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Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients

2019; Springer Nature; Volume: 28; Issue: 4 Linguagem: Inglês

10.1038/s41431-019-0485-3

1476-5438

Jair Tenorio, Pablo Alarcón, Pedro Arias, Irene Dapía, Sixto García‐Miñaúr, María Palomares‐Bralo, Jaume Campistol, Salvador Climent, Irene Valenzuela, S. Ramos, Antonio Martínez Monseny, Fermina López Grondona, Javier Botet, Mercedes Serrano, Mario Solís, Fernando Santos‐Simarro, Sara Álvarez, Gisela Teixidó‐Turà, Alberto Fernández‐Jaén, Gema Gordo, Maria Rivera, Julián Nevado, Alicia Hernández, Juan C. Cigudosa, Víctor L. Ruiz‐Pérez, Eduardo F. Tizzano, Alberto L. Rosa, Aleixandre Blanquer, Alfredo García Alix, Alfredo Santana, Alicia Delicado, Almudena Alonso, Amaya Rodríguez, Amparo Sanchís, Ana Carolina Ramos Moreno, Ana Patiño-Garcı́a, Ana Vega, Analía Bredani, Andrea Solari, A. Villavicencio, Angelina Xavier Acosta, A. Nieto, Anna M. Cueto‐González, Antonio Baldellon, Antonio González Meneses, Antonio Martínez Carrascal, Aránzazu Díaz de Bustamante, Arteche Ocasar, Blanca Gener, Belén De Frutos González, Boris Groisman, Bradford Coffee, Carlos Alcalde Martín, Carmen Aragón Fernández, Carmen Benito, C. González Armengod, Carmen Martín Seisdedos, Carmen Roche, Claudia Arberas, Claudia Perandones, Claudia Toledo Pacheco, C. Contessotto, Cristina Olivas, Daniel Armenta, Denise P. Cavalcanti, Dolores Elorza, Eduardo E. Castilla, Elena Zamora-Flores, Elisa Zambrano, Elisabeth Steichen, Encarna Guillén‐Navarro, Enrique Caro Cruz, Enrique Galán Gómez, Enriqueta Román, Ernesto Goldschmidt, Esteban Marfil, Esther Geán, E. Antolín, Fernando Jiménez, Fco. Javier Martínez Sarries, Feliciano J. Ramos, Fermina López Grondona, Fernández Córdoba, Fernando Santos, Fernando Vargas, Francisco Martínez, Giovannucci Uzielli, Gloria Gacio, Graciela Mercado, Hamilton Cassinelli, Iêda M. Orioli, Ignacio Arroyo, Ignacio Díez López, Ignacio Onsurbe Ramírez, Ignacio Pascual Castroviejo, Samuel Ignacio Pascual Pascual, Ignacio Vázquez Rio, Inés Bueno, Isabel Espejo Portero, Isabel Lorda Sánchez, Jaime Sánchez del Pozo, Jaume Campistol, J Arcas, Javier Fernández, Javier García‐Planells, Javier López Pisón, Jesús Barreiro, Jesús del Valle Núñez, Joaquín Fernández Toral, Joaquín Ramírez, Jordi Rosell, Joan Manuel Vilaplana, José Carlos Cabral de Almeida, José Ignacio Labarta, J L Herranz, José Luis Fernández Luna, José Luís Fuster, José Manuel Cid Díaz, Jose Maria Gairi, José Miguel García Sagredo, Juan A. Piñero, Juan Carlos López‐Gutiérrez, Juan Manuel Fernández, Juan Pedro López Siguero, Juan A. Tovar, Judith Armstrong, Julián Lara, Laura Rodríguez Leandro Soriano, Leila Cabral de Almeida Cardoso, Leonor Arranz, Liliana De Alba, Loreta Cimbalistienė, Loreto Martorell, Luis González Gutiérrez Solana, Luis Pérez Jurado, M Asunción López Ariztegui, M. Antonia Molina, M. Cruz García, Marta Ferrer Lozano, M. Jesús Alija Merillas, M L Martínez-Frías, M. Rocío Jadraque, M. A. Pérez, Ma Montserrat Rodríguez Pedreira, Ma Nieves Martínez Guardia, Ma Pilar Ribate, Ma Teresa González López, Ma Teresa Moral Pumarega, Mabel Segovia, Macarena Lizama, Manuel J. Lorente, Manuel Pombo, Margarita Martínez, Margarita Tabernero, María Antonia Ramos, Maria Jose Ballesta, María Belar, María Jesús Lautre, Marta Cruz, Mercedes Artigas, Mercedes Villanueva, Meritxell Torrabías, Miguel Del Campo, Miguel Tomás Vila, Miguel Urioste, Mónica Roselló, Nazneen Rahman, Nik Kantaputra, Pablo Prieto‐Matos, Paloma Dorao, Paula Casano, Paula Lalaguna Mallada, Pedro R. Olivares, Pilar Martínez Tirado, Pricila Bernardi, Rafael Camino León, Ramón Cañete, Ramón Gaztañaga, Ramón Velázquez, Ramón Vidal Samahuja, Raquel Pérez Delgado, Raquel Sáez Villaverde, Ricardo Gracía, Richard Scott, Rita Valdéz, Rosa Arteaga, Rosa Alicia Vázquez Cedeño, Rosario Cazorla, Rosario Iglesias, Rubén Bronberg, Salvador Climent, Santiago Conde Barreiro, Seema Kapoor, Selma Vázquez Martín, Sixto García Miñaúr, Soledad Kleppe, Sonia Santillán, Teresa Calvo, Teresa Vendrell, V. López González, Vanesa Valiño López, Vanesa Lotersztein, Vanesa Méndez, Vicente Albiach, Víctor M. Navas López, Virginia Soler, Viviana Cosentino, Yoko Aoki, Pablo Lapunzina,

Acute Myeloid Leukemia Research

Tatton-Brown-Rahman (TBRS) syndrome is a recently described overgrowth syndrome caused by loss of function variants in the DNMT3A gene. This gene encodes for a DNA methyltransferase 3 alpha, which is involved in epigenetic regulation, especially during embryonic development. Somatic variants in DNMT3A have been widely studied in different types of tumors, including acute myeloid leukemia, hematopoietic, and lymphoid cancers. Germline gain-of-function variants in this gene have been recently implicated in microcephalic dwarfism. Common clinical features of patients with TBRS include tall stature, macrocephaly, intellectual disability (ID), and a distinctive facial appearance. Differential diagnosis of TBRS comprises Sotos, Weaver, and Malan Syndromes. The majority of these disorders present other clinical features with a high clinical overlap, making necessary a molecular confirmation of the clinical diagnosis. We here describe seven new patients with variants in DNMT3A, four of them with neuropsychiatric disorders, including schizophrenia and psychotic behavior. In addition, one of the patients has developed a brain tumor in adulthood. This patient has also cerebral atrophy, aggressive behavior, ID, and abnormal facial features. Clinical evaluation of this group of patients should include a complete neuropsychiatric assessment together with psychological support in order to detect and manage abnormal behaviors such as aggressiveness, impulsivity, and attention deficit-hyperactivity disorder. TBRS should be suspected in patients with overgrowth, ID, tall stature, and macrocephaly, who also have some neuropsychiatric disorders without any genetic defects in the commonest overgrowth disorders. Molecular confirmation in these patients is mandatory.