Dyskeratosis congenita associated with a novel missense variant in TERT: Approach for the dermatologists.

Dyskeratosis congenita (DC) is a telomeropathy presenting diagnostic and therapeutic challenges across multiple specialties; yet, subtle dermatological signs enable early detection, altering patient prognosis. A specific DC genetic sequencing was performed according to the clinical criteria of our patient in study. Subsequently, cross-checked information in the main genetic databases was carried out. Additionally, an extensive review of the literature was made to organize the main dermatological aspects in DC. We report a novel variant of DC. Additionally, we share 10 useful and practical messages for dermatologists and any specialist caring for this group of patients.

Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study.

BACKGROUND: Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes. OBJECTIVE: To describe the outcome of TBD patients transplanted for marrow failure. STUDY DESIGN: This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019. RESULTS: The median age at transplantation was 14 years (range, 3-30 years). Most patients received a RIC regimen (n = 28) and bone marrow (BM) from an unrelated donor (n = 16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20 days (13-36 days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6 years; 1.4-19 years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p = .05; CI = 95%). Overall, 15 patients died after HCT, most of them (n = 11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD. CONCLUSIONS: Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.

Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico.

Introduction: The inherited bone marrow failure syndromes (IBMFSs) are a group of rare disorders characterized by bone marrow failure (BMF), physical abnormalities, and an increased risk of neoplasia. The National Institute of Pediatrics (INP) is a major medical institution in Mexico, where patients with BMF receive a complete approach that includes paraclinical tests. Readily recognizable features, such as the hematological and distinctive physical phenotypes, identified by clinical dysmorphologists, remain crucial for the diagnosis and management of these patients, particularly in circumstances where next-generation sequencing (NGS) is not easily available. Here, we describe a group of Mexican patients with a high clinical suspicion of an IBMFS. Methods: We performed a systematic retrospective analysis of the medical records of patients who had a high IBMFS suspicion at our institution from January 2018 to July 2021. An initial assessment included first ruling out acquired causes of BMF by the Hematology Department and referral of the patient to the Department of Human Genetics for physical examination to search for specific phenotypes suggesting an IBMFS. Patients with high suspicion of having an IBMFS were classified into two main groups: 1) specific IBMFS, including dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome (SDS), thrombocytopenia with absent radii (TAR), and severe congenital neutropenia (SCN); 2) undefined IBMFS (UI). Results: We established a high suspicion of having an IBMFS in 48 patients. At initial evaluation, the most common hematologic features were bicytopenia (20%) and aplastic anemia (16%); three patients received hematopoietic stem cell transplantation. Among patients with a suspicion of an IBMFS, the most common physical abnormality was minor craniofacial features in 83% of patients and neurodevelopmental disorders in 52%. The specific suspicions that we built were DBA (31%), SDS (18%), DC (14%), TAR (4%), and SCN (4%), whereas 27% of cases remained as undefined IBMFS. SDS, TAR, and SCN were more commonly suspected at an earlier age (<1 year), followed by DBA (2 years) and DC (5 years). Conclusions: Thorough examination of reported clinical data allowed us to highly suspect a specific IBMFS in approximately 70% of patients; however, an important number of patients remained with suspicion of an undefined IBMFS. Implementation of NGS and telomere length measurement are forthcoming measures to improve IBMFS diagnosis in Mexico.

Novel TINF2 gene mutation in dyskeratosis congenita with extremely short telomeres: A case report.

BACKGROUND: Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia, nail dystrophy, and abnormal skin pigmentation. The genetics of dyskeratosis congenita include mutations in genes involved in telomere maintenance, including TINF2. CASE SUMMARY: Here, we report a female patient who presented thrombocytopenia, anemia, reticulate hyperpigmentation, dystrophy in fingernails and toenails, and leukoplakia on the tongue. A histopathological study of the skin showed dyskeratocytes; however, a bone marrow biopsy revealed normal cell morphology. The patient was diagnosed with dyskeratosis congenita, but her family history did not reveal significant antecedents. Whole-exome sequencing showed a novel heterozygous punctual mutation in exon 6 from the TINF2 gene, namely, NM_001099274.1:c.854delp.(Val285Alafs*32). An analysis of telomere length showed short telomeres relative to the patient's age. CONCLUSION: The disease in this patient was caused by a germline novel mutation of TINF2 in one of her parents.

Recent advances in understanding telomere diseases.

Germline genetic defects impairing telomere length maintenance may result in severe medical conditions in humans, from aplastic anemia and myeloid neoplasms to interstitial lung disease and liver cirrhosis, from childhood (dyskeratosis congenita) to old age (pulmonary fibrosis). The molecular mechanisms underlying these clinically distinct disorders are pathologically excessive telomere erosion, limiting cell proliferation and differentiation, tissue regeneration, and increasing genomic instability. Recent findings also indicate that telomere shortening imbalances stem cell fate and is associated with an abnormal inflammatory response and the senescent-associated secretory phenotype. Bone marrow failure is the most common phenotype in patients with telomere diseases. Pulmonary fibrosis is a typical phenotype in older patients, and disease progression appears faster than in pulmonary fibrosis not associated with telomeropathies. Liver cirrhosis may present in isolation or in combination with other phenotypes. Diagnosis is based on clinical suspicion and may be confirmed by telomere length measurement and genetic testing. Next-generation sequencing (NGS) techniques have improved genetic testing; today, at least 16 genes have been implicated in telomeropathies. NGS also allows tracking of clonal hematopoiesis and malignant transformation. Patients with telomere diseases are at high risk of developing cancers, including myeloid neoplasms and head and neck cancer. However, treatment options are still limited. Transplant modalities (bone marrow, lung, and liver) may be definitive to the respective organ involvement but limited by donor availability, comorbidities, and impact on other affected organs. In clinical trials, androgens elongate telomeres of peripheral blood leukocytes and improve hematopoiesis. Further understanding of how telomere erosion impairs organ function and how somatic mutations evolve in the hematopoietic tissue may help develop new strategies to treat and prevent telomere diseases.

Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability.

Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.

Dyskeratosis congenita and a rare brain abscess.

Dyskeratosis congenita is a rare inheritable disease which causes peculiar dermatological features and bone marrow failure with an increased risk of severe infections and neoplasia. Actinomyces spp. is part of the oral cavity flora. Invasive infections are mostly seen in immunocompromised hosts. We report a case of a rare central nervous infection and an underling inheritable disease.

La disqueratosis congénita es una enfermedad hereditaria, caracterizada por alteraciones cutáneas y aplasia medular. La principal causa de muerte son las infecciones y el desarrollo de neoplasias. Actinomices spp. son patógenos comensales de la cavidad oral y el tracto urinario, que en raras ocasiones suelen causar infecciones invasivas en el ser humano. Suelen ser más frecuentes en pacientes inmunocomprometidos o con mala higiene dental. Presentamos el caso de una lesión ocupante de espacio a nivel del sistema nervioso central con una inmunodeficiencia heredable.

Dyskeratosis congenita and a rare brain abscess / Disqueratosis congénita y absceso del sistema nervioso central

Abstract Dyskeratosis congenita is a rare inheritable disease which causes peculiar dermatological features and bone marrow failure with an increased risk of severe infections and neoplasia. Actinomyces spp. is part of the oral cavity flora. Invasive infections are mostly seen in immunocompromised hosts. We report a case of a rare central nervous infection and an underling inheritable disease.

Resumen La disqueratosis congénita es una enfermedad hereditaria, caracterizada por alteraciones cutáneas y aplasia medular. La principal causa de muerte son las infecciones y el desarrollo de neoplasias. Actinomices spp. son patógenos comensales de la cavidad oral y el tracto urinario, que en raras ocasiones suelen causar infecciones invasivas en el ser humano. Suelen ser más frecuentes en pacientes inmunocomprometidos o con mala higiene dental. Presentamos el caso de una lesión ocupante de espacio a nivel del sistema nervioso central con una inmuno deficiencia heredable.

Gastrointestinal Hemorrhage: A Manifestation of the Telomere Biology Disorders.

OBJECTIVE: To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. STUDY DESIGN: Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record. RESULTS: Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor. CONCLUSIONS: GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.

Dyskeratosis congenita.

Dyskeratosis congenita (DC) is a genetic syndrome with progressive multisystem involvement classically characterized by the clinical triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. Frequent complications are bone marrow failure, increased rate of malignancy, lung and liver diseases. DC results from an anomalous progressive shortening of telomeres resulting in DNA replication problems inducing replicative senescence. We report a death due to DC in a 16-year-old male with bone marrow failure and multiple organ dysfunction. At autopsy, nail dystrophy and skin hypopigmentation were observed. Gross and microscopic examinations of the internal organs showed cardiac hypertrophy, multiple lung consolidations and prominent interstitial fibrosis, liver cirrhosis, and fibrosis. Multiple foci of extramedullary hematopoiesis were identified, including on the epidural surface of the dura, that is an infrequent location, mimicking a focal area of epidural hemorrhage. Only a few autopsy studies about DC are reported in the literature. Further research should be done to understand the pathophysiology of the disease and its complications.

Dyskeratosis congenita

Dyskeratosis congenita (DC) is a genetic syndrome with progressive multisystem involvement classically characterized by the clinical triad of oral leukoplakia, nail dystrophy, and reticular hyperpigmentation. Frequent complications are bone marrow failure, increased rate of malignancy, lung and liver diseases. DC results from an anomalous progressive shortening of telomeres resulting in DNA replication problems inducing replicative senescence. We report a death due to DC in a 16-year-old male with bone marrow failure and multiple organ dysfunction. At autopsy, nail dystrophy and skin hypopigmentation were observed. Gross and microscopic examinations of the internal organs showed cardiac hypertrophy, multiple lung consolidations and prominent interstitial fibrosis, liver cirrhosis, and fibrosis. Multiple foci of extramedullary hematopoiesis were identified, including on the epidural surface of the dura, that is an infrequent location, mimicking a focal area of epidural hemorrhage. Only a few autopsy studies about DC are reported in the literature. Further research should be done to understand the pathophysiology of the disease and its complications.

Telomere dynamics and hematopoietic differentiation of human DKC1-mutant induced pluripotent stem cells.

Telomeropathies are a group of phenotypically heterogeneous diseases molecularly unified by pathogenic mutations in telomere-maintenance genes causing critically short telomeres. X-linked dyskeratosis congenita (DC), the prototypical telomere disease, manifested with ectodermal dysplasia, cancer predisposition, and severe bone marrow failure, is caused by mutations in DKC1, encoding a protein responsible for telomerase holoenzyme complex stability. To investigate the effects of pathogenic DKC1 mutations on telomere repair and hematopoietic development, we derived induced pluripotent stem cells (iPSCs) from fibroblasts of a DC patient carrying the most frequent mutation: DKC1 p.A353V. Telomeres eroded immediately after reprogramming in DKC1-mutant iPSCs but stabilized in later passages. The telomerase activity of mutant iPSCs was comparable to that observed in human embryonic stem cells, and no evidence of alternative lengthening of telomere pathways was detected. Hematopoietic differentiation was carried out in DKC1-mutant iPSC clones that resulted in increased capacity to generate hematopoietic colony-forming units compared to controls. Our study indicates that telomerase-dependent telomere maintenance is defective in pluripotent stem cells harboring DKC1 mutation and unable to elongate telomeres, but sufficient to maintain cell proliferation and self-renewal, as well as to support the primitive hematopoiesis, the program that is recapitulated with our differentiation protocol.

Disceratose congênita - relato de caso e revisão de literatura / Dyskeratosis congenita - case report and literature review

A Disceratose Congênita (DC) é uma síndrome hereditária rara que exibe marcada heterogeneidade clínica e genética, constituindo-se em anormalidades cutaneomucosas, falência medular e predisposição ao câncer. Esta é caracterizada pela tríade de pigmentação reticulada da pele, distrofia ungueal e leucoplasia em mucosas. Alterações dentárias, gastrintestinais, geniturinárias, neurológicas, oftalmológicas, pulmonares e esqueléticas associadas têm sido relatadas. A falência medular é a principal causa de morte precoce e também é descrita predisposição para doenças malignas. Afeta principalmente homens e, reconhecem-se formas recessivas ligadas ao X, autossômicas dominantes e recessivas. Relata-se o caso de um paciente de 40 anos, sexo masculino, que há 7 evolui com quadro de anemia e necessidades transfusionais (sanguíneas). Investigadas causas hemofílica e carencial sem êxito. Mielograma com normocelularidade das linhagens; solicitada biópsia de medula óssea por suspeita de Disceratose Congênita, tendo em vista sintomatologia com presença da tríade da Disceratose Congênita: leucoplasia mucosa, distrofia ungueal, e áreas de hiperpigmentação reticular. Paciente progride sob acompanhamento no serviço hematológico do Hemocentro do Pará. Em função da raridade da doença, pouco mais de 500 casos relatados no mundo, da dificuldade de se chegar ao seu diagnóstico, e de sua gravidade, é de fundamental importância a difusão do conhecimento e ratifica-se a necessidade do acompanhamento médico multidisciplinar, de modo a permitir diagnóstico e tratamento precoce das possíveis complicações.

Dyskeratosis Congenita (DC) is a rare hereditary syndrome that shows marked clinical and genetic heterogeneity, like mucocutaneous abnormalities, bone marrow failure and predisposition to cancer. Dyskeratosis congenita triad is: abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia. Dental, gastrointestinal, genitourinary, neurological, ophthalmic, pulmonary and skeletal disorders have been reported. The leading cause of early death and an additional predisposition to malignancy is bone marrow failure. Dyskeratosis congenita mainly affects men and recessive X-linked, autosomal dominant and recessive forms are recognized. We report the case of a 40-year-old male, 7 years evolving symptoms of anemia and transfusion requirements. Unsuccessfully research by deficiency causes and hemophilia were done. Normal cellular lineages myelogram. Patient progresses under supervision of Hemocenter of Pará (HEMOPA). Depending on the rarity of the disease, little more than 500 cases reported worldwide, the difficulty of arriving at a diagnosis, and its severity, is crucial to spreading knowledge and it confirms the need for a multidisciplinary approach, the to enable early diagnosis and treatment of possible complications.

Telomere dysfunction and hematologic disorders.

Aplastic anemia is a disease in which the hematopoietic stem cell fails to adequately produce peripheral blood cells, causing pancytopenia. In some cases of acquired aplastic anemia and in inherited type of aplastic anemia, dyskeratosis congenita, telomere biology gene mutations and telomere shortening are etiologic. Telomere erosion hampers the ability of hematopoietic stem and progenitor cells to adequately replicate, clinically resulting in bone marrow failure. Additionally, telomerase mutations and short telomeres are genetic risk factors for the development of some hematologic cancers, including myelodysplastic syndrome, acute myeloid leukemia, and chronic lymphocytic leukemia.

Vohwinkel syndrome, ichthyosiform variant - by Camisa - Case report / Sindrome de Vohwinkel, variante ictiosiforme - de Camisa - Relato de caso

Vohwinkel syndrome or keratoderma hereditaria mutilans is a rare autosomal dominant palmoplantar keratosis, which manifests in infants and becomes more evident in adulthood. Its mode of inheritance is autosomal dominant with mutation in loricrin and Connexin 26 genes. Patients with this mutation present hyperkeratosis of the palms and soles, constricting bands of the digits, usually on the fifth, and starfish-shaped hyperkeratosis on the dorsal aspects of the hands and feet. The disease mostly occurs in white women, where constricting fibrous bands appear on the digits and can lead to progressive strangulation and auto-amputation (pseudo-ain-hum).The authors report a rare case of a patient with a clinical ichthyosiform variant of Vohwinkel syndrome.

A síndrome de Vohwinkel ou queratodermia hereditária mutilante é uma queratose palmo-plantar rara, autossômica dominante, que se manifesta em crianças e se torna mais evidente na vida adulta. Seu modo de herança é autossômica dominante com mutação na loricrina e no gen da Conexina 26. Os pacientes com esta mutação apresentam hiperqueratose das palmas das mãos e plantas dos pés, com bandas constritivas dos dígitos, normalmente no quinto dedo e hiperqueratose em forma de estrela do mar nas regiões dorsais das mãos e dos pés. A doença ocorre principalmente em mulheres brancas, onde as bandas constritivas fibrosas aparecerem nos dígitos e podem levar ao estrangulamento progressivo e auto-amputação (pseudo-ainhum).Os autores relatam o caso de uma variante ictiosiforme da síndrome de Vohwinkel.

Disqueratosis congénita ligada al cromosoma X / X-linked congenital dyskeratosis

La disqueratosis congénita es una genodermatosis muy poco frecuente, existiendo aproximadamente 180 casos reportados. Objetivo: Presentar el caso de un paciente de sexo masculino en quien se sospechó el diagnóstico basado en la presentación clínica, confirmado posteriormente mediante estudio molecular. Caso clínico: Escolar de sexo masculino con antecedentes de anemia refractaria a tratamiento e infecciones bacterianas severas, que se presentó clínicamente con hiperpigmentación cutánea reticular, distrofia ungueal, leucoplaquia y falla medular. En el estudio molecular se detectó una mutación del gen DKC1 que determina una sustitución aminoacídica en la posición 353 de Alanina por Valina. Discusión: La disqueratosis congénita es un desorden genético multisistémico, muy poco frecuente. Clínicamente se caracteriza por la presencia de hiperpigmentación cutánea de tipo reticular, distrofia ungueal, leucoplaquia de la mucosa oral y pancitopenia progresiva. La mutación detectada en este caso es una causa importante de Disqueratosis congénita en el mundo.

Dyskeratosis congenita is a rare genetic disorder with approximately 180 cases reported in the literature. Objective: To present the case of a boy, in whom the diagnosis was clinically suspected and later confirmed by molecular analysis of the Dyskerin gene. Clinical Case: A school age boy with a history of anemia resistant to treatment, and severe bacterial infections, who presented with reticulated pigmentation of the skin, nail dystrophy, oral leukoplakia and progressive pancitopenia. Molecular analysis revealed a mutation in the DKC1 gene, that results in an aminoacid change from alanine to valine. Conclusion: Dyskeratosis congenita is a rare inherited disease characterised by cutaneous reticulated hyperpigmentation, nail dystrophy, oral leukoplakia and progressive pancytopenia. The mutation detected in this patient is an important cause of dyskeratosis congenita worldwide.