Kabuki syndrome. A clinical approach

Asensio Fierro, Fidel; Cabanillas Farpón, Rubén; Bernardo-Cofiño, Joaquín

doi:10.1016/j.medcle.2021.05.015

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Oviedo, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Área de Medicina de Precisión, Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome de Kabuki. Estudio de un caso" ] ] "textoCompleto" => "The immune system arranges humoral and cellular defences in the form of a continuum that reacts to external and internal aggression. Its dysfunctions - either as an autoimmune disease or as an immune deficiency - are not mutually exclusive and are sometimes combined.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In some cases, they share a genetic or epigenetic origin,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> although this is rarely tangible in clinical reality given the difficulty of access to genetic studies. The chain of processes, together with an adequate identification of physical stigmata (phenotyping), are key to a well-founded call for precision medicine.We report the case of a 41-year-old woman with a recognised disability due to severe mental impairment, diagnosed in March 2007 with idiopathic thrombotic purpura after admission to another centre for massive epistaxis and gynaecological bleeding. She had received steroid treatment without response, requiring 4 cycles of rituximab. An initial diagnostic approach identified hypogammaglobulinemia secondary to a common variable immunodeficiency, for which she received regular treatment with parenteral immunoglobulins. Two years prior to her current evaluation she had presented with diarrhoea and abdominal pain, showing a pattern of cholestasis and cytolysis, and mild splenomegaly on outpatient assessments. Her symptoms included gothic palate, short stature and multiple melanotic lesions on the scalp, back and thoracic region.An extensive battery of biochemical, immunological, microbiological and endoscopic studies proved inconclusive. Gastric biopsies were performed on fundic polyps, and on the duodenum papilla, also without findings. Screening was extended to include anti-gliadin antibodies (very positive), anti-transglutaminase antibodies (negative) and a genetic study for coeliac disease, which showed triple positive results. The gluten-free diet improved the diarrhoea, while the liver function remained unchanged. For this reason, a pending biopsy had been recommended, a matter on which a second opinion was requested. Considering her age, other aspects of her personal history had an impact on the clinician: congenital dislocation of both hips (multiple surgical interventions) leading to a left hip replacement; rickets diagnosed at 3 years of age, and bilateral hearing loss after multiple otitis, which required a right tympanoplasty.The concurrence of physical stigmata, mental retardation, autoimmune diseases and immunodeficiency<a class="elsevierStyleCrossRef" href="#bib0015">3</a> led to the possibility of a genetic/syndromic condition, and she was referred to a specific unit for further study. A clinical exome identified a probable heterozygous germline pathogenic variant c.12430C > T (p.Q4144*) in the KMT2D gene. This variant has been associated with Kabuki syndrome (MIM#147920) with an autosomal-dominant mode of inheritance. Truncating variants in this gene, such as the one detected, compromise methyltransferase function and interfere with its activity as an epigenetic regulator. The consequence of its dysfunction is interference with gene expression during embryonic development and cell differentiation, an aspect that is particularly relevant for the correct functioning of the immune system (lymphocyte maturation and autoreactive clone deletion).The genetic basis of this syndrome is not limited only to KTM2D gene mutations, but KMT2A or KDM6A, involved in chromatin remodelling through modification of histone epigenetic marks, may also be implicated. The phenotypic impact and the clinical implications are overlapping.The problem case expresses multiple stigmata and meets the diagnostic criteria of an international panel<a class="elsevierStyleCrossRef" href="#bib0015">3</a>: she had developed early hypotonia and feeding difficulties, showed the characteristic phenotypic changes in the outer canthus of the eyes, gothic palate, dermatoglyphic changes and growth retardation. Mental retardation is common, and, incidentally, epilepsy and cardiac malformations are not uncommon.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Autoimmune cytopenias, as seems to be the norm in patients with immunodeficiencies, are the most prevalent autoimmune-associated manifestations.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>Precision medicine clarifies the role of the rare entities it identifies. Poor response to steroids and biliary involvement due to atresia are characteristic of Kabuki syndrome<a class="elsevierStyleCrossRef" href="#bib0025">5</a> or cystic degeneration, whereas autoimmune liver disease has not been described. The initial therapeutic approach would have been different, and a liver biopsy could have been omitted. It is therefore advantageous to break down the walls around this emerging diagnostic resource and look at a clinically very effective tool for dealing with and even anticipating decisions in difficult-to-manage clinical cases.Ethical responsibilitiesThe current manuscript does not involve the conduct of clinical research in humans or animals.FundingThe authors have not received funding.Conflict of interestsThe authors have no conflict of interest." 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Med Clin (Barc). 2022;158:194." ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Primary immunodeficiency and autoimmunity: a comprehensive review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "L. Amaya-Uribe" 1 => "M. Rojas" 2 => "G. Azizi" 3 => "J.M. Anaya" 4 => "M.E. Gershwin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaut.2019.01.011" "Revista" => array:6 [ "tituloSerie" => "J Autoimmun" "fecha" => "2019" "volumen" => "99" "paginaInicial" => "52" "paginaFinal" => "72" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30795880" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmunity and primary immunodeficiency: two sides of the same coin?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R.E. Schmidt" 1 => "B. Grimbacher" 2 => "T. Witte" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrrheum.2017.198" "Revista" => array:5 [ "tituloSerie" => "Nat Rev Rheumatol" "fecha" => "2018" "volumen" => "14" "paginaInicial" => "7" "paginaFinal" => "18" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Kabuki syndrome: international consensus diagnostic criteria" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.P. Adam" 1 => "S. Banka" 2 => "H.T. Bjornsson" 3 => "O. Bodamer" 4 => "A.E. Chudley" 5 => "J. Harris" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Med Genet" "fecha" => "2019" "volumen" => "56" "paginaInicial" => "89" "paginaFinal" => "95" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Kabuki syndrome: review of the clinical features, diagnosis and epigenetic mechanisms" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Y.R. Wang" 1 => "N.X. Xu" 2 => "J. Wang" 3 => "X.M. Wang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s12519-019-00309-4" "Revista" => array:6 [ "tituloSerie" => "World J Pediatr" "fecha" => "2019" "volumen" => "15" "paginaInicial" => "528" "paginaFinal" => "535" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31587141" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic fibrosis in Kabuki syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "V. Nobili" 1 => "M. Marcellini" 2 => "R. Devito" 3 => "R. Capolino" 4 => "L. Viola" 5 => "M.C. Digilio" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Am J Med Genet" "fecha" => "2004" "volumen" => "124 A" "paginaInicial" => "209" "paginaFinal" => "212" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015800000004/v1_202202170636/S2387020622000432/v1_202202170636/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015800000004/v1_202202170636/S2387020622000432/v1_202202170636/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020622000432?idApp=UINPBA00004N"]

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3.1

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Vol. 158. Issue 4.