BRIEF REPORT Pediatric Dermatology Vol. 32 No. 4 e165–e166, 2015
Pulmonary Arteriovenous Malformations in Dyskeratosis Congenita Abstract: Pulmonary arteriovenous malformations (PAVMs) are rare lesions known to cause cyanosis due to abnormal communication between the pulmonary arteries and veins. They are commonly seen in association with hereditary hemorrhagic telangiectasia, congenital heart disease, hepatopulmonary syndrome, and portopulmonary shunting, but rarely in patients with dyskeratosis congenita (DC). We describe a patient previously diagnosed with DC confirmed to have microscopic PAVMs after bone marrow transplantation and discuss possible pathogenic mechanisms.
A 12-year-old white boy presented with progressive breathlessness. He had been diagnosed at age 3 years with dyskeratosis congenita (DC) (XLD, DCK1+) with manifestations of bone marrow failure, abnormal pigmentation, and nail dystrophy. Multiple early deaths due to cancer and pulmonary fibrosis were noted in family members with DC. Initial interventions included an unsuccessful attempt to treat with oxandrolone, darbepoetin alfa, filgrastim, and antithymocyte globulin before a bone marrow transplant (BMT). At age 6 years he underwent a BMT from an unrelated donor. During follow-up, he did not experience significant adverse symptoms but gradually became hypoxic and was examined for pulmonary fibrosis. His oxygen saturation on room air was in the mid-80s. Pulmonary function tests excluded significant bronchospasm. Bubble contrast echocardiogram showed evidence of intrapulmonary shunting. Eye examination revealed arteriovenous malformations in the peripheral temporal retinal blood vessels. A small patent foramen ovale was noted on threedimensional transesophageal echocardiogram, with left-to-right shunting, but without significant chamber dilatation or other cardiac abnormalities. Pulmonary artery angiography showed evidence of microscopic
DOI: 10.1111/pde.12589
© 2015 Wiley Periodicals, Inc.
pulmonary arteriovenous malformations (PAVMs) and significant runoff with dense left atrial filling within three cardiac cycles. DISCUSSION Approximately 60% to 90% of patients with PAVMs have hereditary hemorrhagic telangiectasia (HHT), but only 15% to 25% of patients with HHT have PAVMs. Patients with HHT have high plasma levels of transforming growth factor b1 (TGF-b1) and vascular endothelial growth factor (VEGF), but VEGF and TGF-b1 levels were within normal limits in our patient. He had no history of atrial isomerism or cyanotic congenital heart disease with diversion of hepatic venous blood away from pulmonary circulation. His portal pressure was within normal limits and he had normal liver function, suggesting that these factors were unlikely to be involved in the pathogenesis of PAVMs (1–3). The underlying diagnosis of DC was entertained as the potential cause because DC can lead to bone marrow failure, cancer, liver disease, pulmonary fibrosis, and many other complications. Although allogeneic hematopoietic stem cell transplantation (HSCT) can correct bone marrow failure in patients with DC (4), our case illustrates a complication profile that can evolve over time as a result of the extramedullary manifestations of the disease. A recent case report described PAVMs unrelated to a diagnosis of DC arising as a complication of graft-versus-host disease (5). It is possible that the pluripotent stem cells give rise to the progenitors for neovascularization. Our patient did not have other signs of graft-versushost disease. The development of PAVMs in DC suggests that this association must be duly recognized for appropriate management of these patients. The occurrence of PAVMs in our patient with DC may represent a primary and associated complication, a primary and unassociated complication, or a secondary complication of BMT. Further research into this complex association is necessary to understand the putative molecular activation for pathogenesis of this complication. REFERENCES 1. Vettukattil JJ. Pathogenesis of pulmonary arteriovenous malformations: role of hepatopulmonary interactions. Heart 2002;88:561–563. 2. Aidala E, Chiappa E, Cascarano MT et al. Partial hepatic vein diversion in pulmonary arteriovenous
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malformations in congenital heart disease. Ann Thorac Surg 2004;78:1089–1090. 3. Hoffman JL. Normal and abnormal pulmonary arteriovenous shunting: occurrence and mechanisms. Cardiol Young 2013;23:629–641. 4. Ayas M, Nassar A, Hamidieh AA et al. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure. Bone Marrow Transplant 2013;48:1168–1172. 5. Anderson M, Wayangankar S, Selby G et al. Pulmonary arteriovenous malformations presenting as platypneaorthodeoxia in graft-versus-host-disease. Echocardiography 2014;31:E145–E146.
Bennett P. Samuel, M.H.A., B.S.N., R.N.* Ulrich A. Duffner, M.D.† Aly S. Abdel-Mageed, M.D.† Joseph J. Vettukattil, M.D., D.N.B.* *Congenital Heart Center, †Blood and Bone Marrow Transplant, Helen DeVos Children’s Hospital of Spectrum Health, Grand Rapids, Michigan Address correspondence to Joseph J. Vettukattil, M.D., D.N.B., Co-Director, Congenital Heart Center and Division Chief, Pediatric Cardiology, Helen DeVos Children’s Hospital of Spectrum Health, 100 Michigan NE (MC273), Grand Rapids, MI 49503, or e-mail: [email protected].
Pulmonary Arteriovenous Malformations in Dyskeratosis Congenita Abstract: Pulmonary arteriovenous malformations (PAVMs) are rare lesions known to cause cyanosis due to abnormal communication between the pulmonary arteries and veins. They are commonly seen in association with hereditary hemorrhagic telangiectasia, congenital heart disease, hepatopulmonary syndrome, and portopulmonary shunting, but rarely in patients with dyskeratosis congenita (DC). We describe a patient previously diagnosed with DC confirmed to have microscopic PAVMs after bone marrow transplantation and discuss possible pathogenic mechanisms.
A 12-year-old white boy presented with progressive breathlessness. He had been diagnosed at age 3 years with dyskeratosis congenita (DC) (XLD, DCK1+) with manifestations of bone marrow failure, abnormal pigmentation, and nail dystrophy. Multiple early deaths due to cancer and pulmonary fibrosis were noted in family members with DC. Initial interventions included an unsuccessful attempt to treat with oxandrolone, darbepoetin alfa, filgrastim, and antithymocyte globulin before a bone marrow transplant (BMT). At age 6 years he underwent a BMT from an unrelated donor. During follow-up, he did not experience significant adverse symptoms but gradually became hypoxic and was examined for pulmonary fibrosis. His oxygen saturation on room air was in the mid-80s. Pulmonary function tests excluded significant bronchospasm. Bubble contrast echocardiogram showed evidence of intrapulmonary shunting. Eye examination revealed arteriovenous malformations in the peripheral temporal retinal blood vessels. A small patent foramen ovale was noted on threedimensional transesophageal echocardiogram, with left-to-right shunting, but without significant chamber dilatation or other cardiac abnormalities. Pulmonary artery angiography showed evidence of microscopic
DOI: 10.1111/pde.12589
© 2015 Wiley Periodicals, Inc.
pulmonary arteriovenous malformations (PAVMs) and significant runoff with dense left atrial filling within three cardiac cycles. DISCUSSION Approximately 60% to 90% of patients with PAVMs have hereditary hemorrhagic telangiectasia (HHT), but only 15% to 25% of patients with HHT have PAVMs. Patients with HHT have high plasma levels of transforming growth factor b1 (TGF-b1) and vascular endothelial growth factor (VEGF), but VEGF and TGF-b1 levels were within normal limits in our patient. He had no history of atrial isomerism or cyanotic congenital heart disease with diversion of hepatic venous blood away from pulmonary circulation. His portal pressure was within normal limits and he had normal liver function, suggesting that these factors were unlikely to be involved in the pathogenesis of PAVMs (1–3). The underlying diagnosis of DC was entertained as the potential cause because DC can lead to bone marrow failure, cancer, liver disease, pulmonary fibrosis, and many other complications. Although allogeneic hematopoietic stem cell transplantation (HSCT) can correct bone marrow failure in patients with DC (4), our case illustrates a complication profile that can evolve over time as a result of the extramedullary manifestations of the disease. A recent case report described PAVMs unrelated to a diagnosis of DC arising as a complication of graft-versus-host disease (5). It is possible that the pluripotent stem cells give rise to the progenitors for neovascularization. Our patient did not have other signs of graft-versushost disease. The development of PAVMs in DC suggests that this association must be duly recognized for appropriate management of these patients. The occurrence of PAVMs in our patient with DC may represent a primary and associated complication, a primary and unassociated complication, or a secondary complication of BMT. Further research into this complex association is necessary to understand the putative molecular activation for pathogenesis of this complication. REFERENCES 1. Vettukattil JJ. Pathogenesis of pulmonary arteriovenous malformations: role of hepatopulmonary interactions. Heart 2002;88:561–563. 2. Aidala E, Chiappa E, Cascarano MT et al. Partial hepatic vein diversion in pulmonary arteriovenous
e165
e166 Pediatric Dermatology Vol. 32 No. 4 July/August 2015
malformations in congenital heart disease. Ann Thorac Surg 2004;78:1089–1090. 3. Hoffman JL. Normal and abnormal pulmonary arteriovenous shunting: occurrence and mechanisms. Cardiol Young 2013;23:629–641. 4. Ayas M, Nassar A, Hamidieh AA et al. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure. Bone Marrow Transplant 2013;48:1168–1172. 5. Anderson M, Wayangankar S, Selby G et al. Pulmonary arteriovenous malformations presenting as platypneaorthodeoxia in graft-versus-host-disease. Echocardiography 2014;31:E145–E146.
Bennett P. Samuel, M.H.A., B.S.N., R.N.* Ulrich A. Duffner, M.D.† Aly S. Abdel-Mageed, M.D.† Joseph J. Vettukattil, M.D., D.N.B.* *Congenital Heart Center, †Blood and Bone Marrow Transplant, Helen DeVos Children’s Hospital of Spectrum Health, Grand Rapids, Michigan Address correspondence to Joseph J. Vettukattil, M.D., D.N.B., Co-Director, Congenital Heart Center and Division Chief, Pediatric Cardiology, Helen DeVos Children’s Hospital of Spectrum Health, 100 Michigan NE (MC273), Grand Rapids, MI 49503, or e-mail: [email protected].
