Dyskeratosis Congenita Treatment & Management

Updated: Jan 27, 2020
  • Author: David T Robles, MD, PhD, FAAD; Chief Editor: William D James, MD  more...
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Treatment

Medical Care

The only long-term, curative treatment option for bone marrow failure in dyskeratosis congenita (DKC) patients is hematopoietic stem cell transplantation (SCT), although long-term outcomes remain poor, with an estimated 10-year survival rate of 23%. [61] Nonmyeloablative hematopoietic SCT conditioning regimens (ie, reduced-intensity conditioning) with fludarabine may offer better outcomes. A 2007 review showed a 22% mortality rate with reduced-intensity conditioning in DKC treatment versus a 71% mortality rate with traditional myeloablative regimens. [62] Similarly, a 2016 study has shown that reduced-intensity conditioning, that is, chemotherapy without radiation for those receiving SCT, has improved overall survival post treatment. [63] The success rate of SCT is limited because of a high prevalence of fatal pulmonary complications, which likely reflect preexisting pulmonary disease in these patients. [64] Drugs that cause pulmonary toxicity (eg, busulfan) and exposure to unnecessary radiation should be avoided in these patients. The best candidates for SCT may be patients with sibling donors and with no preexisting pulmonary disease.

Short-term treatment options for bone marrow failure in patients with DKC include anabolic steroids (eg, oxymetholone), granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin. [65]

Oxymetholone has a 70% response rate, yet adversely affects female patients through its liver toxicity and strong masculinizing adverse effects. [66] An androgen derivative drug that functions similarly to oxymetholone is danazol. This drug has been reported to have good hematological response and a better adverse effect profile for women, although concerns regarding liver toxicity remain. [66] Androgen therapy (eg, danazol) has been recommended as a first-line treatment in DKC patients after hematopoietic SCT for prophylaxis against pulmonary fibrosis. [61]

Approximately 50% of patients experience a temporary increase in blood counts with androgen therapy; the duration of treatment is limited by adverse effects. In addition, reports have described splenic peliosis and rupture in patients treated concomitantly with androgens and granulocyte colony-stimulating factor. [67] One study found that androgen therapy does not produce a difference in telomere attrition rates. [68]

Many DKC patients are at high risk of cancer; therefore, proton therapy has been a better treatment option than strong radiation, because of its ability to spare normal tissue and deliver a nontoxic form of radiation therapy. [69]

The elucidation of the genetic basis of X-Iinked DKC enables prenatal testing and carrier detection. Early diagnosis of DKC through genetic analysis also may help identify patients for early harvest and storage of their bone marrow for use after anticipated marrow failure. In the future, patients with DKC may be candidates for hematopoietic gene therapy.

Findings have shown that the internal fragment of dyskerin, GSE24.2, has been able to reduce the pathological effects caused by the DKC1 mutation. [70]

An association with sirtuins, specifically SIRT6, is another important target for DKC patients. It was found that sirtuins have properties to increase the longevity of proteins. Specifically with DKC patients, they has proven the ability to protect the telomeric chromatin shortening from deacetylation of histones at the replication sites. [71]

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Surgical Care

To date, the only curative therapy is bone marrow transplantation; however, surgical preparation in itself can cause harm to the patient. [72]

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Complications

Patients with dyskeratosis congenita (DKC) should avoid drugs with pulmonary toxicity (eg, busulfan) and should have their lungs shielded from radiation during bone marrow transplantation. Additionally, some authorities recommend routine endoscopic surveillance beginning at age 30 in known cases of DKC, along with general precautions like sun and tobacco avoidance.

Patients who undergo hematopoietic stem cell transplantation (SCT) for treatment should be warned of the increase risk of posttransplantation lymphoproliferative disorders. [73] A special case reported a patient with the TINF2 mutation treated with hematopoietic SCT who experienced irreversible leukoencephalopathy. [74] Other post-transplantation complications include iron overload and other late effects. [66]

DKC patients are also at risk for low bone mineral density, necessitating the need for continual monitoring. [75]

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