Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by the classic triad of congenital anomalies of the anus, thumbs, and ears, with variable expressivity. Additionally, renal malformations, cardiac anomalies, and endocrine and eye abnormalities can accompany TBS, although less frequently. TBS is inherited in an autosomal dominant fashion; however, about 50% of patients have a family history of TBS and the remaining 50% have
Townes-Brocks syndrome (TBS) is a rare genetic disorder caused by mutations in
Cytogenetic findings provided the first indication of the causative gene for TBS, and
Because of its rarity, there have been only three reports of TBS in Korea [9-11]. Among them, TBS has been confirmed in only one patient by
As a 10-month-old male infant, patient 1 visited the Seoul National University Children’s Hospital outpatient clinic to exclude VACTERL syndrome. He was delivered by Cesarean section because of fetal deceleration at the 40th week of gestation with a birth weight of 2,660 g (<3rd percentile). He was the first child of his parents. With the exception of his mother (patient 2), the other family members did not present with any congenital anomalies (Fig. 1). At birth, he had a low type imperforate anus with a penoscrotal fistula, preaxial polydactyly in both hands and triphalangeal thumbs, and dysplastic external ears (Fig. 2A and B). He underwent anoplasty when he was two days old. Chromosomal analysis of his peripheral blood revealed karyotype 46,XY. Echocardiography, performed at nine days of age to evaluate multiple anomalies, revealed a muscular ventricular septal defect (VSD) and patent foramen ovale. Bilateral abnormal results from an automated auditory brainstem response screening test were noted, but no further evaluation had been performed before his visit to our hospital. There was no abnormal result in a neonatal screening test for inherited metabolic diseases.
The patient was referred to the Seoul National University Children’s Hospital for further evaluation and management of VACTERL syndrome at the age of eight months. Physical examination during his visit revealed that his height was 73.7 cm (50th-75th percentile), weight was 9.2 kg (25th-50th percentile), and head circumference was 44.5 cm (25th-50th percentile). His right ear was microtia grade I and the superior helix was overfolded (Fig. 2B), and the left ear was a lop ear. He had bilateral supernumerary thumbs and radiography showed preaxial polydactyly with triphalangeal thumbs (Fig. 2A and B). Follow-up echocardiography revealed that the VSD had spontaneously closed. There were no abnormalities of his intra-abdominal organs, including the genitourinary system, as determined from abdominal ultrasonography. Ophthalmologic examination showed bilateral coloboma of the irises and no abnormal findings of the fundi. Audiometric examinations suggested bilateral hearing loss; auditory brainstem response threshold was 45 dB on the right side and 50 dB on the left. Furthermore, distortion product otoacoustic emission and transiently evoked otoacoustic emission tests yielded no response. The results of laboratory examination showed isolated thyroid stimulating hormone (TSH) elevation without an abnormal free T4 level (TSH 11.39 ?U/mL, free T4 1.25 ng/dL). However, TSH levels became normalized on the follow-up test (TSH 3.56 ?U/mL). The patient’s developmental milestones were grossly normal: he could crawl and say “mama” at eight months, and stand with support at nine months. Surgery for polydactyly was scheduled for 20 months.
Patient 2 was patient 1’s mother at 31 years of age, and had a history of preaxial polydactyly in both hands and triphalangeal thumbs, which were surgically corrected twice during her childhood (Fig. 2C). She also had bilateral dysplastic ears (Fig. 2C) and bilateral sensorineural hearing loss, requiring hearing aids. However, she did not have an imperforate anus or iris coloboma. She had completed a high school educational course and was of normal intelligence.
The boy and his mother were suspected of having familial TBS based on the medical history and findings of the physical examinations, and molecular genetic analysis for TBS was performed. Written informed consent for the analysis was obtained from the mother. Genomic DNA was isolated from peripheral blood leukocytes. All coding exons and exon-intron boundaries in
Townes and Brocks  first reported a father and five of his seven children who had variable anal, hand, foot, and ear anomalies. Later, reports of similar abnormalities in familial and isolated cases were published and these patients were diagnosed of having TBS . To date, at least 66 cases have been reported worldwide . In 1987, Friedman et al.  noted that TBS was associated with a pericentric inversion of chromosome 16. Many molecular analyses had followed and the critical region for TBS was suggested to be located on the distal 1-1.2 Mb of chromosome 16q12.1 . Subsequently,
TBS is a rare genetic disease with an autosomal dominant inheritance pattern; however, the proportion of
We found that a p.Q272* mutation to be the cause of TBS in this family. p.Q272* was reported in a patient whose anomalies included an imperforated anus, triphalangeal bifid thumb, left ear anomaly with hearing loss, facial asymmetry, unilateral renal agenesis with impaired renal function, and 12 pairs of ribs. However, ophthalmic anomalies including iris coloboma and cardiac anomalies were not observed in a previously reported patient with a p.Q272* mutation . There have been reports showing wide clinical variations and different levels of severity in TBS, even within one family with the same
Clinically, the characteristics of TBS notably overlap with those seen in other syndromes. VACTERL syndrome is the disorder likely to feature most prominently in differential diagnosis. Anal atresia is commonly accompanied by VACTERL-like TBS; however, the frequent presence of vertebral anomalies and tracheoesophageal fistulas favors VACTERL syndrome, which has no ear abnormalities or hearing loss. Besides this, Baller-Gerold syndrome, Goldenhar syndrome, cat eye syndrome, and Holt-Oram syndrome should be excluded when diagnosing TBS [1,6]. Therefore, TBS should be considered as a rare causative disorder in the evaluation and differential diagnosis of patients suspected to have multiple malformations.
In this study, we report a Korean family with TBS resulting from a nonsense mutation in
We thank the patients and their families for participating in this study. This study was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI12C0014).
Pedigree and sequence electropherogram. Partial sequences of
Radiographs and photographs of patients 1 and 2. The simple radiograph and photograph of the son (patient 1: A, B) show bilateral preaxial polydactyly, triphalangeal thumbs and a small and dysplastic external ear. The photograph of the mother (patient 2: C) shows surgical scars and remnant deformities in both thumbs and her external ear is small and malformed.