Townes-Brocks Syndrome

Clinical characteristics Townes-Brocks syndrome (TBS) is characterized by the triad of imperforate anus (84%), dysplastic ears (87%; 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 (42%), including end-stage renal disease (ESRD), 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 individuals. Rare features include iris coloboma, Duane anomaly, Arnold-Chiari malformation type 1, and growth retardation. Diagnosis/testing The diagnosis of TBS is based on clinical findings; identification of a heterozygous SALL1 pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive. Management Treatment of manifestations: Immediate surgical intervention for imperforate anus; early treatment of hearing loss; surgery for severe malformations of the hands; hemodialysis and possibly kidney transplantation for ESRD; surgery or medical treatment by a cardiologist for congenital heart defects. Surveillance: Annual hearing evaluation; regular monitoring of renal function in individuals with and without renal anomalies, even if renal function is normal on initial examination. Agents/circumstances to avoid: Medications that cause renal or otic toxicity. Genetic counseling TBS is inherited in an autosomal dominant manner. The proportion of cases caused by de novo pathogenic variants is estimated at 50%. Each child of an individual with TBS caused by a SALL1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family.