Clinical Guidance

No clinically relevant genotype-phenotype correlations have been identified for the majority of pathogenic variants, most of which are private. The most common pathogenic variant, , is associated with greater frequency (50%) and severity of congenital heart defects than other SALL1 pathogenic variants. Fifteen of 16 individuals with this pathogenic variant showed the characteristic triad of anal, thumb, and ear malformations (94%), indicating that this pathogenic variant is associated with a more severe phenotype. In general, pathogenic variants within the hot spot region that is toward the 5' end in exon 2 appear to be associated with a more severe outcome than pathogenic variants towards the 3' end in exon 2.

Source: GeneReviews — "SALL1-Related Townes-Brocks Syndrome"

Penetrance

Penetrance is likely 100%, if individuals at the mild end of the phenotypic spectrum are included. Note: One SALL1 variant, , was associated with a severe phenotype when present in homozygosity. Eleven individuals heterozygous for p.Arg1054Ter had no features of SALL1-TBS, but this variant preserved some degree of SALL1 function.

Source: GeneReviews — "SALL1-Related Townes-Brocks Syndrome"

Diagnostic Criteria

Suggestive Findings

SALL1-related Townes-Brocks syndrome (SALL1-TBS) should be suspected in individuals with the following major and minor clinical features and family history.

Major features

• Imperforate anus or anal stenosis

• Dysplastic ears (overfolded superior helices, preauricular tags, microtia)

• Typical thumb malformations (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without hypoplasia of the radius

Minor features

• Sensorineural and/or conductive hearing impairment

• Foot malformations

• Impaired kidney function with or without kidney malformations

• Genitourinary malformations

• Congenital heart disease

Source: GeneReviews — "SALL1-Related Townes-Brocks Syndrome"

Differential Diagnosis

Table 3. Genes of Interest in the Differential Diagnosis of SALL1-Related Townes-Brocks Syndrome

Management Guidelines

No clinical practice guidelines for SALL1-related Townes-Brocks syndrome (SALL1-TBS) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SALL1-TBS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

SALL1-Related Townes-Brocks Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Gastrointestinal

| • Referral to surgeon for anal anomalies if present

• Assessment for constipation /or gastroesophageal reflux

|

Hearing

| Hearing eval (See Genetic Hearing Loss Overview.) |

Musculoskeletal

| • Clinical assessment for upper- lower-extremity anomalies

• Radiographs as recommended by orthopedist

| Referral to orthopedist as needed

Kidney

| • Renal ultrasound

• Assessment of kidney function w/serum electrolyte concentrations, BUN, creatinine

|

Genitourinary anomalies

| Referral to urologist/gynecologist as needed |

Cardiac

| Eval by cardiologist w/echocardiogram |

Neurodevelopment

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ special education

Neuropsychiatric eval | For persons age 12 mos: screening for behavior concerns

Endocrine

| Assessment for growth deficiency | Referral to endocrinologis...

Source: GeneReviews — "SALL1-Related Townes-Brocks Syndrome"

Clinical Guidance

Medications that cause renal or otic toxicity should be avoided.

Source: GeneReviews — "SALL1-Related Townes-Brocks Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "SALL1-Related Townes-Brocks Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. SALL1-Related Townes-Brocks Syndrome: Recommended Surveillance

Source: GeneReviews — "SALL1-Related Townes-Brocks Syndrome"