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

Gene(s)	Disorder	MOI	Features of Disorder	Comment / Distinguishing Features
CCNQ	STAR syndrome (OMIM 300707)	XL	Toe syndactyly, telecanthus, anogenital & renal malformations similar to TBS Likely lethal in males	Facial features & toe syndactyly distinguish STAR syndrome from SALL1-TBS.
DACT1	Townes-Brocks syndrome 2 (TBS2) (OMIM 617466)	AD	DACT1 pathogenic variants have been identified in families w/incompletely penetrant AD CAKUT. ¹ In 1 family w/loss-of-function DACT1 pathogenic variant, affected persons had CAKUT, anal, &/or external ear anomalies, leading to the designation TBS2. ²	Thumb anomalies have not been reported.
EYA1 SIX1 SIX5	Branchiootorenal (BOR) syndrome (See Branchiootorenal Spectrum Disorder.)	AD	Ear malformations assoc w/hearing impairment, branchial fistulae & cysts, & renal malformations	In 2 families later determined to have SALL1-TBS, the presence of dysplastic ears & renal malformations / impaired kidney function initially led to consideration of BOR syndrome. Note: No affected family members had the typical SALL1-TBS triad of thumb, anal, & ear malformations. ³
SALL4	Duane-radial ray syndrome (DRRS, Okihiro syndrome) (See SALL4-Related Disorders.)	AD	Duane anomaly & radial ray defects Less commonly, hearing loss & renal position anomalies	In persons w/features suggestive of SALL1-TBS, both SALL1 & SALL4 molecular genetic testing should be considered. SALL4 pathogenic variants have been identified in a few persons w/clinical features suggestive of SALL1-TBS. ⁴ Molecular genetic testing of SALL4 rather than SALL1 is suggested as the first molecular test if the radius is involved &/or if Duane anomaly is present (Duane anomaly is an atypical finding in SALL1-TBS; radial hypoplasia/aplasia & thumb aplasia have not been observed in SALL1-TBS).
SF3B2	SF3B2-related hemifacial microsomia (Goldenhar syndrome, oculo-auriculo-vertebral spectrum) (OMIM 164210)	AD	SF3B2 pathogenic variants are identified in ~3% of persons representing simplex cases (i.e., the only person w/hemifacial microsomia in a family) & ~25% of individuals w/positive family history. ⁵	The majority of persons w/hemifacial microsomia do not have upper-limb or anal malformations. However, some persons w/SALL1 pathogenic variants have hemifacial microsomia. Therefore, while isolated hemifacial microsomia is not suggestive of SALL1-TBS, hemifacial microsomia may be present w/other typical findings of SALL1-TBS.
FREM1	Bifid nose w/ or w/o anorectal & renal anomalies (BNAR) (See FREM1 Autosomal Recessive Disorders.)	AR	Bifid or wide nasal tip, anorectal anomalies, & renal malformations	Facial features & absence of thumb anomalies distinguish BNAR from SALL1-TBS.
TBX5	Holt-Oram syndrome (HOS)	AD	Upper-limb defects involving carpal bone(s) &, variably, radial &/or thenar bones Congenital heart malformation Thumb anomalies can resemble those in SALL1-TBS.	External ear & anal anomalies are not typical in HOS.

Gene(s)

Disorder

MOI

Features of Disorder

Comment / Distinguishing Features

CCNQ

STAR syndrome (OMIM 300707)

Toe syndactyly, telecanthus, anogenital & renal malformations similar to TBS
Likely lethal in males

Facial features & toe syndactyly distinguish STAR syndrome from SALL1-TBS.

DACT1

Townes-Brocks syndrome 2 (TBS2) (OMIM 617466)

DACT1 pathogenic variants have been identified in families w/incompletely penetrant AD CAKUT. ¹ In 1 family w/loss-of-function DACT1 pathogenic variant, affected persons had CAKUT, anal, &/or external ear anomalies, leading to the designation TBS2. ²

Thumb anomalies have not been reported.

EYA1
SIX1
SIX5

Branchiootorenal (BOR) syndrome (See Branchiootorenal Spectrum Disorder.)

Ear malformations assoc w/hearing impairment, branchial fistulae & cysts, & renal malformations

In 2 families later determined to have SALL1-TBS, the presence of dysplastic ears & renal malformations / impaired kidney function initially led to consideration of BOR syndrome.
Note: No affected family members had the typical SALL1-TBS triad of thumb, anal, & ear malformations. ³

SALL4

Duane-radial ray syndrome (DRRS, Okihiro syndrome) (See SALL4-Related Disorders.)

Duane anomaly & radial ray defects
Less commonly, hearing loss & renal position anomalies

In persons w/features suggestive of SALL1-TBS, both SALL1 & SALL4 molecular genetic testing should be considered. SALL4 pathogenic variants have been identified in a few persons w/clinical features suggestive of SALL1-TBS. ⁴
Molecular genetic testing of SALL4 rather than SALL1 is suggested as the first molecular test if the radius is involved &/or if Duane anomaly is present (Duane anomaly is an atypical finding in SALL1-TBS; radial hypoplasia/aplasia & thumb aplasia have not been observed in SALL1-TBS).

SF3B2

SF3B2-related hemifacial microsomia (Goldenhar syndrome, oculo-auriculo-vertebral spectrum) (OMIM 164210)

SF3B2 pathogenic variants are identified in ~3% of persons representing simplex cases (i.e., the only person w/hemifacial microsomia in a family) & ~25% of individuals w/positive family history. ⁵

The majority of persons w/hemifacial microsomia do not have upper-limb or anal malformations. However, some persons w/SALL1 pathogenic variants have hemifacial microsomia. Therefore, while isolated hemifacial microsomia is not suggestive of SALL1-TBS, hemifacial microsomia may be present w/other typical findings of SALL1-TBS.

FREM1

Bifid nose w/ or w/o anorectal & renal anomalies (BNAR) (See FREM1 Autosomal Recessive Disorders.)

Bifid or wide nasal tip, anorectal anomalies, & renal malformations

Facial features & absence of thumb anomalies distinguish BNAR from SALL1-TBS.

TBX5

Holt-Oram syndrome (HOS)

Upper-limb defects involving carpal bone(s) &, variably, radial &/or thenar bones
Congenital heart malformation
Thumb anomalies can resemble those in SALL1-TBS.

External ear & anal anomalies are not typical in HOS.

From: SALL1-Related Townes-Brocks Syndrome

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Adam MP, Feldman J, Mirzaa GM, et al., editors.

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