Dyskeratosis Congenita Complicated by Hepatic Fibrosis With Hepatic Vein Thrombosis Hideki Yoshida, MD, PhD,* Toshihiko Imamura, MD, PhD,* Kenichi Sakamoto, MD,* Daisuke Asai, MD,* Takuya Nakatani, MD, PhD,w Akira Morimoto, MD, PhD,z and Hajime Hosoi, MD, PhD*

Summary: We describe the case of 2 male siblings with dyskeratosis congenita (DC). Extensive genetic analysis failed to identify a causative genetic abnormality. The elder brother developed hepatic fibrosis accompanied with hepatic vein thrombosis at the age of 9 years. Recent studies have found that patients with DC sometimes develop hepatic complications, including cirrhosis. However, little is known about hepatic complications in patients with DC who lack these mutations. Further genetic studies are required to understand the relationship between DC and hepatic complications. In addition, although danazol can sometimes be effective for treating bone marrow failure, hepatotoxicity can be a major complication. Therefore, when danazol is administered to patients with DC, careful monitoring for hepatic complications is important. Key Words: dyskeratosis congenita, hepatic complication, telomere, danazol

(J Pediatr Hematol Oncol 2014;36:308–311)


yskeratosis congenita (DC) is an inherited bone marrow (BM) failure syndrome characterized by a mucocutaneous triad of nail dystrophy, abnormal skin pigmentation, and oral leukoplakia.1,2 In addition, the clinical presentation of patients with DC is highly variable, even if the patients share the same genetic alteration. It is well known that DC is caused by alterations in a variety of genes associated with telomere function, such as DKC1, TINF2, TERT, TERC, NOP10, NHP2, CTC1, TCAB1, and RTEL1.3–7 These genes encode the main constituents of the telomerase complex that plays a role in replicating telomeres and stabilizing them against shortening. Mutations in these genes can cause telomere shortening and impair the proliferative capacity of hematopoietic stem cells, eventually causing DC.8 However, genetic abnormalities are

Received for publication December 20, 2012; accepted August 20, 2013. From the *Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto; wDepartment of Pediatrics, Matsushita Memorial Hospital, Osaka; and zDepartment of Pediatrics, Jichi Medical University, Tochigi, Japan. Written informed consent was obtained from the patients and their parents for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. The authors declare no conflict of interest. Reprints: Toshihiko Imamura, MD, PhD, Department of Pediatrics, Kyoto Prefectural University of Medicine, 465 Kajii-cho Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan (e-mail: imamura@koto. Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, Copyright r 2013 by Lippincott Williams & Wilkins

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undetectable in approximately 40% of DC cases.1 Recent studies found that loss-of-function mutations in the telomerase gene are associated with congenital BM failure, idiopathic aplastic anemia (AA), and idiopathic pulmonary fibrosis.9,10 Here, the case of 2 siblings with DC who presented with hepatic fibrosis accompanied by hepatic vein thrombosis is described. Although hepatic complications in patients with DC are rare, some reports have suggested that loss-of-function telomerase gene variants are risk factors for sporadic cirrhosis.11 In this context, the current case study is of interest as it provides insight into the relationship between BM failure and hepatic fibrosis.

CASE REPORT A 4-year-old boy who was born to nonconsanguineous and healthy parents developed thrombocytopenia (0.9 104/mL). There was nothing particularly notable in the family history. He did not show any dysmorphic features or developmental delay. Peripheral blood analysis suggested no abnormal findings except for the thrombocytopenia. Thus, he was initially diagnosed with idiopathic thrombocytopenic purpura. Although he was treated with intravenous immunoglobulin and prednisolone, his platelet count remained at around 3.0104/mL. At the age of 6 years, a BM aspiration revealed a conspicuous decrease in megakaryocytes and he was provisionally diagnosed with mild AA instead of idiopathic thrombocytopenic purpura, and treated with danazol (100 mg/d) in combination with prednisolone, between the ages of 6 and 9 years. However, his platelet count remained low (0.9 to 3.2 104/mL). When he was 8 years old, his neutrophil count began to decrease (0.6 to 1.2104/mL). A BM aspiration revealed hypocellular BM without abnormal blasts or dysplasia. G-banding, fluorescence in situ hybridization (FISH) analysis for monosomy 7 and trisomy 8, and a chromosome breakage test also showed normal results. At the age of 9 years, a blood examination revealed the elevation of liver enzymes (aspartate aminotransferase, 100 to 130 IU/L; alanine aminotransferase, 160 to 200 IU/L). A serological study confirmed the absence of hepatitis B virus antigen or antihepatitis C virus antibody. IgG titers for cytomegalovirus and Epstein-Barr virus were positive showing that he had previously suffered from both. A subsequent abdominal computed tomography (CT) scan showed an irregularly shaped liver, prominent narrowing of the central hepatic vein, and portal-hepatic vein shunt (Figs. 1A, B). Coagulation studies did not reveal a state of hypercoagulation (prothrombin time, 12.8 s; activated partial thromboplastin time, 46.2 s; fibrinogen, 352 mg/dL; D-dimer, 0.6 mg/mL; anticardiolipin [aCL]-b2 glycoprotein 1 IgG,

Dyskeratosis congenita complicated by hepatic fibrosis with hepatic vein thrombosis.

We describe the case of 2 male siblings with dyskeratosis congenita (DC). Extensive genetic analysis failed to identify a causative genetic abnormalit...
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