistent method of measuring a maxillary transverse deficiency nor does it report a numerical maxillary threshold deficiency that requires expansion in pediatric patients with OSA. Our aims are to compare two different orthodontic diagnostic methods for measuring the maxillary transverse dimension and to assess whether patients diagnosed with mild, moderate, or severe OSA have a numerical threshold for maxillary deficiency. Methods Participants were ages 7-17 years old (average 11.7 years) with no history of orthodontic treatment, craniofacial syndromes, craniosynostosis forms, or nasal abnormalities. Those with and without adenoids and tonsils were included. Participants presented to the Mayo Clinic Sleep Center for their polysomnogram. Their dentition was scanned, and a digital model was rendered. The maxillary transverse dimension was measured via two different methods: McNamara’s Analysis and Andrew’s Six Elements of Orofacial Harmony. Results There were 65 participants: 31 diagnosed with OSA (13 Mild, 4 Moderate, 5 Severe, and 9 Other) and 34 without (controls). Patients in the Other category were diagnosed based on clinical findings. No statistical difference was found between the maxillary transverse measurements of patients with versus without OSA or between the OSA categories. Patients with OSA were more likely to have permanent teeth (61.3% vs 32.4%, p=0.019), tonsils removed (54.8% vs 26.5%, p=0.020), and to have snored during the PSG (83.9% vs 55.9%, p=0.048). Conclusion Conclusions based on this pilot study should be interpreted carefully due to limited sample sizes. No statistically significant differences of the maxillary transverse dimension were found between those with and without OSA using either diagnostic method. No numerical maxillary deficiency threshold was found. Maxillary expansion should not be recommended based on OSA diagnosis alone. Referral to a dental specialist is recommended based on dental needs. Support (if any) Support was provided by Mayo Clinic CTSA grant UL1TR002377.

Lymphedema is associated with CELSR1 in Phelan-McDermid syndrome.

Lymphedema is a troubling condition present in many disorders including the rare genetic disorder known as Phelan-McDermid syndrome (PMS). The neurobehavioral features of PMS, also known as 22q13.3 deletion syndrome, have been investigated, but little research exists on lymphedema in PMS. In this investigation, clinical and genetic data from 404 people with PMS were reviewed from the PMS-International Registry revealing a prevalence of 5% with lymphedema. Lymphedema was reported in 1 out of 47 people (2.1%) with PMS due to a SHANK3 variant and 19 out of 357 people (5.3%) with PMS due to 22q13.3 deletions. Lymphedema was more common among those in their teens or adulthood (p = 0.0011) and those with deletions >4 Mb. People with lymphedema had significantly larger deletions (mean 5.375 Mb) than those without lymphedema (mean 3.464 Mb, p = 0.00496). Association analysis identified a deletion of the CELSR1 gene to be the biggest risk factor (OR = 12.9 95% CI [2.9-56.2]). Detailed assessment of 5 subjects identified all had deletions of CELSR1, developed symptoms of lymphedema starting at age 8 or older, and typically responded well to standard therapy. In conclusion, this is the largest assessment of lymphedema in PMS to date and our results suggest that individuals with deletions >4 Mb or those with CELSR1 deletions should be assessed for lymphedema.