DiGeorge Research Articles

22q11.2 deletion syndrome

George F Winter discusses DiGeorge syndrome, also known as 22q11.2 deletion syndrome, the most common chromosomal condition after Down's syndrome

Decreased T helper 1cell function underlies recurrent sinopulmonary infections in the 17q12 deletion syndrome.

The 17q12 deletion syndrome (17q12DS) is a heterozygous deletion of a 1.4 megabase‒spanning DNA sequence on chromosome 17. The clinical characteristics of 17q12DS include neurodevelopmental disorders, kidney and urinary tract abnormalities. In our cohort of 37 subjects with 17q12DS, we observed increased atopic disorders and recurrent sinopulmonary infections, raising the possibility of immune dysregulation in 17q12DS, a feature that has not been previously reported. We tested the hypothesis that individuals with 17q12DS have altered T-cell function, contributing to recurrent infections and atopy. Alteration of CD4+ T-cell functions was assessed on FACS sorted CD4+ T-cells using RNA-seq analysis, and flow cytometry and multiplex assays. We found that individuals with 17q12DS had a substantially decreased frequency of CD4+ T-cells producing the T helper (Th) 1 cytokine IFN-γ but not Th2 and Th17 cytokines when compared to age-matched healthy controls (HCs). RNA-seq analysis of CD4+ T-cells from subjects with 17q12DS, when compared to HCs, revealed decreased levels of TBX21 encoding the Th1 transcription factor T-bet, IFNG, and other Th1 chemokine genes. These findings were validated using flow cytometry and multiplex assay. Our study is the first to demonstrate immune alterations in 17q12DS characterized by decreased T-bet and its downstream effector cytokines such as IFN-γ. These findings warrant further investigation into underlying mechanisms, which would inform precision therapy for individuals with 17q12DS. National Institutes of HealthKL2 TR001862 to JJS, T35DK104689 to AG, 5T32AR007107 to JPY and LO, 1R01AG056728 to IK, and 1R21AI161838 to IK and JJS.

Co-occurrence of Phelan-McDermid syndrome and metachromatic leukodystrophy

Very few cases have been described so far with co-occurrence of Phelan-McDermid syndrome (PMS) and metachromatic leukodystrophy (MLD). Those patients harbour a chromosome (chr) 22q13deletion encompassing at least the SHANK3 and ARSA genes and a pathogenic variant in the arylsulfatase A (ARSA) gene residing on the other allele. The deletion in chr22q13 results in PMS phenotype and the presence of pathogenic variation on the other intact copy of ARSA gene, leads to MLD phenotype due to biallelic loss of ARSA function. We describe a male infant, born to a third-degree consanguineous couple, who exhibited neuroregression at the age of 8 months, presented with developmental delay, hypotonia which rapidly progressed to feeding difficulties, axial hypotonia, ptosis, sleep disturbance, dystonia, spasticity, and abnormal eye movements. Brain MRI showed T2 hyperintensities consistent with MLD. Biochemical workup showed deficiency of ARSA enzyme activity. Genetic investigations revealed heterozygous deletion of size 2.5 Mb on chr 22q13.3 encompassing the entire ARSA gene and a pathogenic variant in the other copy of ARSA gene. Parents and sibling were tested and informed about the disease management and genetic testing in extended family members to understand the risk and preventive measures. Few case reports have proposed screening for urine sulfatides levels at the time of PMS diagnosis to identify pre-symptomatic or asymptomatic MLD patients to facilitate management and our case supports this proposal.

Identification of a cryptic unbalanced translocation Der(22)t(12;22)(q24.33;q13.33) in a large Chinese family with Phelan-McDermid syndrome by nanopore sequencing

To explore the genetic cause of a four-generation severe intellectual disability in a Chinese family using nanopore sequencing and to provide genetic counseling and reproductive guidance for family members. Multiple genetic analyses of the proband and family members were performed, including chromosome karyotype analysis, whole exome sequencing, nanopore sequencing, PCR amplification, and Sanger sequencing. The results of G-binding karyotyping, CGG repeats for FMR1, GGC repeats for NOTCH2NCL, and trio-whole-exome sequencing were negative for the proband and his parents. Nanopore sequencing showed that the proband carried 12q24.33 microduplication (3.26 Mb) and 22q13.33 microdeletion (1.5 Mb). According to the guidelines of the American Society for Medical Genetics and Genomics (ACMG), the 22q13.33 microdeletion was classified as pathogenic, whereas the 12q24.33 microduplication was classified as a variant of uncertain significance (VUS). The precise karyotype and location of chromosomal breakpoints in the patient and family members were determined through PCR. According to the results of Sanger sequencing, a cryptic balanced translocation was detected in the proband’s father. Additionally, informative SNPs were identified near the breakpoints for preimplantation genetic testing for structure rearrangement (PGT-SR) treatment by nanopore sequencing. We identified a cryptic unbalanced translocation in a large Chinese family with Phelan-McDermid syndrome (22q13.33 deletion syndrome) by nanopore sequencing. Nanopore sequencing can be a powerful tool for the genetic diagnosis of unexplained intellectual disability and the detection of precise breakpoints of chromosomal rearrangement in PGT-SR treatment.

DiGeorge syndrome with specific endocrine abnormalities in 2 children

DiGeorge syndrome with specific endocrine abnormalities in 2 children

Jacobsen Syndrome with 11q Deletion, Trigonocephaly, and MYBPC3 Mutation: A Unique Case Report

Jacobsen Syndrome with 11q Deletion, Trigonocephaly, and MYBPC3 Mutation: A Unique Case Report

Like milk on the stove: Healthcare professionals navigating uncertainty when caring for families with 22q11DS.

22q11 deletion syndrome (22q11DS) results from a microdeletion on chromosome 22 and is the most common microdeletion disorder in humans, affecting 1 in 2148 live births. Clinical manifestations vary widely among individuals and across different life stages. Effective management requires the involvement of a specialized multidisciplinary team. This study aims to explore the experiences of healthcare professionals in caring for the families of children with 22q11DS, focusing on their challenges, rewards, and coping strategies. Data for this interview study were collected as part of a broader mixed methods research project aimed at enhancing the psychosocial well-being of children aged 3-15 years with 22q11DS and their families. The qualitative aspect of this study focused on capturing the experiences of healthcare professionals involved in their care, recruited purposively through collaborators and snowball sampling methods. Reflexive thematic analysis of semi-structured interviews was performed after verbatim transcription. Twenty healthcare providers from different specialties were interviewed. The majority had a working experience of more than 10 years and were part of a 22q11DS clinic. After data analysis, four themes (and many sub-themes) were identified that were all related to the topic of uncertainty: acknowledging uncertainty, sharing uncertainty, acting on uncertainty and coping with uncertainty. Many experts showed a sense of humbleness when caring for the families and most of the participants emphasized the role of peer support and multidisciplinary teams. Our study reveals how healthcare professionals manage the uncertainty associated with 22q11DS, highlighting the importance of peer support and multidisciplinary team collaboration. Providers recognize the limits of their medical expertise and value the perspectives of families living with the condition. Their coping strategies play a critical role in handling uncertainty and suggest a need for further emphasis in the literature on the experiences of healthcare professionals dealing with rare diseases.

Acute Idiopathic Severe Thrombocytopaenia in a Young Child with Unidentified DiGeorge Syndrome

Acute Idiopathic Severe Thrombocytopaenia in a Young Child with Unidentified DiGeorge Syndrome

Topoisomerase 1 is required for the development and function of thymus

Abstract Thymus organogenesis is critical for proper maturation of developing T cells. In this study, we identified Top1 as a novel gene involved in thymus development and function. We created a mouse line with deletion of Top1 in thymic epithelial cells (TECs), and our results demonstrate that biallelic loss of Top1 in TECs causes congenital thymic aplasia, precipitating T cell immunodeficiency. Transcriptomic analysis provides insights into the molecular mechanism of Top1 in thymus development as we identify key genes involved in thymus organogenesis as the transcriptional targets of Top1 in TECs. Analysis of peripheral immunological compartments revealed severe loss of αβ T cells complemented with a disproportionate accumulation of γδ T cells and myeloid cells upon deletion of Top1 in TECs. The residual αβ T cells in Top1 knockout mice were effector and oligoclonal in nature highlighting their self-reactivity. These results reveal a previously unknown role of Top1 in thymus development and T cell homeostasis. We propose Top1 as a genetic target for altered thymic development and T cell lymphopenia.

Accuracy of Two Different Patient-Specific Drill/Cutting Guides for Maxillary Repositioning When Used for Minimally Invasive Bimaxillary Orthognathic Surgery.

Minimally invasive orthognathic surgery (MIOS) involves smaller incisions and minimal tissue dissection. Most MIOS is done using interim splints to position the first jaw. The application of patient-specific implants in MIOS is difficult due to the size of traditional cutting/drill guides, which require larger incisions. As a result, MIOS guides were redesigned for this study to fit into smaller incisions. The study purpose was to estimate and compare the accuracy of the smaller and redesigned bone-borne versus bone/tooth-borne (BTB) cutting/drilling guides used in minimally invasive bimaxillary orthognathic surgery. This retrospective cohort study included consecutive MIOS patients treated by a single surgeon at the University of Texas Health San Antonio from June 2023 to September 2024. It included patients that underwent bimaxillary MIOS with complete preoperative and postoperative cone-beam computed tomographic records. Exclusion criteria included craniofacial syndromes, severe medical comorbidities, or single-jaw surgery. The primary predictor variable was the type of cutting/drilling guide (BB vs BTB) used to perform maxillary osteotomy. The primary outcome variable was accuracy, defined as mean linear discrepancy that is closest to 0mm. Linear discrepancies between planned and actual maxillary movements were measured. Demographics and malocclusion type. χ2 tests compared categorical variables, and Student's t-tests assessed accuracy differences. A P value < .05 was considered significant, with a Bonferroni correction applied for multiple comparisons. The sample consisted of 20 patients (15 females, 75%; 5 males, 25%; mean age 24±11.3years) evenly divided into BB (n=10) and BTB (n=10) guide groups. The BTB guide demonstrated superior vertical accuracy for the upper incisor (mean difference: 0.67mm, standard deviation=0.33, P=.02) and the upper left canine (mean difference: 0.11mm, standard deviation=0.04, P=.03) when comparing means. However, no significant differences were found in root mean square discrepancies (P>.2) or other measurements (P>.06). Both guides achieved acceptable accuracy overall, with the BTB guide showing superior precision for 2 of the 11 landmarks.

A newborn with 22q11.2 deletion without phenotypical features of Di George syndrome

A newborn with 22q11.2 deletion without phenotypical features of Di George syndrome

Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53.

Germline inactivating mutations of the SLC25A1 gene contribute to various human disorders, including Velocardiofacial (VCFS), DiGeorge (DGS) syndromes and combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic disease characterized by the accumulation of 2-hydroxyglutaric acid (2HG). The mechanisms by which SLC25A1 loss leads to these syndromes remain largely unclear. Here, we describe a mouse model of SLC25A1 deficiency that mimics human VCFS/DGS and D/L-2HGA. Surprisingly, inactivation of both Slc25a1 alleles results in alterations in the development of multiple organs, and ina severe proliferation defect by activating two senescence programs, oncogene-induced senescence (OIS) and mitochondrial dysfunction-induced senescence (MiDAS), which converge upon the induction of the p53 tumor suppressor. Mechanistically, cells and tissues with dysfunctional SLC25A1 protein undergo metabolic and transcriptional rewiring leading to the accumulation of 2HG via a non-canonical pathway and to the depletion of nicotinamide adenine dinucleotide, NAD+, which trigger senescence. Replenishing the pool of NAD+ or promoting the clearance of 2HG rescues the proliferation defect of cells with dysfunctional SLC25A1 in a cooperative fashion. Further, removal of p53 activity via RNA interference restores proliferation, indicating that p53 acts as a critical barrier to the expansion of cells lacking functional SLC25A1. These findings reveal unexpected pathogenic roles of senescence and of p53 in D/L-2HGA and identify potential therapeutic strategies to correct salient molecular alterations driving this disease.

Factors Influencing Fronto-Orbital Relapse in Patients With Syndromic Craniosynostosis: A 2 Decade Review.

Fronto-orbital retrusion may occur after primary surgical correction of craniosynostosis, particularly in patients with syndromic craniosynostosis. This study investigated reoperation rates and factors contributing to FO relapse among this cohort. A retrospective review evaluated reoperation for FO relapse in patients with syndromic multisuture craniosynostosis who underwent primary fronto-orbital advancement (FOA) + calvarial vault remodeling (CVR) at our institution between 2004 and 2024. Revision surgeries included repeat FOA or monobloc advancement/distraction. FOA advancement distance was measured using postoperative computed tomography and Mimics software. ROC analysis evaluated the accuracy of FOA distance in predicting subsequent FO relapse. Conditional margins identified optimal advancement distances. Logistic regression of predictors of FO relapse adjusted for age at surgery, craniofacial syndrome, posterior vault distraction osteogenesis (PVDO), advancement distance, and postoperative helmet therapy. Fifty-two patients underwent a mean of 2.8±1.9 skeletal craniofacial procedures each. With a mean follow-up time of 9.2±6.5 years, 16 (30.8%) patients required reoperation for FO relapse. Larger advancement distances were the sole significant predictor of relapse, increasing the odds by 49.6% (OR 1.496, 95% CI: 1.085-2.063; P=0.014). Relapse rates were lower with advancements ≤17.2mm (0.0%) than with further advancements (42.0%, P=0.002). Specifically, advancements >18.8mm were associated with significantly higher relapse rates (P<0.05). Almost one-third of patients with multisuture syndromic craniosynostosis underwent FO region readvancement. Advancements <17.2mm during initial FOA appeared to mitigate relapse, while advancing beyond 18.8mm may increase the risk. Investigation of additional protective factors against FO relapse is encouraged to minimize surgical burden.

Rare Expression Of Van Der Wound Syndrome: A Case Report Revisited

Background: Van der Woude syndrome (VWS) is a rare developmental malformation, characterized by pits in the lower lip. Van der Woude syndrome is an autosomal dominant craniofacial syndrome with various expression: lower lip pits, cleft lip with or without cleft palate, syngnathia, hypoodontia, and ankyloglossia. Extra-oral abnormalities findings can be found: syndactily, corpus callosum dysgenesis, megacolon, ventricular septal defect and genital abnormality. Methods: We reported a case of 5-month-old male with rare expression of VWS: bilateral cleft lip and palate, syngnathia, lower lip pits, ptosis of upper left eyelid and macropenis. Results: We perform surgery to release the fibrous band to achieve satisfactory maximum mouth opening. Next we perform cheiloplasty and lower lip pit removal. Conclusion: Proper surgical intervention in VWS patients can improve feeding and prevent further temporomandibular complications. Careful examination of patients with cleft lip and lower lip pit should be done to avoid misdiagnosis.

Вариабельность признаков синдрома делеции 2q37 на примере клинических наблюдений

2q37 deletion syndrome is characterized by terminal deletions of the long arm of chromosome 2 and a variable clinical picture that includes type E brachydactyly, obesity, delayed motor and psychomotor development, congenital malformations of internal organs and the facial phenotype particular qualities. Authors present the two clinical case reports of patients with 2q37 deletions demonstrating different clinical manifestations. Proband 1 complained exclusively of brachydactyly while proband 2 had almost the full spectrum of clinical symptoms characterizing the syndrome. The Face2Gene AI-Powered Diagnosis &amp; Care Management Tool suggested the correct diagnosis in both cases based on the features of the facial phenotype that in its turn became the key factors in choosing the tactics for further molecular genetic diagnostics. Conclusion: careful collection of anamnesis data, description of the facial phenotype and the use of artificial intelligence-based tools can become the key factors in choosing the tactics for the molecular genetic diagnostics available for practitioners of various specialties.

Tetralogy of Fallot and pulmonary valvular agenesis syndrome in 22q11 deletion syndrome

Tetralogy of Fallot and pulmonary valvular agenesis syndrome in 22q11 deletion syndrome

Behavioral decline in Shank3Δex4–22 mice during early adulthood parallels cerebellar granule cell glutamatergic synaptic changes

BackgroundSHANK3, a gene encoding a synaptic scaffolding protein, is implicated in autism spectrum disorder (ASD) and is disrupted in Phelan-McDermid syndrome (PMS). Despite evidence of regression or worsening of ASD-like symptoms in individuals with PMS, the underlying mechanisms remain unclear. Although Shank3 is highly expressed in the cerebellar cortical granule cells, its role in cerebellar function and contribution to behavioral deficits in ASD models are unknown. This study investigates behavioral changes and cerebellar synaptic alterations in Shank3Δex4–22 mice at two developmental stages.MethodsShank3Δex4–22 wildtype, heterozygous, and homozygous knockout mice lacking exons 4–22 (all functional isoforms) were subjected to a behavioral battery in both juvenile (5–7 weeks old) and adult (3–5 months old) mouse cohorts of both sexes. Immunostaining was used to show the expression of Shank3 in the cerebellar cortex. Spontaneous excitatory postsynaptic currents (sEPSCs) from cerebellar granule cells (CGCs) were recorded by whole-cell patch-clamp electrophysiology.ResultsDeletion of Shank3 caused deficits in motor function, heightened anxiety, and repetitive behaviors. These genotype-dependent behavioral alterations were more prominent in adult mice than in juveniles. Reduced social preference was only identified in adult Shank3Δex4–22 knockout male mice, while self-grooming was uniquely elevated in males across both age groups. Heterozygous mice showed little to no changes in behavioral phenotypes in most behavioral tests. Immunofluorescence staining indicated the presence of Shank3 predominantly in the dendrite-containing rosette-like structures in CGCs, colocalizing with presynaptic markers of glutamatergic mossy fiber. Electrophysiological findings identified a parallel relationship between the age-related exacerbation of behavioral impairments and the enhancement of sEPSC amplitude in CGCs.LimitationsOther behavioral tests of muscle strength (grip strength test), memory (Barnes/water maze), and communication (ultrasonic vocalization), were not performed. Further study is necessary to elucidate how Shank3 modulates synaptic function at the mossy fiber-granule cell synapse in the cerebellum and whether these changes shape the behavioral phenotype.ConclusionsOur findings reveal an age-related exacerbation of behavioral impairments in Shank3Δex4–22 mutant mice. These results suggest that Shank3 may alter the function of glutamatergic receptors at the mossy fiber-cerebellar granule cell synapse as a potential mechanism causing cerebellar disruption in ASD.

An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene. Approximately 25% of individuals with PMS have epilepsy. Treatment of epilepsy in PMS may require multiple anticonvulsants, and in a minority of cases, seizures remain poorly controlled. Converging lines of evidence in different experimental models indicate that the Ras-ERK pathway is implicated in the pathophysiology of seizure generation and neurobehavioral symptoms in PMS. The goal of this study was to evaluate the safety, tolerability, and efficacy in treating seizures in adults and adolescents with PMS using AMO-01, a Ras-ERK pathway inhibitor . A single 6-hour intravenous infusion of AMO-01 at 120 mg/m2 was administered to six participants using an open-label design. Safety was assessed during the infusion and for four weeks post-infusion. Caregivers completed seizure diaries and recorded individual seizures during a baseline period and for four weeks following the infusion. Exploratory clinical and biomarker assessments were completed throughout the study. AMO-01 was well tolerated with no serious adverse events (AEs) reported. All AEs were mild or moderate in severity. Seizures were reduced by at least 25% compared to baseline at each follow-up (Weeks 1, 2, 4). Exploratory clinical measures did not change significantly from baseline, but visual evoked potentials (VEPs) and phosphorylated ERK blood levels revealed trending changes in a subset of participants. These results provide preliminary support for the safety of AMO-01 and its efficacy in reducing seizures in adults with PMS. Future placebo-controlled studies with larger sample sizes and repeated dosing are warranted.

Aortopathy in repaired tetralogy of Fallot and David procedure.

Tetralogy of Fallot (TOF) is a condition that often leads to long-term enlargement of the aortic root in after surgery. The aortic dilation is believed to be caused by histological abnormalities of the aortic media and the hemodynamic characteristics of increased aortic flow, compared to pulmonary flow. Severe cyanosis, severe right ventricular outflow tract (RVOT) obstruction, older age at repair, a larger aortic size at the time of repair, and a history of an aortopulmonary shunt parameters related to long-standing volume overload of the aortic root were the reported risk factors. Right aortic arch, male sex, and the association of chromosome 22q11 deletion were also reported to be risk factors. The enlargement of the aortic root can cause aortic regurgitation (AR), leading to left ventricular dysfunction and an increased risk of aortic dissection, necessitating surgical intervention. The outcomes of aortic valve repair for AR have improved, leading to an increasing trend of choosing this approach, particularly in younger patients who would otherwise require mechanical valve replacement, thereby avoiding the need for anticoagulation therapy. The indications and timing of prophylactic aortic root replacement in adult patients with congenital heart disease have not been described, and the current consensus recommends surgical intervention for an ascending aorta with a diameter of ≥55 mm. In this review article, we focus on valve-sparing root replacement (VSRR) in TOF.

Successful treatment of psychosis with metyrosine in a young adult with velocardiofacial syndrome: a case report

Velocardiofacial syndrome (VCFS) has many psychiatric manifestations along with multiple physical findings such as developmental delay, cardiac abnormalities, palatal anomalies, and immune deficiency. As many as 41% of individuals with VCFS have experienced a psychotic disorder– a disabling and distressing condition. One of the missing genes in the syndrome is catechol-O-methyltransferase (COMT) that is involved in dopamine metabolism and neurotransmission, and one possible implication of this haploinsufficiency is higher dopamine levels in the prefrontal cortex. We present a case of VCFS- associated psychosis that was unresponsive to traditional antipsychotic agent trials but responded to a trial of metyrosine, an older antihypertensive medication that inhibits catecholamine synthesis. Since the initiation of metyrosine, the patient has had no psychiatric hospitalizations in three years, a distinct and dramatic difference from the two years prior to the initiation of the medication. Metyrosine is not a first line treatment for VCFS-related psychosis. Prior to its initiation, traditional antipsychotics should be tried and clozapine would be an option for treatment-resistant cases.