Clinical, Etiological and Therapeutic Aspects of Dyskeratosis Congenita Periodontal De Los Escolares De 7 a 12 Años Medicina De Familia.2015; 8(2): 110-118

76 Basilio-Bernardo Y, Cavalié-Martel K, Ortega-Buitron M. REVIEW ARTICLE 77 REVISTA PERUANA DE INVESTIGACIÓN EN SALUD http://revistas.unheval.edu.pe/index.php/repis/ http://revistas.uladech.edu.pe/index.php/in 12. Tirado A, Díaz C, Ramos M. Salud bucal en https://doi.org/10.35839/repis.4.2.606 crescendoalud/article/view/1790/1420 escolares con síndrome de Down en 5. Gómez S, Doreste J, Sierra A. Estado Cartagena (Colombia). Revista Clínica de Clinical, etiological and therapeutic aspects of Dyskeratosis Congenita periodontal de los escolares de 7 a 12 años Medicina de Familia.2015; 8(2): 110-118. de edad en Canarias. Revista del Ilustre 13. Morinushi T, Ueda Y, Tanaka C. Autistic Aspectos clínicos, etiológicos y terapéuticos de la disqueratosis congénita Consejo general de Odontología y children: experience and severity of dental Estomatología de España.3 (8). Disponible caries between 1980 and 1995 in Rosario Perona1, Leandro Sastre1, Michele Callea2 y Francisco Cammarata-Scalisi3,* en http// medigraphic.com. Consultado 6 Kagoshima City, Japan. Journal of Clinical 1Biomedical Research Institute CSIC/ abril 2015. Pediatric Dentistry: july 2001; 25 (4): 323- Abstract UAM. CIBER of rare diseases, IDIPaz, Madrid, España. 2 6. Beck A, Beyond T. A theory of modes, 328. The Dyskeratosis congenita corresponds to the first genetic entity described among Unit of Dentistry, Bambino Gesù Chil- dren's Hospital, IRCSS, Rome, Italy. personality, and psychopathology. 1996; 14. Bowley A, Gardner L. El niño minusvalido: telomeropathies, whose classic form is characterized by presenting the mucocutaneous triad of 3 Medical Genetics Unit, Childcare and 35(1): 1-25. Guía educativa y psicológica para el reticulated skin-lace pigmentation, nail dystrophy and oral leukoplakia. It can also occur with bone Pediatrics Department, University of the marrow failure, hematological and solid tumors, corresponding to the most serious complications. In Andes, Mérida, Venezuela. 7. Jenkins W, Papapanou P. Epidemiology of minusvalido organico. Editorial continental addition to immunodeficiencies, dental, lung and liver disorders and other aspects considered minor. periodontal disease in children and 1985; 2(6): 221-235. In turn, it presents varied genetic locus heterogeneity, with at least 14 genes involved in the ORCID: * adolescents. Periodontology. 2000; 26(1): 15. Toledo B, López M, Yamamoto N. telomere´s shortening, therefore associated with dyskeratosis congenita or similar phenotypes. This https://orcid.org/0000-0002-0193-2171 review discusses in addition to the clinical characteristics, the various etiological causes, evolution, 16-32. Enfermedad periodontal en pacientes available therapeutic options, and the differential diagnostic of this entity in order to provide an Corresponding author: Francisco Cammarata Scalisi 8. Marchena P. Relación entre el nivel de adolescentes con síndrome de Down. interdisciplinary and individualized medical evaluation that includes adequate genetic counseling. Address: Unidad de Genética Médica, conocimiento sobre salud bucal de los Presentación de caso. Revista odontológi- Instituto Autónomo Hospital Uni-versita- rio de Los Andes, Nivel Mezzani-na, Av. padres y el índice de higiene oral en niños ca mexicana. 2014; 18(3): 191-198. Keywords: dyskeratosis congenita, telomeropathies, clinic, etiology, treatment. 16 de Septiembre. Sector Campo de Oro. con habilidades diferentes del centro de 16. Motta A. Higiene bucal y gingivitis en Mérida, 5101. Venezuela. 58 424 Resumen 7296843.. educación básica especial la Victoria- alumnos con discapacidades intelectuales Email: [email protected] 2015.Universidad Señor de Sipan. Facultad del Colegio Especial "Santa Teresa de La disqueratosis congénita corresponde la primera entidad genética descrita entre las de Ciencias de la Salud. Académico Courdec" mayo-junio 2011 [Tesis para optar telomeropatías, cuya forma clásica se caracteriza por presentar la tríada mucocutánea de Reception date: 07 de enero de 2020 pigmentación reticulada de encaje en piel, distrofia ungueal y leucoplasia oral. Puede cursar Profesional de Estomatología. Tesis para el grado de Cirujano Dentista]. Lima, Perú: además con insuficiencia de la médula ósea, tumores hematológicos y sólidos que corresponde las Approval date: 18 de enero de 2020 obtener grado de cirujano dentista. 2015. Universidad San Martin de Porres; 2014. complicaciones más graves. Además de inmunodeficiencias, alteraciones dentales, pulmonares y hepáticas y otros aspectos considerados menores. Presenta a su vez una variada heterogeneidad Quote as: Perona R, Sastre L, Callea M, 9. Yirina P, Baonelys T, Arelis B. Factores de 17. Kutsch, V. Caries dental: un modelo médico genética de locus, con al menos 14 genes implicados en el acortamiento de los telómeros, Cammarata-Scalisi F. Aspectos clínicos, etiológicos y terapéuticos de la riesgo de periodontopatías. Rev. 2015; actualizado de evaluación de riesgos. Pub. asociados por lo tanto a la disqueratosis congénita o a fenotipos similares. Esta revisión discute disqueratosis congénita. Rev. Peru. 19(2). Disponible en: Med. 2014; 111(4): 280-5. además de las características clínicas, las diversas causas etiológicas, evolución, opciones Investig. Salud. [Internet]; 4(2): 77-82. terapéuticas disponibles y diagnóstico diferenciales de esta entidad con el objeto de brindar una Available from: http://scielo.sld.cu/scielo.php?script=sci_a 18. Opal S, Garg S, Jain J, Walia. Factores evaluación médica interdisciplinaria e individualizada que incluya un adecuado asesoramiento http://revistas.unheval.edu.pe/index.php rttext&pid=S1560-3812015000200009 genéticos que afectan el riesgo de caries genético. /repis/article/view/606. 10. Perdomo B, Torres D, Paredes Y. Síndrome dental. PubMed. 2015; 60 (1): 2-11. 2616-6097/©2020. Peruvian Journal of Health Research. Palabras clave: disqueratosis congénita, telomeropatías, clínica, etiología, tratamiento. This is an Open Access article under the CC-BYlicense de Down e higiene bucal: Lineamientos 19. Rodríguez A, León M, Arada A, Martínez M. (https://creativecommons.org/licenses/by/4.0). It allows copying and redistributing the material in any medium or format. You must give credit appropriately, provide a link para padres, cuidadores y docentes de Factores de riesgo y enfermedades bucales to the license, and indicate if changes have been made. investigación Odontológica Revista en gestantes. Revista de Ciencias Médicas. venezolana de investigación odontológica. 2013; 17 (5): 51-63 2014; 2 (2): 156-169. 11. Folstein S, Rutter M. Infantile autism a Introduction The typical dermatological manifestations genetic study of 21 twin pairs. J Child occur in the first years of life, however, the Psychol Psychiatry. 1977; 18(4): 297-321. The disorders in the telomeres´ biology called presentation can be heterogeneous (8,9). The telomeropathies represent a group of genetic aforementioned nail dystrophy first affects the entities, in which dyskeratosis congenita (DC) fingernails, begins with grooves and longitu- was the first to be described (1), whose classic dinal divisions, which progresses resulting in form is clinically characterized by presenting rudimentary, small or absent nails. For its part, the diagnostic mucocutaneous triad of the leukoplakia affects the oral mucosa, tongue Reticulated skin lace pigmentation (1,2), and oropharynx, and treatment is sympto- mainly affecting the neck area and the upper matic. Approximately the 30% present anterior thorax (2), nail dystrophy and oral malignant transformation to squamous cell leukoplakia (1-10) (Fig. 1). carcinoma (4), so they require frequent follow- up with early biopsy in suspected areas (4,8). Figure1. Nail dystrophy and oral leukoplakia. Posteriorly, it was shown to be associated with bone marrow failure (1-5), with cytopenia of one or more hematopoietic cell lineages, and the most serious complication corresponded (1). It can affect up to 80-90% of cases at the age of 30 years and its sequelae represent more than 70% of deaths in patients with this entity (8). The presence of the mucocutaneous

ISSN 2616 - 6097, Rev Peru Investig Salud. 2020; 4(2), april - june 2020, 77-82 ISSN 2616 - 6097, Rev Peru Investig Salud. 2020; 4(2), april - june 2020, 70-76 78 Perona R, Sastre L, Callea M, Cammarata-Scalisi F. Clinical, etiological and therapeutic aspects of Dyskeratosis Congenita 79 triad can help differentiate the DC from other the telomerase genes. In the most severe in the dyskerin 1 (DKC1) gene, which encodes dyskerin and the shortening of the telomeres types of bone marrow failure (10). It also cases and with the telomere shortening less a pseudouridine synthase, and whose gene is (3). Therefore, the germline mutations in genes presents with immunodeficiencies, predispo- than the 1% percentile of the population, the It is located in Xq28, among the most common involved in the telomere´s biology result in sition to present dental caries, hypodontia, disease appears in the first 10 years of life or and classic of the DC, as well as autosomal abnormal shortening of these structures for bleeding, recession and bone loss that even during the prenatal stage. In the cases of dominant (OMIM # 127550) and / or recessive age, resulting in chromosomal instability and simulate juvenile periodontitis, taurodontism, less severe telomeric shortening, the disease (OMIM # 224230) (1-6,8,9) patterns. However, the progressive cell death (2). gingival inflammation and brown intraoral appears at an age between 15 and 25 years, in between 20 to 40% of cases, genetic causes pigmentation (1,2,4,6,8,10). The evidence of these cases it is below the 10% percentile of are undetectable (2,4). Therefore, it is a disease with a defective multiple permanent teeth with decreased root / the population and can appear as spinal maintenance of the telomeres, which leads to a crown ratio may suggest the diagnostic of the aplasia or pulmonary fibrosis and whose Table 1. Etiopathogenesis in the alteration premature shortening, to a replicative DC (4). Other clinical findings include pulmo- probability is associated with the gene of the telomere biology associated with senescence, to a premature exhaustion of the nary fibrosis, and liver failure or fibrosis (1- mutated. The genetic diagnostic is essential the DC (3,5,7-9). stem cells and the failure in different tissues, 3,5,7,10). They also have a 50-fold increased due to the limited efficacy of therapeutic Genetic and it manifests itself mainly in the highly risk of developing hematologic and solid options, and the common genetic anticipation Mechanism of proliferating of the mucocutaneous tissues Gene Inheritance tumors, including myelodysplastic syndrome, in DC makes genetic counseling a priority (1). action (1,4, 10). However, the mutations in the acute myeloid leukemia, non-Hodgkin Pattern telomerase and the telomere´s components lymphoma, the squamous cell carcinoma of the Incidence DKC1* LX have also been identified in patients with head and neck, the esophageal cancer, The DC has an estimated annual incidence of Telomerase TERC* AD aplastic anemia, pulmonary fibrosis and liver anogenital cancer and basal cell carcinoma, as less than 1 in 1,000,000 (4), it was first descri- holoenzyme TERT* AD o AR disease (4). serious complications (1,2,4,5,8,10). bed by Zinsser in 1906, in male patients with complex NOP10* AR the aforementioned mucocutaneous triad NHP2* AR Additionally, the genotype-phenotype correla- The squamous cell carcinoma of the head and (3,4,6). It was recognized as a clinical entity by tion is very complex due to various factors, to neck is the most frequent solid tumor in Engman in 1926 and Cole in 1930, and is Telomere´s ACD AD o AR including a variety of underlying hypomorphic patients with DC, with a mean age of onset of known as the Zinsser-Cole-Engman syndro- Protection TINF2* AD gene mutations, to the disease anticipation, as 32 years, compared to 67 years in the general me, which will be discussed later (4). In 1963, Complex POT1 AD well as genetic and environmental modifying population. the first female case was documented (3). Proteins that effects (4). CTC1 AR limit the The recognition includes additional minor Etiopathogenesis and diagnostic Treatment telomeres STN1 AR features such as intrauterine growth retarda- The telomeres are made up of 6 nucleotide There is not curative therapy for the DC, and tion, developmental delay and microcephaly, repeats at the ends of chromosomes (5). It is a Other proteins the patients generally die prematurely from the signs of premature aging, premature nucleoprotein complex essential for chromoso- bone marrow failure, due to the poor that directly or RTEL1 AD o AR graying of hair, excessive sweating, and short mal stability, and they shorten with each cell hematopoietic stem cell turnover, so an option stature (4.7-10). Among the ocular abnorma- division (5,7). The regulation of the telomere´s indirectly is the allogeneic transplantation, which may be interact with lities are described nasolacrimal duct stenosis, length is implicated in cell aging and tumori- NAF1 - associated with complications. Furthermore, epiphora, blepharitis, few eyelashes, ectro- genesis (6). Therefore, mutations in the key key cellular the follow-up is crucial in the presence of WRAP53 pion, entropion, and trichiasis (2-4,10). On the genes of the telomere maintenance machinery processes AR tumors or serious infection by opportunistic other hand, the retinal changes are rare and are related to entities such as the DC, which PARN AR agents, among the main causes of death include the bleeding, infarction of the nerve can cause bone marrow failure and cancer * Implicated in the regulation in the telomere´s length between the second and the third decades of fiber layer, arteriosclerosis, macular edema, (6,7,9,10). (9) the life (2,4,5,11). AD: autosomal dominant. preretinal fibrosis, and optic atrophy (4). This knowledge allowed the development of a AR: autosomal recessive. Furthermore, cardiomyopathy, enteropathy diagnostic test through flow cytometry with XL: X-linked recessive chromosome. The treatment of the squamous cell carcinoma with malabsorption, esophageal and urethral fluorescent in situ with hybridization in of the head and the neck may involve surgical stenosis, hypogonadism, testicular atrophy, leukocyte subsets. The size of the telomeres in The DC associated with the X chromosome treatment, radiation, and chemotherapy, while osteoporosis, and avascular necrosis of the leukocytes less than the first percentile for age occurs in the male sex. It manifests clinically avoiding the exposure to potential carcinogens shoulder and hip joints can be seen (2-4,7,10). is more than 95% sensitive and specific in between 5 to 12 years, it can present a variable such as ultraviolet radiation, alcohol, and These clinical manifestations affect patients in patients with the DC (3,5,7). In addition to age of onset, symptoms and severity, even in tobacco (8). different ways and with a variable percentage intervening in the diagnostic, the study of individuals with the same mutation. In this (4). The DC often goes unnoticed due to the telomeres has greatly contributed to disco- pattern of inheritance, the women may exhibit The use of low doses of systemic retinoids has late onset of mucocutaneous findings and in vering the genetic causes of the DC (3). less severe clinical features until more shown some improvement in the skin and the some cases may not occur. The broad advanced ages (4). The DKC1 gene has a nails, but the secondary effects and the long- spectrum of clinical presentation and the lack At least 14 genes involved in the telomere´s highly conserved sequence that binds to small term effectivity are uncertain (11). Further- of conclusive laboratory evidence can shortening, associated with DC or similar nucleolar RNAs, it is responsible for the more, it has been described that up to 70% of sometimes make clinical diagnostic challen- phenotypes have been identified (Table 1), and biogenesis of ribosomes and is part of the the patients with the CD and severe bone ging (1). represent between 70 to 80% of patients with telomerase complex when it binds to marrow failure may temporarily benefit from this disorder (3,5,7). They exhibit various telomerase RNA or TERC (2,9). The Mitchell therapy with androgens or androgen In the DC like other telomere diseases, the patterns of inheritance, including that linked to and Collins studies were the first to show a derivatives, but there is no cure for the disease symptoms are associated with the degree of the recessive X chromosome (OMIM # connection between the telomeres and human (8, eleven). The biological mechanisms by telomere´s shortening, caused by mutation in 305000) (1,3-5), due to the pathogenic variants disease through the aberrant function of which these compounds effectively treat the

ISSN 2616 - 6097, Rev Peru Investig Salud. 2020; 4(2), april - june 2020, 77-82 ISSN 2616 - 6097, Rev Peru Investig Salud. 2020; 4(2), april - june 2020, 77-82 78 Perona R, Sastre L, Callea M, Cammarata-Scalisi F. Clinical, etiological and therapeutic aspects of Dyskeratosis Congenita 79 triad can help differentiate the DC from other the telomerase genes. In the most severe in the dyskerin 1 (DKC1) gene, which encodes dyskerin and the shortening of the telomeres types of bone marrow failure (10). It also cases and with the telomere shortening less a pseudouridine synthase, and whose gene is (3). Therefore, the germline mutations in genes presents with immunodeficiencies, predispo- than the 1% percentile of the population, the It is located in Xq28, among the most common involved in the telomere´s biology result in sition to present dental caries, hypodontia, disease appears in the first 10 years of life or and classic of the DC, as well as autosomal abnormal shortening of these structures for bleeding, recession and bone loss that even during the prenatal stage. In the cases of dominant (OMIM # 127550) and / or recessive age, resulting in chromosomal instability and simulate juvenile periodontitis, taurodontism, less severe telomeric shortening, the disease (OMIM # 224230) (1-6,8,9) patterns. However, the progressive cell death (2). gingival inflammation and brown intraoral appears at an age between 15 and 25 years, in between 20 to 40% of cases, genetic causes pigmentation (1,2,4,6,8,10). The evidence of these cases it is below the 10% percentile of are undetectable (2,4). Therefore, it is a disease with a defective multiple permanent teeth with decreased root / the population and can appear as spinal maintenance of the telomeres, which leads to a crown ratio may suggest the diagnostic of the aplasia or pulmonary fibrosis and whose Table 1. Etiopathogenesis in the alteration premature shortening, to a replicative DC (4). Other clinical findings include pulmo- probability is associated with the gene of the telomere biology associated with senescence, to a premature exhaustion of the nary fibrosis, and liver failure or fibrosis (1- mutated. The genetic diagnostic is essential the DC (3,5,7-9). stem cells and the failure in different tissues, 3,5,7,10). They also have a 50-fold increased due to the limited efficacy of therapeutic Genetic and it manifests itself mainly in the highly risk of developing hematologic and solid options, and the common genetic anticipation Mechanism of proliferating of the mucocutaneous tissues Gene Inheritance tumors, including myelodysplastic syndrome, in DC makes genetic counseling a priority (1). action (1,4, 10). However, the mutations in the acute myeloid leukemia, non-Hodgkin Pattern telomerase and the telomere´s components lymphoma, the squamous cell carcinoma of the Incidence DKC1* LX have also been identified in patients with head and neck, the esophageal cancer, The DC has an estimated annual incidence of Telomerase TERC* AD aplastic anemia, pulmonary fibrosis and liver anogenital cancer and basal cell carcinoma, as less than 1 in 1,000,000 (4), it was first descri- holoenzyme TERT* AD o AR disease (4). serious complications (1,2,4,5,8,10). bed by Zinsser in 1906, in male patients with complex NOP10* AR the aforementioned mucocutaneous triad NHP2* AR Additionally, the genotype-phenotype correla- The squamous cell carcinoma of the head and (3,4,6). It was recognized as a clinical entity by tion is very complex due to various factors, to neck is the most frequent solid tumor in Engman in 1926 and Cole in 1930, and is Telomere´s ACD AD o AR including a variety of underlying hypomorphic patients with DC, with a mean age of onset of known as the Zinsser-Cole-Engman syndro- Protection TINF2* AD gene mutations, to the disease anticipation, as 32 years, compared to 67 years in the general me, which will be discussed later (4). In 1963, Complex POT1 AD well as genetic and environmental modifying population. the first female case was documented (3). Proteins that effects (4). CTC1 AR limit the The recognition includes additional minor Etiopathogenesis and diagnostic Treatment telomeres STN1 AR features such as intrauterine growth retarda- The telomeres are made up of 6 nucleotide There is not curative therapy for the DC, and tion, developmental delay and microcephaly, repeats at the ends of chromosomes (5). It is a Other proteins the patients generally die prematurely from the signs of premature aging, premature nucleoprotein complex essential for chromoso- bone marrow failure, due to the poor that directly or RTEL1 AD o AR graying of hair, excessive sweating, and short mal stability, and they shorten with each cell hematopoietic stem cell turnover, so an option stature (4.7-10). Among the ocular abnorma- division (5,7). The regulation of the telomere´s indirectly is the allogeneic transplantation, which may be interact with lities are described nasolacrimal duct stenosis, length is implicated in cell aging and tumori- NAF1 - associated with complications. Furthermore, epiphora, blepharitis, few eyelashes, ectro- genesis (6). Therefore, mutations in the key key cellular the follow-up is crucial in the presence of WRAP53 pion, entropion, and trichiasis (2-4,10). On the genes of the telomere maintenance machinery processes AR tumors or serious infection by opportunistic other hand, the retinal changes are rare and are related to entities such as the DC, which PARN AR agents, among the main causes of death include the bleeding, infarction of the nerve can cause bone marrow failure and cancer * Implicated in the regulation in the telomere´s length between the second and the third decades of fiber layer, arteriosclerosis, macular edema, (6,7,9,10). (9) the life (2,4,5,11). AD: autosomal dominant. preretinal fibrosis, and optic atrophy (4). This knowledge allowed the development of a AR: autosomal recessive. Furthermore, cardiomyopathy, enteropathy diagnostic test through flow cytometry with XL: X-linked recessive chromosome. The treatment of the squamous cell carcinoma with malabsorption, esophageal and urethral fluorescent in situ with hybridization in of the head and the neck may involve surgical stenosis, hypogonadism, testicular atrophy, leukocyte subsets. The size of the telomeres in The DC associated with the X chromosome treatment, radiation, and chemotherapy, while osteoporosis, and avascular necrosis of the leukocytes less than the first percentile for age occurs in the male sex. It manifests clinically avoiding the exposure to potential carcinogens shoulder and hip joints can be seen (2-4,7,10). is more than 95% sensitive and specific in between 5 to 12 years, it can present a variable such as ultraviolet radiation, alcohol, and These clinical manifestations affect patients in patients with the DC (3,5,7). In addition to age of onset, symptoms and severity, even in tobacco (8). different ways and with a variable percentage intervening in the diagnostic, the study of individuals with the same mutation. In this (4). The DC often goes unnoticed due to the telomeres has greatly contributed to disco- pattern of inheritance, the women may exhibit The use of low doses of systemic retinoids has late onset of mucocutaneous findings and in vering the genetic causes of the DC (3). less severe clinical features until more shown some improvement in the skin and the some cases may not occur. The broad advanced ages (4). The DKC1 gene has a nails, but the secondary effects and the long- spectrum of clinical presentation and the lack At least 14 genes involved in the telomere´s highly conserved sequence that binds to small term effectivity are uncertain (11). Further- of conclusive laboratory evidence can shortening, associated with DC or similar nucleolar RNAs, it is responsible for the more, it has been described that up to 70% of sometimes make clinical diagnostic challen- phenotypes have been identified (Table 1), and biogenesis of ribosomes and is part of the the patients with the CD and severe bone ging (1). represent between 70 to 80% of patients with telomerase complex when it binds to marrow failure may temporarily benefit from this disorder (3,5,7). They exhibit various telomerase RNA or TERC (2,9). The Mitchell therapy with androgens or androgen In the DC like other telomere diseases, the patterns of inheritance, including that linked to and Collins studies were the first to show a derivatives, but there is no cure for the disease symptoms are associated with the degree of the recessive X chromosome (OMIM # connection between the telomeres and human (8, eleven). The biological mechanisms by telomere´s shortening, caused by mutation in 305000) (1,3-5), due to the pathogenic variants disease through the aberrant function of which these compounds effectively treat the

ISSN 2616 - 6097, Rev Peru Investig Salud. 2020; 4(2), april - june 2020, 77-82 ISSN 2616 - 6097, Rev Peru Investig Salud. 2020; 4(2), april - june 2020, 77-82 80 Perona R, Sastre L, Callea M, Cammarata-Scalisi F. Clinical, etiological and therapeutic aspects of Dyskeratosis Congenita 81 bone marrow failure are still unknown. Howe- the manifestation of the disease is ambiguous. abnormalities; In addition, it may present Conclusions ver, it has been proposed that the androgens The aplastic anemia occurs at a mean age of intrauterine growth retardation, cerebellar can directly increase the erythropoietin presentation of 11 years, it is macrocytic, with hypoplasia, and developmental delay production or act on the erythropoietin receptor high levels of fetal hemoglobin. It begins with (4,6,11,17). A wide range of genetic alterations generates a to generate a hematological response. A thrombocytopenia and during the evolution, it wide spectrum of clinical manifestations with limited number of studies on human´s cell lines becomes general and severe bone marrow The Coats Plus syndrome (OMIM #612199) is variable age of onset, this fact make and mouse models with aplastic anemia failure develops. The premature mortality can an infrequent disorder with an autosomal challenging the diagnostic in this disorder of suggest that the androgens can increase occur in up to 80% of cases from opportunistic recessive pattern of inheritance, due to the telomere´s biology. Therefore, the DC is a telomerase expression and telomere´s length infections. Besides, they can progress in nonsense mutations in the CTC1 gene, hereditary, clinical and genetically hetero- (8). different ways with the appearance of the characterized by the cerebroretinal microan- geneous syndrome of the bone marrow failure myelodysplasia in one or more lineages (4). giopathy, with intracranial calcifications, and a prototype of this type of disorder. For this Other exogenous therapies can correct the osteopenia, and gastrointestinal bleeding reason, the medical evaluation must be telomerase´s defect and improve the cell There is an excessive shortening of the (4,18,19). interdisciplinary and individualized, offering the growth, as well as the use of the modulators telomere that can lead to genomic instability. available therapeutic options and timely gene- involved in the maintenance of the telomeres, The Electronic Microscopy studies revealed Differential diagnostic tic counseling based on genetic diagnostic and have been suggested as new therapeutics that the cells in the DC have an immature The Naegeli-Franceschetti-Jadassohn the telomeric length studies. methods (11). Among them, the expression of a embryonic nucleus and a predisposition to syndrome (OMIM #161000), is differentiated dysquerin-derived peptide, a genetic suppres- undergo a malignant transformation. Besides, by the lack of the leukoplakia, the bone marrow References sor element 24.2 (GSE24.2), which increases the epithelial barrier is less effective than in the failure and an increased risk of malignancy the telomerase activity, reduces the patho- normal epithelium, so there is a greater (11). However, this and the reticular pigmen- genic effects of Dkc1 mutations, decreases the permeability of the harmful and carcinogenic tary dermatopathy (OMIM # 125595), allelic 1.Trotta L, Norberg A, Taskinen M, Béziat V, DNA damage and the oxidative stress, thus substances in the germ layers. Therefore, an alterations, can have a similar reticulated Degerman S, Wartiovaara-Kautto U, et al. suggesting a new therapeutic approach. increase in the rate of malignant transformation hyperpigmentation (20,21). Diagnostics of rare disorders: whole-exome Likewise, the expression of the GSE4 activates is observed in the leukoplastic areas, requiring sequencing deciphering locus heterogeneity the c-myc and TERT promoters, in addition to the periodic monitoring. In addition, they have a On the other hand, the Fanconi anemia (OMIM in telomere biology disorders. Orphanet J increasing the expression of c-myc, TERT and cumulative incidence of the risk of malignancy # 227650) generally presents diffuse or Rare Dis. 2018;13:139. TERC (12-14). of 40 to 50% at 50 years, for example, they can uniform pigmentary abnormalities, and the 2.Ratnasamy V, Navaneethakrishnan S, Siri- develop Hodgkin´s lymphoma, laryngeal and pancytopenia has an earlier onset compared to sena ND, Grüning NM, Brandau O, Thiru- Additionally, the activation of the telomerase bronchial carcinoma, adenocarcinoma of the the DC (11,16). It also presents eyes, kidney navukarasu K, et al. Dyskeratosis congenita through the use of vectors in genetic therapy of gastrointestinal tract, among others at the and limbs abnormalities (16). As well as other with a novel genetic variant in the DKC1 adeno-associated viruses that carry the skeletal and genitourinary level (4). chromosome reorganization and break gene: a case report. BMC Med Genet. telomerase´s Tert gene in mouse models syndromes such as the Bloom syndrome 2018;19:85. independent of aplastic anemia due to short Clinical variations (OMIM # 210900) 16,22, the Nijmegen break 3.Savage SA. Beginning at the ends: telome- telomeres showed that a high dose of this The Zinsser-Engman-Cole syndrome (OMIM syndrome (OMIM # 251260), the Seckel res and human disease. F1000Res. 2018;7. vector was targeted at the bone marrow #305000) is the most severe variant and is syndrome (OMIM # 210600), and finally the pii: F1000 Faculty Rev-524. compartment level, including the hemato- characterized by the progressive marrow pseudo-TORCH syndrome, due to the brain 4.Fernández García MS, Teruya-Feldstein J. poietic stem cells, that improve substantially failure, intrauterine growth retardation, develo- calcifications (22). The diagnosis and treatment of dyskeratosis the survival, it results in a significant increase in pmental delay, microcephaly, cerebellar congenita: a review. J Blood Med. 2014; 5: the telomere length in the peripheral blood and hypoplasia, mental retardation, progressive Other entities include the Rothmund-Thomson 157-67. in the bone marrow cells, as well as a better immunodeficiency and the mucocutaneous syndrome (OMIM # 268400), and the simple 5.Khincha PP, Bertuch AA, Gadalla SM, Giri N, blood count. These findings indicate that the triad, which usually leads to death in the early epidermolysis bullosa (OMIM # 131900), both Alter BP, Savage SA. Similar telomere telomerase genetic therapy represents a novel childhood ( 1,4,6,8,10,11,16). It is due to the of which have mottled pigmentation with similar attrition rates in androgen-treated and therapeutic strategy to treat the aplastic mutations in the DKC1 and RTEL1 genes, poikiloderma (18,20). In addition, the Kindler's untreated patients with dyskeratosis conge- anemia caused or associated with short mainly due to the decreased telomerase´s syndrome (OMIM # 173650), and the nita. Blood Adv. 2018;2:1243-9. telomeres (9,15). activity. The diagnostic can be made if you poikiloderma with Clericuzio-type neutropenia 6.Olivieri C, Mondino A, Chinello M, Risso A, have four or more of these findings, or if you (OMIM # 604173) (16,23,24). In the Bloom, Finale E, Lanciotti M, et al. Clinical heteroge- The integration of an interdisciplinary team is have cerebellar hypoplasia and additional Kindler and Rothmund-Thomson syndromes, neity in a family with DKC1 mutation, independent in each case, but will generally features of the DC (4). the skin lesions may be similar to those seen in dyskeratosis congenita and Hoyeraal- include to Dermatology, Otorhinolaryngology, the DC, but are more sensitive to the sun and Hreidarsson syndrome in first cousins. Dentistry, Maxillofacial Surgery, Oncology, The Revesz syndrome (OMIM #268130) was differ in associated characteristics (16). Finally, Pediatr Rep. 2017;9:7301. Gynecology (8), Medical Genetics and include first described in 1992, it is due to the mutations the patients with graft-versus-host disease 7.Ungar RA, Giri N, Pao M, Khincha PP, Zhou early genetic tests to carry out timely genetic in the TINF2 gene, it is another infrequent have poikiloderma, lichen planus-like changes W, Alter BP, et al. Complex phenotype of counseling (8,11). variant of the DC, the defining characteristic is in the mucosa, and obvious nail dystrophy after dyskeratosis congenita and mood dysregu- the bilateral exudative retinopathy, which the bone marrow transplantation (16,20). lation with novel homozygous RTEL1 and Evolution of the DC occurs in most cases in association with the TPH1 variants. Am J Med Genet A. During the follow-up of the disease when the intracranial calcification and the alterations 2018;176:1432-7. mucocutaneous triad occurs, the bone marrow more associated to the DC disorders, as the 8.Bongiorno M, Rivard S, Hammer D, Kentosh failure usually appears. However, sometimes bone marrow failure and the mucocutaneous J. Malignant transformation of oral

ISSN 2616 - 6097, Rev Peru Investig Salud. 2020; 4(2), april - june 2020, 77-82 ISSN 2616 - 6097, Rev Peru Investig Salud. 2020; 4(2), april - june 2020, 77-82 82 Perona R, Sastre L, Callea M, Cammarata-Scalisi F. CLINICAL CASES 83 REVISTA PERUANA DE INVESTIGACIÓN EN SALUD http://revistas.unheval.edu.pe/index.php/repis/ leukoplakia in a patient with dyskeratosis 17.McElnea EM, van der Spek N, Smith O, https://doi.org/10.35839/repis.4.2.618 congenita. Oral Surg Oral Med Oral Pathol Fitzsimon S, Patel CK, O'Marcaigh A. The syncope as a debut form of mitral stenosis Oral Radiol. 2017;124:e239-42. Revesz syndrome masquerading as bilateral 9.Perona R, Machado-Pinilla R, Manguan C, cicatricial retinopathy of prematurity. J Síncope como forma de debut de la estenosis mitral Carrillo J. Telomerase deficiency and cancer AAPOS. 2013;17:634-6. susceptibility syndromes. Clin Transl Oncol. 18.Romaniello R, Arrigoni F, Citterio A, Tonelli Rodolfo Vega-Candelario1,a,* 2009;11:711-4. A, Sforzini C, Rizzari C, et al. Cerebroretinal 1Assistant Professor at the Faculty of 10.Carrillo J, Martínez P, Solera J, Moratilla C, microangiopathy with calcifications and cysts Abstract Medical Sciences of Ciego de Avila, González A, Manguán-García C, et al. High associated with CTC1 and NDP mutations. J Cuba. Introduction: The common mechanism to the syncope is a transient alteration in cerebral blood flux, this fact resolution melting analysis for the identifi- Child Neurol. 2013;28(12):1702-8. generate a temporary decrease in the brain metabolism with involvement of the ascending reticular system and aCardiologist cation of novel mutations in DKC1 and TERT 19.Gu P, Jia S, Takasugi T, Smith E, Nandaku- cerebral cortex. The syncope due to mitral stenosis does not appear in the reviewed literature. Objectives: To show a clinical case from a patient with mitral stenosis that debuts with recurrent syncope. ORCID: genes in patients with dyskeratosis conge- mar J, Hendrickson E, et al. CTC1-STN1 Clinical case: A 45-year-old patient, mestizo without history of disease, a farmer, is admitted to the internal *https://orcid.org/0000-0003-4459-8350 nita. Blood Cells Mol Dis. 2012;49:140-6. coordinates G- and C-strand synthesis to medicine ward for recurrent syncope. He was evaluated by a neurologist and a cardiologist; he was diagnosed with critical mitral stenosis with severe pulmonary hypertension and a right ventricular Systo-diastolic dysfunction. After Corresponding author: 11.Zhang J, Li M, Yao Z. Updated review of regulate telomere length. Aging Cell. the mitral valve replacement by cardiovascular surgery, he did not suffer syncopal episodes again and leads a Rodolfo Vega Candelario normal biopsychosocial and work life. Address: Provincial Teaching Hospital genetic reticulate pigmentary disorders. Br J 2018:e12783. Comments: The critical mitral stenosis causes decreased in the ventricular filling and decreased the cardiac output ¨Roberto Rodríguez Fernández, Morón, Dermatol. 2017;177:945-59. 20.Garofola C, Gross GP. Dyskeratosis with decreased cerebral blood flux, accentuated by the severe pulmonary hypertension and the right heart failure. Ciego de Ávila, Cuba. This fact caused repetitive syncope. 12.Iarriccio L, Manguán-García C, Pintado- Congenita. Source Stat Pearls. Treasure Email: [email protected] Berninches L, Mancheño JM, Molina A, Island (FL): Stat Pearls Publishing; 2018. Keywords: syncope, mitral stenosis, pulmonary hypertension, cardiac output, cerebral blood flux. Reception date: 02 de febrero de 2020 Perona R, et al. GSE4, a small dyskerin- and 21.Belligni EF, Dokal I, Hennekam RC. Resumen Approval date: 18 de marzo de 2020 GSE24.2-related peptide, induces telome- Prenatal and postnatal growth retardation, Introducción: El mecanismo común a todo síncope es una alteración transitoria del flujo sanguíneo cerebral, que rase activity, cell proliferation and reduces microcephaly, developmental delay, and provoca una disminución momentánea del metabolismo cerebral, con afectación del sistema reticular ascendente Quote as: Vega-Candelario R. Síncope y córtex cerebral. El síncope por estenosis mitral, no aparece en la literatura revisada. como forma de debut de la estenosis DNA damage, oxidative stress and cell pigmentation abnormalities: Naegeli syndro- Objetivos: Presentar un paciente con estenosis mitral que debuta con cuadro de síncope recurrente. mitral. Rev. Peru. Investig. Salud. Senescence in dyskerin mutant cells. PLoS me, dyskeratosis congenita, poikiloderma Caso clínico: Paciente de 45 años, mestizo, sin antecedentes de enfermedad, trabajador agrícola, ingresa en sala [Internet]; 4(2): 83-86. Available from: de medicina interna por padecer síncopes recurrentes. Fue valorado por neurólogo y cardiólogo; se diagnosticó http://revistas.unheval.edu.pe/index.php One. 2015 Nov 16;10(11):e0142980. Clericuzio type, or separate entity? Eur J estenosis mitral crítica con hipertensión pulmonar grave y disfunción sistodiastólica de ventrículo derecho. Luego /repis/article/view/618 13.Manguan-Garcia C, Pintado-Berninches L, Med Genet. 2011;54:231-5. de la sustitución valvular mitral por cirugía cardiovascular no volvió a padecer episodios sincopales y lleva una vida normal biopsicosocial y laboral. 2616-6097/©2020. Peruvian Journal of Health Research. This is an Open Access article under the CC-BYlicense Carrillo J, Machado-Pinilla R, Sastre L, 22.Dehmel M, Brenner S, Suttorp M, Hahn G, Comentarios: La estenosis mitral crítica ocasiona disminución del llenado ventricular y disminución del gasto (https://creativecommons.org/licenses/by/4.0). It allows cardiaco con disminución del flujo sanguíneo cerebral, acentuado por la hipertensión pulmonar grave e copying and redistributing the material in any medium or Pérez-Quilis C, et al. Expression of the Schützle H, Dinger J, et al. Novel mutation in insuficiencia cardíaca derecha. Ocasionó síncopes repetitivos. format. You must give credit appropriately, provide a link genetic suppressor element 24.2 (GSE24.2) the DKC1 gene: neonatal Hoyeraal-Hrei- to the license, and indicate if changes have been made. decreases DNA damage and oxidative stress darsson syndrome as a rare differential Palabras clave: síncope, estenosis mitral, hipertensión pulmonar, gasto cardiaco, flujo sanguíneo cerebral. in X-linked dyskeratosis congenita cells. diagnosis in pontocerebellar hypoplasia, PLoS One. 2014;9:e101424. primary microcephaly, and progressive bone 14.Machado-Pinilla R1, Sánchez-Pérez I, marrow failure. Neuropediatrics. 2016; 47: Introduction The treatment of the syncope must be oriented Murguía JR, Sastre L, Perona R. A dyskerin 182-6. to solving the underlying cause and avoiding motif reactivates telomerase activity in X- 23.Anwar MI, Rashid A, Ghafoor R, Tahir M, The common mechanism to the syncope is a the recurrences. The cardiogenic syncope linked dyskeratosis congenita and in Rao SU, Mir F. Kindler's syndrome: a report transient alteration in cerebral blood flux, this should be treated by the specialists, with telomerase-deficient human cells. Blood. of five cases in a family. J Coll Physicians fact generate a temporary decrease in the specific treatments (pacemakers, defibrilla- 2008;111:2606-14. Surg Pak. 2014;24:763-5. brain metabolism with involvement of the tors, drugs, surgery and cardiac intervention). 15.Bär C, Povedano JM, Serrano R, Benitez- 24.Mostefai R, Morice-Picard F, Boralevi F, ascending reticular system and cerebral In the cases to the neurally - mediated Buelga C, Popkes M, Formentini I, et al. Sautarel M, Lacombe D, Stasia MJ, et al. cortex, which causes a decrease in the level of syncope, the postural and hygienic measures Telomerase gene therapy rescues telomere Poikiloderma with neutropenia, Clericuzio consciousness. Based on previous experien- should be the first therapeutic step. Other length, bone marrow aplasia, and survival in type, in a family from Morocco. Am J Med ces in the tilting - table test, the drop in mean treatments (drugs, pacemakers) have not mice with aplastic anemia. Blood. 2016; 127: Genet A. 2008;146A:2762-9. arterial pressure below 60 mmHg causes an shown great benefits (4-9). 1770-9. alteration of the self-regulating mechanism of 16.Penmatsa C, Jampanapalli SR, Bezawada the cerebral flux with the consequent appea- There are many causes of syncope to be S, Birapu UK, Radharapu VK. Zinsser-Cole- rance of syncope. If this loss of brain flux is known, but the mitral stenosis does not appear Engman syndrome: A rare case report. J Clin maintained above a critical time, around 5 in any, less as the unique symptom. This debut Diagn Res. 2016;10:ZD07-9. minutes, it can cause irreversible neurological is frequent in the aortic stenosis, in primary and damage. The causes of the syncope are secondary cardiac tumors, in second and third numerous; however, it is necessary to make a degree atrioventricular blocks, in the sinus differential diagnosis with other causes of node disease, cardiac arrhythmias (especially decreased consciousness, which are not ventricular), the cardiac tamponade, the considered syncope, such as the vertebro- primary pulmonary hypertension, the Brugada basilar transient ischemic attacks (TIA), syndrome, the long QT syndrome, but not in metabolic disorders such as hypoglycemia, the mitral stenosis (9-13). hypoxia, poisoning, etc. There are two types of syncope: the syncope of cardiovascular origin The syncope of cardiovascular origin (14-16) is and the neurally - mediated syncope (1-4). frequent (from 3 to 5% of emergencies attended; from 1 to 2% of hospital admissions).

ISSN 2616 - 6097, Rev Peru Investig Salud. 2020; 4(2), april - june 2020, 83-86 ISSN 2616 - 6097, Rev Peru Investig Salud. 2020; 4(2), april - june 2020, 77-82