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Auriculo-condylar syndrome is associated with highly variable ear and mandibular defects in multiple kindreds

Auriculo-condylar syndrome is associated with highly variable ear and mandibular defects in multiple kindreds
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   American Journal of Medical Genetics 138A:141–145 (2005) Clinical Report  Auriculo-Condylar Syndrome Is Associated With Highly Variable Ear and Mandibular Defects in Multiple Kindreds  Andrea L. Storm, 1 * Jason M. Johnson, 1 Edward Lammer, 3 Glenn E. Green, 2 and Christopher Cunniff  1 1  Department of Pediatrics, Section of Medical and Molecular Genetics, University of Arizona College of Medicine, Tucson, Arizona  2  Department of Surgery, University of Arizona College of Medicine, Tucson, Arizona 3  Division of Medical Genetics, Children’s Hospital of Oakland, Oakland, California  We report on 20 individuals in 4 kindreds withauriculo-condylar syndrome (ACS),anautosomaldominant disorder characterized by congenitalauricular clefts, mandibular condyle hypoplasia,temporomandibular joint (TMJ) abnormalities,micrognathia, microstomia, and a round facialappearance with prominent cheeks. Affected in-dividuals have varying degrees of glossoptosis,respiratory distress, masticatory abnormalities,and malocclusion. Data from these families andthose previously described suggest that this is aunique disorder with widely variable expression,including lack of obvious external anomalies insome individuals and severe ear malformations,condyle agenesis, and characteristic facial fea-turesinothers.Earlyrecognitionofthisconditionshould permit appropriate counseling and anti-cipatory guidance, including evaluation forreconstructive surgery and orthodontia andintervention for upper airway obstruction andsleep apnea.   2005 Wiley-Liss, Inc. KEY WORDS: auriculo-condylar syndrome; earmalformation;congenitalauricularcleft; question mark ear; mandi- bular condyle hypoplasia; micro-gnathia; microstomia; temporo-mandibular joint abnormality INTRODUCTION The auriculo-condylar syndrome (ACS), first described byUuspa¨a¨ in 1978, is now recognized to be a distinct autosomal dominant disorder. Clinical descriptions have been publishedon 16 patients in seven families [Uuspa¨a¨, 1978; Jampol et al.,1998; Guion-Almeida et al., 1999; Erlich et al., 2000; Priolo etal.,2000;Guion-Almeidaetal.,2002].Thepublishedreportshave indicated that there are many other affected relativesfor whom they have not included descriptive information. ACS is characterized by prominent malformed ears withauricular clefts, mandibular condyle aplasia or hypoplasia,and a number of other features that are secondary tothe auricular and oral abnormalities. In its most severeform, there is severe micrognathia and a characteristicallyround facial appearance with prominent cheeks. Inter- andintrafamilial variability are marked. The purposes of thisreport are to describe four additional families with thisdisorder and to document its distinguishing characteristics,especially the associated complications of upper respiratoryobstruction,apnea,andorthodonticabnormalitiesthatshouldbe considered when providing health supervision and antici-patory guidance. CLINICAL REPORTS The following case reports describe one affected individualfrom each of the families reported. For additional informationon these families, please refer to Table I and Figures 1 and 3. Patient 1 Thisboy(Fig.1,individualIV-4;Fig.2A)wasreferredinthenewborn period for evaluation of ear anomalies and micro-gnathia. He had cupped ears with overfolding of the superiorhelices and a cleft at the junction of the lobule and the helix.The left lobule appeared completely separated from theremainder of the external ear and was attached to the skininferior to the helix. He had micrognathia, microstomia, and around facial appearance with prominent cheeks. Other thanthe craniofacial findings, the remainder of the examinationwas normal. On follow-up at age 6 years, his growth anddevelopment were normal.The family history revealed eight other affected familymembersinfourgenerationsasdepictedinFigure1.Themostseverely affected individual is the propositus’ grand aunt(Fig. 1, individual II-1). She was socially isolated and did notallow photographs. By the family’s description, she had amarked cleft of the superior portion of the pinnae in additionto a cleft at the junction of the lobule and helix. She alsohad mandibular condyle agenesis, severe micrognathia,TMJ abnormalities, microstomia, malocclusion, and promi-nent cheeks. Throughout childhood, she had difficulties withmastication, glossoptosis, snoring, and apnea. Reconstructivesurgical procedures were unsuccessful, and prolonged ortho-dontia was required. On physical examination and review of earlierphotographsandrecords,thepropositus’paternalaunt(Fig. 1, individual III-11; Fig. 2B) had similar condylar andfacial anomalies, but her ears were normal. She underwentmultiple reconstructive surgical procedures, including alipectomy of the face and neck to remove prominent adiposetissue.Her son (Fig. 1, individual IV-2; Fig. 2C) was examinedand had asymmetric clefts between the lobules and helices,micrognathia, and prominent cheeks. Interestingly, the pro-band’s father (Fig. 1, individual III-13) had no obvious ab-normalities on external examination with the exception of asmall papule at the junction of the lobule and the helix on theleft ear. He was also noted to have high frequency hearing   Andrea L. Storm’s present address is Medical Genetics/ Metabolism, Children’s Hospital Central California, 9300 ValleyChildren’s Place, Mail Stop SE-17, Madera, CA, 93638.Glenn E. Green’s present address is Department of Surgery,University of Michigan, Ann Arbor, MI.*Correspondence to: Andrea L. Storm, M.D., Medical Genetics/ Metabolism, Children’s Hospital Central California, 9300 ValleyChildren’s Place, Mail Stop SE-17, Madera, CA 93638.E-mail: Received 22 December 2004; Accepted 30 May 2005DOI 10.1002/ajmg.a.30883   2005 Wiley-Liss, Inc.  lossintherightear.ImagingstudiesofthemandibleandTMJwerenotavailable.Findingsoftheotherfamilymemberswerenoted on facial photographs. Patient 2 This newborn boy (Fig. 3, individual IV-6; Fig. 4A–C) wasreferred for abnormal ears and micrognathia. Physicalexamination showed underdeveloped superior helices and adeep cleft at the junction of the lobule and helix. On his right,he had pre- and post-auricular cartilaginous tags. He hadmicrognathia, microstomia, and prominent cheeks. He wasunabletoopenhismouthwidely.Theremainderofthephysicalexamination was normal. On follow-up at age 8 months, hisgrowth and development were normal. An audiology evalua-tion initially showed unilateral conductive hearing loss, butsubsequent evaluations have been normal.The maternal family history is remarkable for eight otheraffected individuals with variable malformations as illus-trated in Figs. 3 and 4D–F. This information was obtainedfrom physical examinations, facial photographs, and imaging studies when available. Patient 3 Thisnewbornboy(Fig.5A–C)wasreferredforauricularandmandibular abnormalities. His medical history throughoutinfancy and early childhood was unremarkable. He receivedspeechtherapyforarticulationerrorsbeginningatage4years.Growth, development, and hearing tests were normal. A headCT scan with 3-D reconstruction done at age 7 years 8 months(Fig. 6A,B) showed severe micrognathia and absence of themandibular condyle. At age 8 years, an attempt was made tolengthen his mandible using distraction osteogenesis.Physical examination at age 10 years was significant forbilateral, low set, posteriorly rotated ears with a cleft at the junction of the lobule and helix. He had severe micrognathiaand crowding of the mandibular and maxillary teeth with anopenanteriorbiteandaposteriorcrossbite.Themandiblewasasymmetric. The remainder of the physical examination wasnormal. There is no family history of ACS, and both parentsappear normal. TABLE I. Clinical Signs of the Patients With Auriculo-Condylar SyndromeCharacteristicPreviouslypublishedCurrentpaper Total Abnormalities of TMJ/condyle14/14 7/7 21/21 (100%)Ear constriction 13/13 17/18 30/31 (96.8%)Micrognathia 9/12 13/19 22/31 (71.0%) Abnormal palate 8/12 2/4 10/16 (62.5%)Prominent cheeks 7/12 9/16 16/28 (57.1%)Microstomia 7/13 7/14 14/27 (51.9%)Glossoptosis 2/6 3/5 5/11 (45.5%)Respiratory distress 6/8 2/14 8/22 (36.4%)Stenotic ear canals 2/6 1/4 3/10 (30.0%)Ptosis 2/7 1/4 3/11 (27.3%)Macrocephaly 3/8 0/4 3/12 (25.0%)Milddevelopmentaldelay 2/7 1/6 3/13 (23.1%)Feeding difficulties 3/7 1/12 4/19 (21.1%)Hearing loss 3/15 1/4 4/19 (21.1%)Hypotonia 2/7 0/4 2/11 (18.2%)Microglossia 2/7 0/4 2/11 (18.2%)  Articles used for the previously reported column: Uuspa¨a¨ [1978], Jampol et al. [1998], Guion-Almeida et al. [1999], Erlich et al. [2000], Priolo et al.[2000], and Guion-Almeida et al. [2002].Fig. 1. Pedigree for Patient 1.Fig. 2. ClinicalfindingsinFamily1.  A :Thepropositus(Fig.1,individualIV-4) at age 10 weeks. He has micrognathia, prominent cheeks, andcharacteristic ear abnormalities. B : The propositus’ aunt (Fig. 1, individualIII-11) before reconstructive surgery. Note the micrognathia, round facialappearance with prominent cheeks, and normal appearing ears.  C : Thepropositus’ cousin at age 17 months (Fig. 1, individual IV-2), with anauricular cleft between the helix and lobule and prominent cheeks. 142 Storm et al.  Patient 4 Thisgirl(Fig.7A–C)wasbornfollowinga35-weekgestationcomplicatedbypolyhydramnios.Shehadseveremicrognathia,malformed ears, microstomia, and difficulty in opening hermouth. She had progressive respiratory distress requiring atracheostomy on day 3.Thepatient’ssubsequentcoursewascomplicatedbynumer-ous episodes of otitis media requiring multiple myringotomytube placement. Hearing was normal. She had severe phono-logical problems and expressive language delays. Otherwiseher developmental progress was unremarkable. A 3-D headCT scan at age 2.5 years showed severe micrognathia withshort rami, small coronoid processes, and poorly formedtemporomandibular joints (TMJs). At age 3 years, autologouscostochondral bone grafting was attempted to lengthen themandible. During the surgery, ankylosis of the TM joints wasnoted. Later, distraction osteogenesis of the mandible wasattempted twice, with limited success. Bronchoscopy showeda very posterior tongue overlying the more anterior larynxand mobile vocal cords. The original tracheostomy wasdecannulated at age 3 years, but she subsequently requiredplacement of a second tracheostomy, which remains in placeat age 11 years. Fig. 3. Pedigree for Patient 2.Fig. 4. Clinical findings in Family 2.  A–C : The propositus (Fig. 3, individual IV-6) demonstrates micrognathia, microstomia, prominent cheeks, andasymmetric ear malformations with preauricular tags.  D : The propositus’ mother (Fig. 3, individual III-7) following reconstructive ear surgery. Jaw isprominent,andcheeksarenotfull. E :Earmalformationfollowingsurgicalremovalofeartags(Fig.3,individualIV-3). F :Earmalformationwithsubtlenotchbetween the helix and lobule (Fig. 3, individual IV-7).  Auriculo-Condylar Syndrome 143  Her physical examination was remarkable for symmetrical,low set, posteriorly rotated ears with clefts at the junction of the lobule and the helix. She had microstomia and severemicrognathia. She had a round face with prominent cheeks.Her oral excursion was so limited that it was difficult tovisualizetheposteriorpalate,butsheappearedtohaveashortpalate and a bifid uvula. The remainder of the physicalexamination was normal.She is the only affected individual in her family. DISCUSSION In 1978, Uuspa¨a¨ described a mother and two sons withbilateral external ear malformations and hypoplasia of themandible; and in 1998, Jampol et al. reported on a fivegeneration family with similar findings including prominentconstricted ears, microstomia, and abnormalities of the TMJand mandibular condyle. Guion-Almeida et al. [1999, 2002]andPriolo et al.[2000]each reported on similar cases. We alsobelieve that the family of Erlich et al. [2000], with what hetermed the dysgnathia complex, had ACS. This parent andchild had severe mandibular hypoplasia or agenesis, earanomalies, cleft palate, microstomia, and microglossia. Thefeaturesofallreported individuals aresummarizedinTableI.Because ear malformations are what generally bring affectedindividuals to the attention of medical personnel, they are themost commonly reported feature. Mandibular abnormalitiesarealsoobserved,andthereisawiderangeofothermajorandminor malformations, often secondary to abnormal ear andmandibular development.The characteristic congenital auricular cleft malformationin ACS consists of a protuberant cupped pinna with a cleft ornotching between the lobule and the helix. The cleft may besevere enough to detach the lobule from the helix (Fig. 4B) ormaybeverysubtle(Fig.4F).Theanomaliescanbeunilateralorbilateralandmaybeasymmetric.Someindividualhavelowsetand posteriorly rotated ears. Pre- and post-auricular tags maybe present. Hearing and middle ear function are generallynormal, however, sensorineural hearing loss was noted in thefather of Patient 1 (Fig. 1, individual III-13) and in a patientdescribed by Guion-Almeida et al. [2002]. There are previousreports in the otolaryngology and plastic surgery literature-describing patients with similar ear malformations [Cosmanet al., 1970; Fumiiri and Hyakusoku, 1983; Cosman, 1984;Takatoetal.,1989;BrodovskyandWestreich,1997; Al-Qattan,1998; Park, 1998, 1999]. This particular ear anomaly is most commonly referred to as ‘‘question mark ear’’ or congenitalauricular cleft. Of particular interest is the report by Takatoet al. [1989], which describes two siblings and their motherwithvaryingdegreesofbilateralearmalformationsconsistentwith congenital auricular clefts. It is possible that thesepatients have ACS, but because the other characteristicfeatures of ACS were not described, it is impossible todetermine whether the features were not present or werepresent and unrecognized.Complete mandibular condyle agenesis or hypoplasia ormore subtle clinical and radiographic anomalies as seen onimaging studies may be present. These findings includemicrognathia, short mandibular rami, small coronoid proces-ses, poorly formed TMJs, small condylar necks with anteriorplacement of the condylar articulations, and increased dis-tances between the external auditory canals and the posteriorglenoid fossa. From a functional perspective, these oroman-dibular abnormalities require the most intensive medicalinterventions. In severe cases of mandibular hypoplasia,such as in Patient 4, glossoptosis leads to upper respiratorytract obstruction. Glossoptosis is also associated with snoring,apnea, and sleep disturbance. In less severe cases, malocclu-sion may lead to masticatory abnormalities that requireorthodontic treatment or orthognathic surgery. Speech ther-apy may also be required to treat the articulation defectsthat have been observed in some patients. Microstomia andlimited mandibular excursion can produce difficulty withintraoral examinations and treatments that require intraoralmanipulation.In large kindreds with ACS, it is apparent that the clinicalphenotype is highly variable. A number of obligate hetero-zygotes who have been examined personally by the authorsshow no significant abnormalities on external examination,while some of their affected relatives have had severe ear Fig. 5.  A–C : Clinical findings in Patient 3 at 10 years of age, with micrognathia and characteristic ear malformations.Fig. 6.  A : Frontal and ( B ) lateral 3D CT scans of Patient 3 at 7 years8 months. There is severe microretrognathia with mandibular asymmetry,anindistinctmandibularangle,andabsenceofthemandibularcondyle.Thetemporomandibular joints are present, but the condylar fossae are poorlyformed. There is severe dental crowding, especially mandibular, and ananterior open bite. The zygomatic arches and orbital rims are normal. 144 Storm et al.  malformations, condyle agenesis, and a characteristic facialappearance. For those individuals who do show some clinicalsigns,theymaybeverysubtlewithonlyunilateralnotchingof the middle portion of the helix. Therefore, caution should beexercised when counseling about the risk of recurrence,especially if other family members have not been examined.Inourexperience,theminimaleffectsthatmaybedetectedareseen on examination of the external ears. In individuals whoappear non-penetrant, in-depth radiographic analysis of themandible and TMJ might show abnormalities not otherwisenotedandmaybehelpfulinidentifyingthemasheterozygotesfor the mutation. However, this issue has not been system-atically investigated. ACS is clearly an autosomal dominant disorder with somefeatures that overlap with well-described syndromes. Thedifferential diagnosis for ACS should include primarily otherdisorders associated with abnormal development of first andsecond branchial arch derivatives. Such disorders includeisolated microtia, Treacher Collins syndrome, and the facio-auriculo-vertebral spectrum of defects. The related midfaceabnormalities in patients with Treacher Collins syndromeshould readily distinguish this condition from ACS, but thedistinction between ACS and isolated microtia or facio-auriculo-vertebralspectrummaybemoredifficulttorecognize. Although the ear malformations in ACS tend to be distinctive,with the well-described ‘‘question mark’’ appearance, thisfeature alone may not be diagnostic. The absence of hearing loss in a patient with microtia is suggestive of ACS and mayhelp distinguish it from other disorders, but in the newbornthis may not be readily apparent. The bilateral nature of the ear abnormalities in ACS and the autosomal dominantinheritance pattern may be helpful distinguishing factors,but it should be recognized that even after careful examina-tion of the proband and other family members, a definitivediagnosis of ACS versus another first and second branchialarch related disorder may not be possible. In such circum-stances,itmaybeprudenttoobtainvertebralradiographsanda renal ultrasound examination and to perform a detailedcardiac evaluation to assess for possible features of the facio-auriculo-vertebral spectrum. As with other disorders of firstandsecondbranchialarchdevelopment,growth,development,andintellectaregenerallynormalinpatientswithACSanddonot distinguish between it and other disorders.  ACKNOWLEDGMENTS Theauthorsextendtheirsincereappreciationtothemembersof these families whose cooperation made this publicationpossible. We thank Lynn Hauck, Ginny Curtin, PNP and Peg Langham,PNPfortheirassistancewithpatientinformationandphotographs. REFERENCES  Al-Qattan MM. 1998. Cosman (question mark) ear: Congenital auricularcleft between the fifth and sixth hillocks. Plast Reconstr Surg 102:439– 441.Brodovsky S, Westreich M. 1997. Question mark ears: A method for repair.Plast Reconstr Surg 100:1254–1257.Cosman B. 1984. The question mark ear: An unappreciated major anomalyof the auricle. Plast Reconstr Surg 73:572–576.Cosman B, Bellin H, Crikelair GF. 1970. The question mark ear. PlastReconstr Surg 46:454–457.Erlich MS, Cunningham ML, Hudgins L. 2000. Transmission of thedysgnathia complex from mother to daughter. Am J Med Genet95:269–274.Fumiiri M, Hyakusoku H. 1983. Congenital auricular cleft. Plast ReconstrSurg 71:249–250.Guion-Almeida ML, Kokitsu-Nakata NM, Zechi-Ceide RM, Vendramini S.1999.Auriculo-condylarsyndrome:Furtherevidenceforanewdisorder. Am J Med Genet 86:130–133.Guion-Almeida ML, Zechi-Ceide RM, Vendramini S, Kokitsu-Nakata NM.2002. Auriculo-condylar syndrome: Additional patients. Am J MedGenet 112:209–214. Jampol M, Repetto G, Keith DA, Curtin H, Remensynder J, Holmes LB.1998. New syndrome? Prominent, constricted ears with malformedcondyle of the mandible. Am J Med Genet 75:449–452.ParkC.1998.Correctionoftheunilateralquestionmarkear.PlastReconstrSurg 101:1620–1623.Park C. 1999. Lower auricular malformations: Their representation,correction,andembryologiccorrelation.PlastReconstrSurg104:29–40.Priolo M, Lerone M, Rosaia L, Calcagno EP, Sadeghi AK, Ghezzi F,RavazzoloR,SilengoM.2000.Questionmarkears,temporo-mandibular joint malformation and hypotonia: Auriculo-condylar syndrome or adistinct entity? Clin Dysmorphol 9:277–280.Takato T, Takeda H, Kamei M, Uchiyama K. 1989. The question mark ear(congenital auricular cleft): A familial case. Ann Plast Surg 22:69–73.Uuspa¨a¨ V.1978.Combinedbilateralexternaleardeformityandhypoplasticmandible. Scand J Plast Reconstr Surg 12:165–167.Fig. 7. ClinicalfindingsinPatient4.  A , B :Thereismicrostomia,severemicrognathia,andatracheostomy. C :Theearsarelowsetandposteriorlyrotatedwith clefts between the helix and lobule.  Auriculo-Condylar Syndrome 145
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