86Med Genet 1995;32:806-808

Syndrome of the month

Treacher Collins syndrome

Michael J Dixon

Although the condition was probably first de-scribed by Thompson' in 1846, Treacher Col-lins syndrome is eponymously named after ETreacher Collins2 who described the essentialcomponents of the condition in 1900. The firstextensive review of the condition was detailedby Franceschetti and Klein3 in 1949, who usedthe term mandibulofacial dysostosis to describethe clinical features.

Clinical featuresTreacher Collins syndrome is an autosomaldominant disorder of craniofacial developmentwhich has an incidence of approximately onein 50000 live births.45 The disorder is char-acterised by (1) abnormalities of the pinnae(fig 1) which are frequently associated withatresia of the external auditory canals and an-omalies of the middle ear ossicles. As a resultbilateral conductive hearing loss is common.6(2) Hypoplasia of the facial bones, particularly

the mandible and zygomatic complex (fig 1).(3) Antimongoloid slanting of the palpebralfissures with colobomata of the lower eyelidsand a paucity of lid lashes medial to the defect(fig 2). (4) Cleft palate.45 These clinical featuresare usually bilaterally symmetrical7 (fig 2).While non-penetrance is rare,8 diagnosis andsubsequent genetic counselling may be verydifficult as expression of the gene is extremelyvariable. Indeed, some patients are so mildlyaffected that it is difficult to reach a diagnosis.It is therefore important to be able to recognisethe minimal diagnostic criteria for thedisorder.89 While 40% of cases have a previousfamily history, the remaining 60% appear toarise as a result of a de novo mutation. This cancreate an additional complication in providinggenetic counselling where the diagnosis ineither of an affected child's parents is in doubt.Conversely, in cases where apparently un-affected parents have produced an affectedchild, it is very important to be sure that neitherparent is, in fact, minimally affected. In thisregard the use of craniofacial radiographs, par-ticularly the occipitomental view, which enablesvisualisation of the zygomatic complex, mayon occasion prove to be useful.9

Differential diagnosisIn the differential diagnosis one should considerthe acrofacial dysostoses, where limb abnor-malities occur in a patient whose facial gestaltresembles that of Treacher Collins syndrome(Treacher Collins syndrome itself is not as-sociated with anomalies of the limbs). In Nager

School of BiologicalSciences andDepartments of DentalMedicine and Surgery,3.239 StopfordBuilding,University ofManchester,Oxford Road,Manchester M13 9PT,UKM J Dixon

Figure 1 Typical features of Treacher Collins syndromewith anomalies of the pinnae and hypoplasia of thezygomatic complex and mandible.

Figure 2 The same child as in fig 1 displayingdownward-slanting palpebral fissures with colobomata ofthe lower eyelids and a paucity of eyelid lashes medial tothe defect. Note the bilateral symmetry of the clinicalfeatures.

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Treacher Collins syndrome

Figure 3 A child with Nager syndrome displaying afacial gestalt similar to that of Treacher Collins syndrome,but with hypoplasia of the thumb.

syndrome the limb defects are preaxial, whilein Miller syndrome they are postaxial. Thefacial features of Nager syndrome are similarto those of Treacher Collins syndrome withzygomatic hypoplasia leading to downwardslanting palpebral fissures, micrognathia, an-omalies of the external ears, and cleft palate(fig 3). The limb defects, which are often asym-metrical, most commonly include hypoplasticor absent thumbs (fig 3), radial hypoplasia oraplasia, and radioulnar synostosis. In Millersyndrome, as in Nager syndrome, there is somesimilarity in the facial features to TreacherCollins syndrome, although the limb defectsare postaxial, most commonly with absence orincomplete development of the fifth digital rayof all four limbs. While most cases ofNagar andMiller syndromes are sporadic, both autosomaldominant and autosomal recessive trans-mission have been reported.The oculoauriculovertebral (OAV) spectrum

should also be considered in the differentialdiagnosis. This is a complex and heterogeneousset of conditions which includes hemifacialmicrosomia, which primarily affects devel-opment of the ear, mouth, and mandible (fig4). This condition varies from mild to severeand usually affects only one side of the face(fig 4). Bilateral involvement has occasionallybeen documented, but in such cases expressionis usually more severe on one side of the face.7Goldenhar syndrome, which has vertebral an-omalies and epibulbar dermoids in addition tothe facial involvement, is also considered partof the OAV spectrum. In most instances, OAV

Figure 4 A girl with hemifacial microsomia in which thepinna and the mandible are affected unilaterally.

spectrum occurs sporadically, although 1 to 2%of cases have a previous family history. Overall,the spectrum is characterised by a low (em-pirical) recurrence risk, although counsellingshould be provided on an individual familybasis. While it is usually straightforward toexclude OAV from the differential diagnosis ofTreacher Collins syndrome on the basis of thefacial gestalt, caution should be exercised wherepatients are only mildly affected so that theminimal diagnostic criteria that constitute Tre-acher Collins syndrome are not overlooked.

Aetiology and geneticsOn the basis that the tissues affected in TCOF1arise during early embryonic development fromthe first and second branchial arches, clefts,and pouches, it has been proposed that thecondition may arise from abnormal neural crestcell migration or anomalies in the extracellularmatrix. 011 Sulik et al"12" have produced pheno-copies ofTreacher Collins syndrome and Nageror Miller syndrome in mice via acute maternalexposure to 13-cis-retinoic acid (a vitamin Aanalogue) at 9-0 to 9-5 days postfertilisation.These studies showed that the craniofacial andlimb anomalies resulted from excessive celldeath in the proximal aspect of the maxillaryand mandibular processes of the first branchialarch and the apical ectodermal ridge of thelimb bud. Theories advanced to explain thepossible teratogenic mechanisms of vitamin Ainclude its effects on neural crest cell migrationand DNA synthesis.' '6 However, the natureof the genetic defect underlying TCOF1 isunknown.The gene mutated in TCOF1 was initially

mapped at 5q31-34.'718 Owing to the low in-formativity of the majority of restriction frag-ment length polymorphisms and the relativeshortage of large families, subsequent linkagestudies have concentrated on the use of highlyinformative short tandem repeat polymor-phisms (STRPs). These studies have permittedthe refinement of the localisation of TCOF1to 5q32-33. 1 and the establishment ofmarkersclosely flanking the disease locus.'920 The cre-ation of a combined genetic linkage and ra-diation hybrid map around TCOF1 haspermitted a yeast artificial chromosome contigto be created across the TCOF1 critical re-gion." Additional STRPs isolated from theseYACs, and cosmids derived from them, havepermitted the critical region to be reduced toless than 540 kb.The high density of STRPs surrounding the

TCOF1 locus has permitted postnatal diag-nostic predictions to be made.8 Ideally, diag-nostic predictions of this type should only beundertaken in families showing significant evid-ence of linkage to markers in this region of thegenome or when the possibility ofheterogeneityhas been further minimised by the study ofadditional families. However, as the majorityof TCOF1 pedigrees are relatively small itwould be difficult to detect genetic hetero-geneity, should this be a feature of the disorder.In this regard TCOF1 has been associatedwith a number of different chromosomal

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anomalies: two apparently balanced trans-locations, t(6;16)(p21.31;p13.11)9 and t(5;13)(qll;pl1),22 and two interstitial deletionsdel(4) (p15.32p 14)23 and del(3) (p23p24. 12),24which raise the possibility that the disorder maybe heterogeneous. However, in each of thesecases linkage analysis with a series of familialcases from well documented TCOF1 familiesfailed to show cosegregation with markers forthe relevant region. Moreover, the chromosome6 translocation did not ultimately completelycosegregate with the disease phenotype,9 whilein the remaining cases the facial gestalt of thepatients did not entirely conform to the clinicalcriteria of TCOF1. Furthermore, while geneticheterogeneity in TCOF1 can not be excluded,all of the families that have been analysed todate support linkage of the disease locus to thesame region of the genome,17-'925-27 with noneshowing unequivocal evidence of non-linkage.To date prenatal diagnosis has only been

performed in families with a history ofTCOF1 using either fetoscopy28 or ultrasoundimaging.2930 While the quality of ultrasoundimaging has improved markedly in recent years,allowing non-invasive prenatal diagnosis to bemade, it can still be difficult to make a positivediagnosis where the fetus is mildly affected.Prenatal diagnosis using either of thesemethods can only be performed in the secondtrimester of pregnancy (approximately 18weeks) when termination of pregnancy is aparticularly traumatic procedure. First tri-mester prenatal diagnosis would be preferable,particularly if the family feel that terminationof pregnancy is desirable in the event that thefetus is affected. The high density of STRPsisolated from the TCOF1 region make thisprocedure a realistic possibility.

I should like to thank all the Treacher Collins families for theircooperation. I should also like to thank collaborators in thelaboratories of Drs John Wasmuth, Katherine Klinger, GregLandes, and Rakesh Anand, members of my own laboratoryJill Dixon, Sara Edwards, Amanda Gladwin, and Rahat Per-veen), and clinicians who provided patient samples. The fin-ancial support of the Wellcome Trust (grant number 036797/Z/92/Z), the Medical Research Council (G9010336CB andG9204430), the Hearing Research Trust, and the IndependentOrder of Odd Fellows is gratefully acknowledged.

1 Thompson A. Notice of several cases of malformation ofthe external ear, together with experiments on the stateof hearing in such persons. Monthly J Med Sci 1846;7:420.

2 Treacher Collins E. Cases with symmetrical congenitalnotches in the outer part of each lid and defective de-velopment of the malar bones. Trans Ophthalmol Soc UK1900;20: 190-2.

3 Franceschetti A, Klein D. Mandibulo-facial dysostosis: newhereditary syndrome. Acta Ophthalmol 1949;27:143-224.

4 RovinS, Dachi SF, Borenstein DB, CotterWB. Man-dibulofacial dysostosis, a familial study of five generations.J Pediatr 1964;65:215-21.

5 Frazen LE, ElmoreJ, Nadler HL. Mandibulo-facial dy-sostosis (Treacher Collins syndrome). Am J Dis Child1967;113:406-10.

6 Phelps PD. Poswillo D. Lloyd GAS. The ear deformitiesin mandibulofacial dysostosis. Clin Otolaryngol 1981;6:15-28.

7 Kay ED, Kay CN. Dysmorphogenesis of the mandible,zygoma, and middle ear ossicles in hemifacial microsomiaand mandibulofacial dysostosis. Am Jf Med Genet 1989;32:27-31.

8 Dixon MJ, Marres HAM, Edwards SJ, Dixon J, CremersCWRJ. Treacher Collins syndrome: correlation betweenclinical and genetic linkage studies. Clin Dysmorphol 1994;3:96-103.

9 Dixon MJ, Haan E, Baker E, et al. Association of TreacherCollins syndrome and translocation 6p21.31/16pl3.11:exclusion of the locus from these candidate regions. AmJ7Hum Genet 1991;48:274-80.

10 Poswillo D. The pathogenesis of the Treacher Collins syn-drome (mandibulofacial dysostosis). BrJ Oral Surg 1975;13: 1-26.

11 Herring SW, Rowlatt UF, Pruzansky S. Anatomical ab-normalities in mandibulofacial dysostosis. AmJMed Genet1979;3:225-59.

12 Sulik KK, Johnston MC, Smiley SJ, Speight HS, Jarvis BE.Mandibulofacial dysostosis (Treacher Collins syndrome):a new proposal for its pathogenesis. AmJMed Genet 1987;27:359-72.

13 Sulik KK, Dehart DB. Retinoic-acid induced limb mal-formations resulting from apical ectodermal ridge celldeath. Teratology 1988;37:527-37.

14 Pick JB, Evans CA. Growth inhibition and occurrence ofcleft palates due to hypervitaminosis A. Expenimentia 1981;37:1189-91.

15 Thorogood PV, Smith L, Nicol A, McGinty R, Garrod D.Effects of vitamin A on the behaviour of migratory neuralcrest cells in vitro. Jf Cell Sci 1982;57:331-50.

16 Wiley MJ, Cauwenbergs P, Taylor IM. Effects of retinoicacid on the development of the facial skeleton in hamsters;early changes involving neural crest cells. Acta Anat 1983;116: 180-92.

17 Dixon MJ, Read AP, Donnai D, Colley A, Dixon J, Wil-liamson R. The gene for Treacher Collins syndrome mapsto the long arm of chromosome 5. Am JHum Genet 1991;49:17-22.

18 Jabs EW, Li X, Coss CA, Taylor EW, Meyers DA, WeberJL. Mapping the Treacher Collins syndrome locus to5q31.33-q33.3.Genomics 1991;11:193-8.

19 Dixon MJ, Dixon J, Houseal T, et al. Narrowing the positionof the Treacher Collins syndrome locus to a small intervalbetween three new microsatellite markers at 5q32-33. 1.AmJHum Genet 1993;52:907-14.

20 Loftus SK, Edwards SJ, Scherpbier-Heddema T, BuetowKH, Wasmuth Jl, Dixon MJ. A combined genetic andradiation hybrid map surrounding the Treacher Collinssyndrome locus on chromosome5q. Hum Mol Genet 1993;2:1785-92.

21 Dixon J, Gladwin AJ, Loftus SK, et al. A yeast artificialchromosome contig encompassing the Treacher Collinssyndrome critical region at 5q31.3-32. AmJf Hum Genet1994;55:372-8.

22 Balestrazzi P, Baeteman MA, Mattei MG, Mattei JF.Franceschetti syndrome in a child with a de novo balancedtranslocation (5; 13)(ql 1;pl 1) and significant decrease ofhexosaminidase B. Hum Genet 1983;64:305-8.

23 Jabs EW, Coss CA, Hayflick SJ, et al. Chromosomal deletion4pl5.32-pl4 in a Treacher Collins syndrome patient:exclusion of the disease locus from the mapping of an-onymous DNA sequences to this region. Genomics 1991;11:188-92.

24 Am PH, Mankinen C, Jabs EW. Mild mandibulofacialdysostosis in a child with a deletion of 3p. Am J MedGenet 1993;46:534-6.

25 Dixon MJ, Dixon J, Raskova D, et al. Genetic and physicalmapping of the Treacher Collins syndrome locus: re-finement of the localization to chromosome 5q32-33.2.Hum Mol Genet 1992;1:249-53.

26 Jabs EW, Li X, Lovett M, et al. Genetic and physicalmapping of the Treacher Collins syndrome locus withrespectto loci in the chromosome 5q3 region. Genomics1993;18:7-13.

27 Edery P, Manach Y, Le Merrer M, et al. Apparent genetichomogeneity of the Treacher Collins-Franceschetti syn-drome. Am JMed Genet 1994;52:174-7.

28 Nicolaides KH,Johansson D, Donnai D, Rodeck CH.Prenatal diagnosis of mandibulofacial dysostosis. PrenatDiagn 1984;4:201-5.

29 MeiznerI, Carmi R, Katz M. Prenatal ultrasonic diagnosisof mandibulofacial dysostosis (Treacher Collins syn-drome).Jf ClinUltrasound 1991;19:124-7.

30 Milligan DA, Harlass FE, Duff P, KopelmanJN. Recurrenceof Treacher Collins syndrome with sonographic findings.Mil Med 1994;159:250-2.

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