Townes-Brocks syndrome (TBS) is characterized by the triad of imperforate anus (82%), dysplastic ears (88%) (overfolded superior helices and preauricular tags) frequently associated with sensorineural and/or conductive hearing impairment (65%), and thumb malformations (89%) (triphalangeal thumbs, duplication of the thumb (preaxial polydactyly), and rarely hypoplasia of the thumbs). Renal impairment (27%), including end-stage renal disease (ESRD) (42%), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoutereral reflux). Congenital heart disease occurs in 25%. Foot malformations (52%) (flat feet, overlapping toes) and genitourinary malformations (36%) are common. Intellectual disability occurs in approximately 10% of cases. Rare features include iris coloboma, Duane anomaly, Arnold-Chiari malformation type 1, and growth retardation.
SALL1 is the only gene in which mutations are known to cause TBS. The diagnosis of TBS is based on clinical findings; detection of a SALL1 mutation confirms the diagnosis. Direct sequencing of the complete SALL1 coding region and quantitative real-time PCR analysis identify intragenic and larger deletions.
TBS is inherited in an autosomal dominant manner. The proportion of cases caused by de novo mutations is estimated at 50%. Each child of an individual with TBS caused by a SALL1 mutation has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family.