Immunological Aspects of Kabuki Syndrome: A Retrospective Multicenter Study of the Italian Primary Immunodeficiency Network (IPINet)

Linda Rossini^{1

2}, Silvia Ricci^{3

4}, Davide Montin⁵, Chiara Azzari^{3

4}, Eleonora Gambineri^{6

7}, Marco Tellini⁶, Francesca Conti^{8

9}, Andrea Pession^{8

9}, Francesco Saettini¹⁰, Samuele Naviglio¹¹, Erica Valencic¹¹, Andrea Magnolato¹¹, Lucia Baselli¹², Sara Azzolini¹³, Rita Consolini¹⁴, Lucia Leonardi¹⁵, Irene D'Alba¹⁶, Elisa Carraro¹, Roberta Romano¹⁷, Daniela Melis¹⁸, Stefano Stagi^{4

19}, Emilia Cirillo¹⁷, Giuliana Giardino¹⁷, Alessandra Biffi^{1

2}, Claudio Pignata¹⁷, Maria Caterina Putti¹, Antonio Marzollo²⁰

Affiliations

¹ Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Via Giustiniani 3, Padua, 35128, Italy.
² Maternal and Child Health Department, Padua University, Via Giustiniani, 3, Padua, 35128, Italy.
³ Immunology, Pediatric Unit, IRCCS Meyer Children's Hospital, viale G.Pieraccini 24, Florence, 50139, Italy.
⁴ Department of Health Sciences, University of Florence, Florence, Italy.
⁵ Immunology and Rheumatology Unit, Regina Margherita Children Hospital, Turin, Italy.
⁶ Centre of Excellence, Department of Pediatric Hematology-Oncology, IRCCS Meyer Children's Hospital, Florence, Italy.
⁷ Department of "NEUROFARBA", Section of Child's Health, University of Florence, Florence, Italy.
⁸ Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, 40138, Italy.
⁹ Dept. of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
¹⁰ Tettamanti Research Center, University of Milano-Bicocca, University of Milano Bicocca, Monza, Italy.
¹¹ Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy.
¹² Department of Pediatrics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
¹³ UOC Pediatria, San Bortolo Hospital, Vicenza, Italy.
¹⁴ Section of Clinical and Laboratory Immunology, Division of Pediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
¹⁵ Maternal, Infantile and Urological Sciences Department, Sapienza University of Rome, Rome, Italy.
¹⁶ Paediatric Haematology-Oncology, Maternal Infant Hospital "G. Salesi", Ancona, Italy.
¹⁷ Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy.
¹⁸ Department of Medicine, Surgery and Dentistry, University of Salerno, Via Salvador Allende Baronissi, Campania, 84081, Italy.
¹⁹ Auxoendocrinology Division, Meyer Children's Hospital, IRCCS, viale G.Pieraccini 24, Florence, 50139, Italy.
²⁰ Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Via Giustiniani 3, Padua, 35128, Italy. antonio.marzollo@aopd.veneto.it.

PMID: 38676773
DOI: 10.1007/s10875-024-01676-y

Observational Study

Immunological Aspects of Kabuki Syndrome: A Retrospective Multicenter Study of the Italian Primary Immunodeficiency Network (IPINet)

Linda Rossini et al. J Clin Immunol. 2024.

. 2024 Apr 27;44(5):105.

doi: 10.1007/s10875-024-01676-y.

Authors

Affiliations

¹ Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Via Giustiniani 3, Padua, 35128, Italy.
² Maternal and Child Health Department, Padua University, Via Giustiniani, 3, Padua, 35128, Italy.
³ Immunology, Pediatric Unit, IRCCS Meyer Children's Hospital, viale G.Pieraccini 24, Florence, 50139, Italy.
⁴ Department of Health Sciences, University of Florence, Florence, Italy.
⁵ Immunology and Rheumatology Unit, Regina Margherita Children Hospital, Turin, Italy.
⁶ Centre of Excellence, Department of Pediatric Hematology-Oncology, IRCCS Meyer Children's Hospital, Florence, Italy.
⁷ Department of "NEUROFARBA", Section of Child's Health, University of Florence, Florence, Italy.
⁸ Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, 40138, Italy.
⁹ Dept. of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
¹⁰ Tettamanti Research Center, University of Milano-Bicocca, University of Milano Bicocca, Monza, Italy.
¹¹ Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy.
¹² Department of Pediatrics, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
¹³ UOC Pediatria, San Bortolo Hospital, Vicenza, Italy.
¹⁴ Section of Clinical and Laboratory Immunology, Division of Pediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
¹⁵ Maternal, Infantile and Urological Sciences Department, Sapienza University of Rome, Rome, Italy.
¹⁶ Paediatric Haematology-Oncology, Maternal Infant Hospital "G. Salesi", Ancona, Italy.
¹⁷ Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy.
¹⁸ Department of Medicine, Surgery and Dentistry, University of Salerno, Via Salvador Allende Baronissi, Campania, 84081, Italy.
¹⁹ Auxoendocrinology Division, Meyer Children's Hospital, IRCCS, viale G.Pieraccini 24, Florence, 50139, Italy.
²⁰ Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Via Giustiniani 3, Padua, 35128, Italy. antonio.marzollo@aopd.veneto.it.

PMID: 38676773
DOI: 10.1007/s10875-024-01676-y

Abstract

Kabuki Syndrome (KS) is a multisystemic genetic disorder. A portion of patients has immunological manifestations characterized by increased susceptibility to infections and autoimmunity. Aiming to describe the clinical and laboratory immunological aspects of KS, we conducted a retrospective multicenter observational study on patients with KS treated in centers affiliated to the Italian Primary Immunodeficiency Network.Thirty-nine patients were enrolled, with a median age at evaluation of 10 years (range: 3 m-21y). All individuals had organ malformations of variable severity. Congenital heart defect (CHD) was present in 19/39 patients (49%) and required surgical correction in 9/39 (23%), with associated thymectomy in 7/39 (18%). Autoimmune cytopenia occurred in 6/39 patients (15%) and was significantly correlated with thymectomy (p < 0.002), but not CHD. Individuals with cytopenia treated with mycophenolate as long-term immunomodulatory treatment (n = 4) showed complete response. Increased susceptibility to infections was observed in 22/32 patients (69%). IgG, IgA, and IgM were low in 13/29 (45%), 13/30 (43%) and 4/29 (14%) patients, respectively. Immunoglobulin substitution was required in three patients. Lymphocyte subsets were normal in all patients except for reduced naïve T-cells in 3/15 patients (20%) and reduced memory switched B-cells in 3/17 patients (18%). Elevated CD3 + TCRαβ + CD4-CD8-T-cells were present in 5/17 individuals (23%) and were correlated with hematological and overall autoimmunity (p < 0.05).In conclusion, immunological manifestations of KS in our cohort include susceptibility to infections, antibody deficiency, and autoimmunity. Autoimmune cytopenia is correlated with thymectomy and elevated CD3 + TCRαβ + CD4-CD8-T-cells, and benefits from treatment with mycophenolate.

Keywords: Autoimmunity; Epigenetic; Inborn errors of immunity; Kabuki syndrome; Primary immunoregulatory disorder; Recurrent infections; Thymectomy.

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References

1. Margot H, Boursier G, Duflos C, Sanchez E, Amiel J, Andrau J-C et al. Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals. Genet Med. 2019;0(0). Available from: http://www.nature.com/articles/s41436-019-0623-x .
1. Sobreira N, Brucato M, Zhang L, Ladd-Acosta C, Ongaco C, Romm J et al. Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities. Eur J Hum Genet. 2017;25(12):1335–44. https://doi.org/10.1038/s41431-017-0023-0 .
1. Makrythanasis P, van Bon BW, Steehouwer M, Rodríguez-Santiago B, Simpson M, Dias P, et al. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study. Clin Genet. 2013;84(6):539–45. - DOI - PubMed
1. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010.
1. Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M, Ghariani SC et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet. 2012;90(1):119–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22197486 .

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Immunological Aspects of Kabuki Syndrome: A Retrospective Multicenter Study of the Italian Primary Immunodeficiency Network (IPINet)

Affiliations

Immunological Aspects of Kabuki Syndrome: A Retrospective Multicenter Study of the Italian Primary Immunodeficiency Network (IPINet)

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Supplementary concepts

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous