European Society of Immunodeficiencies guidelines for the management of patients with congenital athymia.

Congenital athymia is a life-limiting disorder due to rare inborn errors of immunity causing impaired thymus organogenesis or abnormal thymic stromal cell development and function. Athymic infants have a T-B+NK+ immunophenotype with profound T lymphocyte deficiency and are susceptible to severe infections and autoimmunity. Patients variably display syndromic features. Expanding access to newborn screening for severe combined immunodeficiency (SCID) and T lymphocytopaenia and broad genetic testing, including next-generation sequencing technologies, increasingly facilitate their timely identification. The recommended first-line treatment is allogeneic thymus transplantation, which is a specialized procedure available in Europe and the United States. Outcomes for athymic patients are best with early diagnosis and thymus transplantation before the development of infectious and inflammatory complications. These guidelines on behalf of the European Society of Immunodeficiencies provide a comprehensive review for clinicians who manage patients with inborn thymic stromal cell defects, and offer clinical practice recommendations focused on the diagnosis, investigation, risk stratification and management of congenital athymia, with the aim of improving patient outcomes.

The Co-Occurrence of 22q11.2 Deletion Syndrome and Epithelial Basement Membrane Dystrophy: A Case Report and Review of the Literature.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a genetic disorder caused by the deletion of the q11.2 band of chromosome 22. It may affect various systems, including the cardiovascular, immunological, gastrointestinal, endocrine, and neurocognitive systems. Additionally, several ocular manifestations have been described. RESULTS: We report a case of a 34-year-old female diagnosed with 22q11.2DS who presented with visual discomfort and foreign body sensation in both eyes. She had no history of recurrent ocular pain. A comprehensive ophthalmological examination was performed, including anterior segment optical coherence tomography and in vivo confocal microscopy. Overall, the exams revealed bilateral corneal map-like lines, dots, and fingerprint patterns, consistent with a diagnosis of epithelial basement membrane dystrophy (EBMD). In addition to presenting with this novel corneal manifestation for 22q11.2 DS, we review the ocular clinical features of 22q11.2DS in the context of our case. CONCLUSIONS: The EBMD may represent a new corneal manifestation associated with 22q11.2 syndrome, although the link between these conditions is unknown. Further research is warranted to investigate potentially shared genetic or molecular pathways to the understanding of the phenotypic variety observed among this rare syndrome.

Differential inflammatory profiles in carriers of reciprocal 22q11.2 copy number variants.

BACKGROUND: Genetic copy number variants (CNVs; i.e., a deletion or duplication) at the 22q11.2 locus confer increased risk of neuropsychiatric disorders and immune dysfunction. Inflammatory profiles of 22q11.2 CNV carriers can shed light on gene-immune relationships that may be related to neuropsychiatric symptoms. However, little is known about inflammation and its relationship to clinical phenotypes in 22q11.2 CNV carriers. Here, we investigate differences in peripheral inflammatory markers in 22q11.2 CNV carriers and explore their relationship with psychosis risk symptoms and sleep disturbance. METHODS: Blood samples and clinical assessments were collected from 22q11.2 deletion (22qDel) carriers (n=45), 22q11.2 duplication (22qDup) carriers (n=29), and typically developing (TD) control participants (n=92). Blood plasma levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), and anti-inflammatory cytokine interleukin-10 (IL-10) were measured using a MesoScale Discovery multiplex immunoassay. Plasma levels of C-reactive protein (CRP) were measured using Enzyme-linked Immunosorbent Assay (ELISA). Linear mixed effects models controlling for age, sex, and body mass index were used to: a) examine group differences in inflammatory markers between 22qDel, 22qDup, and TD controls, b) test differences in inflammatory markers between 22qDel carriers with psychosis risk symptoms (22qDelPS+) and those without (22qDelPS-), and c) conduct an exploratory analysis testing the effect of sleep disturbance on inflammation in 22qDel and 22qDup carriers. A false discovery rate correction was used to correct for multiple comparisons. RESULTS: 22qDup carriers exhibited significantly elevated levels of IL-8 relative to TD controls (q<0.001) and marginally elevated IL-8 levels relative to 22qDel carriers (q=0.08). There were no other significant differences in inflammatory markers between the three groups (q>0.13). 22qDelPS+ exhibited increased levels of IL-8 relative to both 22qDelPS- (q=0.02) and TD controls (p=0.002). There were no relationships between sleep and inflammatory markers that survived FDR correction (q>0.14). CONCLUSION: Our results suggest that CNVs at the 22q11.2 locus may have differential effects on inflammatory processes related to IL-8, a key mediator of inflammation produced by macrophages and microglia. Further, these IL-8-mediated inflammatory processes may be related to psychosis risk symptoms in 22qDel carriers. Additional research is required to understand the mechanisms contributing to these differential levels of IL-8 between 22q11.2 CNV carriers and IL-8's association with psychosis risk.

Multiplex droplet digital PCR for 22q11.2 microdeletions screening and DiGeorge syndrome diagnostics.

BACKGROUND AND AIMS: DiGeorge syndrome (DGS) is a genetic disorder manifesting in polymorphic symptoms related to developmental abnormalities of various organs including thymus. DGS is caused by microdeletions in the 22q11.2 region between several low copy repeats (LCR) occurring in approximately 1 in 4000 live births. Diagnosis of DGS relies on phenotypic examination, qPCR, ultrasound, FISH, MLPA and NGS which can be relatively inaccurate, time-consuming, and costly. MATERIALS AND METHODS: A novel multiplex droplet digital PCR (ddPCR) assay was designed, optimized and validated for detection and mapping 22q11.2 microdeletions by simultaneous amplification of three targets - TUPLE1, ZNF74, D22S936 - within the deletion areas and one reference target - RPP30 - as an internal control. RESULTS: The assay reliable identified microdeletions when the template concentration was >32 copies per reaction and successfully detected LCR22A-B, LCR22A-C, LCR22A-D, and LCR22B-C deletions in clinical samples from 153 patients with signs of immunodeficiency. In patients with the microdeletions, flow cytometry detected a significant increase in B-cell and natural killer cell counts and percentages, while T-cell percentages and T-cell receptor excision circle (TREC) numbers decreased. CONCLUSION: The designed ddPCR assay is suitable for diagnosing DGS using whole blood and blood spots.

Short communication: catechol-O-methyltransferase allelic variation in relation to psychological and hormonal indices of stress in children and adolescents with chromosome 22q11.2 deletion syndrome (22q11.2DS).

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a developmental disorder with high rates of anxiety and psychosis. Catechol-O-methyltransferase (COMT) regulates epinephrine (E), norepinephrine (NE), and dopamine (DA) and is implicated in both anxiety and psychotic disorders. The aim of this study was to determine how COMT variation relates to psychological anxiety and associated stress physiology responsiveness to better understand symptom heterogeneity in people with 22q11.2DS. We examined COMT allelic variation in relation to anxiety and hypothalamic-pituitary-adrenocortical (HPA) and sympathetic-adrenomedullary (SAM) hormonal stress indicators in 30 children and adolescents with 22q11.2DS. Contrary to expectation, individuals with the higher activity COMTval allele had higher anxiety levels versus those with the low activity (COMTmet) allele (p = 0.021; Glass' Δ = 0.69). Anxiety was not correlated with salivary cortisol (CORT) or alpha-amylase (sAA) in either group. Groups did not differ in CORT levels (p = 0.58), but the COMTmet group had higher sAA (p = 0.026; Glass' Δ = 0.67, uncorrected) suggesting greater SAM reactivity but not HPA activity. This suggests that COMT allelic variation may contribute to differences in acute SAM but not slower HPA stress reactivity in those with 22q11.2DS.

Multiple Intestinal Anomalies in a Newborn with 22q11.2 Microdeletion Syndrome: A Case Report and Literature Review.

Although 40 years have passed since the first case of DiGeorge's syndrome was described, and the knowledge about this disorder has steadily increased since that time, 22q11.2 deletion syndrome (DS) remains a challenging diagnosis because its clinical presentation varies widely. We describe an infant with 22q11.2 DS who presented with annular pancreas, anorectal malformation, Morgagni-type congenital diaphragmatic hernia, and ventricular septal defect. This constellation of anomalies has never been described in DiGeorge's syndrome. Here, we provide a case presentation and a thorough review of the literature.

Multiple Major Aortopulmonary Collateral Arteries With Tetralogy of Fallot and Other Congenital Cardiac Disorders Detected in the Fourth Decade: A Report of a Rare Case.

The occurrence of MAPCAs (major aortopulmonary collateral arteries) with TOF (tetralogy of Fallot) and bilateral hypoplastic pulmonary arteries together is a rare condition. Patients are typically middle-aged men who usually present with acute signs of cardiac manifestations. The anomalies have survival up to the fourth decade of life and are fraught with clinical challenges. Additionally, various congenital syndromic associations, such as DiGeorge syndrome, are associated with these anomalies. We report an extremely rare case of a 41-year-old male who came with complaints of chest pain, dyspnea on exertion, and headaches. The patient had a previous history of tuberculosis and a rare combination of MAPCAs with TOF and bilateral hypoplastic pulmonary arteries, with a right-sided aortic arch with an aplastic left subclavian artery. The importance of the case comes from the need to perform surgery on a middle-aged male who was completely asymptomatic prior to this.

Conotruncal Heart Defects: A Narrative Review of Molecular Genetics, Genomics Research and Innovation.

Congenital heart defects (CHDs) are most prevalent cardiac defects that occur at birth, leading to significant neonatal mortality and morbidity, especially in the developing nations. Among the CHDs, conotruncal heart defects (CTDs) are particularly noteworthy, comprising a significant portion of congenital cardiac anomalies. While advances in imaging and surgical techniques have improved the diagnosis, prognosis, and management of CTDs, their molecular genetics and genomic substrates remain incompletely understood. This expert review covers the recent advances from January 2016 onward and examines the complexities surrounding the genetic etiologies, prevalence, embryology, diagnosis, and clinical management of CTDs. We also emphasize the known copy number variants and single nucleotide variants associated with CTDs, along with the current planetary health research efforts aimed at CTDs in large cohort studies. In all, this comprehensive narrative review of molecular genetics and genomics research and innovation on CTDs draws from and highlights selected works from around the world and offers new ideas for advances in CTD diagnosis, precision medicine interventions, and accurate assessment of prognosis and recurrence risks.

An Unusual Relation in an Infant With Left Hemitruncus and Tetralogy of Fallot Along With Pulmonary Valve Syndrome: A Case Report.

The abnormal origin of the left pulmonary artery (LPA) from the ascending aorta is a rare cardiac condition that is often associated with several other congenital defects. In this paper, we report the case of an infant who presented with recurrent infections and was prenatally diagnosed with tetralogy of Fallot (TOF). During echocardiography, various other cardiac defects such as ventricular septal defects (VSD), pulmonary stenosis (PS), and dilated right heart chambers were identified. Furthermore, cardiac catheterization revealed an anomalous origin of the LPA arising from the aorta associated with a narrow pulmonary annulus. Due to both conditions sharing a similar embryological course, the condition is commonly associated with a conotruncal defect known as DiGeorge syndrome. Together, the overall combination of cardiac anomalies is both unusual and unique. This case study explains the clinical associations, embryological origin, and surgical management of this condition in an infant.

Multidisciplinary Velopharyngeal Dysfunction Evaluation Helps Detect Non-classic Cases of 22q11.2 Deletion.

OBJECTIVE: To explore the role of multidisciplinary velopharyngeal dysfunction (VPD) assessment in diagnosing 22q11.2 deletion syndrome (22q) in children. DESIGN: Retrospective cohort study. SETTING: Multidisciplinary VPD clinic at a tertiary pediatric hospital. PATIENTS, PARTICIPANTS: Seventy-five children with genetically confirmed 22q evaluated at the VPD clinic between February 2007 and February 2023, including both previously diagnosed patients and those newly diagnosed as a result of VPD evaluation. INTERVENTIONS: Comprehensive review of medical records, utilizing ICD-10 codes and an institutional tool for keyword searches, to identify patients and collect data on clinical variables and outcomes. MAIN OUTCOME MEASURES: Characteristics of children with 22q, pathways to diagnosis, and clinical presentations that led to genetic testing for 22q. RESULTS: Of the 75 children, 9 were newly diagnosed with 22q following VPD evaluation. Non-cleft VPI was a significant indicator for 22q in children not previously diagnosed, occurring in 100% of newly diagnosed cases compared to 52% of cases with existing 22q diagnosis (P = .008). Additional clinical findings leading to diagnosis included congenital heart disease, craniofacial abnormalities, and developmental delays. CONCLUSIONS: VPD evaluations, particularly the presence of non-cleft VPI, play a crucial role in identifying undiagnosed cases of 22q. This underscores the need for clinicians, including plastic surgeons, otolaryngologists, and speech-language pathologists, to maintain a high degree of suspicion for 22q in children presenting with VPI without a clear etiology. Multidisciplinary approaches are essential for early diagnosis and management of this complex condition.

Hybrid management of descending thoracic pseudoaneurysm in a patient with DiGeorge syndrome.

We present a case of a 42-year-old man with DiGeorge syndrome and congenital cardiac anomalies including a type B interrupted aortic arch who had previously undergone two bypasses between the ascending and descending thoracic aorta in childhood. He was found to have a 7.4-cm pseudoaneurysm of the descending thoracic aorta with the left subclavian artery arising from the aneurysm. The patient was treated with a single stage hybrid repair including left common carotid to subclavian bypass followed by thoracic endovascular aortic aneurysm repair.

DiGeorge Syndrome Diagnosed at Age 38: Challenges in Low-resource Settings and Implications of a Missed Diagnosis.

22q11.2 deletion syndrome (22.q11.2 DS) is a genetic syndrome resulting from a microdeletion on chromosome 22. It has a diverse array of manifestations, and most cases are diagnosed early in childhood. We present the case of a 38-year-old female born in a developing country who presented to our clinic to establish care for a history of primary hypothyroidism. She was clinically and biochemically euthyroid on thyroid supplementation. She was also noted to have hypocalcemia in the setting of low PTH, for which the patient was previously prescribed calcitriol. Given a history of cleft palate, abnormal facial features, mild recurrent sinopulmonary infections, and her endocrine history (including short stature with height in the 6th percentile), genetic testing was obtained. She was diagnosed with a heterozygous whole gene deletion of the TBX1 gene. Additional genetic evaluation demonstrated a 2.6-Mb microdeleted segment of the 22a11.2 region encompassing 62 genes. The patient was referred to cardiology for evaluation of cardiac involvement given a history of tachyarrhythmia. This case highlights challenges in diagnosis and the implications of a delayed diagnosis of 22.q11.2 DS.

Multicenter appraisal of comorbid TANGO2 deficiency disorder in patients with 22q11.2 deletion syndrome.

TANGO2 deficiency disorder (TDD) is a rare, autosomal recessive condition caused by pathogenic variants in TANGO2, a gene residing within the region commonly deleted in 22q11.2 deletion syndrome (22q11.2DS). Although patients with 22q11.2DS are at substantially higher risk for comorbid TDD, it remains underdiagnosed within 22q11.2DS, likely due to overlapping symptomatology and a lack of knowledge about TDD. Initiation of B-vitamin supplementation may provide therapeutic benefit in TDD, highlighting the need for effective screening methods to improve diagnosis rates in this at-risk group. In this retrospective, multicenter study, we evaluated two cohorts of patients with 22q11.2DS (total N = 435) for possible comorbid TDD using two different symptom-based screening methods (free text-mining and manual chart review versus manual chart review alone). The methodology of the cohort 1 screening method successfully identified a known 22q11.2DS patient with TDD. Combined, these two cohorts identified 21 living patients meeting the consensus recommendation for TANGO2 testing for suspected comorbid TDD. Of the nine patients undergoing TANGO2 sequencing with del/dup analysis, none were ultimately diagnosed with TDD. Of the 12 deaths in the suspected comorbid TDD cohort, some of these patients exhibited symptoms (rhabdomyolysis, cardiac arrhythmia, or metabolic crisis) suspicious of comorbid TDD contributing to their death. Collectively, these findings highlight the need for robust prospective screening tools for diagnosing comorbid TDD in patients with 22q11.2DS.

Human Genetics of Ventricular Septal Defect.

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

Neural Crest.

This chapter discusses the role of cardiac neural crest cells in the formation of the septum that divides the cardiac arterial pole into separate systemic and pulmonary arteries. Further, cardiac neural crest cells directly support the normal development and patterning of derivatives of the caudal pharyngeal arches, including the great arteries, thymus, thyroid, and parathyroids. Recently, cardiac neural crest cells have also been shown to indirectly influence the development of the secondary heart field, another derivative of the caudal pharynx, by modulating signaling in the pharynx. The contribution and function of the cardiac neural crest cells has been learned in avian models; most of the genes associated with cardiac neural crest function have been identified using mouse models. Together these studies show that the neural crest cells may not only critical for normal cardiovascular development but also may be involved secondarily because they represent a major component in the complex tissue interactions in the caudal pharynx and outflow tract. Cardiac neural crest cells span from the caudal pharynx into the outflow tract, and therefore may be susceptible to any perturbation in or by other cells in these regions. Thus, understanding congenital cardiac outflow malformations in human sequences of malformations resulting from genetic and/or environmental insults necessarily requires better understanding the role of cardiac neural crest cells in cardiac development.

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

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

Human Genetics of Semilunar Valve and Aortic Arch Anomalies.

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.

Human Genetics of Truncus Arteriosus.

Integrated human genetics and molecular/developmental biology studies have revealed that truncus arteriosus is highly associated with 22q11.2 deletion syndrome. Other congenital malformation syndromes and variants in genes encoding TBX, GATA, and NKX transcription factors and some signaling proteins have also been reported as its etiology.

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.