Treatment of dyskeratosis congenita with Granulocyte Colony-Stimulating Factor and Erythropoietin

Aplastic anaemia is both frequent and difficult to manage in patients with dyskeratosis congenita (DC). We recently treated a 23-year-old male for a year with granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Ep), with an excellent neutrophil response, and a transient effect on haemoglobin levels. G-CSF alone or combined with other cytokines may provide at least a partial effect in pancytopenic patients with DC.     

Dyskeratosis congenita: Unusual onset with isolated neutropenia at an early age

A 3.5 year old male patient with dyskeratosis congenita (DC) presented at the age of 13 months with isolated neutropenia preceding characteristic skin findings. The average absolute neutrophil count of 500/mm³ persisted without the presence of anemia or thrombocytopenia during the follow up. Neutropenia responded to granulocyte-colony stimulating factor (G-CSF) at a dose of 10 μg/kg per day. Immunologic findings were normal as was the chromosomal stability and sister chromatid exchange.     

Molecular basis of telomere syndrome caused by CTC1 mutations

Mutations in CTC1 lead to the telomere syndromes Coats Plus and dyskeratosis congenita (DC), but the molecular mechanisms involved remain unknown. CTC1 forms with STN1 and TEN1 a trimeric complex termed CST, which binds ssDNA, promotes telomere DNA synthesis, and inhibits telomerase-mediated telomere elongation. Here we identify CTC1 disease mutations that disrupt CST complex formation, the physical interaction with DNA polymerase α-primase (polα-primase), telomeric ssDNA binding in vitro, accumulation in the nucleus, and/or telomere association in vivo. While having diverse molecular defects, CTC1 mutations commonly lead to the accumulation of internal single-stranded gaps of telomeric DNA, suggesting telomere DNA replication defects as a primary cause of the disease. Strikingly, mutations in CTC1 may also unleash telomerase repression and telomere length control. Hence, the telomere defect initiated by CTC1 mutations is distinct from the telomerase insufficiencies seen in classical forms of telomere syndromes, which cause short telomeres due to reduced maintenance of distal telomeric ends by telomerase. Our analysis provides molecular evidence that CST collaborates with DNA polα-primase to promote faithful telomere DNA replication.     

Dyskeratosis congenita: clinical report and review of the literature

Abstract:  Dyskeratosis congenita (DKC) is an inherited disorder that usually presents in males, consisting of the triad of leukoplakia of the mucous membranes, nails dystrophy and skin pigmentation. Oral and dental abnormalities may also be present. Most cases are X-linked autosomal dominant, but recessive forms have also been reported. This study describes herein a case in which the classic triad of signs was present, along with the development of leukoplakia in the buccal mucosa. Our patient, a 25-year-old man, presented with several characteristic systemic features of this condition, together with the following oral features: hypodontia, delayed dental eruption, short blunt roots, extensive caries, gingival inflammation and bleeding, loss of alveolar bone and buccal mucosa with leukoplakia and irregular ulcers. The patient was given full preventive care. The primary teeth were extracted under local anaesthesia. After establishing optimal oral health, oral hygiene instructions were given to the patient and he was rehabilitated with fixed and removable partial denture. Prosthetic treatments were carried out after establishing optimal oral health. This treatment option appears beneficial in this patient, resulting in rehabilitation of occlusion and less mechanical irritation to the oral mucosa.     

Diverse Pathological Findings of Interstitial Lung Disease in a Patient with Dyskeratosis Congenita

A 42-year-old man with a history of surgery for tongue cancer was referred to our hospital due to an abnormal chest shadow. High-resolution computed tomography showed lower lobe reticulation. A physical examination revealed nail dystrophy, oral leukoplakia, and reticulated hypopigmentation. Lung biopsy revealed subpleural and perilobular fibrosis, suggestive of usual interstitial pneumonia. However, multiple pathological findings, including homogenous fibrosis and cell infiltration in the centrilobular region, which were compatible with nonspecific interstitial pneumonia, and bronchiolitis were also seen. Genetic testing showed a hemizygous missense mutation in the DKC1 gene, and the patient was diagnosed with dyskeratosis congenita. Although anti-fibrotic therapy was initiated, the patient''s respiratory function has continued to decrease.     

Unusual complications after bone marrow transplantation for dyskeratosis congenita

Dyskeratosis congenita (DC) is a rare inherited disorder often associated with aplastic anaemia. We report the cases of five boys transplanted with an HLA-identical related donor for severe aplastic anaemia (SAA) associated to DC; in all cases successful engraftment was observed. Three patients died 2–8 years after bone marrow transplantation (BMT) with signs of endothelial cell damage syndrome (kidney microangiopathy and liver veno-occlusive disease). Another boy died 1 year after BMT from Evans syndrome and invasive aspergillosis. One boy currently presents anaemia, polyarthritis of unknown origin, pulmonary fibrosis and gut malabsorption 7.5 years after BMT. SAA associated with DC can be successfully treated by allogeneic BMT. However, these early and late complications observed are very unusual after BMT and probably reflect the association of transplanted-related factors, evolution of the underlying disease, and increased sensitivity of endothelial cells. Modified conditioning approaches, advances in supportive care and surveillance of these unusual complications offer the possibility of improved outcome for these patients.     

Squamous cell carcinoma of the tongue in 5-year-old girl with dyskeratosis congenita

Dyskeratosis congenita is a rare inherited bone marrow failure syndrome with three distinct clinical features: nail dystrophy, reticular skin pigmentation, and oral leukoplakia. The case of a 5-year-old female patient diagnosed with squamous cell carcinoma of the tongue is reported here. An autosomal dominant type 3 TINF2 mutation subsequently confirmed the diagnosis of dyskeratosis congenita. The traditional tongue cancer treatment was adapted for this young patient. While the tongue cancer lesions and leukoplakia were removed, the deep margins were minimized to preserve the tongue muscles and flap surgery was avoided. Additional conservative measures were applied to suppress new leukoplakia lesions.     

A novel DKC1 mutation,severe combined immunodeficiency (T+B-NK- SCID) and bone marrow transplantation in an infant with Hoyeraal-Hreidarsson syndrome

X-linked Hoyeraal-Hreidarsson syndrome (XL-HHS) is the severe infantile variant of X-linked dyskeratosis congenita (XL-DC) and both are due to mutations in the DKC1 gene within Xq28. We report a novel missense mutation in DKC1 exon 3 (T113-->C, Ile38Thr) in a Sardinian infant with XL-HHS in whom the disease was characterized by 'T+B-NK-' severe combined immunodeficiency and bone marrow failure. He underwent sibling bone marrow transplantation using a conditioning regimen (fludarabine, rabbit antithymocyte globulin, low-dose melphalan) selected according to the HHS/DC phenotype. This was associated with low toxicity, prompt engraftment with adequate immune reconstitution and full donor haemopoiesis.     

Response to androgen therapy in patients with dyskeratosis congenita

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome and telomere biology disorder characterized by dysplastic nails, reticular skin pigmentation and oral leucoplakia. Androgens are a standard therapeutic option for bone marrow failure in those patients with DC who are unable to undergo haematopoietic stem cell transplantation, but there are no systematic data on its use in those patients. We evaluated haematological response and side effects of androgen therapy in 16 patients with DC in our observational cohort study. Untreated DC patients served as controls. Seventy percent of treated DC patients had a haematological response with red blood cell and/or platelet transfusion independence. The expected age‐related decline in telomere length was noted in androgen‐treated patients. All treated DC patients had at least one significant lipid abnormality. Additional treatment‐related findings included a significant decrease in thyroid binding globulin, accelerated growth in pre‐pubertal children and splenic peliosis in two patients. Liver enzymes were elevated in both androgen‐treated and untreated patients, suggesting underlying liver involvement in DC. This study suggests that androgen therapy can be effectively used to treat bone marrow failure in DC, but that side effects need to be closely monitored.