Clinical characteristics: SALL1-related Townes-Brocks syndrome (SALL1-TBS) is characterized by the triad of imperforate anus or anal stenosis, dysplastic ears (overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment), and thumb malformations (duplication of the thumb [preaxial polydactyly], triphalangeal thumbs, and, rarely, hypoplasia of the thumbs) without hypoplasia of the radius. Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux). Foot malformations (flat feet, overlapping toes) and genitourinary malformations are common. Congenital heart disease occurs in 15% of affected individuals. Developmental delay and/or learning difficulties occur in approximately 15% of affected individuals. Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation.

Diagnosis/testing: The diagnosis of SALL1-TBS is established in a proband with characteristic clinical findings and a heterozygous pathogenic variant in SALL1 identified by molecular genetic testing.

Management: Treatment of manifestations: Immediate surgical intervention for imperforate anus; stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation; standard treatment of gastroesophageal reflux; early treatment of hearing loss; surgery for severe malformations of the hands; hemodialysis and possibly kidney transplantation for ESKD; management of genitourinary anomalies per urologist or gynecologist; surgery or medical treatment by cardiologist for congenital heart defects; developmental and educational support as needed; neuropsychiatric management as needed for behavioral issues; growth hormone therapy for those with growth hormone deficiency; management of ocular issues per ophthalmologist.

Surveillance: Assess for constipation and assess growth and thyroid function at each visit; annual audiology evaluation; monitor kidney function annually in individuals with and without kidney anomalies, even if kidney function is normal on initial examination; monitor developmental progress, educational needs, and behavioral assessment annually; ophthalmology examination per ophthalmologist.

Agents/circumstances to avoid: Medications that cause renal or otic toxicity.

Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with SALL1-TBS in order to identify as early as possible those who would benefit from clinical evaluation and prompt initiation of treatment for kidney disease and other features of SALL1-TBS.

Pregnancy management: Consider prenatal cardiac and nephrology evaluations in pregnant women with SALL1-TBS.

Genetic counseling: SALL1-TBS is inherited in an autosomal dominant manner. About 50% of individuals diagnosed with SALL1-TBS have the disorder as the result of a de novo pathogenic variant. Each child of an individual with SALL1-TBS has a 50% chance of inheriting the pathogenic variant. Once the SALL1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.