ß 2006 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 140A:1923–1930 (2006) A Previously Unreported Mutation in a Currarino Syndrome Kindred Raymond Y. Wang, 1,2 * Julie R. Jones, 3 Steve Chen, 4 R. Curtis Rogers, 3 Michael J. Friez, 3 Charles E. Schwartz, 3 and John M. Graham Jr. 1 1 Medical Genetics Institute, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, California 2 Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California 3 Greenwood Genetic Center, Greenwood, South Carolina 4 Department of Pediatric Surgery, Cedars-Sinai Medical Center, Los Angeles, California Received 21 March 2006; Accepted 29 June 2006 Currarino syndrome consists of autosomal dominant heredi- tary sacral dysgenesis that is caused by mutations of the HOX gene, HLXB9. Sacral malformation, presacral mass, and anorectal malformations comprise the classic triad, but other common symptoms and malformations include neonatal- onset bowel obstruction, chronic constipation, recurrent perianal sepsis, renal/urinary tract anomalies, female internal genital anomalies, tethered spinal cord, and anterior meningocele. Up to 33% of patients are asymptomatic. There is marked inter- and intrafamilial variability in expression, and no genotype/phenotype correlations have been identi- fied. To date, 32 different mutations have been identified in HLXB9: all nine missense mutations were found in the homeodomain, while the others were nonsense, frameshift, splice site mutations, or heterozygous whole-gene deletions. We report a four-generation family with Currarino syndrome varying in severity from very mild to full expression of the Currarino triad. They were found to carry a previously unreported nonsense mutation, E283X, absent in tested asymptomatic first-degree relatives. This family provides additional information on the degree of intrafamilial variability associated with HLXB9 mutations. ß 2006 Wiley-Liss, Inc. Key words: Currarino; presacral mass; sacral dysgenesis; HLXB9; mutation How to cite this article: Wang RY, Jones JR, Chen S, Rogers RC, Friez MJ, Schwartz CE, Graham JM Jr. 2006. A previously unreported mutation in a Currarino syndrome kindred. Am J Med Genet Part A 140A:1923 – 1930. INTRODUCTION Currarino et al. [1981] first described the combina- tion of sacral dysgenesis, presacral mass, and anal malformations that Kirks et al. [1984] later termed ‘‘the Currarino triad’’. As more cases were reported, various authors termed the disorder as hereditary sacral agenesis, ASP (Anorectal malformation, Sacral bony defect, Presacral mass), or Currarino syndrome. Lynch et al. [2000] proposed that Currarino syndrome be the accepted designation of the disorder because he was the first to describe the classic triad, and malformations aside from the triad are also seen. The characteristic sacral malformation of Currarino syndrome consists of an intact first sacral vertebra with a ‘‘sickle-shaped’’ hemisacrum composed of S2–S5. The presacral mass is typically a benign teratoma, dermoid tumor, and/or anterior meningo- cele, but neuroenteric cysts and hamartomas have also been reported [Holthusen et al., 1985; Heij et al., 1990]. Anal malformations include anal atresia, ano- rectal stenosis, anteriorly placed anus, rectal dupli- cation, and fistulae (rectourethral, rectovaginal, rectovesicular, rectomeningeal). Clinical manifesta- tions of Currarino syndrome are extremely variable and not all components of the classic triad need be present. Other manifestations such as neonatal-onset bowel obstruction, chronic constipation, recurrent perianal infections, renal/urinary tract anomalies, gynecological anomalies, and tethered spinal cord are common. Up to 33% of patients are asymptomatic, although 14% of these have sacrococcygeal mal- formations [Lynch et al., 2000]. Spinal epidural Grant sponsor: SHARE’s Childhood Disability Center; Grant sponsor: Steven Spielberg Pediatric Research Center; Grant sponsor: Cedars-Sinai Burns and Allen Research Institute; Grant sponsor: Skeletal Dysplasias NIH/NICHD Program Project; Grant number: HD22657-11; Grant sponsor: Medical Genetics NIH/NIGMS Training Program; Grant number: GM08243. *Correspondence to: Raymond Y. Wang, M.D., 444 S. San Vicente Blvd #1001, Los Angeles, CA 90048. E-mail: Raymond.wang@cshs.org DOI 10.1002/ajmg.a.31420