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.

Integrated proteogenomic analysis for inherited bone marrow failure syndrome.

Recent advances in in-depth data-independent acquisition proteomic analysis have enabled comprehensive quantitative analysis of >10,000 proteins. Herein, an integrated proteogenomic analysis for inherited bone marrow failure syndrome (IBMFS) was performed to reveal their biological features and to develop a proteomic-based diagnostic assay in the discovery cohort; dyskeratosis congenita (n = 12), Fanconi anemia (n = 11), Diamond-Blackfan anemia (DBA, n = 9), Shwachman-Diamond syndrome (SDS, n = 6), ADH5/ALDH2 deficiency (n = 4), and other IBMFS (n = 18). Unsupervised proteomic clustering identified eight independent clusters (C1-C8), with the ribosomal pathway specifically downregulated in C1 and C2, enriched for DBA and SDS, respectively. Six patients with SDS had significantly decreased SBDS protein expression, with two of these not diagnosed by DNA sequencing alone. Four patients with ADH5/ALDH2 deficiency showed significantly reduced ADH5 protein expression. To perform a large-scale rapid IBMFS screening, targeted proteomic analysis was performed on 417 samples from patients with IBMFS-related hematological disorders (n = 390) and healthy controls (n = 27). SBDS and ADH5 protein expressions were significantly reduced in SDS and ADH5/ALDH2 deficiency, respectively. The clinical application of this first integrated proteogenomic analysis would be useful for the diagnosis and screening of IBMFS, where appropriate clinical screening tests are lacking.

Telomere biology disorders may manifest as common variable immunodeficiency (CVID).

Telomere biology disorders (TBD) are caused by germline pathogenic variants in genes related to telomere maintenance and are characterized by critically short telomeres. In contrast to classical dyskeratosis congenita (DC), which is typically diagnosed in infancy, adult or late onset TBD frequently lack the typical DC triad and rather show variable organ manifestations and a cryptic disease course, thus complicating its diagnosis. Common variable immunodeficiency (CVID), on the other hand, is a primary antibody deficiency (PAD) syndrome. PADs are a heterogenous group of diseases characterized by hypogammaglobulinemia which occurs due to dysfunctional B lymphocytes and additional autoimmune and autoinflammatory complications. Genetic screening reveals a monogenic cause in a subset of CVID patients (15-35%). In our study, we screened the exomes of 491 CVID patients for the occurrence of TBD-related variants in 13 genes encoding for telomere/telomerase-associated proteins, which had previously been linked to the disease. We found 110/491 patients (22%) carrying 91 rare candidate variants in these 13 genes. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we classified two variants as benign, two as likely benign, 64 as variants of uncertain significance (VUS), four as likely pathogenic, and one heterozygous variant in an autosomal recessive disease gene as pathogenic. We performed telomere length measurement in 42 of the 110 patients with candidate variants and CVID. Two of these 42 patients showed significantly shorter telomeres compared to controls in both lymphocytes and granulocytes. Following the evaluation of the published literature and the patient's manifestations, we re-classified two VUS as likely pathogenic variants. Thus, 0.5-1% of all CVID patients in our study carry possibly pathogenic variants in telomere/telomerase-associated genes. Our data adds CVID to the broad clinical spectrum of cryptic adult-onset TBD. As the molecular diagnosis greatly impacts patient management and treatment strategies, we advise inclusion of all TBD-associated genes-despite their low prevalence-into the molecular screening of patients with antibody deficiencies.

Bilateral cytomegalovirus retinitis as the presenting feature of Dyskeratosis Congenita.

PURPOSE: To describe a young male with bilateral sequential Cytomegalovirus retinitis (CMVR) as the presenting feature of Dyskeratosis Congenita. CASE REPORT: A 25-year-old human immunodeficiency virus (HIV) negative male developed CMVR in his left eye, while on a three week course of oral valganciclovir therapy for CMV retinitis in his right eye. Systemic examination revealed reticular hypopigmentation of the forearms, dystrophic nails, oral leukoplakia and complete blood counts showed pancytopenia. A diagnosis of Dyskeratosis Congenita was confirmed with genetic testing. CONCLUSION: CMVR in non-HIV individuals should be considered as a harbinger of systemic immunosuppressive conditions. Ophthalmologists may be the first ones to suspect and diagnose congenital immunosuppressive disorders like Dyskeratosis Congenita in these patients.

Successful Second Unrelated Donor Hematopoietic Stem Cell Transplant in a Patient With Dyskeratosis Congenital After First Graft Rejection.

Dyskeratosis congenita is a rare congenital telomeropathy characterized by cutaneous and nail dystrophy, oral leukoplakia, and bone marrow failure. Pulmonary fibrosis and cancers are late manifestations. Allogeneic hematopoietic stem cell transplant represents the only cure for those with bone marrow failure with this disease, but outcomes reported are overall poor, with organ toxicities, graft failure, and graft-versus-host disease as main issues. Although reduced intensity conditioning regimens seem to be related to better outcomes, a standard regimen for dyskeratosis congenita has never been defined. Here, we report a successful long-term outcome of an 8-year-old girl with dyskeratosis congenita who received 2 consecutive allogeneic hematopoietic stem cell transplants from different unrelated donors, because of rejection after the first one, both conditioned with fludarabine-based reduced intensity conditioning regimen. The second transplant was complicated by severe hemorrhagic cystitis and acute grade IV graft-versus-host disease in the early phase and mild chronic graft-versus-host disease and ureteral stenosis in the late phase. This experience confirms that dyskeratosis congenita is at high risk for transplant-related morbidity but that a fludarabine-based reduced intensity conditioning regimen is a safe and feasible option as a preparative regimen, as shown here in a second transplant after first graft rejection. To reduce the risk of graft-versus-host disease, more effective prophylaxis schedules should be chosen in cases of unrelated donor, and haploidentical hematopoietic stem cell transplant with in vitro α/ ß + and CD19+ depletion should be considered.

Severe immunochemotherapy-induced toxicities in a patient with dyskeratosis congenita and literature review.

OBJECTIVES: Dyskeratosis congenita (DC) is a rare inherited disease characterized by the triad of reticulate hyperpigmentation, nail dystrophy and oral leukoplakia. DC patients are considered vulnerable to external pressure, such as immunochemotherapy. There are very few cases reporting severe therapy-induced toxicities in patients with DC. METHODS: A 27-year-old woman was admitted to our hospital with a 4-month history of pancytopenia and a 7-day history of dyspnea with coughing. She was diagnosed with non-Hodgkin's lymphoma 5 months ago. She received immunochemotherapy due to non-Hodgkin's lymphoma but experienced recurrent fever, oral ulcer, pancytopenia, dyspnea and other symptoms during immunochemotherapy. On admission, she experienced an aggravation of respiratory symptoms, recurrent infections and acute heart failure. RESULTS: Laboratory examination confirmed pancytopenia, and chest computed tomography showed interstitial lung disease (ILD). Genetic analysis results confirmed the presence of DC and a TINF2 gene mutation. With continuous supportive and anti-infection treatment, her condition finally stabilized. She was discharged from the hospital after nearly 2 months. DISCUSSION: We reviewed similar cases and found common features that could be useful. However, the reported cases are very limited. More cases and studies are needed. CONCLUSION: These cases indicate that DC patients seem more vulnerable to therapy toxicities; thus, physicians should be careful when treating these patients with chemotherapy drugs or radiation therapy. Reduced-intensity therapy may be considered.

The biology and management of dyskeratosis congenita and related disorders of telomeres.

BACKGROUND: Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer. Studies over the last 25 years have led to the identification of 18 disease genes. These have a principal role in telomere maintenance, and patients usually have very short/abnormal telomeres. The advances have also led to the unification of DC with a number of other diseases, now collectively referred to as the telomeropathies or telomere biology disorders. WHAT IS COVERED: Clinical features, genetics, and biology of the different subtypes. Expert view on diagnosis, treatment of the hematological complications and future. EXPERT VIEW: As these are very pleotropic disorders affecting multiple organs, a high index of suspicion is necessary to make the diagnosis. Telomere length measurement and genetic analysis of the disease genes have become useful diagnostic tools. Although hematological defects can respond to danazol/oxymetholone, the only current curative treatment for these is hematopoietic stem cell transplantation (HSCT) using fludarabine-based conditioning protocols. New therapies are needed where danazol/oxymetholone is ineffective and HSCT is not feasible.

Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita.

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 differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.

Biallelic TERT variant leads to Hoyeraal-Hreidarsson syndrome with additional dyskeratosis congenita findings.

Short telomere syndromes constitute a heterogeneous group of clinical conditions characterized by short telomeres and impaired telomerase activity due to pathogenic variants in the essential telomerase components. Dyskeratosis congenita (DC) is a rare, multisystemic telomere biology disorder characterized by abnormal skin pigmentation, oral leukoplakia and nail dysplasia along with various somatic findings. Hoyeraal-Hreidarsson syndrome (HHS) is generally an autosomal recessively inherited subgroup showing growth retardation, microcephaly, cerebellar hypoplasia and severe immunodeficiency. We here report on a consanguineous family from Turkey, in which a missense variant in the reverse transcriptase domain of the TERT gene segregated with short telomere lengths and was associated with full-blown short telomere syndrome phenotype in the index; and heterogeneous adult-onset manifestations in heterozygous individuals.

Liver Histology in Short Telomere Syndrome: A Case Report and Review of the Literature.

Short telomere syndrome (STS) encompasses a broad family of genetically inherited conditions caused by various mutations in telomerase and other telomere maintenance genes, resulting in premature telomere shortening. STS involves a variety of clinical manifestations, including dyskeratosis congenita, premature achromotrichia, bone marrow failure, immunodeficiency, pulmonary fibrosis and liver disease. Liver histopathologic features in STS patients have not been well characterized. We report a 46-year-old male patient who presented for dyspnea. The patient had a complicated medical history significant for immune thrombocytopenic purpura and splenectomy, recurrent respiratory tract infections, pneumonia, primary immunodeficiency, and severe hepatopulmonary syndrome. He and his brother both developed gray hair by their late 20s. He had a long history of intermittently elevated liver enzymes starting at age 33. These clinical manifestations prompted an evaluation for a possible telomere biology disorder, which revealed the telomere length was critically short and fell at or below the first percentile for age, supporting the diagnosis. The liver biopsy showed marked portal inflammation with interface hepatitis, ductular reaction and frequent foci of lobular inflammation with focal hepatocyte dropout. Hepatocytes around the portal tracts demonstrated ballooning degeneration and occasional Mallory-Denk bodies. A trichrome stain highlighted bridging fibrosis. A literature review shows liver histology is available in only a small number of STS patients, demonstrating a variety of morphologic features. Our case and others suggest liver disease associated with STS exhibits a spectrum of histopathology. Being aware of these features is important for establishing the correct diagnosis of STS which is under recognized.

Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline.

Telomerase extends chromosome ends in somatic and germline stem cells to ensure continued proliferation. Mutations in genes critical for telomerase function result in telomeropathies such as dyskeratosis congenita, frequently resulting in spontaneous bone marrow failure. A dyskeratosis congenita mutation in TPP1 (K170∆) that specifically compromises telomerase recruitment to telomeres is a valuable tool to evaluate telomerase-dependent telomere length maintenance in mice. We used CRISPR-Cas9 to generate a mouse knocked in for the equivalent of the TPP1 K170∆ mutation (TPP1 K82∆) and investigated both its hematopoietic and germline compartments in unprecedented detail. TPP1 K82∆ caused progressive telomere erosion with increasing generation number but did not induce steady-state hematopoietic defects. Strikingly, K82∆ caused mouse infertility, consistent with gross morphological defects in the testis and sperm, the appearance of dysfunctional seminiferous tubules, and a decrease in germ cells. Intriguingly, both TPP1 K82∆ mice and previously characterized telomerase knockout mice show no spontaneous bone marrow failure but rather succumb to infertility at steady-state. We speculate that telomere length maintenance contributes differently to the evolutionary fitness of humans and mice.

Liver Transplant for Management of Hepatic Complications of Dyskeratosis Congenita: A Case Report.

Dyskeratosis congenita, a rare genetic disorder typified by progressive bone marrow failure, is classically characterized by the triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia; however, it is a multisystem disease. Although hepatic involvement occurs in about 7% of patients with dyskeratosis congenita, end-stage liver disease is rare. Treatment of dyskeratosis congenita generally involves hematopoietic stem cell transplant. For patients with hepatic failure, liver transplant can be an option. Here, we describe a case of a patient with dyskeratosis congenita who presented with liver failure and pulmonary failure, precluding him from hematopoietic stem cell transplant. After liver transplant, the patient had significant improvements in pulmonary function and transfusion requirements, allowing the patient to qualify for hematopoietic stem cell transplant. Although hematopoietic stem cell transplant is typically the first step in the management of dyskeratosis congenita, for patients with severe hepatic manifestations of the disease, a liver transplant first approach may result in better disease management.

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.