Clinical Features and Follow-Up in Patients with 22q11.2 Deletion Syndrome

doi:10.1016/j.jpeds.2014.01.056

The Journal of Pediatrics

Volume 164, Issue 6, June 2014, Pages 1475-1480.e2

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https://doi.org/10.1016/j.jpeds.2014.01.056 Get rights and content

Objective

To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease.

Study design

A retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis.

Results

The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations (P = .015) and speech disorders (P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis.

Conclusions

Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.

Section snippets

Methods

In May 2005, Italian Network for Primary Immunodeficiencies and the Working Group of the Italian Association of Pediatric Haematology and Oncology (AIEOP) issued guidelines for management of patients with 22q11DS and invited through a questionnaire to register clinical data of patients in a secure database, compliant to International Conference on Harmonisation for Good Clinical Practice guidelines and European regulations. The AIEOP database registry is approved by the Ethical Committee of the

Results

Two hundred twenty-eight patients (112 males and 116 females) with a diagnosis of 22q11DS were included in the present study. The median age at diagnosis was 4 months (range 0-36 years 10 months, mean age 24 months). Prenatal diagnosis was made in 3 cases.

In 71% of patients (162/228), the diagnosis was made before 2 years of age: cardiac defects and neonatal hypocalcemia were the most relevant clinical features (Table I). The remaining 29% of patients (66/228) were diagnosed after 2 years of

Discussion

Our results confirm that congenital cardiac defects associated with neonatal hypocalcemia are the most frequent features leading to diagnosis in the first months of life,¹² thus strongly suggesting that newborns with typical cardiac defects associated with facial features should be investigated for 22q11.2 microdeletions.

Conotruncal and aortic arch defects were the most typical cardiac malformations associated with 22q11DS, in agreement with previous reports.¹⁴ Importantly, although cardiac

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We aimed to evaluate adult-onset obstructive sleep apnea (OSA) and related risk factors, including history of pediatric palatal/pharyngeal surgery to remediate velopharyngeal dysfunction, in 22q11.2 deletion syndrome (22q11.2DS).
Using a retrospective cohort design and standard sleep study-based criteria, we determined presence of adult-onset OSA (age ≥16 years) and relevant variables through comprehensive chart review in a well-characterized cohort of 387 adults with typical 22q11.2 microdeletions (51.4% female, median age 32.3, interquartile range 25.0–42.5, years). We used multivariate logistic regression to identify independent risk factors for OSA.
Of the 73 adults with sleep study data, 39 (53.4%) met criteria for OSA at median age 33.6 (interquartile range 24.0–40.7) years, indicating a minimum OSA prevalence of 10.1% in this 22q11.2DS cohort. History of pediatric pharyngoplasty (odds ratio 2.56, 95% confidence interval 1.15–5.70) was a significant independent predictor of adult-onset OSA, while accounting for other significant independent predictors (asthma, higher body mass index, older age), and for male sex. An estimated 65.5% of those prescribed continuous positive airway pressure therapy were reported as adherent.
In addition to factors of known importance in the general population, delayed effects of pediatric pharyngoplasty may contribute to risk of adult-onset OSA in individuals with 22q11.2DS. The results support increased index of suspicion for OSA in adults with a 22q11.2 microdeletion. Future research with this and other homogeneous genetic models may help to improve outcomes and to better understand genetic and modifiable risk factors for OSA.
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The thymus is the crucial tissue where thymocytes develop from hematopoietic precursors that originate from the bone marrow and differentiate to generate a repertoire of mature T cells able to respond to foreign antigens while remaining tolerant to self-antigens. Until recently, most of the knowledge on thymus biology and its cellular and molecular complexity have been obtained through studies in animal models, because of the difficulty to gain access to thymic tissue in humans and the lack of in vitro models able to faithfully recapitulate the thymic microenvironment. This review focuses on recent advances in the understanding of human thymus biology in health and disease obtained through the use of innovative experimental techniques (eg. single cell RNA sequencing, scRNAseq), diagnostic tools (eg. next generation sequencing), and in vitro models of T-cell differentiation (artificial thymic organoids) and thymus development (eg. thymic epithelial cell differentiation from embryonic stem cells or induced pluripotent stem cells).
Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome
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This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.
COVID-19 Severity, Cardiological Outcome, and Immunogenicity of mRNA Vaccine on Adult Patients With 22q11.2 DS
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The contemporaneous presence of immune defects and heart diseases in patients with 22q11.2 deletion syndrome (22q11.3DS) might represent risk factors for severe coronavirus 2019 disease (COVID-19).
To analyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcome in 22q11.2DS patients and immunogenicity of different doses of mRNA SARS-CoV-2 vaccine.
Longitudinal observational study on SARS-CoV-2 outcome in 60 adults with 22q11.2DS (March 2020–June 2022). Anti-Spike, and anti–receptor binding domain (RBD) antibody responses, generation of Spike-specific memory B cells (MBCs) and Spike-specific T cells at different time points before and after the mRNA BNT162b2 vaccination were evaluated in 16 22q11.2DS patients.
We recorded a 95% rate of vaccination, with almost all patients being immunized with the booster dose. Twenty-one patients had SARS-CoV-2 infection. Three patients were infected before vaccine availability, 6 after receiving 2 doses of vaccine, and 12 after one booster dose. The SARS-CoV-2- infection had a mild course, except in one unvaccinated patient with several comorbidities who died from acute respiratory distress syndrome (fatality rate 5%). Infected patients had more frequently moderate/severe intellectual disability, lymphopenia, and lower CD4+ count. Despite major congenital heart diseases, COVID-19 did not impact cardiological conditions. The BNT162b2 vaccine induced S1–immunoglobulin G (IgG) responses, low serum S1-IgA, and slightly impaired specific MBCs response. Specific T-cell responses observed were related to lymphocytes and CD4+ T cell counts.
The SARS-CoV-2 infection had a mild course in most patients with 22q11.2DS, even in patients with major cardiovascular diseases. Immunization induced Spike-specific IgG responses and generated specific MBCs and memory T cells. The weaker memory responses in patients with lymphopenia suggested the need for additional doses.
Early developmental concerns in 22q11.2 deletion and duplication carriers
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22q11.2 deletions (22qDEL) and duplications (22qDUP) are among the most common copy number variants (CNVs) associated with neurodevelopmental disorders (NDDs). Little is known about the earliest developmental features of 22q11.2 CNVs and whether developmental delays are detected in early childhood. This study primarily aimed to assess general development and social communication in 22q11.2 CNV carriers age 5 and under.
Participants included parents of children age 5 and under with a reported genetic diagnosis of 22qDEL (N = 63) or 22qDUP (N = 30). In addition to questions addressing clinical and intervention information, two standardized parent questionnaires—the Ages & Stages Questionnaires, Third Edition (ASQ-3) and the Communication and Symbolic Behavior Scales Developmental Profile Infant/Toddler Checklist (ITC)—screened for developmental and social communication delays, respectively.
Developmental delay and speech and/or language delay were the most commonly reported NDD diagnoses among young 22q11.2 CNV carriers, with prevalences at 19% and 17%, respectively. In the vast majority (91%) of 22q11.2 CNV carriers, parents reported concerns in at least one developmental domain, with 71% reporting global developmental concerns. 70% of parents of 22q11.2 CNV carriers age 2 and under also reported social communication concerns.
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2022, The Chromosome 22q11.2 Deletion Syndrome: A Multidisciplinary Approach to Diagnosis and Treatment
Herein, we will describe the spectrum of craniofacial features associated with the chromosome 22q11.2 deletion syndrome including anatomic and functional differences in the craniofacial skeleton, the facial soft tissues, and the velopharyngeal mechanism. Palatal findings including clefting and velopharyngeal dysfunction will be described in detail including incidence, diagnosis, and indications for surgical treatment. Surgical management will be discussed including the timing of interventions, preoperative assessment of speech, and imaging of the velopharyngeal mechanism, as well as preoperative screening recommendations specific to 22q11.2 deletion syndrome to evaluate for internal carotid artery malposition, cervical spine anomalies, and obstructive sleep apnea. Surgical techniques, complications, and reported outcomes will also be discussed.

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: Funded by European Commission (CELL-PID HEALTH-F5-2010-261387), Italian Ministry of Health (Ricerca corrente). The authors declare no conflicts of interest.

^∗: A list of additional members of the Italian Network for Primary Immunodeficiencies is available at www.jpeds.com (Appendix).

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Original ArticleClinical Features and Follow-Up in Patients with 22q11.2 Deletion Syndrome

Objective

Study design

Results

Conclusions

Section snippets

Methods

Results

Discussion

J Pediatr

Lancet

Am J Cardiol

J Pediatr

Otolaryngol Clin North Am

Lancet

J Pediatr

J Pediatr

J Pediatr

J Pediatr

A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population

Pediatrics

Incidence and prevalence of the 22q11 deletion syndrome: a population-based study in Western Sweden

Arch Dis Child

Velo-cardio-facial syndrome: 30 years of study

Dev Disabil Res Rev

Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study

J Med Genet

The Philadelphia story: the 22q11.2 deletion: report on 250 patients

Genet Couns

Presenting symptoms and clinical features in 130 patients with the velo-cardio-facial syndrome. The Leuven experience

Genet Couns

Molecular and clinical study of 183 patients with conotruncal anomaly face syndrome

Hum Genet

Familial recurrence of nonsyndromic congenital heart defects in first degree relatives of patients with deletion 22q11.2

Am J Med Genet A

FISH investigation of 22q11.2 deletion in patients with immunodeficiency and/or cardiac abnormalities

Pediatr Surg Int

Original Article
Clinical Features and Follow-Up in Patients with 22q11.2 Deletion Syndrome