Immunologic, Molecular, and Clinical Profile of Patients With Chromosome 22q11.2 Duplications

The aim of this study was to investigate the clinical, immunologic, and cytogenetic data of patients with 22q11.2 duplication syndrome (22q11.2dup) to identify key features.

This study included 216 patients diagnosed with 22q11.2dup at the Children’s Hospital of Philadelphia from January 1997 to March 2022.

In this single-center retrospective chart review, the diagnosis of 22q11.2dup was made using various genetic testing modalities. Demographics, clinical details, hematologic and immunologic data, cytogenetics, and therapeutics were collected, analyzed, and compared using SPSS software.

The study cohort was comprised of children (75.5%), adults (19%), and fetuses (5.6%) with a near even ratio of males to females (1.096:1). The mean age at diagnosis was 9.8 years for all patients, with mean age at diagnosis for children at 4.35 years. The majority of patients were diagnosed by microarray (52.8%), and more than half of patients had a duplication of LCR22A to D. Duplications distal to the LCR22D site was observed in 21% of patients and a nested duplication (within -A to -D region) was identified in 16%. Common clinical abnormalities identified in this cohort included developmental delay (48.6%), cardiac abnormality (33.8%), and endocrine abnormality (30.5%). Immunologic abnormalities commonly identified were decreased switched memory B cells (25%), hypogammaglobulinemia (44% had 1 immunoglobulin isotype low, 21% had 2 isotypes low, 11% had all 3 isotypes low), and low specific antibodies. Only 4 patients were on immunoglobulin replacement. T cell counts were generally normal. Recurrent fevers, infections, and autoimmunity were uncommonly seen in 22q11.2dup (2.3% respectively), whereas 22q11.2dup patients had high rates of atopy (25% with asthma, 9.4% with eczema).

Immunodeficiency is a key clinical feature in 22q11.2dup syndrome with humoral immunodeficiency, not T cell deficiency, most commonly identified.

This is the first large cohort study to focus on the immunologic profiles of patients diagnosed with 22q11.2dup syndrome. Although 22q11.2dup shares clinical similarities with 22q11.2 deletion (22q11.2del) syndrome, including developmental delay, cardiac and endocrine abnormalities, the immunologic phenotype is more distinct. This study provides a more robust representation of the immune profile of patients with 22q11.2dup syndrome. Limitations of the study include a single center study and disproportionate sample sizes for T and B cell subsets. 22q11.2 deletion commonly impacts T cells, whereas 22q11.2dup has a relatively preserved T cell compartment with more noticeable B cell and antibody impairment. Despite this, recurrent fevers, infections, and autoimmunity are not commonly seen in patients with 22q11.2dup. General pediatricians and subspecialists should be familiar with the key clinical features of 22q11.2dup syndrome and recognize the importance of multidisciplinary care for these patients.