Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals

Henri Margot, Guilaine Boursier, Claire Duflos, Elodie Sanchez, Jeanne Amiel, Jean-Christophe Andrau, Stéphanie Arpin, Elise Brischoux-Boucher, Odile Boute, Lydie Burglen, Charlotte Caille, Yline Capri, Patrick Collignon, Solène Conrad, Valérie Cormier-Daire, Geoffroy Delplancq, Klaus Dieterich, Hélène Dollfus, Mélanie Fradin, Laurence Faivre, Helder Fernandes, Christine Francannet, Vincent Gatinois, Marion Gerard, Alice Goldenberg, Jamal Ghoumid, Sarah Grotto, Anne-Marie Guerrot, Agnès Guichet, Bertrand Isidor, Marie-Line Jacquemont, Sophie Julia, Philippe Khau Van Kien, Marine Legendre, K H Le Quan Sang, Bruno Leheup, Stanislas Lyonnet, Virginie Magry, Sylvie Manouvrier, Dominique Martin, Godelieve Morel, Arnold Munnich, Sophie Naudion, Sylvie Odent, Laurence Perrin, Florence Petit, Nicole Philip, Marlène Rio, Julie Robbe, Massimiliano Rossi, Elisabeth Sarrazin, Annick Toutain, Julien Van Gils, Gabriella Vera, Alain Verloes, Sacha Weber, Sandra Whalen, Damien Sanlaville, Didier Lacombe, Nathalie Aladjidi, David Geneviève, Henri Margot, Guilaine Boursier, Claire Duflos, Elodie Sanchez, Jeanne Amiel, Jean-Christophe Andrau, Stéphanie Arpin, Elise Brischoux-Boucher, Odile Boute, Lydie Burglen, Charlotte Caille, Yline Capri, Patrick Collignon, Solène Conrad, Valérie Cormier-Daire, Geoffroy Delplancq, Klaus Dieterich, Hélène Dollfus, Mélanie Fradin, Laurence Faivre, Helder Fernandes, Christine Francannet, Vincent Gatinois, Marion Gerard, Alice Goldenberg, Jamal Ghoumid, Sarah Grotto, Anne-Marie Guerrot, Agnès Guichet, Bertrand Isidor, Marie-Line Jacquemont, Sophie Julia, Philippe Khau Van Kien, Marine Legendre, K H Le Quan Sang, Bruno Leheup, Stanislas Lyonnet, Virginie Magry, Sylvie Manouvrier, Dominique Martin, Godelieve Morel, Arnold Munnich, Sophie Naudion, Sylvie Odent, Laurence Perrin, Florence Petit, Nicole Philip, Marlène Rio, Julie Robbe, Massimiliano Rossi, Elisabeth Sarrazin, Annick Toutain, Julien Van Gils, Gabriella Vera, Alain Verloes, Sacha Weber, Sandra Whalen, Damien Sanlaville, Didier Lacombe, Nathalie Aladjidi, David Geneviève

Abstract

Purpose: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry.

Methods: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis.

Results: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027).

Conclusion: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

Keywords: KDM6A; KMT2D; Kabuki syndrome; immunity.

References

    1. Niikawa N, Matsuura N, Fukushima Y, et al. Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr. 1981;99:565–569.
    1. Ng SB, Bigham AW, Buckingham KJ, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42:790–793.
    1. Lederer D, Grisart B, Digilio MC, et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet. 2012;90:119–124.
    1. Hu D, Gao X, Morgan MA, et al. The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol Cell Biol. 2013;33:4745–4754.
    1. Miyake N, Koshimizu E, Okamoto N, et al. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet. 2013;161:2234–2243.
    1. Banka S, Lederer D, Benoit V, et al. Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2). Clin Genet. 2015;87:252–258.
    1. Hoffman JD, Ciprero KL, Sullivan KE, et al. Immune abnormalities are a frequent manifestation of Kabuki syndrome. Am J Med Genet A. 2005;135A:278–281.
    1. Lin J-L, Lee W-I, Huang J-L, et al. Immunologic assessment and KMT2D mutation detection in Kabuki syndrome: immunologic and genetic KMT2D analysis in Kabuki syndrome. Clin Gen. 2015;88:255–260.
    1. De Dios JAA, Javaid AA, Ballesteros E, Metersky ML. An 18-year-old woman with Kabuki syndrome, immunoglobulin deficiency and granulomatous lymphocytic interstitial lung disease. Conn Med. 2012;76:15–18.
    1. Ming JE, Russell KL, McDonald-McGinn DM, Zackai EH. Autoimmune disorders in Kabuki syndrome. Am J Med Genet. 2005;132A:260–262.
    1. Almécija AC, Pérez V, Baro M, et al. Atypical autoimmune hematologic disorders in a patient with Kabuki syndrome. J Pediatr Hematol Oncol. 2019;41:e114–e115.
    1. Zannolli R, Buoni S, Macucci F, et al. Kabuki syndrome with trichrome vitiligo, ectodermal defect and hypogammaglobulinemia A and G. Brain Dev. 2007;29:373–376.
    1. Gürbüz F, Yüreğir ÖÖ, Ceylaner S, et al. Coexistence of Kabuki syndrome and autoimmune thyroiditis. J Clin Res Pediatr Endocrinol. 2016;8:105.
    1. Fujishiro M, Ogihara T, Tsukuda K, et al. A case showing an association between type 1 diabetes mellitus and Kabuki syndrome. Diabetes Res Clin Pract. 2003;60:25–31.
    1. Ho J, Fox D, Innes AM, et al. Kabuki syndrome and Crohn disease in a child with familial hypocalciuric hypercalcemia. J Pediatr Endocrinol Metab. 2010;23:975–979.
    1. Nishizaki N, Fujinaga S, Hirano D, et al. Membranoproliferative glomerulonephritis type 3 associated with Kabuki syndrome. Clin Nephrol. 2014;81:369–373.
    1. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93:190–197.
    1. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113:2386–2393.
    1. Börgershausen N, Gatinois V, Riehmer V, et al. Mutation update for Kabuki syndrome genes KMT2D and KDM6A and further delineation of X‐linked Kabuki syndrome subtype 2. Hum Mutat. 2016;37:847–864.
    1. Kopanos C, Tsiolkas V, Kouris A, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:1978–1980.
    1. Lee MG, Villa R, Trojer P, et al. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science. 2007;318:447–450.
    1. Smith E, Lin C, Shilatifard A. The super elongation complex (SEC) and MLL in development and disease. Genes Dev. 2011;25:661.
    1. Lindsley AW, Saal HM, Burrow TA, et al. Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome. J Allergy Clin Immunol. 2016;137:179–187.
    1. Borchert GM, Holton NW, Edwards KA, et al. Histone H2A and H2B are monoubiquitinated at AID-targeted loci. PLoS ONE. 2010;5:e11641.
    1. Wei G, Wei L, Zhu J, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009;30:155.
    1. Stagi S, Gulino AV, Lapi E, Rigante D. Epigenetic control of the immune system: a lesson from Kabuki syndrome. Immunol Res. 2016;64:345–359.
    1. Westh L, Mogensen TH, Dalgaard LS, et al. Identification and characterization of a nationwide Danish adult common variable immunodeficiency cohort. Scand J Immunol. 2017;85:450–461.
    1. Cooper GS, Bynum MLK, Somers EC. Recent insights in the epidemiology of autoimmune diseases: Improved prevalence estimates and understanding of clustering of diseases. J Autoimmun. 2009;33:197–207.
    1. Moulis G, Palmaro A, Montastruc J-L, et al. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France. Blood. 2014;124:3308–3315.
    1. Grimaldi-Bensouda L, Nordon C, Leblanc T, et al. Childhood immune thrombocytopenia: a nationwide cohort study on condition management and outcomes. Pediatr Blood Cancer. 2017;64:e26389.
    1. Aladjidi N, Leverger G, Leblanc T, et al. New insights into childhood autoimmune hemolytic anemia: a French national observational study of 265 children. Haematologica. 2011;96:655.
    1. Krüger C, Schallreuter KU. A review of the worldwide prevalence of vitiligo in children/adolescents and adults. Int J Dermatol. 2012;51:1206–1212.
    1. Zhang Y, Cai Y, Shi M, et al. The prevalence of vitiligo: a meta-analysis. PLoS ONE. 2016;11:e0163806.
    1. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997;84:223–243.
    1. Warnatz K, Voll RE. Pathogenesis of autoimmunity in common variable immunodeficiency. Front Immunol. 2012;3:210.
    1. Mahlaoui N, Warnatz K, Jones A, et al. Advances in the care of primary immunodeficiencies (PIDs): from birth to adulthood. J Clin Immunol. 2017;37:452–460.
    1. Hannibal MC, Buckingham KJ, Ng SB, et al. Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. Am J Med Genet A. 2011;155A:1511–1516.
    1. Li Y, Bögershausen N, Alanay Y, et al. A mutation screen in patients with Kabuki syndrome. Hum Genet. 2011;130:715–724.
    1. Makrythanasis P, van Bon BW, Steehouwer M, et al. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype–phenotype study. Clin Genet. 2013;84:539–545.
    1. Micale L, Augello B, Fusco C, et al. Mutation spectrum of MLL2 in a cohort of Kabuki syndrome patients. Orphanet J Rare Dis. 2011;6:38.

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