Pediatric Pulmonology 50:E48–E51 (2015)
Case Report
Treatment of Dyskeratosis Congenita-Associated Pulmonary Fibrosis With Danazol Bozana Zlateska,1,2 Amanda Ciccolini,1,2 and Yigal Dror1,2* Summary. Individuals with Dyskeratosis Congenita (DC) are at increased risk for complications in variety of systems including pulmonary fibrosis. Idiopathic and DC-associated pulmonary fibrosis are progressive and fatal disorders without known treatment. Here we describe, for the first time, marked improvement in the clinical and laboratory parameters of the pulmonary disease of a child who suffered from TINF2-associated DC and severe pulmonary fibrosis after initiation of therapy with Danazol. We recommend that the clinical efficacy of Danazol in slowing down the progression of pulmonary fibrosis in patients with telomere-related disorders is evaluated in prospective studies. Pediatr Pulmonol. 2015;50:E48–E51. © 2015 Wiley Periodicals, Inc. Key words: Dyskeratosis congenita; pulmonary fibrosis; Danazol. Funding source: C17 Research Network, Candlelighters Canada.
INTRODUCTION
Dyskeratosis congenita (DC) is a progressive, multisystem disorder. Patients with the disorder manifest bone marrow failure, mucocutaneous changes (dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia), pulmonary fibrosis, cancer predisposition, and multiple other potential complications. The disease is caused by mutations in telomere maintenancerelated genes such as those that are part of the telomerase complex (TERT, DKC1, TERC, NHP2, and NOP10), shelterin complex (TCAB1), telomerase trafficking (TCAB1) or part of the CTC1-STN1-TEN1 complex that promote telomere replication (CTC1), or disruption of the telomere’s D-loop (RTEL1).1 Consequently, patients with DC and the above mutations have short telomeres for their age.2 DC-associated pulmonary fibrosis is progressive and fatal. Spontaneous improvement has not been reported.3 We report herein the course of DC-associated pulmonary fibrosis treated with the androgen-stimulating hormone Danazol. CASE REPORT
The patient was enrolled on the Canadian Inherited Marrow Failure Registry after obtaining consent from the parents. The study was approved by the Sick Kids Hospital Research Ethics Board. ß 2015 Wiley Periodicals, Inc.
At 3 years of age the girl presented with bruises and recurrent upper respiratory tract infections and bladder infection. She developed moderate thrombocytopenia and complete blood count revealed platelets of 29–54 109/L, hemoglobin of 130–146 g/L, white blood cells 6.9 109/L, absolute neutrophils count 1.86 109/L, lymphocytes 4.49 109/L, and mean corpuscular volume of 102 fl.
1
Genetics and Genome Biology Program, Research Institute, University of Toronto, Toronto, Ontario, Canada. 2 Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Bozana Zlateska and Amanda Ciccolini contributed equally to the manuscript and should be considered co-primary authors. Conflict of interest: None
Correspondence to: Yigal Dror, Division of Hematology Oncology, Sick Kids Hospital, 555 University Avenue, Toronto, Ontario, Canada M5G1 8,. E-mail: [email protected] Received 13 February 2015; Revised 24 April 2015; Accepted 29 April 2015. DOI 10.1002/ppul.23235 Published online 17 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
Treatment of Dyskeratosis Congenita-Associated Pulmonary Fibrosis
Bone marrow aspirate showed decreased cellularity with rare megakaryocytes, reduced granulopoiesis at all stages of maturation, normoblastic erythropoiesis with mild dyserythropoietic changes. Marrow cytogenetics was normal. The cytopenia rapidly progressed to severe thrombocytopenia (platelets 14 109/L), severe neutropenia (0.38 109/L), and moderate anemia (hemoglobin 95 g/L). The patient was diagnosed with idiopathic aplastic anemia and was treated with cyclosporine, antithymocyte globin, granulocyte colony-stimulating factor, and prednisone for 3 months without response. At
E49
the age of 6 years she underwent Hematopoietic Stem Cell Transplantation (HSCT) from her full (6/6) HLAmatched father. The preparative regimen consisted of cyclophosphamide (50 mg/kg 4days) and rabbit antithymocyte globin (2.5 mg/kg 2 days). Cyclosporine and four doses of methotrexate were used for graft versus host disease (GVHD) prophylaxis. She was engrafted on day 19 and did not develop acute GVHD, major infections or other HSCT-related complications. Two years after HSCT she developed severe osteoporosis with multiple fractures.
Fig. 1. A: Sequence of the patient’s TINF2 gene. The mutation is in exon 6. It is consistent with missense alteration, c.860T > C that results in an amino acid change, Leu287Pro. B–D: Computerized tomography of the lungs. The images show diffuse reticular opacities bilaterally with interstitial changes, most prominent at both lung apices and largely in a peripheral distribution honeycombing evident in the apices (arrows). E–G: Thorascopic wedge lung biopsy. The figures shows pleural and septal-based fibrous foci with established scarring concomitant with active fibroplasia (marked with black arrows) and only mild chronic inflammation with relatively uninvolved intervening pulmonary parenchyma and a usual interstitial pneumonia pattern. The slides in Figure D were stained with Hematoxylin and Eosin (pink color shows fibrosis). The slides in Figure E and F were stained with Elastic-Trichrome (green color shows fibrosis) (Magnifications of A and B 10; Magnification of C 40).
Pediatric Pulmonology
E50
Zlateska et al.
She had finger and toe nail dystrophy and skin pigmentation noted prior to HSCT but the diagnosis of DC was made later. It was found that she had a heterozygous mutation in exon 6 of the TINF2 gene (c. 860T > C, Leu287Pro) (Fig. 1A). Peripheral blood telomere length measurement was not done since the patient had prior HSCT. At the age of 17 years after several days of rhinorrhea and sore throat she developed a persistent dry cough and exertional dyspnea. Chest radiograph demonstrated a diffuse uniform nodular pattern in both lungs with honeycombing and peripheral septal thickening. Highresolution computerized tomography of the chest showed diffuse reticular opacities bilaterally with interstitial changes, largely in a peripheral distribution with honeycomb appearance in the apices (Fig. 1B–D). Spirometry revealed a forced vital capacity of 1.68 L (56%), forced expiratory volume in 1 sec of 1.61 L (63%), total lung capacity of 2.91 L (77%), forced expiratory volume in 1 sec/forced vital capacity of 96%, and a significant reduction in diffusion capacity for carbon monoxide at 40% of predicated (Table 1). Thoracoscopic wedge biopsy from right superior lobe showed pleural and septal-based fibrous foci with established scarring concomitant with active fibroplasia and only mild chronic inflammation, with usual interstitial pneumonia pattern (Fig. 1E–G). Our patient also had mild right to left shunt as evaluated by cardiac catheterization and bubble studies. Also, the CT scan showed diffuse pulmonary AV malformation. Three months after presentation with pulmonary symptoms she became oxygen dependent and required 2 L/min at rest and 5 L/min during activity. Since her pulmonary disease gradually progressed, but not yet meets criteria for lung transplantation, a discussion about off-label treatment with Danazol was held with the patient and family. Baseline liver function tests were normal: alanine aminotransferase (ALT) 25 U/L, and aspartate aminotransferase (AST) 31 U/L and conjugated
bilirubin of 0 mmol/L. Ultrasonographic examination of the liver showed non-specific increase in echogenicity. At age 17.5 years, therapy with Danazol was initiated with 100 mg daily that was increased gradually to 200 mg once per day. No other medications have been prescribed to the patient. During the first month of therapy while receiving oxygen, her oxygen saturation at rest was 94%. Within the next 4 months on Danazol, the patient stopped requiring any supplemental oxygen. Pulmonary function testing showed nearly normal lung volumes. The DLCO remained very low due to diffuse pulmonary shunting at the very small vessels (Table 1). Liver enzymes were mildly elevated (ALT 80 U/L, AST 60 U/L). Ultrasonographic evaluation of the liver revealed no evidence of peliosis or tumors. The patient’s pulmonary condition remained stable without oxygen requirement while continuing treatment with Danazol. After improvement, her oxygen saturation was 98% at room air. Since the patient respiratory illness gradually improved a repeat lung biopsy was not performed. Also, since dyskeratosis congenita is a genomic instability disorder a routine follow-up CT chest has not been performed. Unfortunately, at the age of 18 years and 11 months, the patient developed another complication of DC; thrombotic macroangiopathy and she died 13 months later from sepsis. A repeat CT of the chest was done before the patient deceased at the stage of multi-organ failure. At that time the scan showed peripheral fibrotic changes with primarily apical distribution bilaterally. The patient continued treatment with Danazol until deceased. DISCUSSION
Pulmonary fibrosis is a progressive and lethal complication of DC that occurs regardless of previous treatment with HSCT. HSCT can cure the bone marrow failure in the patients with DC, but it does not eliminate the risks of other complications such as pulmonary fibrosis.
TABLE 1— Pulmonary Function Test Results Before and After Danazol Therapy Before Danazol Spirometry
Four months after initiation of Danazol therapy
Predicated
Patient best
Predicated (%)
Predicated
Patient best
Predicated (%)
3.77 3.00 2.55 85 3.16 5.09 3.00 15.45
2.91 1.68 1.61 96 2.89 6.68 1.75 6.2
77 56 63
3.77 3.00 2.55 85 3.16 5.09 3.00 17.03
3.10 2.21 2.09 95 3.29 6.90 2.24 6.7
82 74 82
TLC (L) FVC (L) FEV1 (L) FEV1/FVC (%) FEF25–75 (L/sec) PEF (L/sec) VC (L) DLCO
91 131 58 40
104 135 75 40
DLCO, Carbon Monoxide Diffusing Capacity; FEF, Forced Expiratory Flow; FEV1, Forced Expiratory Volume in 1 second; FVC, forced vital capacity; L, liter; FEF25–75, Forced Expiratory Flow Between 25% and 75% of Forced Vital Capacity; PEF, Peak Expiratory Flow; Sec, second; TLC, Total Lung Capacity; VC, vital capacity.
Pediatric Pulmonology
Treatment of Dyskeratosis Congenita-Associated Pulmonary Fibrosis
DC-associated pulmonary fibrosis may occur at an early age but is more common later in life in patients with or without significant hematological manifestations. It usually develops after the appearance of the skin abnormalities and bone marrow failure. Indeed, our patient who had a TINF2 mutation, with characteristic early onset of mucocutaneous manifestations and bone marrow failure manifest pulmonary disease 15 years after. Treatment of pulmonary fibrosis is primarily supportive and lung transplantation may be considered in very rare cases.4 To our knowledge, Danazol or androgen therapy has not been reported for DC-related pulmonary fibrosis. It was suggested that androgen therapy might ameliorate progressive telomere attrition in vivo.5 Recently published study showed that oxymethalone might down regulate transcription of osteopontin, whose expression is associated with inflammation, tissue scaring and fibrosis.6 Our patient showed improvement in her pulmonary disease after initiation of Danazol therapy. We cannot exclude the possibility of clinical and laboratory evidence of improvement due to unknown patient-related factors. However, based on the known natural history of pulmonary fibrosis in DC patients, the in vitro effect of androgens on telomeres and the in vivo effect on bone marrow failure, it is possible that the improvement was related to Danazol. Correlation between clinical improvement and telomere length on peripheral blood cells was not feasible since the patient was diagnosed with dyskeratosis congenita after she underwent bone marrow transplantation. The modest improvement in FVC and FEV1 support a positive effect on pulmonary fibrosis; however, we cannot exclude the possibility that the improvement in oxygen requirement was at least in part
E51
attributed to an effect of Danazol on the pulmonary shunting. The pulmonary shunting could not be attributed to hepatic fibrosis as the later was excluded by CT scan of the abdomen done at age of 19 years. This previously undescribed link of Danazol improvement related to DCassociated pulmonary fibrosis should be further studied in prospective studies. ACKNOWLEDGEMENTS
Leslie Steels, Erika Mann, Glenn Taylor, Sharon Dell, Katerina Pavenski, and Jeffrey H Lipton have made academic contribution to the manuscript and should be considered as Co-Authors. REFERENCES 1. Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol 2013;6:327–337. 2. Bessler M, Du HY, GU B, Mason PJ. Dysfunctional telomeres and dyskeratosis congenita. Haematologica 2007;92:1009–1012. 3. Behr J. The diagnosis and treatment of idiopathic pulmonary fibrosis. Dtsch Arztebl Int 2013;110:875–881. 4. Giri N, Lee R, Faro A, Huddleston CB, White FV, Alter BP, Savage SA. Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review. BMC Blood Disord 2011;3. 5. Islam A, Rafiq S, Kirwan M, Walne A, Cavenagh J, Vulliamy T, Dokal I. Hematological recovery in dyskeratosis congenita patients treated with danazol. Br J Haematol 2013;162:854–856. 6. Zhang QS, Benedetti E, Deater M, Schubert K, Major A, Petz C, Impey S, Marquez-Loza L, Rathbun RK, Kato S, Bagby GC, Grompe M. Oxymethalone therapy of Fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling. Stem Cell Rep 2015;4:90–102.
Pediatric Pulmonology
Case Report
Treatment of Dyskeratosis Congenita-Associated Pulmonary Fibrosis With Danazol Bozana Zlateska,1,2 Amanda Ciccolini,1,2 and Yigal Dror1,2* Summary. Individuals with Dyskeratosis Congenita (DC) are at increased risk for complications in variety of systems including pulmonary fibrosis. Idiopathic and DC-associated pulmonary fibrosis are progressive and fatal disorders without known treatment. Here we describe, for the first time, marked improvement in the clinical and laboratory parameters of the pulmonary disease of a child who suffered from TINF2-associated DC and severe pulmonary fibrosis after initiation of therapy with Danazol. We recommend that the clinical efficacy of Danazol in slowing down the progression of pulmonary fibrosis in patients with telomere-related disorders is evaluated in prospective studies. Pediatr Pulmonol. 2015;50:E48–E51. © 2015 Wiley Periodicals, Inc. Key words: Dyskeratosis congenita; pulmonary fibrosis; Danazol. Funding source: C17 Research Network, Candlelighters Canada.
INTRODUCTION
Dyskeratosis congenita (DC) is a progressive, multisystem disorder. Patients with the disorder manifest bone marrow failure, mucocutaneous changes (dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia), pulmonary fibrosis, cancer predisposition, and multiple other potential complications. The disease is caused by mutations in telomere maintenancerelated genes such as those that are part of the telomerase complex (TERT, DKC1, TERC, NHP2, and NOP10), shelterin complex (TCAB1), telomerase trafficking (TCAB1) or part of the CTC1-STN1-TEN1 complex that promote telomere replication (CTC1), or disruption of the telomere’s D-loop (RTEL1).1 Consequently, patients with DC and the above mutations have short telomeres for their age.2 DC-associated pulmonary fibrosis is progressive and fatal. Spontaneous improvement has not been reported.3 We report herein the course of DC-associated pulmonary fibrosis treated with the androgen-stimulating hormone Danazol. CASE REPORT
The patient was enrolled on the Canadian Inherited Marrow Failure Registry after obtaining consent from the parents. The study was approved by the Sick Kids Hospital Research Ethics Board. ß 2015 Wiley Periodicals, Inc.
At 3 years of age the girl presented with bruises and recurrent upper respiratory tract infections and bladder infection. She developed moderate thrombocytopenia and complete blood count revealed platelets of 29–54 109/L, hemoglobin of 130–146 g/L, white blood cells 6.9 109/L, absolute neutrophils count 1.86 109/L, lymphocytes 4.49 109/L, and mean corpuscular volume of 102 fl.
1
Genetics and Genome Biology Program, Research Institute, University of Toronto, Toronto, Ontario, Canada. 2 Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Bozana Zlateska and Amanda Ciccolini contributed equally to the manuscript and should be considered co-primary authors. Conflict of interest: None
Correspondence to: Yigal Dror, Division of Hematology Oncology, Sick Kids Hospital, 555 University Avenue, Toronto, Ontario, Canada M5G1 8,. E-mail: [email protected] Received 13 February 2015; Revised 24 April 2015; Accepted 29 April 2015. DOI 10.1002/ppul.23235 Published online 17 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
Treatment of Dyskeratosis Congenita-Associated Pulmonary Fibrosis
Bone marrow aspirate showed decreased cellularity with rare megakaryocytes, reduced granulopoiesis at all stages of maturation, normoblastic erythropoiesis with mild dyserythropoietic changes. Marrow cytogenetics was normal. The cytopenia rapidly progressed to severe thrombocytopenia (platelets 14 109/L), severe neutropenia (0.38 109/L), and moderate anemia (hemoglobin 95 g/L). The patient was diagnosed with idiopathic aplastic anemia and was treated with cyclosporine, antithymocyte globin, granulocyte colony-stimulating factor, and prednisone for 3 months without response. At
E49
the age of 6 years she underwent Hematopoietic Stem Cell Transplantation (HSCT) from her full (6/6) HLAmatched father. The preparative regimen consisted of cyclophosphamide (50 mg/kg 4days) and rabbit antithymocyte globin (2.5 mg/kg 2 days). Cyclosporine and four doses of methotrexate were used for graft versus host disease (GVHD) prophylaxis. She was engrafted on day 19 and did not develop acute GVHD, major infections or other HSCT-related complications. Two years after HSCT she developed severe osteoporosis with multiple fractures.
Fig. 1. A: Sequence of the patient’s TINF2 gene. The mutation is in exon 6. It is consistent with missense alteration, c.860T > C that results in an amino acid change, Leu287Pro. B–D: Computerized tomography of the lungs. The images show diffuse reticular opacities bilaterally with interstitial changes, most prominent at both lung apices and largely in a peripheral distribution honeycombing evident in the apices (arrows). E–G: Thorascopic wedge lung biopsy. The figures shows pleural and septal-based fibrous foci with established scarring concomitant with active fibroplasia (marked with black arrows) and only mild chronic inflammation with relatively uninvolved intervening pulmonary parenchyma and a usual interstitial pneumonia pattern. The slides in Figure D were stained with Hematoxylin and Eosin (pink color shows fibrosis). The slides in Figure E and F were stained with Elastic-Trichrome (green color shows fibrosis) (Magnifications of A and B 10; Magnification of C 40).
Pediatric Pulmonology
E50
Zlateska et al.
She had finger and toe nail dystrophy and skin pigmentation noted prior to HSCT but the diagnosis of DC was made later. It was found that she had a heterozygous mutation in exon 6 of the TINF2 gene (c. 860T > C, Leu287Pro) (Fig. 1A). Peripheral blood telomere length measurement was not done since the patient had prior HSCT. At the age of 17 years after several days of rhinorrhea and sore throat she developed a persistent dry cough and exertional dyspnea. Chest radiograph demonstrated a diffuse uniform nodular pattern in both lungs with honeycombing and peripheral septal thickening. Highresolution computerized tomography of the chest showed diffuse reticular opacities bilaterally with interstitial changes, largely in a peripheral distribution with honeycomb appearance in the apices (Fig. 1B–D). Spirometry revealed a forced vital capacity of 1.68 L (56%), forced expiratory volume in 1 sec of 1.61 L (63%), total lung capacity of 2.91 L (77%), forced expiratory volume in 1 sec/forced vital capacity of 96%, and a significant reduction in diffusion capacity for carbon monoxide at 40% of predicated (Table 1). Thoracoscopic wedge biopsy from right superior lobe showed pleural and septal-based fibrous foci with established scarring concomitant with active fibroplasia and only mild chronic inflammation, with usual interstitial pneumonia pattern (Fig. 1E–G). Our patient also had mild right to left shunt as evaluated by cardiac catheterization and bubble studies. Also, the CT scan showed diffuse pulmonary AV malformation. Three months after presentation with pulmonary symptoms she became oxygen dependent and required 2 L/min at rest and 5 L/min during activity. Since her pulmonary disease gradually progressed, but not yet meets criteria for lung transplantation, a discussion about off-label treatment with Danazol was held with the patient and family. Baseline liver function tests were normal: alanine aminotransferase (ALT) 25 U/L, and aspartate aminotransferase (AST) 31 U/L and conjugated
bilirubin of 0 mmol/L. Ultrasonographic examination of the liver showed non-specific increase in echogenicity. At age 17.5 years, therapy with Danazol was initiated with 100 mg daily that was increased gradually to 200 mg once per day. No other medications have been prescribed to the patient. During the first month of therapy while receiving oxygen, her oxygen saturation at rest was 94%. Within the next 4 months on Danazol, the patient stopped requiring any supplemental oxygen. Pulmonary function testing showed nearly normal lung volumes. The DLCO remained very low due to diffuse pulmonary shunting at the very small vessels (Table 1). Liver enzymes were mildly elevated (ALT 80 U/L, AST 60 U/L). Ultrasonographic evaluation of the liver revealed no evidence of peliosis or tumors. The patient’s pulmonary condition remained stable without oxygen requirement while continuing treatment with Danazol. After improvement, her oxygen saturation was 98% at room air. Since the patient respiratory illness gradually improved a repeat lung biopsy was not performed. Also, since dyskeratosis congenita is a genomic instability disorder a routine follow-up CT chest has not been performed. Unfortunately, at the age of 18 years and 11 months, the patient developed another complication of DC; thrombotic macroangiopathy and she died 13 months later from sepsis. A repeat CT of the chest was done before the patient deceased at the stage of multi-organ failure. At that time the scan showed peripheral fibrotic changes with primarily apical distribution bilaterally. The patient continued treatment with Danazol until deceased. DISCUSSION
Pulmonary fibrosis is a progressive and lethal complication of DC that occurs regardless of previous treatment with HSCT. HSCT can cure the bone marrow failure in the patients with DC, but it does not eliminate the risks of other complications such as pulmonary fibrosis.
TABLE 1— Pulmonary Function Test Results Before and After Danazol Therapy Before Danazol Spirometry
Four months after initiation of Danazol therapy
Predicated
Patient best
Predicated (%)
Predicated
Patient best
Predicated (%)
3.77 3.00 2.55 85 3.16 5.09 3.00 15.45
2.91 1.68 1.61 96 2.89 6.68 1.75 6.2
77 56 63
3.77 3.00 2.55 85 3.16 5.09 3.00 17.03
3.10 2.21 2.09 95 3.29 6.90 2.24 6.7
82 74 82
TLC (L) FVC (L) FEV1 (L) FEV1/FVC (%) FEF25–75 (L/sec) PEF (L/sec) VC (L) DLCO
91 131 58 40
104 135 75 40
DLCO, Carbon Monoxide Diffusing Capacity; FEF, Forced Expiratory Flow; FEV1, Forced Expiratory Volume in 1 second; FVC, forced vital capacity; L, liter; FEF25–75, Forced Expiratory Flow Between 25% and 75% of Forced Vital Capacity; PEF, Peak Expiratory Flow; Sec, second; TLC, Total Lung Capacity; VC, vital capacity.
Pediatric Pulmonology
Treatment of Dyskeratosis Congenita-Associated Pulmonary Fibrosis
DC-associated pulmonary fibrosis may occur at an early age but is more common later in life in patients with or without significant hematological manifestations. It usually develops after the appearance of the skin abnormalities and bone marrow failure. Indeed, our patient who had a TINF2 mutation, with characteristic early onset of mucocutaneous manifestations and bone marrow failure manifest pulmonary disease 15 years after. Treatment of pulmonary fibrosis is primarily supportive and lung transplantation may be considered in very rare cases.4 To our knowledge, Danazol or androgen therapy has not been reported for DC-related pulmonary fibrosis. It was suggested that androgen therapy might ameliorate progressive telomere attrition in vivo.5 Recently published study showed that oxymethalone might down regulate transcription of osteopontin, whose expression is associated with inflammation, tissue scaring and fibrosis.6 Our patient showed improvement in her pulmonary disease after initiation of Danazol therapy. We cannot exclude the possibility of clinical and laboratory evidence of improvement due to unknown patient-related factors. However, based on the known natural history of pulmonary fibrosis in DC patients, the in vitro effect of androgens on telomeres and the in vivo effect on bone marrow failure, it is possible that the improvement was related to Danazol. Correlation between clinical improvement and telomere length on peripheral blood cells was not feasible since the patient was diagnosed with dyskeratosis congenita after she underwent bone marrow transplantation. The modest improvement in FVC and FEV1 support a positive effect on pulmonary fibrosis; however, we cannot exclude the possibility that the improvement in oxygen requirement was at least in part
E51
attributed to an effect of Danazol on the pulmonary shunting. The pulmonary shunting could not be attributed to hepatic fibrosis as the later was excluded by CT scan of the abdomen done at age of 19 years. This previously undescribed link of Danazol improvement related to DCassociated pulmonary fibrosis should be further studied in prospective studies. ACKNOWLEDGEMENTS
Leslie Steels, Erika Mann, Glenn Taylor, Sharon Dell, Katerina Pavenski, and Jeffrey H Lipton have made academic contribution to the manuscript and should be considered as Co-Authors. REFERENCES 1. Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol 2013;6:327–337. 2. Bessler M, Du HY, GU B, Mason PJ. Dysfunctional telomeres and dyskeratosis congenita. Haematologica 2007;92:1009–1012. 3. Behr J. The diagnosis and treatment of idiopathic pulmonary fibrosis. Dtsch Arztebl Int 2013;110:875–881. 4. Giri N, Lee R, Faro A, Huddleston CB, White FV, Alter BP, Savage SA. Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review. BMC Blood Disord 2011;3. 5. Islam A, Rafiq S, Kirwan M, Walne A, Cavenagh J, Vulliamy T, Dokal I. Hematological recovery in dyskeratosis congenita patients treated with danazol. Br J Haematol 2013;162:854–856. 6. Zhang QS, Benedetti E, Deater M, Schubert K, Major A, Petz C, Impey S, Marquez-Loza L, Rathbun RK, Kato S, Bagby GC, Grompe M. Oxymethalone therapy of Fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling. Stem Cell Rep 2015;4:90–102.
Pediatric Pulmonology
