W62 AJR:191, August 2008 clinically overt skeletal abnormalities but did not thoroughly discuss the entire skeletal sys- tem. In a review [1] of the cases of 41 patients with RTS, 75% of the 20 patients who under- went radiographic skeletal surveys were found to have had skeletal abnormalities, whereas only 20% had skeletal abnormalities apprecia- ble at clinical examination alone. Limitations of that study were that the skeletal surveys were performed at various institutions and interpret- ed by different radiologists and that the analy- sis was based on the official diagnostic imaging report, which may or may not have been issued by a radiologist familiar with RTS. Mutation of the RECQL4 gene was discov- ered as a cause of RTS in 1998 [10]. Since then it has been shown that approximately two thirds of RTS patients have mutations in RECQL4 [11]. The presence of mutations cor- relates significantly with the development of osteosarcoma. The exact function of the REC- QL4 protein, particularly in relation to skele- tal development, is not currently understood, but the protein is believed to be important in Radiographic Abnormalities in Rothmund-Thomson Syndrome and Genotype–Phenotype Correlation with RECQL4 Mutation Status Amy R. Mehollin-Ray 1 Claudia A. Kozinetz 2 Alan E. Schlesinger 1 R. Paul Guillerman 1 Lisa L. Wang 3 Mehollin-Ray AR, Kozinetz CA, Schlesinger AE, Guillerman RP, Wang LL 1 Department of Radiology, Baylor College of Medicine, The Edward B. Singleton Department of Diagnostic Imaging, Texas Children’s Hospital, Houston, TX. 2 Department of Pediatrics, Baylor College of Medicine, Houston, TX. 3 Texas Children’s Cancer Center, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin St., MC 3-3320, Houston, TX 77030. Address correspon- dence to L. L. Wang (llwang@bcm.edu). Pediatric฀Imaging฀•฀Original฀Research WEB This is a Web exclusive article. AJR 2008; 191:W62–W66 0361–803X/08/1912–W62 © American Roentgen Ray Society R othmund-Thomson syndrome (RTS) is an autosomal recessive disorder with heterogeneous clin- ical features, including a charac- teristic rash (poikiloderma), small stature, sparse hair, juvenile cataracts, skeletal abnor- malities including radial ray defects, and a predisposition to osteosarcoma, a malignant tumor originating in bone [1]. Rothmund [2] described patients who had a rash and juvenile cataracts, but unlike those patients, the pa- tients described by Thomson [3] had osseous abnormalities, including bilateral thumb apla- sia and hypoplastic radii and ulnae. Subse- quent case reports of RTS mentioned variable skeletal abnormalities. In a review of the world literature by Vennos et al. [4] in 1992, 68% of patients were found to have skeletal abnormalities, including frontal bossing, saddle nose, small hands and feet, and long-bone abnormalities, including radial ray defects. Later publications focused on the oc- currence of osteosarcoma in RTS patients [5–9]. Most of these case reports described Keywords: bone abnormality, RECQL4 mutation, Rothmund-Thomson syndrome, skeletal dysplasia DOI:10.2214/AJR.07.3619 Received January 6, 2008; accepted after revision February 20, 2008. Supported by National Institutes of Health grant NICHD NIH-K08HD42136, a Doris Duke Charitable Foundation Clinical Scientist Development Award, National Institutes of Health grant NIH-RR000188-42 (BCM– General Clinical Research Center), National Institutes of Health grant NIH-HD024064 (BCM–Mental Retardation Developmental Disabilities Research Center, Tissue Culture Core), the Curtis Hankamer Basic Research Fund, The Bone Disease Program of Texas Rolanette, and a Berdon Lawrence Bone Research Award. OBJECTIVE. The purpose of this study was to summarize the radiographic skeletal find- ings in patients with Rothmund-Thomson syndrome (RTS) and to determine whether there is an association between the presence of skeletal abnormalities and the mutational status of the RECQL4 gene. SUBJECTS฀AND฀METHODS. Twenty-eight subjects with RTS underwent skeletal sur- veys and RECQL4 DNA mutation testing. Radiographs were reviewed by two radiologists. RECQL4 mutation testing by DNA sequencing of the gene was performed by a diagnostic labo- ratory. Genotype–phenotype analysis by Fisher’s exact test was performed to investigate wheth- er there was a correlation between mutation status and skeletal abnormalities. RESULTS. Twenty-one (75%) of the subjects had at least one significant skeletal abnor- mality, the more common being abnormal metaphyseal trabeculation, brachymesophalangy, thumb aplasia or hypoplasia, osteopenia, dislocation of the radial head, radial aplasia or hy- poplasia, and patellar ossification defects. Three subjects had a history of destructive bone lesion (osteosarcoma). Genotype–phenotype analysis showed a significant correlation be- tween RECQL4 mutational status and the presence of skeletal abnormalities ( p < 0.0001). CONCLUSION. Skeletal abnormalities are frequent in persons with RTS. Many of these abnormalities are not clinically apparent but are detectable on radiographs. The presence of skel- etal abnormalities correlates with RECQL4 mutation status, which has been found to correlate with risk of osteosarcoma. Skeletal surveys aid in both diagnosis and management of RTS. Mehollin-Ray et al. Radiography in Rothmund-Thomson Syndrome Pediatric Imaging Original Research Downloaded from www.ajronline.org by 52.73.204.196 on 05/16/22 from IP address 52.73.204.196. Copyright ARRS. For personal use only; all rights reserved