Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by the triad of imperforate anus, dysplastic ears often associated with sensorineural and/or conductive hearing impairment, and thumb malformations. These features are often associated with other signs mainly affecting the kidneys and heart.
The prevalence of TBS is unknown. An estimate of 1/250,000 has been reported. More than 100 cases have been reported to date. Exact prevalence is difficult to determine because of overlap with other similar syndromes.
The clinical presentation is variable, even within the same family. Most patients present with imperforate anus (82%), dysplastic ears manifesting as overfolded superior helices and preauricular tags with hearing impairment (65%), and thumb malformations (89%), including triphalangeal thumbs, preaxial polydactyly, and rarely hypoplasia. Other common associated manifestations are renal dysfunction (27%), including end-stage renal disease (ESRD) (42%), with or without structural abnormalities, congenital heart disease (25%), foot malformations (52%) involving flat feet or overlapping toes, and genitourinary malformations such as hypospadias, vaginal aplasia with bifid uterus, bifid scrotum, and cryptorchidism (36%). Rare manifestations are ophthalmological (iris coloboma, microphthalmia, lamellar cataract, and chorioretinal coloboma with loss of vision), renal (kidney agenesis/hypoplasia, polycystic kidneys), and cardiac (atrial or ventricular septal defect, tetralogy of Fallot, lethal truncus arteriosus, pulmonary valve atresia, and persistent ductus arteriosus). Additional rare features are gastrointestinal (anal stenosis, chronic constipation, gastroesophageal reflux) and CNS-related including Duane anomaly (see this term), Type I Arnold-Chiari malformation, intellectual deficit (10%), behavioral disorders, cranial nerve palsy, and hypoplasia of the dorsal part of corpus callosum. Rib and mild vertebral anomalies, growth retardation, and congenital hypothyroidism have been reported in rare cases.
TBS is caused by mutations in the SALL1 gene (16q12.1). Over 70 nonsense, frameshift, and splice mutations have been identified. Large or full deletions have also been described. Some patients with clinical TBS carry a causative mutation in SALL4 rather than SALL1.
The clinical diagnosis is based on the characteristic clinical findings. However, some patients carry SALL1 mutations but present only with a subset of these anomalies. Identification of a mutation confirms the clinical diagnosis. Corresponding sequencing and qRT-PCR/MLPA techniques are clinically available to detect gene mutations. Array CGH/SNP array is recommended to determine the extent and gene content of larger deletions.
Differential diagnoses include VACTERL/VATER association, Okihiro syndrome, and Goldenhar syndrome (see these terms).
Prenatal diagnosis for pregnancies at increased risk is available and usually requires identification of the disease-causing mutation in the family. However, if typical malformations are seen on prenatal ultrasound, complete analysis of the SALL1 gene is also possible from prenatal samples.
TBS follows an autosomal dominant pattern of inheritance and about 50% of cases are de novo. Genetic counseling should be provided.
Treatment involves immediate surgery to correct imperforate anus, with subsequent surgery for severe malformations of the hands and feet. Routine management of congenital heart defects is recommended. Hemodialysis and possible kidney transplantation may be required. Early treatment of hearing loss is essential.
The physical prognosis depends on the severity of the associated renal and cardiac signs. A prognosis with respect to intellectual development is not possible.
Last update: October 2013