Haematological recovery in dyskeratosis congenita patients treated with danazol

Dyskeratosis Congenita (DC) is a multi-system disorder of telomere biology in which bone marrow (BM) failure is the main cause of mortality (Savage & Bertuch, 2010; Mason & Bessler, 2011). The disease spectrum has expanded considerably since its initial description and DC can involve any system with varying severity (Dokal, 2011). To date, 10 genes (DCK1, TERC, TERT, NOP10, NHP2, TINF2, USB1, TCAB1, CTC1 and RTEL1) have been identified; nine of these are important in telomere maintenance. Three modes of inheritance have been recognized: X-linked recessive, autosomal dominant and autosomal recessive. The severity of DC and its age of onset vary widely. The minimal clinical criteria for diagnosis of DC include the presence of at least two of the four major features (mucocutaneous triad and BM failure) and two or more of the other somatic features (Vulliamy et al, 2006). Individuals with DC are at increased risk for progressive BM failure, myelodysplasia, acute myeloid leukaemia, solid tumours, and pulmonary fibrosis. Allogeneic haematopoietic stem cell transplantation is the only curative treatment for the BM failure in DC (Dokal, 2011). BM failure in DC does not respond to immunosuppressive therapy but anabolic steroids can improve haematopoietic function. Approximately 70% of patients will respond to oxymetholone but its potent masculinizing side effects can be unacceptable to female patients. The synthetic androgen derivative, danazol, also known as 17 alpha-ethinyl testosterone, has predominantly antigonadotropic and anti-oestrogenic activities and been routinely used in women with endometriosis and individuals with hereditary angioedema (Pinkerton, 2011). It was reported to have beneficial activities in patients with aplastic anaemia (Jaime-Perez et al, 2011). Here we report the results of danazol treatment in two DC patients with BM failure for the first time. Patient 1 presented with menorrhagia; subsequent investigations concluded she had non-severe aplastic anaemia. Her older brother was diagnosed with severe aplastic anaemia that initially responded to oxymetholone and later required a bone marrow transplant. He died from post-transplant complications. Her father had lung transplantation for pulmonary fibrosis and her paternal grandmother died of fibrosing alveolitis. When referred to our clinic she had subtle abnormalities of skin pigmentation around the neck but no nail dystrophy. Her blood counts when aged 24 years (November 2005) showed: Hb 90 g/l, HbF 3·8%, mean cell volume (MCV) 125 fl, white blood cells (WBC) 2·9 × 109/l, neutrophils 1·5 × 109/l, lymphocytes 1·3 × 109/l, platelets 25 × 109/l; renal and liver biochemistry were normal as were the autoantibody screen, virology screen, B12, folate and iron measurements. Her IgA was slightly raised. TERC gene analysis showed she had autosomal dominant DC due to heterozygous TERC mutation (c.53-87del) which segregated as an autosomal dominant trait in this family (Marrone et al, 2007). In March 2009 (aged 28 years) she complained of increasing tiredness and her blood count showed Hb 81 g/l and platelets 26 × 109/l. After discussing the relative merits of oxymetholone and danazol she was started on danazol 100 mg twice a day. Twelve weeks later her Hb was 106 g/l and platelets 44 × 109/l (Fig 1); both Hb and platelet count rose further, to 118 g/l and 56 × 109/l, respectively, by November 2009. The danazol dose was reduced to 200 mg and 100 mg on alternate days. In March 2010 her danazol dose was reduced further to 100 mg/d as the counts remained stable: Hb 110 g/l, WBC 3·3 × 109/l, neutrophils 1·5 × 109/l, lymphocytes 1·3 × 109/l and platelets 48 × 109/l. In July 2012 she was well, with stable blood counts and normal biochemistry. Patient 2 initially presented in 2003 aged 13 years with bruising following a fall. The blood count was: Hb 106 g/l, WBC 3·4 × 109/l and platelets 21 × 109/l. In November 2008 her blood count showed: Hb 92 g/l, WBC 2·7 × 109/l, neutrophils 1·2 × 109/l and platelets 32 × 109/l. BM examination showed severe hypocellularity. On subsequent visits she had clinical features of DC, genetic analysis showed her to have a heterozygous TERC mutation (c.182G>A, Vulliamy et al, 2011). Further history revealed that her father died of metastatic penile cancer (aged 45 years). Her father's blood test from the local hospital revealed he was anaemic with macrocytosis and thrombocytopenia; suggesting he may have had a similar haematological problem. Investigations in November 2009 showed: Hb 87 g/l, WBC 2·3 × 109/l, neutrophils 1·4 × 109/l, lymphocytes 0·6 × 109/l, platelets 39 × 109/l, HbF was raised (13·3%). Lymphocyte subsets showed no significant abnormalities. Her liver and renal functions were normal as were the B12, folate and iron study. Together with mild mucocutaneous features, evidence of marrow hypocellularity and TERC mutation, the diagnosis of autosomal dominant DC was made. In March 2010 she reported increasing tiredness and investigations showed: Hb 83 g/l, MCV 106 fl, WBC 2·7 × 109/l, neutrophils 1·6 × 109/l, platelets 34 × 109/l, reticulocytes 33 × 109/l and HbF 13%. After a detailed discussion she agreed to a trial of danazol. In May 2010 the blood test showed response to danazol; Hb 100 g/l, WBC 2·9 × 109/l, neutrophils 1·5 × 109/l, platelets 62 × 109/l, reticulocytes 48 × 109/l (Fig 1). In March 2011, 1 year after starting danazol (200 mg/d) she had no obvious side effects and her blood count remained stable: Hb 119 g/l, reticulocytes 48 × 109/l, MCV 110 fl, HbF 8·7%, WBC 4·8 × 109/l, neutrophils 1·5 × 109/l, lymphocytes 0·9 × 109/l, platelets 62 × 109/l. In November 2012 she was stable on the same dose of danazol and blood count showed: Hb 106 g/l, WBC 2·8 × 109/l, neutrophils 1·5 × 109/l, lymphocytes 1·0 × 109/l and platelets 33 × 109/l. Both our patients had autosomal dominant DC due to heterozygous TERC mutations associated with trilineage BM failure. Danazol was used instead of oxymetholone due to a reported better side effect profile in young females. Good haematological response was achieved within 2 months of commencement. This haematological response was maintained despite danazol dose reduction in Patient 1. No adverse effects have been observed after more than 2 years of treatment. Telomerase can be modulated by sex hormones; this may in part explain the activity of androgens in BM failure (Young, 2012). Although this study describes long-term follow-up on only two patients, it suggests danazol has potential as an effective alternative to oxymetholone and might be preferred in female DC patients as it is associated with lower risk of masculinizing side effects. Part of this work was funded by The Wellcome Trust and MRC. Authors declare no competing financial interests.