DiGeorge Research Articles

18q Deletion Syndrome Presenting with Late-Onset Combined Immunodeficiency

Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who presented with late-onset combined immune deficiency (LOCID), which has not been previously reported. Patient 1 was a 29-year-old male with 18q deletion syndrome, who was being managed for severe motor and intellectual disabilities at the Yamabiko Medical Welfare Center for 26 years. Although the patient had few infections, he developed Pneumocystis pneumonia at the age of 28. Patient 2, a 48-year-old female with intellectual disability and congenital malformations, was referred to Tokyo Medical and Dental University Hospital with abnormal bilateral lung shadows detected on her chest radiography. Computed tomography showed multiple lymphadenopathies and pneumonia. A lymph node biopsy of the inguinal region revealed granulomatous lymphadenitis, and a chromosomal examination revealed 18q deletion. Array-based genomic hybridization analysis revealed deletion at 18q21.32-q22.3 for patient 1 and at 18q21.33-qter for patient 2. Immune status work-up of the two patients revealed panhypogammaglobulinemia, decreased number of memory B cells and naïve CD4+ and/or CD8+ cells, reduced response on the carboxyfluorescein diacetate succinimidyl ester T-cell division test, and low levels of T-cell receptor recombination excision circles and Ig κ-deleting recombination excision circles. Consequently, both patients were diagnosed with LOCID. Although patients with 18q deletion syndrome generally experience humoral immunodeficiency, the disease can be further complicated by cell-mediated immunodeficiency, causing combined immunodeficiency. Therefore, patients with 18q deletion syndrome should be regularly tested for cellular/humoral immunocompetence.

Aortic Arch Bare Metal Stenting in a 10-Years-Old Boy with DiGeorge Syndrome Using Overdrive External Pacing

Introduction: In the last decade, percutaneous stent placement has become the standard for treating CoA after childhood. However, stent placement as a treatment for aortic arch hypoplasia has only been described in small series and case reports. Case Report: A nine-year-old boy with DiGeorge syndrome (BW 50 kg, BL 140 cm, BSA 1.4 m2) was admitted to our hospital due to planned heart catheterisation with aortic arch stenting. In the neonatal period, he underwent complete surgical correction of the IAA type B with perimembranous VSD. During the follow-up period, the progressive narrowing of the aortic arch was observed with gradually increasing systolic pressure gradient (PG) on the echocardiography examination (PG 55 mmHg). The cardiac catheterization was performed under general anaesthesia. The peak-to-peak gradient was estimated at 32 mmHg (AoAsc 128/78 mmHg; AoDsc 96/68 mmHg). Aortography pointed out tubular hypoplasia of the aortic arch between branches (17 mm in length) with localized narrowing right behind the first aortic branch, 6 mm in diameter, and post-stenotic dilatation. The stenosis was resolved using a 22mm long uncovered Cheatham Platinum (CP) stent crimped on a 12 mm Balloon-in-Balloon (BiB) catheter with additional flaring of the distal stent part (Figure 1B and C). During the stent implantation, an overdrive external pacemaker (wire was placed into the right ventricle anterograde across the right femoral vein) was used. Control angiography relieved satisfying anterograde flow across the aorta and aortic branches. The peak-to-peak gradient after stenting was 10 mmHg. Conclusion: Although technically challenging, carefully analyzing the arch and vessel morphology allows the dilation of the transverse aortic arch hypoplasia and stenosis using a bare metal stent with good angiographic and hemodynamic results and without complications.

Pharmacological modulation of developmental and synaptic phenotypes in human SHANK3 deficient stem cell-derived neuronal models

Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) with ß-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperine’s effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.

Prenatal detection of chromosome 7q deletion with duplication: A case report and literature review.

With advances in prenatal diagnostic techniques, chromosomal microdeletions and microduplications have become the focus of prenatal diagnosis. 7q partial monosomy or trisomy due to a deletion or duplication of the 7q end is relatively rare and usually originates from parents carrying a balanced translocation. Noninvasive prenatal screening (NIPT) showed a fetus with partial deletion and duplication of chromosome 7q. It was not possible to determine whether the fetus was normal. Conventional chromosome G-banding and chromosome microarray analysis (CMA) were performed on fetal amniotic fluid samples and parental peripheral blood samples. The pregnant women were given detailed genetic counseling by clinicians. The fetal karyotype was 46, XY on conventional G-banding analysis. The CMA test results showed a deletion of approximately 7.8 Mb in the 7q36.1q36.3 region and a duplication of 6.6Mb in the 7q35q36.1 region. The parents' karyotype analysis and CMA results were normal, indicating a new mutation. CMA molecular diagnostic analysis can effectively detect chromosomal microdeletions or microduplications, clarify the relationship between fetal genotype and clinical phenotype, and provide a reference for prenatal diagnosis of chromosomal microdeletion-duplication syndrome.

Genome-scale clustered regularly interspaced short palindromic repeats screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common malignancy that develops in patients with ataxia-telangiectasia, a cancer-predisposing inherited syndrome characterized by inactivating germline ATM mutations. ATM is also frequently mutated in sporadic DLBCL. To investigate lymphomagenic mechanisms and lymphoma-specific dependencies underlying defective ATM, we applied ribonucleic acid (RNA)-seq and genome-scale loss-offunction clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens to systematically interrogate B-cell lymphomas arising in a novel murine model (Atm-/-nu-/-) with constitutional Atm loss, thymic aplasia but residual T-cell populations. Atm-/-nu-/-lymphomas, which phenotypically resemble either activated B-cell-like or germinal center Bcell-like DLBCL, harbor a complex karyotype, and are characterized by MYC pathway activation. In Atm-/-nu-/-lymphomas, we discovered nucleotide biosynthesis as a MYCdependent cellular vulnerability that can be targeted through the synergistic nucleotidedepleting actions of mycophenolate mofetil (MMF) and the WEE1 inhibitor, adavosertib (AZD1775). The latter is mediated through a synthetically lethal interaction between RRM2 suppression and MYC dysregulation that results in replication stress overload in Atm-/-nu-/-lymphoma cells. Validation in cell line models of human DLBCL confirmed the broad applicability of nucleotide depletion as a therapeutic strategy for MYC-driven DLBCL independent of ATM mutation status. Our findings extend current understanding of lymphomagenic mechanisms underpinning ATM loss and highlight nucleotide metabolism as a targetable therapeutic vulnerability in MYC-driven DLBCL.

Outcomes of pediatric heart transplantation in children with selected genetic syndromes

ObjectiveGenetic syndromes (GSs) are often linked to congenital heart disease (CHD) and cardiomyopathy (CM). The effect of GSs on survival following pediatric heart transplant (HT) has not been well described. We aimed to compare outcomes following HT between children with a GS and those without a GS. MethodsThe United Network for Organ Sharing (UNOS) transplantation database was merged with the Pediatric Health Information System (PHIS) administrative database to identify children with GS who underwent HT between 2009 and 2019. Characteristics and outcomes were compared between children with a GS (GS group) and those without a GS (no GS group). ResultsGSs were present in 225 of 2429 HT recipients (9%). The most common GSs were DiGeorge syndrome (n = 28), muscular dystrophy (n = 27), Down syndrome (n = 26), and Turner syndrome (n = 14). The incidence of CHD was higher in the GS group compared to the no GS group (54% vs 38%; P < .1); however, patient demographics, hemodynamics, renal and hepatic dysfunction, and requirements for dialysis, mechanical ventilation, extracorporeal membrane oxygenation, and mechanical circulatory support were not different between the 2 groups. Time on the waitlist was not significantly different between the GS and no GS groups (55 days vs 53 days; P = .4). There also was no between-group difference in the incidence of post-transplantation complications, including dialysis (8% vs 5%; P = .38), stroke (3% vs 4%; P = .34), primary graft dysfunction (2% vs 2%; P = .75), need for pacemaker (1% vs 1%; P = .84) and rejection (3.4% vs 3.4%; P = .96). Survival at 10 years post-HT was 75% for the no GS group and 72% for the GS group (P = .59). The survival curves also did not differ between patients with CM and those with CHD. ConclusionsChildren with certain GSs and end-stage heart failure can be expected to have similar post-transplantation outcomes to those without a GS. Although early and late post-transplantation care is individualized to each patient, the presence of a GS should not influence the decision to list for HT.

Progesterone for Neurodevelopment in Fetuses With Congenital Heart Defects

Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years. To assess the feasibility and tolerability of maternal progesterone therapy as well as the magnitude of the effect on neurodevelopment for fetuses with CHD. This double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD was conducted between July 2014 and November 2021 at a quaternary care children's hospital. Participants included maternal-fetal dyads where the fetus had CHD identified before 28 weeks' gestational age and was likely to need surgery with cardiopulmonary bypass in the neonatal period. Exclusion criteria included a major genetic or extracardiac anomaly other than 22q11 deletion syndrome and known contraindication to progesterone. Statistical analysis was performed June 2022 to April 2024. Participants were 1:1 block-randomized to vaginal progesterone or placebo by diagnosis: hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and other CHD diagnoses. Treatment was administered twice daily between 28 and up to 39 weeks' gestational age. The primary outcome was the motor score of the Bayley Scales of Infant and Toddler Development-III; secondary outcomes included language and cognitive scales. Exploratory prespecified subgroups included cardiac diagnosis, fetal sex, genetic profile, and maternal fetal environment. The 102 enrolled fetuses primarily had HLHS (n = 52 [50.9%]) and TGA (n = 38 [37.3%]), were more frequently male (n = 67 [65.7%]), and without genetic anomalies (n = 61 [59.8%]). The mean motor score differed by 2.5 units (90% CI, -1.9 to 6.9 units; P = .34) for progesterone compared with placebo, a value not statistically different from 0. Exploratory subgroup analyses suggested treatment heterogeneity for the motor score for cardiac diagnosis (P for interaction = .03) and fetal sex (P for interaction = .04), but not genetic profile (P for interaction = .16) or maternal-fetal environment (P for interaction = .70). In this randomized clinical trial of maternal progesterone therapy, the overall effect was not statistically different from 0. Subgroup analyses suggest heterogeneity of the response to progesterone among CHD diagnosis and fetal sex. ClinicalTrials.gov Identifier: NCT02133573.

Population-based study of rare epilepsy incidence in a US urban population.

This study was undertaken to estimate incidence of rare epilepsies and compare with literature. We used electronic health record text search to identify children with 28 rare epilepsies in New York City (2010-2014). We estimated cumulative incidence and compared with literature. Eight of 28 rare epilepsies had five or more prior estimates, and our measurements were within the published range for all. The most common were infantile epileptic spasms syndrome (1 in 2920 live births), Lennox-Gastaut syndrome (1 in 9690), and seizures associated with tuberous sclerosis complex (1 in 14 300). Fifteen of 28 had fewer than five prior estimates, and of these, we provided additional estimates for early infantile developmental and epileptic encephalopathy (1 in 32 700), epilepsy with myoclonic-atonic seizures (1 in 34 100), Sturge-Weber syndrome plus seizures/epilepsy (1 in 40 900), epilepsy in infancy with migrating focal seizures (1 in 54 500), Aicardi syndrome plus seizures/epilepsy (1 in 71 600), hypothalamic hamartoma with seizures (1 in 225 000), and Rasmussen syndrome (1 in 450 000). Five of 28 rare epilepsies had no prior estimates, and of these, we provided a new estimate for developmental/epileptic encephalopathy with spike-and-wave activation in sleep and/or continuous spikes and waves during sleep (1 in 34 100). Data were limited for the remaining 12 rare epilepsies, which were all genetic epilepsies, including PCDH19, CDKL5, Alpers disease, SCN8A, KCNQ2, SCN2A, GLUT1 deficiency, Phelan-McDermid syndrome, myoclonic epilepsy with ragged-red fibers, dup15q syndrome, ring chromosome 14, and ring chromosome 20. We estimated the incidence of rare epilepsies using population-based electronic health record data and literature review. More research is needed to better estimate the incidence of genetic epilepsies with nonspecific clinical features. Electronic health records may be a valuable data source for studying rare epilepsies and other rare diseases, particularly as genetic testing becomes more widely adopted.

The mental health and traumatic experiences of mothers of children with 22q11DS

ABSTRACT Background: 22q11 Deletion Syndrome (22q11DS) is the most common microdeletion syndrome with broad phenotypic variability, leading to significant morbidity and some mortality. The varied health problems associated with 22q11DS and the evolving phenotype (both medical and developmental/behavioural) across the lifespan can strongly impact the mental health of patients as well as their caregivers. Like caregivers of children with other chronic diseases, caregivers of children with 22q11DS may experience an increased risk of traumatisation and mental health symptoms. Objective: The study’s primary objective was to assess the frequency of traumatic experiences and mental health symptoms among mothers of children with 22q11DS. The secondary objective was to compare their traumatic experiences to those of mothers of children with other neurodevelopmental disorders (NDDs). Method: A total of 71 mothers of children diagnosed with 22q11DS completed an online survey about their mental health symptoms and traumatic experiences. Descriptive statistics were used to summarise the prevalence of their mental health symptoms and traumatic experiences. Logistic regression models were run to compare the traumatic experiences of mothers of children with 22q11DS to those of 335 mothers of children with other neurodevelopmental disorders (NDDs). Results: Many mothers of children with 22q11DS experienced clinically significant mental health symptoms, including depression (39%), anxiety (25%), and post-traumatic stress disorder (PTSD) symptoms (30%). The types of traumatic events experienced by mothers of children with 22q11DS differed from those of mothers of children with other NDDs as they were more likely to observe their child undergoing a medical procedure, a life-threatening surgery, or have been with their child in the intensive care unit. Conclusion: 22q11DS caregivers are likely to require mental health support and trauma-informed care, tailored to the specific needs of this population as they experience different kinds of traumatic events compared to caregivers of children with other NDDS.

Genome-wide association exploratory studies in individuals with ultra-high risk for schizophrenia in Chinese Han nationality in two years follow-up: A subpopulation study

BackgroundAlthough ultra-high risk for schizophrenia (UHR) is related to both genetic and environment factors, the precise pathogenesis is still unknow. To date, few studies have explored the Genome-Wide Association Studies (GWAS) in UHR or HR individuals especially in Han population in China. MethodsIn this study, a GWAS analysis for 36 participants with UHR and 43 with HR were performed, and all deletion variations in 22q11 region were also compared. Results: Sixteen individuals with UHR (44.4%) and none with HR converted into schizophrenia in follow-up after two years. Six loci including neurexin-1(NRXN1) (rs1045881), dopamine D1 receptor (DRD1) (rs686, rs4532), chitinase-3-like protein 1 (CHI3L1) (rs4950928), velocardiofacial syndrome (ARVCF) (rs165815), dopamine D2 receptor (DRD2) (rs1076560) were identified higher expression with significant difference in individuals converted into schizophrenia after two years. The Family with Sequence Similarity 230 Member H (FAM230H) gene in the 22q11 region were also found high expression in UHR group. ConclusionsFurther expansion of sample size and validation studies are needed to explore the pathogenesis of these risk loci in UHR conversion into schizophrenia in the future.

Evaluation of a Fully Digital, In-House Virtual Surgical Planning Workflow for Bimaxillary Orthognathic Surgery

The advantages of virtual surgical planning (VSP) for orthognathic surgery are clear. Previous studies have evaluated in-house VSP; however, few fully digital, in-house protocols for orthognathic surgery have been studied. The purpose of this study was to evaluate the difference between the virtual surgical plan and actual surgical outcome for orthognathic surgery using a fully digital, in-house VSP workflow. This is a prospective cohort study from September 2020 to November 2022 of patients at the Victoria General Hospital in Halifax, NS, Canada who underwent bimaxillary orthognathic surgery. Patients were excluded if they had previously undergone orthognathic surgery or were diagnosed with a craniofacial syndrome. The primary outcome variables were the mean 3-dimensional (3D) (Euclidean) distance error, as well as mean error and mean absolute error in the transverse (x axis), vertical (y axis), and anterior-posterior (z axis) dimensions. Covariates included age, sex, and surgical sequence (mandible-first or maxilla-first). The primary outcome was tested using Z and t critical value confidence intervals. The P value was set at .05. The 3D distance error for mandible-first and maxilla-first groups was compared using a 2-sample t-test as well as analysis of variance. The study sample included 52 subjects (24 males and 28 females) with a mean age of 27.7 (± 12.1) years. Forty three subjects underwent mandible-first surgery and 9 maxilla-first surgery. The mean absolute distance error was largest in the anterior-posterior dimension for all landmarks (except posterior nasal spine, left condyle, and gonion) and exceeded the threshold for clinical acceptability (2mm) in 16 of 23 landmarks. Additionally, mean distance error in the anterior-posterior dimension was negative for all landmarks, indicating deficient movement in that direction. The effect of surgical sequence on 3D distance error was not statistically significant (P=.37). In general, the largest contributor to mean 3D distance error was deficient movement in the anterior-posterior direction. Otherwise, mean absolute distance error in the vertical and transverse dimensions was clinically acceptable (< 2mm). These findings were felt to be valuable for treatment planning purposes when using a fully digital, in-house VSP workflow.

A VERY COMPLEX CASE OF DORV TYPE FALLOT: A CASE REPORT

Abstract Double outlet right ventricle (DORV) is a rare CHD characterized by ventriculoarterial connection in which both great arteries arise entirely or predominantly from the right ventricle. Its prevalence is 0.9% of all CHDs. Several chromosomal abnormalities have been associated with DORV, including trisomy 13, trisomy 18, and chromosome 22q11 deletion. Hearts with DORV are an extremely heterogeneous group showing various morphological features, connections, and relationships at each level of the cardiac segments and intersegmental junctions. As a consequence, the clinical manifestations and required surgical procedures for patients with DORV are variable. The anatomical spectrum is higly variable: it can be associated with ventricular septal defect, transposition of the great arteries (TGA) and functional single ventricle. We report the case of an infant with prenatal diagnosis of CHD and finding partial duplication of the short arm of the X chromosome. Pregnant woman at 22 weeks comes to the outpatient clinic to perform follow–up ultrasound. At that site finding of CHD which was later confirmed at birth and therefore prostaglandin therapy was started. Echocardiogram showed a wide DIV from malalignment with antero–cephalic deviation of the conal septum with significant aortic destroposition configuring picture of double outlet right ventricle. It also presents a complex right efflux obstruction already at subvalvular pulmonary departure. The pulmonary valve presented dysplastic, with en dome motion, hypoplastic. Pulmonary perfusion appears to be provided predominantly by the Botallo‘s duct originating from the isthmic region of the aorta and leading with a long and tortuous course to the pulmonary confluence near the left pulmnary artery with high velocity flow. The remaining findings are normal. Therefore, in view of the clinical picture, he was subjected to palliative surgery of right systemic–pulmonary shunt between the brachiocephalic trunk and right pulmonary artery (modified Blalock–Taussing surgery) in 3.5mm PTFE and ligation of Botallo‘s duct. At subsequent follow–up, the systemic–pulmonary shunt appeared pervious with regular flow. Wide DIV from anterior malalignment with aorta cavalier to DIV. Severe stenosis at complex pulmonary outflow with max gradient up to 124mmHg with dynamic and valvular component. For the subsequent course of treatment, the patient will be discussed collegially.

Significant improvement of cardiac outflow tract septation defects in a DiGeorge syndrome model after minoxidil treatment

The T-BOX transcription factor TBX1 is essential for the development of the pharyngeal apparatus and it is haploinsufficient in DiGeorge syndrome (DGS), a developmental anomaly associated with congenital heart disease and other abnormalities. The murine model recapitulates the heart phenotype and showed collagen accumulation.We first used a cellular model to study gene expression during cardiogenic differentiation of WT and Tbx1−/− mouse embryonic stem cells. Then we used a mouse model of DGS to test whether interfering with collagen accumulation using an inhibitor of lysyl hydroxylase would modify the cardiac phenotype of the mutant.We found that loss of Tbx1 in a precardiac differentiation model was associated with up regulation of a subset of ECM-related genes, including several collagen genes. In the in vivo model, early prenatal treatment with Minoxidil, a lysyl hydroxylase inhibitor, ameliorated the cardiac outflow tract septation phenotype in Tbx1 mutant fetuses, but it had no effect on septation in WT fetuses. We conclude that TBX1 suppresses a defined subset of ECM-related genes. This function is critical for OFT septation because the inhibition of collagen cross-linking in the mutant reduces significantly the penetrance of septation defects.

Holoprosencephaly: The Disease and Its Related Disabilities

AbstractHoloprosencephaly (HPE), the most prevalent developmental anomaly affecting the forebrain in humans, occurs in ∼1 in 16,000 liveborn neonates, with an incidence reaching 1 in 250 in conceptuses. This condition is distributed worldwide. HPE is etiologically heterogeneous, and its pathogenesis is variable. Environmental, teratogenic, genetic, or metabolic factors can contribute to the development of HPE. Notably, maternal insulin-dependent diabetes mellitus and maternal alcoholism are among the primary causative factors. HPE may be linked to various well-defined multiple malformation syndromes characterized by a normal karyotype, such as Smith–Lemli–Opitz's, Pallister–Hall's, or velocardiofacial syndrome. Alternatively, it can be associated with chromosomal abnormalities. (i.e., Patau's syndrome and, less frequently, Edwards' syndrome or Down's syndrome). The major genes implicated in HPE are SHH, ZIC2, SIX3, and TGIF. The range of HPE is extensive, covering diverse neuropathological phenotypes of varying severity. Three classical types of HPE can be distinguished in increasing order of severity: lobar HPE, characterized by separated right and left ventricles with some continuity across the frontal cortex; semilobar HPE, featuring a partial separation; and the most severe form, alobar HPE, where there is a single brain ventricle and the absence of an interhemispheric fissure. Additionally, there are other variations of HPE, ranging in severity, including the less severe interhemispheric median HPE (also known as middle interhemispheric variant). The phenotypic spectrum of HPE is highly extensive, encompassing severe cerebral malformations to microforms. Children with HPE often encounter numerous medical challenges; among them neurological disorders, craniofacial malformations, endocrine disorders, oral and motor dysfunction, and dysfunction of the autonomic nervous system. Neurologic problems, such as cerebral palsy and seizures, are common. The diagnosis of HPE is typically made prenatally, relying primarily on ultrasound and magnetic resonance imaging examinations. The prognosis for individuals with HPE is largely dependent on its underlying causes. Those with cytogenetic abnormalities, in particular, face a significantly poorer prognosis, with only 2% surviving beyond 1 year.

Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome

BackgroundPhelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome.MethodsWe report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features.ResultsSeizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype–phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers.ConclusionsThese results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype–phenotype relationships when deletion size is taken into account.

Long-term treatment with insulin-like growth factor-1 in Phelan-McDermid syndrome: a case report

Phelan-McDermid syndrome (PMS) is a chromosomal microdeletion syndrome generally caused by loss-of-function variants or deletions affecting the SHANK3 gene. We report on a case of a 19-year-old woman with a diagnosis of PMS, autism, and developmental disability. She has been under clinical care since the age of 9 and received treatment with subcutaneous IGF-1 from 11 to 15 years of age. The treatment spanned 2 periods, totaling 35 months, interspersed with a 16-month off-treatment interval. Clinically significant improvement was evident during the treatment periods, particularly in the Social Responsiveness Scale, the Aberrant Behavior Checklist, and clinical assessments, contrasted with a clear deterioration during the off-treatment period. Sleep difficulties worsened during the first period, and EKG repolarization abnormalities emerged during the second period, ultimately leading to definitive treatment discontinuation. In conclusion, an experimental long-term on-off-on treatment with IGF-1 in an adolescent with PMS resulted in mixed results, showcasing positive clinical improvements alongside potentially severe adverse events in the long run.

Exploring Disrupted Gene Networks in Human 22q11.2 Microdeletion

Several deletions are observed at the 22q11 locus and are responsible for 22q11.2 deletion syndrome (22q11DS), also known as DiGeorge syndrome, conotruncal anomaly face syndrome, or velocardiofacial syndrome. These microdeletions on human chromosome 22 range from 0.7 to 3 Mb. Many genes are affected by 22q11.2 deletion. However, despite the well-established clinical signs for the diagnosis of 22q11.2 deletion syndrome, the interactome background of 22q11.2 deletion syndrome is unknown. Here, we analyzed protein–protein interaction networks (PPIs) to assess the influences of 3 Mb 22q11.2 deletion on this network. We compared the general human PPI network against a network without 48 genes of the 3 Mb 22q11.2 locus in a homozygous condition: we compared topological metrics, enrichment of gene ontology terms, community assignments, and edge rewiring. The PPI networks revealed that this deletion affected the relevance of hundreds of non-deleted genes. Additionally, this 22q11.2 deletion induces intense rewiring of subnetworks, promoting an accumulation of proteins associated with DiGeorge clinical signs (CTCF, YY1, TFAP2A, PPARG, PAX6, RAX, and E2F3) in a single community (community 1). Therefore, we identified new genes that may be associated with the 22q11.2 deletion syndrome. Altogether, the systemic approaches used here yielded new insights into the 22q11.2 deletion syndrome.

Hypocalcemia revealing digeorge syndrome: case report

Hypocalcemia revealing digeorge syndrome: case report

Hypocalcemia revealing digeorge syndrome: case report

Hypocalcemia revealing digeorge syndrome: case report

Hypocalcemia revealing digeorge syndrome: case report

Hypocalcemia revealing digeorge syndrome: case report