Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome (IBMFS) classically diagnosed by the triad of dysplastic nails, reticular skin pigmentation and oral leukoplakia. Patients with DC are at very high risk of bone marrow failure (BMF), cancer, pulmonary fibrosis, and other medical problems. Germline mutations in key telomere biology genes cause DC (DKC1, TERC, TERT, TINF2, NOP10, NHP2, WRAP53, or CTC1), although about 50% of patients lack a known mutation. Leukocyte telomere lengths <1st percentile for age, measured by flow cytometry with in situ hybridization, are diagnostic of DC. The only current cure for DC-associated BMF is hematopoietic stem cell transplantation (HSCT). However, not all patients are candidates for HSCT due to the lack of a donor, other medical problems, or personal choice. Treatment of BMF with androgens is a therapeutic option for these patients. Androgen-related side effects include virilization, elevated transaminases, blood lipid abnormalities, hepatic tumors, and liver and spleen peliosis. These effects have not been prospectively studied in DC.
Our aim was to evaluate androgen response and androgen–related side effects in an observational study of patients with DC. DC patients who were on androgen therapy for cytopenias were evaluated for hematological response and for changes in serum lipid levels, liver and thyroid function, liver and spleen abnormalities on ultrasound, and changes in growth. Hematological response was defined as red blood cell (RBC) or platelet transfusion independence. Untreated DC patients served as controls. All patients were participants in our IRB-approved longitudinal cohort study of IBMFS. DC was diagnosed by the presence of the diagnostic triad, 1 of the triad plus BMF, or a proven mutation in a known DC gene. We used Fisher's exact and Student's T-Test to compare pre- and post-treatment parameters. P<0.05 was significant. We evaluated a total of 46 patients with DC of whom 16 (35%) received androgen treatment (14 oxymetholone, 1 fluoxymesterone, 1 nandrolone). Eleven treated patients (69%) had a hematological response, nine (82%) of whom responded with both RBC and platelet transfusion independence. The median time to response was 1.5 months for platelets (range 0.6–8 months) and 4 months for hemoglobin (range 2.2–9.4 months). The median duration of therapy was 2.2 years (range 0.4–10.8 years). Serum chemistries, including lipids, were available on 13 androgen-treated and 30 untreated DC patients. Compared with the untreated group, all patients on androgens developed an abnormal lipid profile (P<0.0001) with markedly high total cholesterol (54%), high LDL (100%), elevated triglycerides (38%), or low HDL levels (100%) (all P values <0.0001). Serum bilirubin, transaminases, and gamma-glutamyl transferase did not change significantly. A significant decrease in thyroid binding globulin was noted in 10/11 patients (91%) (P=0.004) who had normal thyroid function prior to androgen therapy. Five out of 9 prepubertal patients experienced an accelerated growth spurt on androgens, and 3 of them had bone fractures after minimal trauma. However, fractures occurred in two untreated patients and these may have been related to corticosteroids received after HSCT. Splenic peliosis with rupture developed in 2 patients on androgens combined with G-CSF (Giri N. et al. 2007). One patient developed a hypoechoic liver lesion, for which the liver biopsy was non-diagnostic but suggestive of changes related to androgen therapy. All males reported priapism; females reported hirsutism and hoarseness of voice.
In summary, patients with DC and BMF may achieve transfusion-independence when treated with androgens. However, major elevations in serum lipids and decreased thyroid binding globulin can result. Rapid growth and early puberty may occur in children treated with androgens. Prolonged exposure to abnormal lipids is likely to increase the risk of atherosclerosis and coronary artery disease in these patients. Despite these limitations, androgen therapy should still be considered in patients with DC and BMF, especially those who are unable to undergo HSCT. Clinicians should be aware of androgen-related side effects and perform frequent monitoring of growth, liver function, lipid profiles, and biannual abdominal ultrasound.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.