Currently there is no curative treatment for DC. The variation in presentation makes it difficult to treat, with bone marrow failure/immunodeficiency being the main cause of premature mortality. Use of the anabolic steroid oxymetholone and haematopoietic growth factors (such as erythropoietin, granulocyte macrophage colony-stimulating factor and granulocyte colony-stimulating factor (Erduran et al, 2003
) can produce improvement in the haematopoietic function. Although the mechanism of action of oxymetholone is not well understood, it is thought to function by promoting the growth of haematopoietic progenitors indirectly through the effect of cytokine production and by supporting haemopoietic production in times of stress (Beran et al, 1982
; Kim et al, 2005
; Hosseinimehr et al, 2006
). It has been found that approximately two thirds of patients with DC will respond to oxymetholone, in some cases the responses can last several years and involve all lineages. Patients with DC can respond to a dose of 0·5 mg oxymetholone/kg/d and this can be increased, if necessary to 2–5 mg/kg/d (I. Dokal, unpublished observation). It is important to monitor for side effects (e.g. liver toxicity). It is possible to maintain reasonable blood counts by this approach in many patients.
The only long term cure for the haemopoietic abnormalities is allogeneic haematopoietic stem cell transplantation, but this is not without risk. There is still significant mortality associated with bone marrow transplants for DC patients when compared with other bone marrow failure syndromes. One of the main reasons for this is the high level of pulmonary/vascular complications that present in these patients probably as a result of the underlying telomere defect. The conditioning regimen appears to have an impact on patient survival. The standard myeloablative conditioning regimes are associated with frequent and severe adverse effects, such as lung fibrosis, interstitial pneumonia and veno-occlusive disease. Recently, the adoption of non-myeloablative fludarabine based protocols (also known as reduced intensity conditioning: RIC) has allowed for successful engraftment in some patients with fewer complications and lower toxicity (de la Fuente & Dokal, 2007
). The long-term survival however is unknown at present but the initial response is encouraging as a more effective treatment for DC. Of the 30 patients with DC who have undergone stem cell transplantation, 9 patients received RIC and the remaining 21 underwent conventional transplantation. Only 2/9 RIC patients have died whereas 15 of 21 patients who received conventional therapy died (Ostronoff et al, 2007
). A recent case of an unrelated cord transplant has been described, again using the fludarabine-based reduced-intensity conditioning regime in a girl with HH (Coman et al, 2008
). When this study was published the patient was still alive 37 months post-transplant and is believed to be only the third HH patient to receive a bone marrow transplant. There are very few reports in the literature of stem cell transplantation using unrelated donors; of the four cases reported; three received a myeloablative transplant and all three died. The remaining case described by Coman et al
survived using the less severe RIC regime (Ostronoff et al, 2007
; Coman et al, 2008
). Further ongoing studies will be able to give a more accurate indication of disease-free survival rates and transplant-related mortality in both patients with DC and related syndromes such as HH.
DC has been accepted as being a haematological disease due to the high prevalence of bone marrow failure seen in patient groups. What has become more obvious over the years is how wide the spectrum of disorders associated with DC extends into other disease types. DC can be seen as an aging disorder as patients have increasingly short telomeres, often present with premature grey hair and have increased risk of osteoporosis and dental loss. At the other end of the age spectrum it is a developmental disorder due to microcephaly, intrauterine growth retardation, learning difficulties and developmental/mental retardation. It is also a cancer syndrome because of the increased risk of malignancy (haematological, squamous cell carcinomas of the skin and gastrointestinal tract and carcinomas of the larynx bronchus and tongue) particularly after the third decade (Baykal et al, 2003
). It is now becoming more apparent that DC can be identified in a dental cohort. The oral phenotype of DC is characterised by leucoplakia, decreased root/crown ratios and mild taurodontism. From a clinical view point a diagnosis of DC or other bone marrow failure syndromes should be considered if a young patient presents with leucoplakia, particularly in those with no history of tobacco use (Auluck, 2007
; Atkinson et al, 2008
). Treatment of these DC complications remains unsatisfactory and will be a challenge for the future. Equally it will be important to establish whether treatments aimed at the restoration of telomere length (as discussed above), have any therapeutic benefit in DC and related haematological disorders.
The expansion of diseases that are now associated with DC has changed our view of what exactly DC is. As stated earlier we need to move away from the very rigid initial diagnostic criteria of the presence of the mucocutaneous triad of skin pigmentation nail dystrophy and oral leucoplakia. In the absence of an internationally accepted diagnosis the best criteria still appears to be that of Vulliamy et al (2006)
, i.e. the presentation of one or more of the mucocutaneous features in combination with hypoplastic bone marrow and two or more of the other somatic features known to occur in DC (such as hair loss, abnormal dentition, malignancy, pulmonary disease, short stature, liver disease, developmental delay etc). As shown in , there is a spectrum of diseases that are all related by their causative mutation and shared pathology of defective telomere maintenance. It is apparent that they are not all pure DC but it is important for clinicians to be aware of the overlap between the similar diseases, particularly when considering therapy options. Defining DC in terms of telomere length can also be misleading. Although in general most patients with classical DC do have significantly shortened telomeres compared with age-matched controls, there are some with telomere lengths within the normal range, so these patients would be incorrectly diagnosed. Equally, in family studies, asymptomatic individuals have been identified to have short telomeres and it remains unclear how they will develop overt disease features. One of the main outstanding issues is the number of patients even with classical DC in whom the genetic mutation is still unknown. Presentation cannot always give the answer as there are many examples where the index case has died at a very young age and the diagnosis of DC has only been made when a subsequent member of the family survived long enough for the more characteristic features to become apparent.