A previously unreported mutation in a Currarino syndrome kindred

Currarino syndrome consists of autosomal dominant hereditary 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 identified. 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.