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.
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