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Current Opinion in Hematology Nov 2016Dyskeratosis congenita is an inherited bone marrow failure syndrome caused by defects in telomere maintenance. Hematopoietic stem cell transplantation (HSCT) is the only... (Review)
Review
PURPOSE OF REVIEW
Dyskeratosis congenita is an inherited bone marrow failure syndrome caused by defects in telomere maintenance. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure because of dyskeratosis congenita. The present review summarizes the literature with respect to the diagnosis and treatment of patients with dyskeratosis congenita who received HSCT, and discusses the recent progress in the management of dyskeratosis congenita.
RECENT FINDINGS
The recent systematic review of the literature showed poor long-term outcome, with 10-year survival estimates of only 23% in 109 patients with dyskeratosis congenita who received HSCT. Multivariate analysis identified age greater than 20 years at HSCT, HSCT before 2000, and alternative donor source to be poor prognostic markers. HSCT for dyskeratosis congenita is characterized by a marked decline in long-term survival because of late deaths from pulmonary complications. However, a prospective study using danazol showed promising results in gain in telomere length and hematologic responses.
SUMMARY
A recent prospective study may support the recommendation that HSCT is not indicated for patients with dyskeratosis congenita; instead, they should receive androgen, particularly danazol, as a first-line therapy. Another option may be routine use of androgen after HSCT for the prophylaxis of pulmonary fibrosis.
Topics: Combined Modality Therapy; Disease Management; Dyskeratosis Congenita; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome
PubMed: 27607446
DOI: 10.1097/MOH.0000000000000290 -
Biology of Blood and Marrow... Jul 2016Dyskeratosis congenita (DC) is a multisystem disorder, with a disruption in telomere biology leading to very short telomeres underpinning its pathophysiology. Bone... (Review)
Review
Dyskeratosis congenita (DC) is a multisystem disorder, with a disruption in telomere biology leading to very short telomeres underpinning its pathophysiology. Bone marrow failure is a key feature in DC and is the leading cause of mortality. Hematopoietic stem cell transplantation (HSCT) is the only curative option for bone marrow failure in DC; however, small case reports and series have suggested a poor outcome after HSCT. We undertook a systematic review of all reported patients with DC who underwent HSCT to better characterize outcome and to identify factors associated with improved survival. The outcome of 109 patients found in the literature was poor, with 5- and 10-year survival estimates of only 57% and 23%, respectively. Patients transplanted after 2000 had improved early survival, with 5-year survival estimates of 70%; however, longer term survival was similar (28%). Pulmonary disease, infection, and graft failure were the leading causes of death. Prognosis after development of pulmonary disease post-HSCT was poor, with only 4 of 15 patients surviving at last follow-up. Multivariate analysis identified age >20 years at HSCT, HSCT before 2000, and alternate donor source to be poor prognostic markers. Reduced-intensity conditioning was not significantly found to be associated with improved survival. This review shows the poor outcome after HSCT in patients with DC and highlights the need for future collaborative clinical trials and extended follow-up of this rare patient population to define whether changes in therapy will lead to improved survival.
Topics: Bone Marrow Diseases; Cause of Death; Dyskeratosis Congenita; Hematopoietic Stem Cell Transplantation; Humans; Prognosis; Risk Factors; Survival Rate
PubMed: 26968789
DOI: 10.1016/j.bbmt.2016.03.001 -
The Annals of Otology, Rhinology, and... Sep 2022Dyskeratosis congenita (DC) is a progressive congenital disorder that predisposes patients to squamous cell cancers (SCC) of the head and neck. We report a case of a...
OBJECTIVES
Dyskeratosis congenita (DC) is a progressive congenital disorder that predisposes patients to squamous cell cancers (SCC) of the head and neck. We report a case of a patient who underwent primary osteocutaneous free flap for mandibular SCC followed by additional treatments for positive margins and discuss a systematic review on therapeutic management for this patient population.
METHODS
Case report of a 39-year-old male with DC who underwent resection and reconstruction with a fibular free flap for mandible SCC, followed by revision surgery and adjuvant radiotherapy for positive margins. A systematic review was completed afterward with the following terms: "dyskeratosis congenita" AND "oral cancer" OR "head and neck" OR "otolaryngology" on Medline and Web of Science for articles between 1980 and 2021. In total, 12 articles were included that reported on DC and SCC in the head and neck.
RESULTS
Of the case reports that were included in this review, half the patients had recurrence within 1 year of primary treatments. Only 2 patients did not require revision surgery, adjuvant, or salvage therapy. Half of patients that received radiation therapy had severe side effects.
CONCLUSIONS
This is the largest review of DC and SCC in the head and neck. Based off our case report and review, these patients have aggressive disease that often requires multi-modality treatment. Consideration should be taken in regards to reports of side effects with radiation therapy.
Topics: Adult; Carcinoma, Squamous Cell; Epithelial Cells; Free Tissue Flaps; Head and Neck Neoplasms; Humans; Male; Plastic Surgery Procedures
PubMed: 34651516
DOI: 10.1177/00034894211047470 -
BMC Pulmonary Medicine Sep 2021Dyskeratosis congenita (DC) is a rare genetic disorder of poor telomere maintenance. Pulmonary fibrosis (PF) related to DC is rarely reported.
BACKGROUND
Dyskeratosis congenita (DC) is a rare genetic disorder of poor telomere maintenance. Pulmonary fibrosis (PF) related to DC is rarely reported.
CASE PRESENTATION
A 23-year-old student presented with a four-year history of progressive cough and exertional dyspnea. Physical examination was remarkable for typical mucocutaneous abnormalities. Chest computerized tomography scan revealed interstitial fibrosis. Testing of peripheral blood leukocytes confirmed that his telomeres were 30th percentile of age-matched controls. A heterozygous missense mutation located in exon 22 of PARN gene was identified in the patient by whole exome sequencing. The patient refused danazol therapy and lung transplantation, and died of respiratory failure 2 years later. In addition, this case and 26 reported cases of DC-related PF identified through the comprehensive search of PubMed, Web of Science, WANFANG and CNKI were reviewed. Later-onset PF was observed in 11 patients (40.7%). Radiological usual interstitial pneumonia (UIP) pattern or possible UIP pattern was noted only in half of patients. However, histopathological UIP or probable UIP patterns were found in 63.6% of patients. Age at bone marrow failure (BMF) and the frequency of normal to mild thrombocytopenia in later-onset patients was significantly higher than in early-onset patients (p = 0.017 and p = 0.021, respectively). Age at PF and age at BMF in DC patients with TERC/TERT variants was significantly higher than in those with TINF2 variants or DKC1/NHP2 variants (p = 0.004 and p = 0.003, respectively). The patients with TERT/TERC/RTEL1/PARN variants had a significantly better transplant-free survival than those with TINF2 variants or DKC1/NHP2 variants (p < 0.05). Patients who underwent surgical lung biopsy had significantly worse transplant-free survival than those without lung biopsy (p = 0.042). Worse survival was found in patients with immunosuppression therapy than in those without (p = 0.012).
CONCLUSIONS
It is common for DC-associated PF to occur later in life without significant hematological manifestations. Mutations in the genes encoding different components of the telomere maintenance pathway were associated with clinical phenotypes and prognosis. PF caused by DC should be kept in mind by clinicians in the differential diagnosis of patients with unexplained PF and should be excluded before diagnostic surgical lung biopsy is undertaken or empirical immunosuppression therapy is prescribed.
Topics: Cell Cycle Proteins; DNA Helicases; Dyskeratosis Congenita; Fatal Outcome; Humans; Idiopathic Pulmonary Fibrosis; Male; Nuclear Proteins; Telomere-Binding Proteins; Young Adult
PubMed: 34479523
DOI: 10.1186/s12890-021-01645-w -
Frontiers in Medicine 2021Pulmonary fibrosis (PF) is a serious lung disease which can result from known genetic or environmental exposures but is more commonly idiopathic (IPF). In familial PF...
Pulmonary fibrosis (PF) is a serious lung disease which can result from known genetic or environmental exposures but is more commonly idiopathic (IPF). In familial PF (FPF), the majority of identified causal genes play key roles in the maintenance of telomeres, the protective end structures of chromosomes. Recent evidence suggests that short telomeres may also be implicated causally in a significant proportion of idiopathic cases. The possible involvement of herpes viruses in PF disease incidence and progression has been examined for many years, with some studies showing strong, statistically significant associations and others reporting no involvement. Evidence is thus polarized and remains inconclusive. Here we review the reported involvement of herpes viruses in PF in both animals and humans and present a summary of the evidence to date. We also present several possible mechanisms of action of the different herpes viruses in PF pathogenesis, including potential contributions to telomere attrition and cellular senescence. Evidence for antiviral treatment in PF is very limited but suggests a potential benefit. Further work is required to definitely answer the question of whether herpes viruses impact PF disease onset and progression and to enable the possible use of targeted antiviral treatments to improve clinical outcomes.
PubMed: 34368196
DOI: 10.3389/fmed.2021.704222