J Med Genet 1999;36:89–93 89 Review article J Med Genet: first published as 10.1136/jmg.36.2.89 on 1 February 1999. Downloaded from Townes-Brocks syndrome Cynthia M Powell, Ron C Michaelis Abstract lies, and anorectal malformation. Intelligence is Townes-Brocks syndrome (TBS) is an usually normal, although mild-moderate men- autosomal dominant disorder with multi- tal retardation has been reported.67 Townes ple malformations and variable expres- and Brocks first described the syndrome in sion. Major findings include external ear 1972.8 Since that time over 65 cases have been anomalies, hearing loss, preaxial polydac- published1–3 5–21 (table 1). tyly and triphalangeal thumbs, imperfo- Diagnostic criteria suggested for TBS in- rate anus, and renal malformations. Most clude two or more of the following: (1) anorec- patients with Townes-Brocks syndrome tal malformation (imperforate anus, anteriorly have normal intelligence, although mental placed anus, anal stenosis); (2) hand malfor- retardation has been noted in a few. mation (preaxial polydactyly, triphalangeal (J Med Genet 1999;36:89–93) thumb, bifid thumb); (3) external ear malfor- mation (microtia, “satyr” or “lop” ear, preau- Keywords: Townes-Brocks syndrome; chromosome ricular tags or pits) with sensorineural hearing 16q12.1; SALL1 loss; (4) a relative with the syndrome.22 REAR syndrome (renal-ear-anal-radial) has also been 10 The gene for Townes-Brocks syndrome was a term used to describe this condition. mapped to 16q12.1 through identifying subjects with TBS and cytogenetic Clinical features 1–4 abnormalities. Mutations in a candidate EAR ANOMALIES/HEARING LOSS gene, SALL1, have been found in one family External auricular anomalies in TBS typically and in an isolated case with typical features of include small ears with an overfolded superior 5 this syndrome. helix and small anthelix, sometimes cupped, http://jmg.bmj.com/ Townes-Brocks syndrome is an autosomal with preauricular tags (fig 1). Other descriptive dominant multiple malformation syndrome terms reported for ear shape include “satyr” characterised by external ear malformations and “lop”. Hearing loss is common in TBS, with sensorineural hearing loss, thumb anoma- ranging from mild to profound. It is usually Table 1 Summary of familial and isolated Townes-Brocks syndrome cases previously reported* No of Ear Hearing Thumb Imperforate Genital-renal Cardiac Develop Other Reference patients Sex anomaly loss anomaly anus anomaly anomaly delay/MR abnormalities on September 28, 2021 by guest. Protected copyright. Familial 8 6 3M/3F 6 4 4 5 Toe 9 19 12M/7F 5 5 4 10 9 5M/4F 6 1 1 2 4 1 2 1M/1F 2 2 Chromosome 1122F222 2 1 1222M122 1 2 Toe 6 3 1M/2F 3 3 2 1 1 1 Scoliosis, Department of CN Pediatrics, Division of 13 6 3M/3F 5 6 5 3 3 Eye, toe 5 3 1M/2F 3 3 3 3 Genetics and Isolated Metabolism, CB 7220, 141F 111 1 1 The University of 151M 111 1 1 1 CN North Carolina at 11 1 F 1 1 1 1 Chapel Hill, Chapel 161F 111 1 1 Hill, NC 27599-7220, 17 1 M 1 1 1 1 CN USA 6 1 F 1 1 1 1 1 Scoliosis 181F 111 1 Toe CMPowell 2 1 F 1 1 1 1 Chromosome 3 1 M 1 1 1 1 1 Chromosome J C Self Research 19 (case 2) 1 F 1 1 1 1 Institute, Greenwood 7 1 M 1 1 1 1 1 Scoliosis Genetic Center, 20 1 F 1 1 Greenwood, South 211M 111 1 Toe 51M1 1111 Carolina, USA Total 66 34M/32F 47 29 37 31 18 7 6 R C Michaelis CN = cranial nerve. Correspondence to: MR = mental retardation. Dr Powell. *A detailed table of clinical features of each reported patient is available from the corresponding author. 90 Powell, Michaelis covered opening to more severe grades of J Med Genet: first published as 10.1136/jmg.36.2.89 on 1 February 1999. Downloaded from imperforation (fig 5). There is often a rec- tovaginal or rectourethral fistula. Anal stenosis without imperforate anus has also been re- ported. Excess perianal skin was also noted in several members of a large kindred with prob- able TBS reported by Reid and Turner.9 GENITOURINARY ANOMALIES A high incidence of genitourinary abnormali- ties is found in TBS. These include unilateral or bilateral hypoplastic or dysplastic kidneys, renal agenesis, multicystic kidney, posterior Figure 1 Dysplastic ear with preauricular tag and cheek urethral valves, vesicoureteral reflux, and tag in a child with Townes-Brocks syndrome. meatal stenosis.10–12 21 In eight reported patients renal failure or impaired renal function was present.6 11–13 21 Several patients have had renal transplantation.13 21 24 This underscores the need for renal imaging and monitoring of renal function in TBS patients. A prominent midline perineal raphe or bifid scrotum or both is common in males with TBS. Hypospadias has also been reported.1121315 DEVELOPMENT As noted above, mental retardation is not typi- cally associated with TBS. Walpole and Hockey14 described a 29 year old female patient with typical features of the syndrome with severe behavioural problems and mild intellec- tual handicap. This was attributed to late diag- Figure 2 Preaxial polydactyly and bifid distal phalanx of thumb with ulnar deviation in a patient with nosis (aged 6) of her hearing loss. Cameron et Townes-Brocks syndrome. al6 described two children with Townes-Brocks congenital and primarily sensorineural, al- syndrome with mental retardation. One was a 9 though a small conductive component is often year 8 month old female with ear anomalies, present. At least in some patients it is progres- anteriorly placed anus, and supernumerary sive, and is worse in the high frequencies.13 thumb. She had mild mental retardation (full scale IQ of 60). The second was an unrelated Structural middle ear anomalies have been http://jmg.bmj.com/ reported and include hypoplastic malleus head 14 year old male with a positive family history and abnormally shaped oval window and of TBS. He had an imperforate anus, small ears incus.16 with preauricular tags, and normal thumbs. He had moderate mental retardation (full scale IQ LIMB DEFECTS of 47). Although his mother and sister also had The most common limb malformations are features of TBS with thumb anomalies, both triphalangeal thumb and preaxial polydactyly had normal intelligence. A 4 year 11 month old with a well formed or vestigial digit. Bifurca- patient with imperforate anus, ear anomalies on September 28, 2021 by guest. Protected copyright. tion, ulnar deviation, or broad appearance of and deafness, a hypoplastic thumb, and a the distal phalanx of the thumb are also developmental quotient of 54 was described by common (figs 2 and 3). Finger syndactyly has Ishikiriyama et al.7 These patients had normal been reported in some patients with TBS. Toe chromosomes. Michaelis et al4 reported a boy anomalies occur less frequently than thumb with TBS and profound mental retardation, anomalies but those described include short who had a deletion that included the distal third toe/metatarsal, overlapping toes (typically portion of 16q12.1 and part or all of 16q13. It second and fourth overlapping third), syndac- is most likely that this patient’s mental retarda- tyly of the third and fourth toes, and absent tion results from disruption of a gene distal to third toe (fig 4, table 1). the TBS gene. Several genes capable of Hypoplasia of the thumb and radial bone influencing brain development reside in the abnormalities are not features of TBS and distal portion of this deleted region, including should raise the likelihood of an alternative the genes encoding the noradrenaline trans- diagnosis in isolated or familial cases. Reports porter (SLC6A2) at 16q12.2, guanine nucle- of TBS in patients with hypoplastic thumbs otide binding protein (GNAO1) at 16q13, and and radial anomalies probably do not represent metallothionein 3 (MT3) located at 16q13. true TBS.23 Thumb or radial hypoplasia with imperforate anus in isolated cases is more likely HEART DEFECTS to be VATER association, although it is impor- Although congenital heart defects have been tant to rule out other diagnoses (see below). described in some sporadic cases of Townes- Brocks syndrome, as pointed out by 25 ANAL ANOMALIES O’Callaghan and Young, none has been The most common anal anomaly reported is reported in familial cases. The true association imperforate anus, varying in degree from a skin of congenital heart defects with TBS has not Townes-Brocks syndrome 91 J Med Genet: first published as 10.1136/jmg.36.2.89 on 1 February 1999. Downloaded from Figure 3 Ulnar deviation of distal phalanges of the thumbs in a patient with Townes-Brocks syndrome. Figure 5 Imperforate anus in a female infant with Townes-Brocks syndrome. common in TBS and the possibility that the reports of them in TBS patients is coincidental cannot be discounted. SPINE ABNORMALITIES Scoliosis has been reported in three patients with TBS. Interestingly these were three patients who also had mental retardation.67 Except for a male with familial TBS, mental retardation, scoliosis, and spina bifida occulta6 http://jmg.bmj.com/ (a common anomaly in the general popula- tion), no TBS patients have had structural ver- tebral abnormalities. This helps to differentiate Figure 4 Second and fourth toes overlapping third and fifth toe clinodactyly in a patient with Townes-Brocks syndrome. TBS from VATER association and syndromes with similar hand and anal malformations.26 27 been proven. Hersch et al15 described an 8 year old male with typical TBS features and DiVerential diagnosis on September 28, 2021 by guest. Protected copyright. tetralogy of Fallot (TOF).