{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T06:50:28Z","timestamp":1772693428755,"version":"3.50.1"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T00:00:00Z","timestamp":1649116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized by a broad and heterogeneous clinical presentation associated with various degrees of T-cell deficiency. We report the clinical, immunologic, and genetic findings of a cohort of eight patients presenting with a clinical phenotype that is highly suggestive of this syndrome but without the 22q11.2 deletion. The cardinal features of 22q11.2DS, such as congenital heart defects, hypoparathyroidism, and facial dysmorphisms, were observed in the majority of the patient cohort. The unusual features are described in detail. The immunologic assessment showed various degrees of immunodeficiency of the T-cell compartment, notably a reduction in the thymic output. Half of the patient cohort exhibited a reduction in total dendritic cells. Array comparative genomic hybridization (CGH) revealed six patients harboring copy number variations (CNVs) never reported in normal subjects. The gene content of these CNVs was carefully analyzed to understand the mechanisms leading to 22q11.2DS phenocopies. According to these results, we suggested that array-CGH should be used as a first-tier tool for patients resembling 22q11.2DS.<\/jats:p>","DOI":"10.3390\/jcm11072025","type":"journal-article","created":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T06:01:34Z","timestamp":1649138494000},"page":"2025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Clinical, Immunological, and Genetic Findings in a Cohort of Patients with the DiGeorge Phenotype without 22q11.2 Deletion"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7929-7342","authenticated-orcid":false,"given":"Antonino Maria Quintilio","family":"Alberio","sequence":"first","affiliation":[{"name":"Pediatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Legitimo","sequence":"additional","affiliation":[{"name":"Section of Clinical and Laboratory Immunology, Pediatric Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Bertini","sequence":"additional","affiliation":[{"name":"Section of Cytogenetics, Department of Laboratory Medicine, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giampiero I.","family":"Baroncelli","sequence":"additional","affiliation":[{"name":"Pediatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4160-3727","authenticated-orcid":false,"given":"Giorgio","family":"Costagliola","sequence":"additional","affiliation":[{"name":"Pediatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo","family":"Valetto","sequence":"additional","affiliation":[{"name":"Section of Cytogenetics, Department of Laboratory Medicine, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5968-1945","authenticated-orcid":false,"given":"Rita","family":"Consolini","sequence":"additional","affiliation":[{"name":"Section of Clinical and Laboratory Immunology, Pediatric Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1002\/ajmg.a.40504","article-title":"Molecular genetics of 22q11.2 deletion syndrome","volume":"176","author":"Morrow","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15071","DOI":"10.1038\/nrdp.2015.71","article-title":"22q11.2 deletion syndrome","volume":"1","author":"Sullivan","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1159\/000438708","article-title":"22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features","volume":"146","author":"Burnside","year":"2015","journal-title":"Cytogenet. Genome Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/MD.0b013e3182060469","article-title":"Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome\/velocardiofacial syndrome)","volume":"90","author":"Sullivan","year":"2011","journal-title":"Medicine (Baltimore)"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1016\/j.jpeds.2014.01.056","article-title":"Clinical features and follow-up in patients with 22q11.2 deletion syndrome","volume":"164","author":"Cancrini","year":"2014","journal-title":"J. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.jpeds.2011.02.039","article-title":"Practical guidelines for managing patients with 22q11.2 deletion syndrome","volume":"159","author":"Bassett","year":"2011","journal-title":"J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.jaci.2019.09.020","article-title":"Recurrent microdeletions at chromosome 2p11.2 are associated with thymic hypoplasia and features resembling DiGeorge syndrome","volume":"145","author":"Bernstock","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s13353-016-0366-1","article-title":"Genomic findings in patients with clinical suspicion of 22q11.2 deletion syndrome","volume":"58","author":"Koczkowska","year":"2017","journal-title":"J. Appl. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/ng0896-458","article-title":"A common region of 10p deleted in DiGeorge and velocardiofacial syndromes","volume":"13","author":"Daw","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1016\/j.jaip.2020.06.051","article-title":"Clinical Phenotype, Immunological Abnormalities, and Genomic Findings in Patients with DiGeorge Spectrum Phenotype without 22q11.2 Deletion","volume":"8","author":"Cirillo","year":"2020","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1136\/adc.81.6.513","article-title":"Towards earlier diagnosis of 22q11 deletions","volume":"81","author":"Tobias","year":"1999","journal-title":"Arch. Dis. Child."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/s13052-021-01150-0","article-title":"Prevention of recurrent respiratory infections: Inter-society Consensus","volume":"47","author":"Chiappini","year":"2021","journal-title":"Ital. J. Pediatrics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1210\/jc.2010-2704","article-title":"The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know","volume":"96","author":"Ross","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1542\/peds.2008-1862","article-title":"Prevention of rickets and vitamin D deficiency in infants, children, and adolescents","volume":"122","author":"Wagner","year":"2008","journal-title":"Pediatrics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1097\/MPG.0b013e31828f3c05","article-title":"Vitamin D in the healthy European paediatric population","volume":"56","author":"Braegger","year":"2013","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/BF03344156","article-title":"Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr)","volume":"29","author":"Cacciari","year":"2006","journal-title":"J. Endocrinol. Invest."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1365-3083.2012.02671.x","article-title":"Paediatric reference values for the peripheral T cell compartment","volume":"75","author":"Gemen","year":"2012","journal-title":"Scand. J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/j.1365-3083.2011.02609.x","article-title":"Age-matched reference values for B-lymphocyte subpopulations and CVID classifications in children","volume":"74","author":"Gemen","year":"2011","journal-title":"Scand. J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.jaci.2003.07.003","article-title":"Lymphocyte subsets in healthy children from birth through 18 years of age: The Pediatric AIDS Clinical Trials Group P1009 study","volume":"112","author":"Shearer","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/cyto.a.22520","article-title":"Lymphocytes subsets reference values in childhood","volume":"87","author":"Tosato","year":"2015","journal-title":"Cytom. A"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1182\/blood-2008-02-139154","article-title":"Life after the thymus: CD31+ and CD31\u2212 human naive CD4+ T-cell subsets","volume":"113","author":"Kohler","year":"2009","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/intimm\/dxs006","article-title":"Enumeration of human peripheral blood dendritic cells throughout the life","volume":"24","author":"Orsini","year":"2012","journal-title":"Int. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1111\/cei.13429","article-title":"Vitamin D status and the immune assessment in 22q11.2 deletion syndrome","volume":"200","author":"Legitimo","year":"2020","journal-title":"Clin. Exp. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1007\/s00439-013-1337-9","article-title":"A hypofunctional PAX1 mutation causes autosomal recessively inherited otofaciocervical syndrome","volume":"132","author":"Pohl","year":"2013","journal-title":"Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1111\/cge.13085","article-title":"A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency","volume":"92","author":"Paganini","year":"2017","journal-title":"Clin. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eaax1036","DOI":"10.1126\/sciimmunol.aax1036","article-title":"PAX1 is essential for development and function of the human thymus","volume":"5","author":"Yamazaki","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1136\/jmedgenet-2015-103621","article-title":"Microduplications at the pseudoautosomal SHOX locus in autism spectrum disorders and related neurodevelopmental conditions","volume":"53","author":"Tropeano","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/ng.2262","article-title":"Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome","volume":"44","author":"Koolen","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9175","DOI":"10.1128\/MCB.25.21.9175-9188.2005","article-title":"A human protein complex homologous to the Drosophila MSL complex is responsible for the majority of histone H4 acetylation at lysine 16","volume":"25","author":"Smith","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/imr.12701","article-title":"Chromosome 22q11.2 deletion syndrome and DiGeorge syndrome","volume":"287","author":"Sullivan","year":"2019","journal-title":"Immunol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1182\/blood-2003-08-2824","article-title":"T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome","volume":"103","author":"Piliero","year":"2004","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"447","DOI":"10.3389\/fimmu.2019.00447","article-title":"Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development","volume":"10","author":"Marcovecchio","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1016\/j.jaip.2019.03.014","article-title":"Immunophenotype Anomalies Predict the Development of Autoimmune Cytopenia in 22q11.2 Deletion Syndrome","volume":"7","author":"Montin","year":"2019","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1038\/s41436-020-0815-4","article-title":"De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy","volume":"22","author":"Singh","year":"2020","journal-title":"Genet. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"624122","DOI":"10.3389\/fendo.2020.624122","article-title":"Role of the Orphan Nuclear Receptor NR4A Family in T-Cell Biology","volume":"11","author":"Odagiu","year":"2021","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1242\/dev.087320","article-title":"Dynamics of thymus organogenesis and colonization in early human development","volume":"140","author":"Farley","year":"2013","journal-title":"Development"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"830","DOI":"10.3389\/fimmu.2020.00830","article-title":"Molecular Insights into the Causes of Human Thymic Hypoplasia with Animal Models","volume":"11","author":"Bhalla","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1093\/hmg\/9.5.695","article-title":"The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome","volume":"9","author":"Schiller","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1038\/s41431-021-00824-x","article-title":"Quantitative facial phenotyping for Koolen-de Vries and 22q11.2 deletion syndrome","volume":"29","author":"Dingemans","year":"2021","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3389\/fgene.2017.00047","article-title":"Deletion Extents Are Not the Cause of Clinical Variability in 22q11.2 Deletion Syndrome: Does the Interaction between DGCR8 and miRNA-CNVs Play a Major Role?","volume":"8","author":"Bertini","year":"2017","journal-title":"Front. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1038\/s41598-017-01896-w","article-title":"Partial microduplication in the histone acetyltransferase complex member KANSL1 is associated with congenital heart defects in 22q11.2 microdeletion syndrome patients","volume":"7","author":"Benavides","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/cge.13775","article-title":"Refinement of the clinical and mutational spectrum of UBE2A deficiency syndrome","volume":"98","author":"Cordeddu","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Wola\u0144ska, E., Pollak, A., Rydzanicz, M., Pesz, K., K\u0142aniewska, M., Rozensztrauch, A., Skiba, P., Stawi\u0144ski, P., P\u0142oski, R., and \u015amigiel, R. (2021). The Role of the Reanalysis of Genetic Test Results in the Diagnosis of Dysmorphic Syndrome Caused by Inherited xq24 Deletion including the UBE2A and CXorf56 Genes. Genes, 12.","DOI":"10.3390\/genes12030350"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/7\/2025\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:49:55Z","timestamp":1760136595000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/7\/2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,5]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["jcm11072025"],"URL":"https:\/\/doi.org\/10.3390\/jcm11072025","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,5]]}}}