  Citation: Callea, M.; Martinelli, D.; Scalisi, F.C.; Grimaldi, C.; Jilani, H.; Grimaldi, P.; Willoughby, C.E.; Morabito, A. Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita. Genes 2022, 13, 496. https://doi.org/10.3390/ genes13030496 Academic Editor: Laura Crisponi Received: 29 November 2021 Accepted: 8 March 2022 Published: 11 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). genes G C A T T A C G G C A T Review Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita Michele Callea 1, * ,† , Diego Martinelli 2,† , Francisco Cammarata Scalisi 3 , Chiara Grimaldi 4 , Houweyda Jilani 5,6 , Piercesare Grimaldi 7 , Colin Eric Willoughby 8 and Antonino Morabito 4,9, * 1 Pediatric Dentistry and Special Dental Care Unit, Meyer Children’s University Hospital, 50139 Florence, Italy 2 Unit of Metabolism, Bambino Gesù Children’s Research Hospital, Piazza Sant’Onofrio, 4, 00165 Rome, Italy; diego.martinelli@opbg.net 3 Servicio de Pediatría, Hospital Regional de Antofagasta, Antofagasta 1240835, Chile; francocammarata19@gmail.com 4 Department of Pediatric Surgery, Meyer Children’s Hospital, Viale Gaetano Pieraccini 24, 50139 Florence, Italy; chiara.grimaldi@meyer.it 5 Genetic Department, Mongi Slim Hospital, Marsa 2046, Tunisia; houweyda.jilani@rns.tn 6 Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1068, Tunisia 7 Department of Public Health and Pediatric Sciences, University of Torino, 10125 Torino, Italy; pcgrimaldi@gmail.com 8 Genomic Medicine, Biomedical Sciences Research Institute, Ulster University, Coleraine Campus, Coleraine BT52 1SA, UK; c.willoughby@ulster.ac.uk 9 Department of Neurofarba, University of Florence, Viale Pieraccini 6, 50121 Florence, Italy * Correspondence: mcallea@gmail.com (M.C.); antonino.morabito@unifi.it (A.M.) † These authors contributed equally to this work. Abstract: Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differen- tial diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling. Keywords: dyskeratosis congenita; telomeropathies; clinic; etiology; treatment 1. Clinical Aspects Disorders in the biology of telomeres or telomeropathies comprise a number of genetic defects, of which dyskeratosis congenita (DC) was the first reported entity [1]. DC presents with a mucocutaneous triad of skin reticulated lace pigmentation [2], principally involving the neck area and the upper anterior thorax, nail dystrophy and oral leukoplakia. The clinical phenotype has expanded considerably since its initial description. Initial dermatological signs appear in the first years; the clinical picture, however, can be heterogeneous [3]. Nail dystrophy involves at the beginning of the fingernails, then it starts with grooves and longitudinal divisions, evolving in rudimentary, small or absent nails. Leukoplakia impacts the oral mucosa, the tongue and the oropharynx [4]. Palmoplantar hyperkeratosis can lead to painful fissures and ulcers [5,6]. Approximately 30% of patients present malignant transformation to squamous cell carcinoma, thus necessitating carcinogenic surveillance, even with the execution of frequent biopsies in the involved areas [4]. Genes 2022, 13, 496. https://doi.org/10.3390/genes13030496 https://www.mdpi.com/journal/genes