RESUMO
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.
Assuntos
Disceratose Congênita , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Feminino , Humanos , Criança , Rejeição de Enxerto/prevenção & controle , Doadores não Relacionados , Disceratose Congênita/diagnóstico , Disceratose Congênita/cirurgia , Disceratose Congênita/complicações , Condicionamento Pré-Transplante/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controleRESUMO
A 13-month-old boy with mild hemophilia A presented for strabismus evaluation and was found to have retinal hemorrhages in the right eye, left exotropia, and left total retinal detachment. These findings were attributed to trauma and hemophilia A. Routine blood work for hemophilia A subsequently showed pancytopenia. A bone marrow aspirate showed marked hypocellularity consistent with severe aplastic anemia, and telomere testing revealed very short telomeres. The patient was found to have a TINF2 mutation consistent with a diagnosis of Revesz syndrome, a variant of dyskeratosis congenita. He underwent successful bone marrow transplantation, and on subsequent evaluation was found to have retinal hemorrhages, vessel sclerosis, and cotton wool spots in the right eye associated with peripheral retinal nonperfusion. He underwent retinal laser treatment to the areas of retinal nonperfusion which resulted in stable visual function.
Assuntos
Doenças Ósseas Metabólicas/diagnóstico , Medula Óssea/anormalidades , Descolamento Retiniano/diagnóstico , Adolescente , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/cirurgia , Medula Óssea/cirurgia , Encéfalo/diagnóstico por imagem , Análise Mutacional de DNA , Disceratose Congênita/diagnóstico , Disceratose Congênita/genética , Disceratose Congênita/cirurgia , Humanos , Fotocoagulação a Laser , Imageamento por Ressonância Magnética , Masculino , Mutação , Retina/cirurgia , Descolamento Retiniano/genética , Descolamento Retiniano/cirurgia , Proteínas de Ligação a Telômeros/genéticaRESUMO
Dyskeratosis congenita (DC) is a rare, inherited, bone marrow failure syndrome caused by premature telomere shortening. The classic mucocutaneous triad of clinical features comprises reticulated skin pigmentation, nail dysplasia, and oral leukoplakia. Multiple somatic features, including bone marrow failure, pulmonary fibrosis, and liver disease, are also common. DC significantly increases the risk for malignant transformation, including myelodysplastic syndrome, acute myeloid leukemia, head and neck squamous cell carcinoma, and anogenital cancer. This case report describes a 23-year-old female with malignant transformation of oral leukoplakia to squamous cell carcinoma, demonstrated in a series of biopsies of the same site. Increased surveillance, proper biopsy technique, and a multidisciplinary approach are critical for patients with DC to ensure rapid diagnosis and treatment.
Assuntos
Carcinoma de Células Escamosas/patologia , Transformação Celular Neoplásica/patologia , Disceratose Congênita/patologia , Leucoplasia Oral/patologia , Neoplasias da Língua/patologia , Biópsia , Carcinoma de Células Escamosas/cirurgia , Disceratose Congênita/cirurgia , Feminino , Humanos , Leucoplasia Oral/cirurgia , Neoplasias da Língua/cirurgia , Adulto JovemRESUMO
We describe outcomes after allogeneic transplantation in 34 patients with dyskeratosis congenita who underwent transplantation between 1981 and 2009. The median age at transplantation was 13 years (range, 2 to 35). Approximately 50% of transplantations were from related donors. Bone marrow was the predominant source of stem cells (24 of 34). The day-28 probability of neutrophil recovery was 73% and the day-100 platelet recovery was 72%. The day-100 probability of grade II to IV acute GVHD and the 3-year probability of chronic graft-versus-host disease were 24% and 37%, respectively. The 10-year probability of survival was 30%; 14 patients were alive at last follow-up. Ten deaths occurred within 4 months from transplantation because of graft failure (n = 6) or other transplantation-related complications; 9 of these patients had undergone transplantation from mismatched related or from unrelated donors. Another 10 deaths occurred after 4 months; 6 of them occurred more than 5 years after transplantation, and 4 of these were attributed to pulmonary failure. Transplantation regimen intensity and transplantations from mismatched related or unrelated donors were associated with early mortality. Transplantation of grafts from HLA-matched siblings with cyclophosphamide-containing nonradiation regimens was associated with early low toxicity. Late mortality was attributed mainly to pulmonary complications and likely related to the underlying disease.
Assuntos
Disceratose Congênita/cirurgia , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Disceratose Congênita/terapia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Hematopoietic stem cell transplantation (HSCT) for dyskeratosis congenita (DC) is challenging due to severe treatment-related adverse effects. Development of pulmonary fibrosis or veno-occlusive disease is well described in DC. However, neurological complication after HSCT has not been reported. A 9-year-old Japanese male with DC harboring the TINF2 mutation received reduced-intensity HSCT. Unfortunately, patient developed posterior reversible encephalopathy syndrome-like symptoms plausibly result by combination of thrombotic microangiopathy, graft-versus-host disease, and persistent hypertension and has been persisted mental retardation. Therefore, to decrease risk in DC cases after HSCT, strict control of hypertension, graft-versus-host disease, and thrombotic microangiopathy is required.
Assuntos
Disceratose Congênita/cirurgia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucoencefalopatias/etiologia , Mutação , Proteínas de Ligação a Telômeros/genética , Pré-Escolar , Disceratose Congênita/sangue , Disceratose Congênita/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucoencefalopatias/sangue , Leucoencefalopatias/genética , MasculinoRESUMO
Dyskeratosis congenita (DC) is a rare inherited disorder characterized by bone marrow failure and cancer predisposition. We present a case of a 28-year-old woman with DC who was admitted for hematopoietic stem cell transplantation (HSCT) for aplastic anemia and who developed acute myeloid leukemia with complex genetic karyotype abnormalities including the MLL (11q23) gene, 1q25, and chromosome 8. After transplantation, a monomorphic Epstein-Barr virus (EBV) negative posttransplant-associated lymphoproliferative disorder (PTLD) diffuse large B-cell lymphoma was discovered involving the liver, omental tissue, and peritoneal fluid samples showing additional MLL (11q23) gene abnormalities by fluorescence in situ hybridization. Despite treatment, the patient died of complications associated with transplantation and invasive fungal infection. This case represents the first bona fide documented case of EBV-negative monomorphic PTLD host derived, with MLL gene abnormalities in a patient with DC, and shows another possible mechanism for the development of a therapy-related lymphoid neoplasm after transplantation.
Assuntos
Disceratose Congênita/cirurgia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Complicações Pós-Operatórias/etiologia , Adulto , Disceratose Congênita/complicações , Disceratose Congênita/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/cirurgia , Transtornos Linfoproliferativos/genética , Complicações Pós-Operatórias/genéticaAssuntos
Soro Antilinfocitário/uso terapêutico , Ciclofosfamida/uso terapêutico , Disceratose Congênita/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Irradiação Corporal Total/métodos , Adulto , Soro Antilinfocitário/administração & dosagem , Soro Antilinfocitário/efeitos adversos , Terapia Combinada , Ciclofosfamida/efeitos adversos , Disceratose Congênita/tratamento farmacológico , Disceratose Congênita/cirurgia , Humanos , Masculino , Vidarabina/efeitos adversos , Vidarabina/uso terapêuticoRESUMO
DC is an inherited bone marrow failure syndrome mainly characterized by nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Bone marrow failure is the most common cause of death in patients with DC. Because previous results of HSCT with a myeloablative regimen were disappointing, we used a reduced-intensity conditioning regimen for two patients with classic DC, and one patient with cryptic DC who harbored the TERT mutation. Graft sources included two mismatched-related bone marrow (BM) donors and one unrelated BM donor. Successful engraftment was achieved with few regimen-related toxicities in all patients. They were alive 10, 66, and 72 months after transplantation, respectively. Long-term follow-up is crucial to determine the late effects of our conditioning regimen.
Assuntos
Disceratose Congênita/cirurgia , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Intervalo Livre de Doença , Disceratose Congênita/diagnóstico , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/fisiopatologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Monitorização Fisiológica/métodos , Cuidados Pré-Operatórios/métodos , Medição de Risco , Estudos de Amostragem , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Dyskeratosis congenita (DC) is a rare inherited disorder characterized by the triad of nail dystrophy, mucosal leukoplakia, and reticular pigmentation. Bone marrow failure is the principal cause of early mortality, and stem cell transplantation is the only cure for these patients. However, the results of conventional hematopoietic stem cell transplantation (HSCT) for patients with DC are poor because of the high incidence of transplant-related complications. We describe the successful treatment of a 21-year-old male with DC by nonmyeloablative HSCT from a matched unrelated donor. The gene responsible for the X-linked form of DC was screened and hemizygosity for the mutation Gln31Lys was found, which is consistent with the diagnosis. The conditioning regimen consisted of only fludarabine and antithymocyte globulin. Additionally, a graft-versus-host disease (GVHD) prophylaxis was administered with cyclosporine A (CSA) and mycophenolate mofetil (MMF). The regimen was well tolerated, no severe posttransplantation complications were observed, and engraftment was rapid and complete (granulocytes on day +11 and platelets on day +13). Seven months after HSCT, the patient developed GVHD of the liver after tapering CSA which was successfully treated with prednisolone, CSA, and MMF. At the time of reporting, 3 years after HSCT, the patient remained in good clinical condition with minimal signs of chronic GVHD of the oral mucosa. Thus, we conclude that a low-intensity conditioning regimen might be sufficient to induce permanent engraftment by using matched unrelated donor HSCT in DC patients and may avoid severe organ toxicity. Although allogeneic HSCT in patients with DC will not cure the underlying genetic defect it may significantly prolong survival through effective therapy for hematologic complications.
Assuntos
Soro Antilinfocitário/uso terapêutico , Disceratose Congênita/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Vidarabina/análogos & derivados , Ciclosporina/uso terapêutico , Disceratose Congênita/genética , Disceratose Congênita/cirurgia , Rejeição de Enxerto/prevenção & controle , Doença Enxerto-Hospedeiro/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Injeções Intravenosas , Masculino , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Vidarabina/uso terapêutico , Adulto JovemRESUMO
Dyskeratosis congenita (DC) is a rare disease characterised by bone marrow failure and skin manifestations. Patients with DC may exhibit short stature that is not usually related to growth hormone (GH) deficiency. Replacement treatment with GH should be done cautiously as it can predispose to haematological malignancy. We present a 10-year-old boy with DC and GH deficiency.
Assuntos
Disceratose Congênita/diagnóstico , Transplante de Medula Óssea , Proteínas de Ciclo Celular/genética , Criança , Disceratose Congênita/etiologia , Disceratose Congênita/genética , Disceratose Congênita/cirurgia , Heterozigoto , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
DC is a multisystem bone marrow failure syndrome exhibiting marked clinical and genetic heterogeneity. X-linked, autosomal dominant and autosomal recessive subtypes are recognized. The gene mutated in X-linked DC (DKC1) encodes a highly conserved nucleolar protein called dyskerin. Dyskerin associates with the H/ACA motif class of small nucleolar RNAs in small nucleolar ribonucleoprotein particles that are important in guiding the conversion of uracil to pseudouracil during the maturation of ribosomal RNA. Dyskerin also associates with the TERC, which is important in the maintenance of telomeres. Mutations in TERC have been identified in patients with autosomal dominant DC and in a subset of patients with aplastic anemia and myelodysplasia. Recently, heterozygous mutations in TERT have been found in some patients with autosomal dominant DC and aplastic anemia. Additionally, patients with the severe multisystem disorder, Hoyeraal-Hreidarsson syndrome, have been found to have DKC1 mutations. Collectively, these observations have demonstrated that classical DC, Hoyeraal-Hreidarsson syndrome and a subset of aplastic anemia are due to a primary defect in telomerase. The critical role of telomeres and telomerase in humans is seen in the multisystem abnormalities found in these patients, including the increased incidence of malignancy. As bone marrow failure is the principal cause of death, conventional allografts have been attempted with limited success due to the high rate of pulmonary and endothelial complications. However, outcomes have improved with the use of non-myeloablative protocols, although the follow up is too short to evaluate long term toxicity and the natural course of the disease and it may be that correction of the telomerase defect is essential for the treatment of these patients.
Assuntos
Proteínas de Ciclo Celular/genética , Disceratose Congênita/genética , Disceratose Congênita/cirurgia , Proteínas Nucleares/genética , Transplante de Células-Tronco , Telomerase/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoAssuntos
Antimetabólitos/administração & dosagem , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Disceratose Congênita/cirurgia , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Pré-Escolar , Humanos , Masculino , Transplante HomólogoRESUMO
BACKGROUND: Zinsser-Engman-Cole syndrome (Z.E.C.) is a very rare type of ectodermal dysplasia, inherited in X-linked recessive manner and characterised by poikiloderma, nail dystrophy, lingual leucoplakia, bone marrow hypoplasia, hyperkeratosis and hyperhidrosis of planta and palms, dental anomalies and caries, premature grey hair. PATIENT AND METHODS: We report on a 46-year-old man who presented with occlusion of lacrimal puncta, trichiasis, severe dry eye, recurrent corneal ulceration and perforation, uveitis. HLA typing, flow cytometry of peripheral lymphocytes, bone marrow biopsy, conjunctival biopsy and extensive laboratory evaluation towards autoimmune and infectious diseases were performed. RESULTS: CD4+ T cells fraction was decreased, CD8+ and CD3+ HLA DR+ elevated. The patient was HLA-B27 positive. Laboratory studies revealed increased erythrocyte sedimentation rate and C-reactive protein level, hypochromic and hypoplastic anaemia, negative serum titers of antibodies to Epstein-Barr virus, HIV, HTLV-I, toxoplasma gondii and treponema pallidum, repeated titers to cytomegalovirus, herpes simplex and herpes zoster viruses--IgM negative, IgG positive. Corneal perforation was treated with amniotic membrane transplantation and corneal transplantation. CONCLUSION: The defect in cell-mediated immune mechanisms in Z.E.C. syndrome explains the corneal perforation, sicca syndrome and uveitis, first reported in this syndrome.
Assuntos
Doenças Autoimunes/imunologia , Úlcera da Córnea/imunologia , Disceratose Congênita/imunologia , Ceratoconjuntivite Seca/imunologia , Pan-Uveíte/imunologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/cirurgia , Biópsia , Túnica Conjuntiva/imunologia , Túnica Conjuntiva/patologia , Transplante de Córnea , Úlcera da Córnea/diagnóstico , Úlcera da Córnea/cirurgia , Diagnóstico Diferencial , Disceratose Congênita/diagnóstico , Disceratose Congênita/cirurgia , Antígeno HLA-B27/sangue , Antígenos HLA-DR/sangue , Humanos , Ceratoconjuntivite Seca/diagnóstico , Ceratoconjuntivite Seca/cirurgia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pan-Uveíte/diagnóstico , Pan-Uveíte/cirurgia , Ruptura EspontâneaRESUMO
Familial dyskeratotic comedones is a rare autosomal dominant genodermatosis. In childhood or adolescence disseminated keratotic papules develop and gradually increase in number with time. The isolated papules show a central keratotic plug which tends to recur after extraction. Pruritus and occasional inflammation are the only symptoms. The lesions appear on the extremities, and less frequently on the trunk and the face. About half of the patients have a history of acne vulgaris. The histologic picture is highly characteristic and shows a deep invagination of an acantholytic and dyskeratotic epidermis with prominent cornification. Familial dyskeratotic comedones are generally refractory to any therapy. We report on two sisters with familial dyskeratotic comedones successfully treated by CO2-laser therapy.