J. Appl. Genet. 43(2), 2002, pp. 223-233
Review article
Clinical features, treatment and genetic background of Treacher Collins syndrome Bo¿ena MARSZA£EK1, Piotr WÓJCICKI2, Kazimierz KOBUS2, Wies³aw H. TRZECIAK1 1
Department of Biochemistry and Molecular Biology, K. Marcinkowski University of Medical Sciences, Poznañ, Poland 2 Hospital of Plastic Surgery, Polanica Zdrój, Poland
Abstract. Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development. The major features of the disease include midface hypoplasia, micrognathia, microtia, conductive hearing loss and cleft palate. Current procedures of surgical treatment of TCS are discussed and novel findings concerning the genetic background of TCS are described. The TCS locus has been mapped to chromosome 5q31.3-32. The TCOF1 gene contains 26 exons and encodes a 1411 amino acid protein named treacle. In the TCOF1 gene 51 mutations have been identified. Most of these mutations are insertions or deletions, which result in an introduction of a premature termination codon into the reading frame. Mutational spectra support the hypothesis that TCS results from haploinsufficiency of treacle. Key words: diagnostics, mutations, TCOF1 gene, Treacher Collins syndrome, treacle, treatment.
Introduction Treacher Collins syndrome (TCS, OMIM 154500), alternatively called mandibulofacial dysostosis (MFD), is an autosomal dominant disorder of craniofacial development that occurs with an incidence of 1 in 50,000 live births (GORLIN et al. 1990). Early descriptions are attributed to BERRY (1889), TREACHER COLLINS (1900) and FRANCESCHETTI and KLEIN (1949). While 40% Received: April 8, 2002. Accepted: April 16, 2002. Correspondence: W.H. TRZECIAK, Department of Biochemistry and Molecular Biology, K. Marcinkowski University of Medical Sciences, ul. Œwiecickiego 6, 60-781 Poznañ, Poland, e-mail:
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of TCS cases have a previous family history, 60% of cases possibly arise as a result of de novo mutations (JONES et al. 1975). From the structures affected and from studies in mice exposed to teratogenic cis- or trans-retinoic acid, it has been deduced that the disease results from interference in the development of the first and second branchial arches (GORLIN et al.1990). The aim of the review is to discuss clinical features and current findings concerning treatment and genetic background of Treacher Collins syndrome.
Diagnostics According to a classification of craniofacial clefts, the complete form of the syndrome shows the presence of clefts 6, 7 and 8 (TESSIER 1976). The obligatory features are antimongoloid palpebral fissures, coloboma of lower eyelids, eyelash malformations, molar defects, preauricular hair displacement, micrognathia and “fishlike” facial appearance (Figure 1). The common features are macrostomia, auricular defects, high-arched palate, nasal deformity, malocclusion, open bite and deafness. Other abnormalities, such as cleft palate, colobomas of the upper lid, hypertelorism and mental retardation, are infrequent. In severely affected patients, the airway is compromised by the temporomandibular joint mandibular de-
Figure 1. View of the patient with severe form of Treacher Collins syndrome A = facial view, B = profile
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ficiency, glossoptosis and choanal atresia. Sleep apnea and sudden infant death syndrome are of particular significance. A unilateral form of TCS does not exist. The only syndrome that TCS resembles in its facial aspects is Nager’s acrofacial dysostosis.
Treatment From the time of birth, in severe cases the airway must be evaluated and secured. Either positioning alone or tracheostomy is required to manage the airway, and a gastrostomy for feeding. Operations of choanal atresia or mandibular lengthening are performed at the age of 2 to 3 years or later. To promote normal language development, cleft palate repair as well as evaluation by an otolaryngologist, audiologist and speech pathologist is recommended. Since the spectrum and degree of deformities related to TCS are extensive, a plan of management and timing of treatment needs to be tailored to the patient’s specific problems. As a rule, bone reconstruction should precede soft tissue corrections. Autogenous tissues, such as calvarial (preferably vascularized) grafts, ribs and iliac bone should be used, while synthetic materials should be avoided. Although by 5 to 7 years of age the cranio-orbitozygomatic bone development is almost complete (WAITZMAN et al. 1992), reconstructing before 10 years of age should be avoided. In order to minimize facial scarring, exposure for reconstruction of zygomatic and skeletal region is provided by a coronal (scalp) incision. Lateral canthopexies are completed during the same procedure. The lower face retrusion and increased facial convexity on profile are consistent features of TCS. Before facial growth is complete, chin augmentation and mandibular distraction are recommended. Definitive orthognatic surgery is delayed until the age of 16 to18 years. Most often the mandible advancement with bilateral sagittal ramus osteotomy, maxillary segmental osteotomies or a Le Fort I osteotomy to lower the posterior maxilla are performed, while Tessier’s “integrale” procedure is reserved for severest cases (TESSIER, TULASNE 1986). The high-bridged nose can be improved by a classical rhinoplasty (Figure 2). Soft tissue reconstruction
Coloboma of the lower eyelid is preferably corrected according to Tessier method (TESSIER 1976), which consists in Z-plasty for cutaneous lengthening, overlapping sutures of the preseptal orbicularis muscle and canthopexy. Our favourite method of eyelid repair is the transposition of pedicled upper eyelid skin-muscle flaps to the lower eyelid deficient region (Z-plasty). Simultaneously the lateral canthi correction is performed to normalize the orbital area. Auricular reconstruction is one of the most difficult problems. The low-set auricular remnants, hairy skin and depressed area produce the main difficulties.
Figure 2. Views of the same patient: preoperative at 4 y.a. (A and B) and postoperative at 19 y.a. (C and D) The girl underwent several operations, including mandibular elongation, rhinoplasty, advancement genioplasty and vascularized cranial bone grafts to the orbits. A and C = facial view; B and D = profiles
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The methods described by BRENT (1992) and NAGATA (1993) represent the current standard of autogenous reconstruction.
Genetic background The TCS locus was initially mapped to a 9-cM region at chromosome 5q31-34 (DIXON et al. 1991). Subsequently, genetic and radiation hybrid mapping permitted to identify a critical region of
