Teunissen-Cremers Syndrome: A Clinical, Surgical, and ... · its clinical presentation, distinct...

Teunissen-Cremers Syndrome: A Clinical, Surgical,and Genetic Report

*H. H. Weekamp, *H. Kremer, †L. H. Hoefsloot, ‡A. M. Kuijpers-Jagtman,§J. R. M. Cruysberg, and *C. W. R. J. Cremers

*Departments of Otorhinolaryngology–Head and Neck Surgery, †Human Genetics, ‡Orthodontics, and§Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Objective: To describe clinical and radiologic features, resultsof ear surgery, and genetic analysis in three families with Teu-nissen-Cremers syndrome.

Design: Case series.

Setting: Tertiary referral center.

Background: The NOG gene encodes the protein noggin,which has antagonist action in osteogenesis. Malformation ofbones and joints may result from defects in noggin. Teunissen-Cremers syndrome is caused by mutations in the NOG gene.Two mutations in this gene were reported previously. Theproximal symphalangism-hearing impairment syndrome, alsocaused by mutations in the NOG gene, is characterized byproximal symphalangism, conductive hearing loss, and occa-sionally synostoses.

Methods: We examined nine affected members of three Dutchfamilies. Reconstructive middle ear surgery was performed infive patients (nine ears), and we sequenced the NOG gene inthese families.

Results: Affected members had conductive hearing impair-ment, hyperopia, and broad thumbs and first toes withbrachytelephalangia. Surgery manifested stapes ankylosis withadditional incudal fixation frequently in the fossa incudis. Air-bone gaps decreased to less than 10 dB in six ears. Geneticanalysis revealed three new mutations in the NOG gene.Conclusion: The Teunissen-Cremers syndrome is an entity inits clinical presentation, distinct from other syndromes withproximal symphalangism and hearing impairment. So far, infive families with Teunissen-Cremers syndrome, four truncat-ing mutations and one amino acid substitution were found inthe NOG gene. The majority of other mutations found in thisgene are missense mutations, which might result in some re-sidual protein activity. Reconstructive middle ear surgery is anoption for treatment. Key Words: Autosomal dominant—Genetic conductive hearing impairment—Congenital incusfixation—Congenital stapes ankylosis—Hyperopia—NOG mu-tations—Teunissen-Cremers syndrome.Otol Neurotol 26:38–51, 2005.

In 1990, Teunissen and Cremers presented five af-fected male members of a Dutch family with hearing losscaused by congenital stapes ankylosis, severe hyperopia(farsightedness), as well as broad thumbs and first toeswith brachytelephalangia (short distal phalanges) (1).Proximal symphalangism (ankylosis of a proximal inter-phalangeal joint) of the fifth digit was seen in one indi-vidual and therefore considered only to be an associatedfeature. This remarkable combination of features wasalso found in three other families (2–4).

Mutation analysis in the families reported by Milun-sky et al. (3) and by Brown et al. (4) revealed pathologicmutations in the noggin (NOG) gene. The NOG geneencodes the protein noggin, which acts as an antagonistto bone morphogenic proteins (BMPs) in osteogenesis

(5). Studies in mice have shown that functional defects ofnoggin can result in malformation of bones and jointcavities (6).

Besides the typical features as seen in the Teunissen-Cremers (TC) syndrome, other symptoms can be causedby mutations in the NOG gene (e.g., syndactyly, facialabnormalities, tarsal or carpal bone coalition, and proxi-mal symphalangism). A minor feature in the TC syn-drome, proximal symphalangism is known to be the mostprominent feature in the proximal symphalangism–hearing impairment (SYM1) syndrome. Proximalsymphalangism is also prominent in the atypical variantof the proximal symphalangism–hearing impairmentsyndrome (SYNS1) and in the tarsal-carpal coalitionsyndrome (TCC) (7–9). Hearing loss caused by stapesankylosis, and fusion of carpal or tarsal bones, which cancause a duck-like gait, are frequently reported in SYM1(8,10). Mutation analysis in families with typical andatypical variants of the SYM1 syndrome have alreadyrevealed 11 pathologic mutations in the NOG gene(17q21-22) (11–13). Genetic defects in the NOG gene

Address correspondence and reprint requests to C. W. R. J. Cremers,M.D., Ph.D., Department of Otorhinolaryngology, University MedicalCenter Nijmegen, Nijmegen, The Netherlands; Email: [email protected]

Otology & Neurotology26:38–51 © 2005, Otology & Neurotology, Inc.

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also turned out to be the cause of the TCC syndrome, anautosomal dominant disorder, which is characterized byextensive fusion of carpal and tarsal bones (14). Sympha-langism, short first metacarpals causing brachydactylyand fusion of humeroradial fusion, is also seen in thissyndrome. The TCC syndrome as well as the SYM1 andSYNS1 syndromes display an interfamilial and intrafa-milial variation in expression of symptoms. Therefore,the lines between these syndromes seem to be rather thin.Fibrodysplasia ossificans progressiva, another connec-tive tissue disorder, is characterized by congenital mal-formation of the first toes and by progressive heterotopicossification of the tendons, ligaments, fasciae, and skel-etal muscles. Whether the fibrodysplasia ossificans pro-gressiva syndrome is caused by a mutation in the NOGgene remains a subject of dispute (15–17).

In this report, the clinical findings and results of earsurgery in nine affected members of three families withthe TC syndrome are described. Recently, we performedadditional ophthalmologic examinations and radiologicexaminations of the orbits in seven affected members ofthese families. The first family (Family A) was alreadyreported (1). The other two families (Families B and C)are newly diagnosed with the TC syndrome.

The clinical features that were seen in the familieswith the TC syndrome described in this article and in thefamilies described in three other reports (2–4) are com-pared with those of associated syndromes to display dis-tinctive features. Furthermore, we report three new mu-tations in the NOG gene that were detected in thepresented families. We compare the NOG mutationsfound in the TC syndrome with those reported in relatedclinical entities, looking at the nature and position of themutations and the possible effect on the noggin protein.

PATIENTS AND METHODS

Clinical examination

Family AWe reexamined Family A. Additional clinical, audiometric,

ophthalmologic, and radiologic examinations were performedin three of five affected members. One person (II:1) had alreadydied and another person (III:1) did not want to participate.Pure-tone audiometry was performed in a sound-treated roomwith an Interacoustics Clinical Audiometer AC 40 (Interacous-tics A/S, Assens, Denmark), calibrated to ISO 389 accord-ing to the ISO 8253-1 standard (18). Air conduction thresholdswere measured in decibels hearing level. Bone-conductionthresholds were also measured to exclude conductive or mixedhearing impairment. For audiometric analysis of reconstruc-tive ear surgery, preoperative impairment in bone conduc-tion was considered equal to postoperative impairment inbone conduction.

The patients had ocular examinations, including assessmentof best-corrected visual acuity, subjective and objective (1%tropicamide [Thea Pharma NV, Ukkel, Belgium]) measurementof refraction, orthoptic examination of binocular functions, slitlamp biomicroscopy, ophthalmoscopy, measurement of intra-ocular pressure, and ultrasound axial length measurement of theeyes. Additional radiographs were obtained of hands and feet.

To detect any possible bony deformities of the skull and facialbones, an orthopantomogram and lateral and anteroposteriorhead films were obtained. The head films were taken using acephalostat (Cranex Tome Cephalostat, 70 kV, 10 mA,Soredex, Helsinki, Finland) with the lips in rest position and theteeth in occlusion. The focus-film distance was 5.04 m, and anintensifying screen (Kodak TMAT, Eastman Kodak, Rochester,NY, U.S.A.) was used. The magnification factor was 1.098.The radiographs were traced and analyzed by one observer(A. K.-J.). To describe the orbital area, the following cephalo-metric points and planes were determined on the anteroposte-rior head film:

Lo: the intersection of the lateral wall of the orbit with thegreater wing of the sphenoid.

Or: the lower most contour of the bony orbit.Frankfort horizontal: line through the left and right Or.Midsagittal plane: a perpendicular plane from the neck of the

crista galli to the Frankfort horizontal line.Lo-Horiz: the horizontal distance from Lo to the midsagittal

plane.Lo-Vert: the vertical distance from Lo to the Frankfort hori-

zontal plane.As no age-related norms for the orbital area are available for

the Dutch population, cephalometric values were comparedwith age-related norms from the atlas of Basyouni and Nanda(19) for individuals from northern and western European an-cestry in the Denver area (U.S.A.).

Families B and CIn both families, only the mother and one daughter displayed

both a hearing impairment and hyperopia and underwent clini-cal, otoscopic, and audiometric examinations. Pure-tone audi-ometry was performed under the conditions as stated above.The ISO standard for presbyacusis was used to identify personswith thresholds above the 95th percentile of presbyacusis. Onlywhen a hearing threshold larger than the 95th percentile wasfound was the individual considered to be affected (20). Forspeech recognition, standard monosyllabic Dutch word listswere presented at either ear (21). Ipsilateral and contralateralstapedial reflexes were examined. Ophthalmologic examina-tions, radiographs, and cephalometric analyses were performedin the affected individuals of Families B and C, as described forFamily A. Computed tomographic (CT) scans of the petrousbones were retrieved.

Genetic analysisDNA from lymphocytes was isolated as described (22). For

amplification of the coding region of the NOG gene, the fol-lowing primers were used: forward primer, 5�-TGTGTG-CCTTTCTTCCGC-3�; and reverse primer, 5�-AGGATCA-AGTGTCCGGGTG-3�. Conditions for amplification are avail-able on request. For sequencing, the above-mentioned primerswere used in addition to the primers 5�-TACGACCCAGGCT-TCATGG-3� and 5�-CCTTTGATCTCGCTCGGCAT-3�. Se-quencing was performed with the ABI PRISM Big Dye Ter-minator Cycle Sequencing V2.0 Kit and the reactions wereanalyzed with the ABI PRISM 3700 DNA analyzer (AppliedBiosystems, Foster City, CA, U.S.A.).

RESULTS

Family case historiesThe clinical findings of the affected family members

are presented in Table 1.

39TEUNISSEN-CREMERS SYNDROME

Otology & Neurotology, Vol. 26, No. 1, 2005

Family AFamily A consists of 22 persons in four consecutive

generations (1). Five individuals in three consecutivegenerations were affected (Cases A II:2, A III:1, A III:5,A IV:4, and A IV:5). The facial appearances of a father(Case A III:5) and his two sons (Cases A IV:4 and AIV:5) are shown in Figure 1. One other person, who didnot want to participate in the study, was only known tohave syndactyly (Case A III:4). Clinical description ofthe five affected persons has already been given by Teu-nissen and Cremers (1). Reconstructive ear surgery, per-formed in Cases A III:5, A IV:4, and A IV:5, was alsodescribed (Table 2) (1). In 1990, after publication of thereport, the contralateral ear was operated on in Cases AIV:4 and A IV:5.

At the age of 59, Case A III:5 was reexamined. Medi-cal and otologic histories only showed a lumbar hernianucleus pulposus at age 58. Clinical examination mani-fested a large, overhanging tip of the nose, but no hemi-cylindrical shape or hypoplasia of the alae of the nosewas seen. His eyes seemed rather small. His cervicalspine did not seem impaired clinically, although an im-pairment on the thoracic or lumbar level could not beexcluded. The range of motion in the wrists was full.Dorsal extension of the fingers of the left hand was im-paired. Bilaterally, the distal phalanx of the thumb wasextremely broad, without brachytelephalangia (Fig. 2).He had a slight degree of clinodactyly in the second digitof the left hand. The feet showed broad distal phalangesof all toes, without brachytelephalangia. Syndactyly wasfound between the second and third toes bilaterally.Symphalangism was found in neither the hands nor thefeet. Radiologic examination at age 44 showed fusion ofvertebrae C6 and C7 and conspicuous short and broadmetatarsal bones of the first toes. Additional radiologicexamination at age 59 manifested a possible subtalarsynostosis in both feet. Synostoses were found in neitherhands nor feet.

In Case A IV:4, preoperative otoscopy manifested nor-mal tympanic membranes and well-aerated middle ear

clefts at 19 years of age. Cortical mastoidectomy withepitympanotomy and posterior tympanotomy on the rightear were performed, which manifested stapes ankylosiswith fixation of the short process of the incus in the fossaincudis. Stapedotomy was followed by interposition of apolytetrafluoroethylene (Teflon) wire piston (Fisch type;Richards Co, Memphis, TN, U.S.A.; shaft length, 5.5mm; diameter, 0.4 mm). Preoperative hearing impair-ment of 43 dB (mean value at 0.5, 1, and 2 kHz) at theright ear was reduced to 17 dB (mean value at 0.5, 1, and2 kHz), with a residual air-bone gap of 20 dB at 0.5 kHz,20 dB at 1 kHz, and 20 dB at 2.0 kHz (mean value of 20dB at 0.5, 1, and 2 kHz; follow-up, 157 mo) (Fig. 3 andTable 2). Except for bilateral stapedotomy, medical andotologic histories at age 33 were normal. Clinical exami-nation showed small eyes compared with other facialstructures. He displayed hypoplasia of the alae of thenose, with a low insertion of the columella but no hemi-cylindric shape of the nose. Lateroflexion of the cervicalspine was moderately impaired, mainly to the left side.The distal phalanges of the thumbs and first toes werebroad without brachytelephalangia (Figs. 2 and 4).Symphalangism was seen in the proximal interpha-langeal joints of the fifth fingers, second toes, and fourthright toe and in the distal interphalangeal joint of theright second toe. Syndactyly was noticed between thesecond and third digits of both feet and hands (Fig. 4).The fifth fingers showed clinodactyly. Radiologic exami-nation of the cervical spinal vertebrae at age 18 did notshow any anomalies. At age 33, radiologic examinationshowed ankylosis of the fifth fingers bilaterally. Synos-toses were found in neither hands nor feet.

At age 13, preoperative otoscopy manifested normaltympanic membranes and well-aerated middle ear cleftsin Case A IV:5. Cortical mastoidectomy with epitympa-notomy and posterior tympanotomy at the left ear wasperformed, which manifested a congenital stapes anky-losis with congenital fixation of the short process in thefossa incudis. The short process of the incus was mobi-lized and stapedotomy was performed with fixation of

TABLE 1. Clinical findings in the affected members of the three presented families

Case A II:2 A III:1 A III:5 A IV:4 A IV:5 B I:1 B II:1 C I:1 C II:1

Hearing loss 60 60 60 40–50 60 35–45 35–65 20–30 30–40Stapes ankylosis Noo Noo + + + Noo + Noo +Fixed short process Noo Noo − + + Noo − Noo PossiblySyndactyly of toes second,

thirdsecond,

thirdsecond,

thirdsecond,

thirdsecond,

thirdsecond,

thirdsecond,

thirdsecond,

thirdsecond,

thirdBroad thumbs/first toes + + + + + + + + +Brachytelephalangia + + + + + + + + +Fused cervical vertebrae on radiography C6–C7 − C6–C7 − − C4–T2 − − −Symphalangism − − − Fifth fingers − − Fifth fingers − Fifth fingersAdditional findings a b–e b,f

aBroad second fingers.bLimitation of the elbow joint.cPossible limitation in hip or knee joint.dSynostoses of distal interphalangeal joints of third to fifth toes.eAdditional bone nucleus proximally of styloid process.fOssification disorder in radiohumeral joint.Noo, not operated on.

40 H. H. WEEKAMP ET AL.


FIG. 1. Facial appearance of father (Case A III:5, 44 years old) and both sons (Case A IV:4, 19 years old; Case A IV:5, 13 years old)in Family A (first row, Case A III:5 [left] and Case A IV:4 [right]; second row, IV:5); the mother (Case B I:1, 42 years old) and daughter(Case B II:1, 10 years old) in Family B (third row, Case B I:1 [left] and Case B II:1 [right]); and the mother (Case C I:1, 42 years old) anddaughter (Case C II:1, 13 years old) in Family C (fourth row, Case C I:1 [left] and Case C II:1 [right]).

the Teflon platinum piston (Fisch type; Richards; shaftlength, 4.75 mm; diameter, 0.4 mm) at the long processof the incus. Preoperative hearing impairment of 58 dB(mean value at 0.5, 1, and 2 kHz) at the left ear wasreduced to 15 dB (mean value at 0.5, 1, and 2 kHz), witha residual air-bone gap of 20 dB at 0.5 kHz, 15 dB at 1kHz, and 0 dB at 2 kHz (mean value of 12 dB at 0.5, 1,and 2 kHz; follow-up, 157 mo) (Fig. 5 and Table 2).Medical and otologic histories at age 33 were normal,except for bilateral stapedotomy. Clinical examinationshowed small eyes compared with other facial structures.The shape of the nose was considered normal. Spinal andelbow ranges of motion were full. The distal phalangesof the thumbs were broad and short (Fig. 2). The secondand third digits on the right and second to fourth digits onthe left were short and slightly broad. Only slight syn-dactyly was found between the third and fourth fingerson the left and bilaterally between the second and thirddigits of hands and feet. Bilaterally, the forefoot wasremarkably broad. Radiologic examination at age 11showed short first metacarpal bones and short distal pha-langes of the first to fourth fingers. Shortness of distalphalanges of the hands is still noticed at age 26. No otheranomalies were seen in hands or feet.

Cephalometric analysis was performed at the age of 59years 11 months for Case A III:5, at 33 years for Case AIV:4, and at 26 years 8 months for Case A IV:5 (Table 3).Generally, the cephalometric values were within normallimits. Case A III:5 had a remarkably long styloid pro-cess extending beyond the gonial angle of the mandible.

Family BIn this family, only 2 of 20 members of four genera-

tions are affected; a mother (Case B I:1) and her daughter(Case B II:1). The 9-year-old daughter (Fig. 1) presentedwith bilateral congenital hearing impairment. Duringpregnancy, her mother had oligohydramnios. The daugh-ter was born by cesarean section, because of a breechposition, at 33 weeks’ gestation. She had congenital hy-pertrophy of the sternocleidomastoideus muscle at theright side, with a tendency to torticollis. She had a his-tory of otitis media with effusion, for which she had beentreated with tympanostomy tube insertions at the age of 5.

At otoscopy, the right ear canal showed extreme up-ward sloping. A slight degree of myringosclerosis of thetympanic membrane and well-aerated middle ear clefts

were noted. Using the microscope, a clearly visible in-cudostapedial joint was seen, shining through the lefttympanic membrane. Pure-tone audiometry showed amainly conductive hearing impairment of 62 dB (meanvalue at 0.5, 1, and 2 kHz) at the right ear and 45 dB(mean value at 0.5, 1, and 2 kHz) at the left ear (Fig. 6).At the right ear, there was a “notch” at 2 kHz in theperceptive threshold. Speech recognition showed a pho-neme score of 100%. CT scan of the temporal bonesshowed no anomalies. During an exploratory tympanot-omy of the right ear, stapes ankylosis was seen. In ad-dition, a severe fixation of the malleoincudal joint wasfound that resolved “spontaneously” by manipulation.Only a slight immobility of the malleoincudal joint re-mained, which was considered acceptable. A Teflonplatinum piston (Fisch type; Richards; shaft length, 4.75mm; diameter, 0.4 mm) was fixated to the long processof the incus. The hearing threshold was reduced to 18 dB(mean value at 0.5, 1, and 2 kHz), with a residual air-bone gap of 20 dB at 0.5 kHz, 15 dB at 1 kHz, and 20 dBat 2 kHz (mean value of 18 dB at 0.5, 1, and 2 kHz;follow-up, 9 mo) (Fig. 6 and Table 2).

During clinical examination, we still observed a torti-collis at the right side. No hypoplasia of the alae of thenose was seen. She had broad and short distal phalangesof the thumbs (Fig. 2) and proximal symphalangism ofthe fifth digit of both hands. Only slight impairment inflexion of the distal interphalangeal joint of the thumbswas noticed. Furthermore, she had a slight degree ofsyndactyly between the second and third fingers bilater-ally and brachydactyly of the fifth fingers. Syndactylywas more prominent between the second and third toesbilaterally. Spinal range of motion was full.

Radiologic investigation manifested synostosis of theproximal phalanges and middle phalanges of the fifthfingers. The proximal phalanx of the first toe of the leftfoot was short. The intervertebral disk was narrow be-tween C5 and C6. No bone or joint abnormalities wereseen in the elbow joint.

The mother (Case B I:1) was 42 years of age (Fig. 1)and presented with congenital conductive hearing im-pairment of the right ear. Bilaterally, the ear canalshowed an extreme upward sloping. The anterior exter-nal canal impaired the sight at one-third of the anteriortympanic membrane. The part of the tympanic mem-brane that could be examined was normal, and middleear clefts were well-aerated. Using the microscope, aclearly visible incudostapedial joint was seen, shiningthrough the tympanic membrane. Pure-tone audiometrymanifested a pure conductive hearing impairment of 40dB (mean value at 0.5, 1, and 2 kHz) in the right ear.Hearing impairment of 7 dB (mean value at 0.5, 1, and 2kHz) in the left ear was not significant. Speech recogni-tion showed a phoneme score of 100%. Contralateralstapedial reflexes could not be elicited. Clinical exami-nation of the mother manifested incomplete range of mo-tion of the neck. No hypoplasia of the nasal alae wasseen. Bilaterally, the distal phalanges of the first twodigits were broad and short (Fig. 2). All fingers were

TABLE 2. Results of reconstructive ear surgerya

Air-bone gap(dB)b

Ears operationon (n)

<10 410–20 425 1Total 9

an � 9 ears; five new reconstructive ear surgeries; details on recon-structive ear surgeries in four ears were previously published by Teu-nissen and Cremers (1990).

bPostoperative mean values of air-bone gaps at 0.5, 1, and 2 kHz.



rather short, especially the fifth digits. The first toes werebroad and short. There was syndactyly between the sec-ond and third toes bilaterally. No symphalangism wasdetected.

Radiologic investigation confirmed short distal pha-

langes of both hands and feet without any symphalang-ism. Synostoses of the talocalcaneal joints could not beconfirmed or excluded. Evident fusion of vertebrae fromC4 to T2 were noticed. No bone or joint abnormalitieswere present in the elbow joint.

FIG. 2. Broad and short distal phalanges of the thumbs in Cases A III:5 (third row, right), A IV:4 (second row, right), and A IV:5 (thirdrow, left) of Family A; Cases B I:1 (first row, left) and B II:1 (second row, left) of Family B; and Cases C I:1 (fourth row, left) and C II:1(first row, right) of Family C.



The mother (Case B I:1) was 42.9 years of age and thedaughter (Case B II:1) was 11.5 years of age at the timeof cephalometric examination (Table 3). Generally, thecephalometric values were within normal limits. Case BI:1 had a long styloid process extending to the gonialangle of the mandible. According to the mother, her 45-year-old sister had short fifth fingers and a short fourthdigit of the right foot.

Family CIn this family, 2 of 22 family members from five con-

secutive generations are affected: a mother (Case C I:1)and her daughter (Case C II:1) (Fig. 1). The 10-year-old

daughter was referred for congenital hearing impairment.Medical history revealed birth by cesarean section be-cause of a breech position and a long stature, for whichshe was referred to a pediatrician. She had a history ofotitis media with effusion, for which she had been treatedwith tympanostomy tube insertions. Otoscopy showednormal tympanic membranes and well-aerated middleear clefts. Pure-tone audiometry revealed a symmetrical,nonprogressive, mainly conductive hearing impairmentof 38 dB (mean value at 0.5, 1, and 2 kHz) at the right earand 40 dB (mean value at 0.5, 1, and 2 kHz) at the leftear, and a notch in the perceptive hearing threshold at 2kHz bilaterally (Fig. 7). Speech recognition was not af-fected (phoneme score, 100%). Contralateral stapedialreflexes could not be elicited. A CT scan of the temporalbones showed no anomalies. Exploratory tympanotomywas performed at the left ear at the age of 11. Congenitalstapes ankylosis with a possible bony fixation of theshort process of the incus in the fossa incudis was found.Mobility of the malleoincudal joint was somewhat less inthe medial direction but was sufficient in the lateral di-rection. A regular stapedotomy was performed with fixa-tion of a Teflon platinum piston (Fisch type; Richards;shaft length, 5.0 mm; diameter, 0.4 mm) to the longprocess of the incus, which reduced the hearing thresholdto 22 dB (mean value at 0.5, 1, and 2 kHz), with aresidual air-bone gap of 25 dB at 0.5 kHz, 15 dB at 1kHz, and 5 dB at 2 kHz (mean value of 15 dB at 0.5, 1,and 2 kHz; follow-up, 32 mo) (Fig. 7 and Table 2).Fifteen months later, an exploratory tympanotomy at theright ear revealed fixation of the stapes in the oval win-

FIG. 4. Feet of Case A IV:4 showing broad and short distalphalanges of the first toes with additional synostoses.

FIG. 3. Preoperative and postoperative audiograms of Case AIV:4. Preoperative (above) and postoperative audiograms (be-low) 157 months after stapedotomy at the right ear in Case AIV:4. O, air conduction OD, [ = bone conduction OD, X = airconduction OS, ] = bone conduction OS.

FIG. 5. Preoperative and postoperative audiograms of Case AIV:5. Preoperative (above) and postoperative audiograms (be-low) 157 months after stapedotomy at the left ear in Case A IV:5.O, air conduction OD (= bone conduction OD, X = air conductionOS) = bone conduction OS.



dow and a diminished mobility of malleus and incus. Byremoving the posterior half of the footplate, a successfulstapedectomy was performed. The anterior half of thefootplate was removed. The incus, which was fixated inboth the epitympanum and in the fossa incudis, was mo-bilized and removed. The head of the malleus was re-moved and the handle of the malleus was only superiorlyseparated from the tympanic membrane. A Teflon plati-num piston (Fisch type; Richards; shaft length, 5.75 mm;diameter, 0.4 mm) was interposed onto the handle of themalleus (23). Thus, malleovestibulopexy was performed.Hearing threshold was reduced to 25 dB (mean value at0.5, 1, 2 kHz), with a residual air-bone gap of 20 dB at0.5 kHz, 0 dB at 1 kHz, and 5 dB at 2 kHz (mean valueof 8 dB at 0.5, 1, and 2 kHz; follow-up, 16 mo) (Fig. 7and Table 2).

Clinical examination showed a long stature (1.84 m;p > 97). The eyes seem to be rather small, comparedwith other facial structures. No abnormalities were seenin the shape of the nose. Spinal range of motion was full.Distal phalanges of the thumbs were broad and short(Fig. 2). There was only a slight degree of syndactylybetween the second and third digits of the left hand andalso between the third and fourth digits bilaterally. Proxi-mal symphalangism of the fifth digits was seen in bothhands (Fig. 8). The basis of the first toes had a conspicu-ous proximal insertion. There was brachytelephalangiaof the left first toe, and both first toes were broad. Bi-laterally, the third and second toes were long, with shortand broad distal phalanges of the second and third toes.There was syndactyly between the second and third toesin both feet, but no symphalangism. Orthopedic exami-

FIG. 6. Preoperative and postoperative audiograms of Case BII:1. Preoperative (above) and postoperative audiograms (below)9 months after stapedotomy at the right ear in Case B II:1. O = airconduction OD, [ = bone conduction OD, X = air conduction OS,] = bone conduction OS.

FIG. 7. Preoperative and postoperative audiograms of Case CII:1. Preoperative (above) and postoperative audiograms (below)of Case C II:1 at 21 months (left ear) and 6 months (right ear)after stapedotomy. O = air conduction OD, [ = bone conductionOD, X = air conduction OS, ] = bone conduction OS.

TABLE 3. Cephalometric findings in seven affected members of the three presented familiesa

Case Sex Age (yr, mo)

Lo-Horiz Lo-VertAdditional

cephalometric findingsRight Left Right Left

A III:5 M 59, 11 47.4 50.1 36.9 40.1 (±1 SD) Long styloid processA IV:4 M 33, 0 46.5 46.5 37.3 35.5A IV:5 M 26, 8 43.7 (−1 SD) 45.9 38.0 38.2B I:1 F 42, 9 47.3 49.2 (+1 SD) 38.2 37.3 Long styloid processB II;1 F 11, 5 41.9 (−1 SD) 42.8 31.9 34.6C I:1 F 42, 2 44.6 (−1 SD) 44.6 (−1 SD) 33.6 (−1 SD) 33.7 (−2 SD)C II:1 F 13, 8 46.0 45.8 34.1 34.0 Broad spinal process C2 articulating with vertebra C1

aCervical vertebrae C1–C4 are visible on the head films.Lo, the intersection of the lateral wall of the orbit with the greater wing of the sphenoid; Lo-Horiz, the horizontal distance from Lo to the midsaggital

plane; Lo-Vert, the vertical distance from Lo to the FH plane.SD, standard deviation.



nation of the right and left elbow joints manifested limi-tations in flexion (110/130 degrees) and slight limitationsin pronation (70/80 degrees) and supination (80/90 de-grees), which did not cause impairment in the patient’sdaily life (Fig. 8).

Radiologic examination manifested broad and shortdistal phalanges of the thumbs. The shaft of the meta-carpal bone was broad in both thumbs. The metacarpalbones of the second to fourth fingers were long com-pared with the surrounding bones. The middle phalangesof the fifth fingers were absent. In the right hand, therewas fusion of the hamatum and capitatum bones. In thefifth finger, the proximal phalanx was long and themiddle phalanx was absent bilaterally. In both feet, themetatarsal bone and the proximal phalanx of the great toewere short and broad. Compared with the surroundingbones, the metatarsal bones of the second to fifth toeswere rather long. The basis of the medial cuneiformbones were broad in both feet. Unilaterally, a slight dis-order in the ossification of the radiohumeral joint wasrevealed. The radial head was not totally congruent. Ra-diologic images of the cervical spine manifested verte-

bral bodies in which the height was greater than thetransverse diameter, which is unusual. The laminae andthe facet joints were rather broad. The spinolaminar linecould not be distinguished. Possibly, the C1 vertebraarticulated with the posterior side of the spinal process ofC2. Generally, the cervical spinal processes were con-spicuously broad. Schmorl nodes were noticed in upperand lower thoracic vertebral endplates and irregularitieswere seen in lumbar vertebrae.

The mother (C I:1), 38 years of age, also had congen-ital hearing impairment. Except for an appendectomyand a cesarean section, her medical and otologic historieswere normal. Otoscopy showed normal tympanic mem-branes and well-aerated middle ear clefts. Pure-tone au-diometry manifested a symmetrical, nonprogressive,mainly conductive hearing impairment of 37 dB (meanvalue at 0.5, 1, and 2 kHz) at the right ear and 32 dB(mean value at 0.5, 1, 2 kHz) and a notch in the percep-tive hearing threshold at 2 kHz bilaterally. Speech rec-ognition was not affected (phoneme score, 100%). Con-tralateral stapedial reflexes could not be elicited. Anexploratory tympanotomy was not performed.

FIG. 8. Proximal symphalangism of fifth digit and elbow impairment in Case C II:1. Proximal symphalangism of the fifth digit (left) andslight impairment of flexion in right elbow joint (right) in Case C II:1 (left elbow joint not shown).



At clinical examination, the eyes seemed to be rathersmall, compared with the face. No abnormalities wereseen in the shape of the nose. In contrast to movementsof the cervical spine, the lumbar spinal range of motionwas moderately impaired. Flexion of the elbow jointswas only slightly impaired. Both hands showed broadand short distal phalanges of the thumbs (Fig. 2); shortdistal phalanges of the second, fourth, and fifth digits; aslight impairment of flexion in the distal interphalangealjoint of the right fifth digit; and a slight degree of syn-dactyly between the second and third digits of bothhands. Both feet showed a slightly proximal insertion ofthe basis of the first toes. The first toes were broad. Thedistal phalanx of the second toe was slightly broad inboth feet. Syndactyly was found between the second andthird digits of both feet. No symphalangism was seen.Extreme exorotation of the hip joints during flexion inthe knee joints when sitting on the floor was also limited.

Radiologic examination revealed conspicuousbrachytelephalangia of the thumbs and fifth fingers. Hy-pophalangia of the middle phalanges and distal phalan-ges of the second, third, and fourth fingers was seen.Metacarpal bones of the second and third fingers wererather long. An additional bone nucleus proximal to thestyloid process of the ulna was seen at the right site. Nocarpal or tarsal synostoses were noted. The metatarsalbone and the proximal phalanx of the first toes wereshort and broad. In addition, the distal phalanx of the firsttoes was also broad. Neither symphalangism nor syndac-tyly was noted in both hands and feet. Radiographs of thecervical spinal vertebrae showed a narrow intervertebralspace between C5 and C6. The spinal processes andlaminae seemed to be broad. The spinolaminar lineseemed to be in the same line as the posterior sides of thelaminae. On the lumbar level of the spine, a convexscoliosis of approximately 5 degrees was noticed.Schmorl nodes were present at the level of the body ofthe L1 vertebra. A separate bone nucleus was seen on theventral side in the body of the L4 vertebra at the level ofthe epiphysis. The transverse diameter of the L5 vertebra

was small. The bodies of the other lumbar vertebrae alsoshowed variation in transverse diameter. The elbowjoints were considered normal. A CT scan of middle andinner ear structures showed no anomalies.

The mother (Case C I:1) was 42 years 2 months of ageand the daughter (Case C II:1) was 13 years 8 months ofage at the time of cephalometric examination (Table 3).For Case C I:1, all measurements related to the bonyorbit were 1 or 2 standard deviations below the normvalues. For Case C II:1, the cephalometric values werewithin normal limits. The head film confirmed the find-ing that the C1 vertebra probably articulates with theposterior side of the spinal process of C2. Generally, thecervical spinal processes were broad.

Measurement of ocular refraction of the seven patients(14 eyes) revealed a bilateral hyperopia in all patients(mean, +8 diopters; range, +3.5–+14.75 diopters). Ultra-sound axial length measurements showed short eyes(mean, 19.4 mm; range, 17.7–20.7 mm). Orthoptic ex-amination showed strabismus in all seven patients (fivewith esotropia and two with exotropia), with unilateralamblyopia in four of them. The rest of the ocular exami-nation showed no unusual findings (Table 4).

In Table 5, the features of the presented families arecompared with features of families with the TC syn-drome (2–4) and literature reports of the SYM1 syn-drome (10,13,24–32), the SYNS1 syndrome (33–51),and the TCC syndrome (9,52,53). Occasionally, varietyin expression of symptoms made it difficult to assign areport to a certain syndrome. Concerning the reports ofthe SYM1 syndrome, we mainly included those reportsthat were referred to as such by Gorlin et al. (54).

Genetic analysisMutation analysis by sequencing the protein-coding

region of the NOG gene revealed mutations in the af-fected members of all three families. In Family A, aninsertion of two nucleotides, guanosines, was detectedbetween nucleotides 130 and 131 of the protein-codingregion (c130–131insGG). For the analysis of the segre-

TABLE 4. Ophthalmologic findings in the affected members of the three presented families

Case

Refraction (D) Axial eye length (mm)

Strabismus

Corneal radius (mm)

OD OS OD OS OD OS

A III:5 +7.75 +6.0 19.22 (−2 SD) 19.64 (−2 SD) ±a 7.52 7.52A IV:4 +3.5 +4.75 20.71 (−1 SD) 20.20 (−1 SD) +b 7.60 7.62A IV:5 +8.25 +8.75 19.72 (−2 SD) 19.40 (−2 SD) +c 7.59 7.58B I:1 +7.0 +7.0 19.63 (−2 SD) 19.78 (−2 SD) −d 7.63 7.58B II:1 +4.75 +4.75 20.14 (−1 SD) 20.30 (−1 SD) +e 7.28 7.34C I:1 +14.75 +13.5 18.20 (−2 SD) 18.00 (−3 SD) +f 7.95 7.84C II:1 +11.75 +12.5 18.50 (−2 SD) 17.70 (−3 SD) +f 7.59 7.43

aAmyblyopia OD and anisometropia.bAlternating divergent strabismus.cConvergent strabismus OS.dLatent divergent strabismus.eAlternant convergent strabismus.fConvergent strabismus OS with amblyopia due to abnormal retinal correspondence.OD, right eye; OS, left eye; SD, standard deviation.



gation of this mutation in the family, samples were avail-able from the Cases A III:5, A III:6, A IV:4, and A IV:5(1). The mutation was not found in the unaffected mother(Case A III:6) but was inherited from their affected father(Case A III:5) by the affected children (Cases A IV:4 andIV:5). The mutation can be predicted to cause a frame-shift mutation in the mRNA in codon 44 (V44fs) and apremature stop codon after the codons for 18 aberrantamino acids.

The transition of nucleotide 608 of the coding se-quence of a thymidine (T) to a cytidine (C) was found inboth the affected mother and daughter of Family B. Atthe protein level, the mutation can be predicted to causethe substitution of proline for leucine, Leu203Pro, whichis a nonconservative amino acid change. The mutationwas not present in 50 control individuals and thereforecan be regarded as causative for the syndrome.

In Family C, a deletion of a cytidine at position 561was found in both the affected mother and daughter. Thismutation can be predicted to cause a frameshift in thecoding sequence at the codon for amino acid 187, proline(187fs), and the incorporation of 76 aberrant amino ac-ids. All three mutations were not described before.

DISCUSSION

Literature review of syndromes with symphalangismor synostoses shows a great diversity in expression ofsymptoms (Table 5). Several families have been reportedin which their members showed conductive hearing im-pairment, hyperopia, and broad thumbs and first toeswith brachytelephalangia (1–4). Except for conductive

hearing loss, these features are rarely seen in associatedsyndromes (Table 5). The assignment of the clinical fea-tures of a family to a certain syndrome might be some-what artificial, because the clinical presentation of thereviewed cases showed both interfamilial and intrafamil-ial variation (Table 5). Furthermore, data were not com-pletely available occasionally. Taking this into account,we consider the TC syndrome to be a distinct clinicalentity, because the combination of features (conductivehearing impairment, high hyperopia, and broad thumbsand first toes with brachytelephalangia) is unique and theintrafamilial prevalence of affected persons is rather high.

High hyperopia, with associated strabismus sincechildhood, was found in all of our patients. The hypero-pia was caused by a short axial length of the eye (<21mm in adults). High hyperopia is a well-known risk fac-tor for development of strabismus. Remarkably, strabis-mus has been reported in only two cases (11%) of otherfamilies with the TC syndrome, although the prevalenceof hyperopia is high (approximately 90%). In one ofthese cases, the strabismus was not explicitly mentionedbut could be seen in a photograph (2). Except for a fewcases of strabismus in families with the SYM1 syndrome(approximately 10%), strabismus and hyperopia had anextremely low prevalence in the associated syndromes.

Even though the distribution of other symptoms in thesyndromes mentioned above varies to some extent (i.e.,syndactyly, elbow involvement, nasal features), there isoverlap in the symptoms. Regarding the fact that thesevarious syndromes are caused by mutations in the samegene (NOG), similarity in defects at the protein levelmight be assumed.

TABLE 5. Features of presented families compared with features in reported families with Teunissen-Cremers andother syndromes

Clinical features (%)aFamily A(n � 5)

Family B(n � 2)

Family C(n � 2)

TC(n � 19)

PS(n � 55)

APS(n � 134)

TCC(n � 26)

Conductive hearing loss 100 100 100 74 42 23 12Hyperopia 100 100 100 89 2 1 0Broad thumbs 100 100 100 63–68 2 3 0Short thumbs 60 100 100 68–89 0 10 8–42Broad first toes 100 50 100 74–79 0 6 0Short first toes 40 50 50 47–74 0 11 0Carpometa carpal fusions 0 0 50 0 24 17 54Tarsometa tarsal fusions 0 0 0 0 35 35–45 100Shortness first metacarpal 20 0 0 0 4 12 42Symphalangism 20 50 50 5 80 87 42Syndactyly 100 100 100 53 24 7 0Strabismus 60–100 50 100 11 9 1 0Hemicylindric nose/hypoplasia alae of nose 20 0 0 74 2 24 0Fusion vertebrae 40 50 0 11 0 7c 0Elbow joint involvement 0 0 50 21–42b 0 13 38Clinodactyly 40 0 0 11 4 13 42Aplasia/hypoplasia distal phalanges 100 50 100 11 11 33 0Aplasia/hypoplasia mesophalanges 0 0 50 0 9 33–40 0Aplasia/hypoplasia proximal phalanges 0 50 100 0 0 5 0

aPrevalence of clinical features is expressed in percentage (including n < 100 cases).bBrown et al. described elbow function of only four of eight affected individuals.cBloom reports some vertebral anomalies, but no synostoses.TC, Teunissen-Cremers syndrome; PS, proximal symphalangism-hearing loss syndrome; APS, atypical variants of PS; TCC, tarsal-carpal coalition

syndrome.



The secreted polypeptide noggin (encoded by theNOG gene) binds and inactivates BMPs. BMPs are mem-bers of the transforming growth factor-ß superfamily ofsignaling proteins. Noggin shows a high affinity forBMP-4 (5,55). Groppe et al. (55) described the three-dimensional structure of the noggin–BMP-7 complex.Noggin binding effectively masks the binding epitopesof BMP-7, thereby blocking the cell-surface receptors(Type I and Type II) of BMP.

During embryogenesis, noggin participates in the con-trol of several processes, such as establishment of thedorsoventral axis and neural induction, and also in theongoing process of neurogenesis (56). Noggin is alsoinvolved in formation of joints in the developing skeletalsystem (6). In mice, complete loss of noggin proteinleads to multiple malformations, including joint fusion,whereas heterozygous noggin null mutants are normal. Incontrary, various skeletal abnormalities are found in hu-mans with heterozygous NOG mutation (6,57). This dif-ference in effects of only one functional NOG gene copyin mice and humans suggests a species-specific dosagedependence for the noggin protein.

So far, 17 different mutations in the NOG gene havebeen found, including the mutations presented in thisreport (4,11–14). Only five NOG mutations are known tocause a syndrome with stapes ankylosis, broad thumbsand first toes, and hyperopia (4). Four of these are trun-cating mutations. The truncating mutation in Family Aleads to a frameshift shortly after the part of the mRNAencoding the signaling sequence, which is cleaved off,and thus very early in the excreted part of the protein.Therefore, it can be assumed that the function of thenoggin protein is completely abolished and that no stableaberrant protein is synthesized. The mutation in FamilyC can be predicted to cause a frameshift in codon 187,which is between the two finger structures of the protein.From here, the amino acid sequence is abnormal. Thesecond finger structure, which is missing from the trun-cated protein, contacts BMP and masks the Type II re-ceptor-binding site of BMP (55). In addition to this, thestructure of the protein might well be drastically dis-turbed, leading to a completely inactive protein. In Fam-ily B, a nucleotide change leads to the replacement ofleucine 203 by a proline. The leucine at this position isconserved in all noggin proteins known so far from dif-ferent species. Proline is known to have a fixed structuralangle and therefore the mutation can be predicted to leadto a structural change of the noggin protein. Leucine 203is located in finger 2 of the protein, which plays a role inmasking the Type II receptor-binding site of BMP (55).

Why do different mutations in the NOG gene lead todifferent phenotypes? With the present knowledge, thisquestion is difficult to answer. Four of the five knownmutations in TC syndrome are truncating mutations andonly 2 of 12 mutations in 14 SYM1, SYNS1, and TCCfamilies. This suggests that truncating mutations mightbe more prone to cause TC syndrome than amino acidsubstitutions in the protein. Analysis of mutant nogginproteins have shown that amino acid substitutions lead to

reduced or undetectable secretion of the protein but donot interfere with the dimerization and secretion of thewild-type protein (57). Therefore, it has been suggestedthat a reduced amount of the secreted noggin protein, andnot the presence of an aberrant protein, leads to diseaseand that the lowest amount of secreted protein leads tothe most severe phenotype (57). At least the c130-131insGG mutation found in one of the present familieswith TC syndrome can be predicted to lead to a drasti-cally reduced amount of secreted noggin protein. Wheth-er the other truncating mutations in TC syndrome havethe same effects as the missense mutations studied byMarcelino et al. (57) remains to be determined, but thisseems likely. Possibly, some symptoms that are seen inthe TC syndrome, but that are absent in associated syn-dromes, might only be generated by a stronger reductionof the amount of functional noggin protein. Assumingthat the amount of functional noggin is lowest in the TCsyndrome, we cannot explain why symptoms that occurin associated syndromes are not seen in the TC syndrome.

That other genetic factors and/or environmental fac-tors play a role in the phenotypic outcome of a specificmutation can be concluded from intra- and interfamilialvariation. For example, the Pro35Arg mutation is foundboth in a family with the SYM1 syndrome and a familywith TCC syndrome (11,14). The tissue-specific dosage-dependent function of noggin during joint formation,suggested by Gong et al. (11) and Marcelino et al. (57),contributes to the variation in the effects of differentmutations.

In five of the presented affected persons, the eyesseemed to be rather small at clinical examination. Thebony measurements on the anteroposterior radiographconfirmed this finding in only one individual. In addi-tion, the axial length of the eye was shorter in all indi-viduals examined. Unfortunately, it is not possible tomeasure the axial length of the bony orbit on conven-tional cephalometric radiographs. In the literature, wecould not find any specific data on the effect of nogginon development of the orbital bones.

CONCLUSION

Reconstructive ear surgery resulted in normal hearingwith a closed or almost closed air-bone gap in four offive ears in Family A (1). The daughter in Family B, whohad reconstructive ear surgery, did not need a hearing aidanymore in the ear that was operated on. A hearing aid oran exploratory tympanotomy of the right ear was alsooffered to the mother. However, because the hearing losscaused only mild impairment in her daily life, she did notconsider either of these options. In Family C, the daugh-ter was operated on bilaterally. In both ears, the air-bonegap was almost closed. In the past, good results couldalso be achieved by reconstructive surgery of stapesankylosis in the SYM1 syndrome (58). In addition tostapes ankylosis, the ear surgery manifested fixation ofthe short process of the incus in the fossa incudis. Thiswas found in four ears, and a possible fixation of this



process was suspected in one ear. These fixations couldbe resolved during the operation. This suprastapedialanomaly, which is very uncommon, was also reported inthe literature regarding proximal symphalangism (29,32,58). One of the hazards in surgery of stapes ankylosis isa recurrent bony closure of the footplate after stape-dotomy (59). Therefore, partial platinectomy might beconsidered to prevent reclosure of the oval window (58).Hearing aids also remain a good option for treatment.

Acknowledgments: The authors thank the families for theirparticipation and J. Bodegom, Ph.D., for contributing to thecephalometric analysis.

REFERENCES

1. Teunissen B, Cremers CWRJ. An autosomal dominant inheritedsyndrome with congenital stapes ankylosis. Laryngoscope 1990;100:380–4.

2. Hilhorst-Hofstee Y, Watkin PM, Hall CM, Baraitser M. The au-tosomal dominant syndrome with congenital stapes ankylosis,broad thumbs and hyperopia. Clin Dysmorphol 1997;6:195–203.

3. Milunsky J, Suntra C, MacDonald CB. Congenital stapes ankylo-sis, broad thumbs, and hyperopia: report of a family and refinementof a syndrome. Am J Med Genet 1999;82:404–8.

4. Brown DJ, Kim TB, Petty EM, et al. Autosomal dominant stapesankylosis with broad thumbs and toes, hyperopia, and skeletalanomalies is caused by heterozygous nonsense and frameshift mu-tations in NOG, the gene encoding noggin. Am J Hum Genet2002;71:618–24.

5. Zimmerman LB, De Jesús-Escobar JM, Harland RM. The Spe-mann organizer signal noggin binds and inactivates bone morpho-genetic protein 4. Cell 1996;86:599–606.

6. Brunet LJ, McMahon JA, McMahon AP, Harland RM. Noggin,cartilage morphogenesis, and joint formation in the mammalianskeleton. Science 1998;280:1455–7.

7. Cushing H. Hereditary ankylosis of the proximal phalangeal joints.Genetics 1916;1:90–106.

8. Strasburger AK, Hawkins MR, Eldridge R, Hargrave RL, McKu-sick VA. Symphalangism: genetic and clinical aspects. Bull JohnsHopkins Hosp 1965;117:108–27.

9. Gregersen HN, Petersen GB. Congenital malformation of the feetwith low body height: a new syndrome, caused by an autosomaldominant gene. Clin Genet 1977;12:255–62.

10. Vesell ES. Symphalangism, strabismus and hearing loss in motherand daughter. N Engl J Med 1960;263:839–42.

11. Gong Y, Krakow D, Marcelino J, et al. Heterozygous mutations inthe gene encoding noggin affect human joint morphogenesis. NatGenet 1999;21:302–4.

12. Takahashi T, Takahashi I, Komatsu M, et al. Mutations of theNOG gene in individuals with proximal symphalangism and mul-tiple synostosis syndrome. Clin Genet 2001;60:447–51.

13. Mangino M, Flex E, Digilio MC, Giannotti A, Dallapiccola B.Identification of a novel NOG gene mutation (P35S) in an Italianfamily with symphalangism. Hum Mutat 2002;19:308.

14. Dixon ME, Armstrong P, Stevens DB, Bamshad M. Identical mu-tations in NOG can cause either tarsal/carpal coalition syndrome orproximal symphalangism. Genet Med 2001;3:349–53.

15. Lucotte G, Bathelier C, Mercier G, et al. Localization of the genefor fibrodysplasia ossificans progressiva (FOP) to chromosome17q21-22. Genet Couns 2000;11:329–34.

16. Sémonin O, Fontaine K, Daviaud C, Ayuso C, Lucotte G. Identi-fication of three novel mutations of the noggin gene in patientswith fibrodysplasia ossificans progressiva. Am J Med Genet 2001;102:314–7.

17. Xu MQ, Feldman G, Le Merrer M, et al. Linkage exclusion andmutational analysis of the noggin gene in patients with fibrodys-plasia ossificans progressiva (FOP). Clin Genet 2000;58:291–8.

18. International Organization for Standardization. ISO 8253-1:

Acoustics—Audiometric Test methods. I: Basic Pure Tone Air andBone-Conduction Threshold Audiometry. Geneva, Switzerland: In-ternational Organization for Standardization, 1989.

19. Basyouni AA, Nanda SK. An Atlas of the Transverse Dimensionsof the Face. Craniofacial Growth Series. Vol 37. Ann Arbor, MI:Center for Human Growth and Development, 2002.

20. International Organization for Standardization. ISO 7029: Acous-tics—Threshold of Hearing by Air Conduction as a Function ofAge and Sex for Otologically Normal Persons. Geneva, Switzer-land: International Organization for Standardization, 1984.

21. Bosman AJ, Smoorenburg GF. Intelligibility of Dutch CVC syl-lables and sentences for listeners with normal hearing and withthree types of hearing impairment. Audiology 1995;34:260–84.

22. Miller SA, Dykes DD, Polesky HF. A simple salting out procedurefor extracting DNA from human nucleated cells. Nucleic Acids Res1988;16:1215.

23. Fisch U, Acar GO, Huber AM. Malleostapedotomy in revisionsurgery for otosclerosis. Otol Neurotol 2001;22:776–85.

24. Harle TS, Stevenson JR. Hereditary symphalangism associatedwith carpal an tarsal fusions. Radiology 1967;89:91–4.

25. Geelhoed GW, Neel V, Davidson RT. Symphalangism and tarsalcoalitions: a hereditary syndrome. J Bone Joint Surg Br 1969;51:278–89.

26. Gorlin RJ, Kietzer G, Wolfson J. Stapes fixation and proximalsymphalangism. Z Kinderheilkd 1970;108:12–6.

27. Schulthess G. Isolierte Stapesankylose als Teilsymptom eineshereditären Mißbildungssyndroms. Laryngol Rhinol Otol 1974;53:643–7.

28. Gloede JF, Stenger HH. Symphalangismus, Strabismus und Mit-telohrmißbildung. Humangenetik 1974;22:23–32.

29. Vase P, Prytz S, Pedersen PS. Congenital stapes fixation, sympha-langism and syndactylia. Acta Otolaryngol 1975;80:394–8.

30. Meinecke P, Passarge E. Symphalangie-Stapesfixation-Syndrom.Dtsch Med Wochenschr 1978;103:1660–5.

31. Baschek V. Stapesfixation und Symphalangie, ein autosomal dom-inant erbliches Krankheitsbild. Laryngol Rhinol 1978;57:299–304.

32. Cremers C, Theunissen E, Kuijpers W. Proximal symphalangiaand stapes ankylosis. Arch Otolaryngol 1985;111:765–7.

33. Duken J. Über die Beziehungen zwischen Assimilationshypopha-langie und Aplasie der Interphalangealgelenke. Virchows ArchPathol Anat 1921;233:204–25.

34. Bloom AR. Hereditary multiple ankylosing arthropathy (congeni-tal stiffness of the fingerjoints). Radiology 1937;29:166–71.

35. Fuhrmann W, Steffens CH, Rompe G. Dominant erbliche dop-pelseitige Dysplasie und Synostose des Ellenbogengelenks: Mitsymmetrischer Brachymesophalangie und Brachymetakarpiesowie Synostosen im Finger-, Hand- und Fußwurzelbereich. Hu-mangenetik 1966;3:64–77.

36. Dubois HJ. Nievergelt-Pearlman syndrome: synostosis in feet andhands with dysplasia of elbows—report of a case. J Bone JointSurg Br 1970;52:325–9.

37. Maroteaux P, Bouvet JP, Briard ML. La maladie des synostosesmultiples. Nouv Presse Med 1972;1:3041–7.

38. Herrmann J. Symphalangism and brachydactyly syndrome: reportof the WL symphalangism-brachydactyly syndrome—review ofliterature and classification. Birth Defects 1974;10:23–53.

39. Murakami Y. Nievergelt-Pearlman syndrome with impairment ofhearing: report of three cases in a family. J Bone Joint Surg Br1975;57:367–72.

40. Ventruto V, Di Girolamo R, Festa B. Family study of inheritedsyndrome with multiple congenital deformities: symphalangism,carpal and tarsal fusion, brachydactyly, craniosynostosis, strabis-mus, hip osteochondritis. J Med Genet 1976;13:394–8.

41. Pedersen JC, Fryns JP, Carpentier G, Heremans G, Van denBerghe H. Multiple synostosis syndrome. Eur J Pediatr 1980;134:273–5.

42. Tsuruta T, Yamazaki M, Yamazaki T. A case of multiple synos-toses syndrome. Jpn J Hum Genet 1980;25:55–61.

43. Learman Y, Katznelson MB-M, Bonné-Tamir B, et al. Sympha-



langism with multiple anomalies of the hands and feet: a newgenetic trait. Am J Med Genet 1981;10:245–55.

44. Higashi K, Inoue S. Conductive deafness, symphalangism, andfacial abnormalities: the WL syndrome in a Japanese family. Am JMed Genet 1983;16:105–9.

45. Poisson D, Zerbib M, Fortier-Beaulieu M, et al. Maladie des synos-toses multiples: etude de la variation des symptômes dans unemême famille. Arch Fr Pediatr 1983;40:35–7.

46. da-Silva EO, Filho SM, de Albuquerque SC. Multiple synostosissyndrome: study of a large Brazilian kindred. Am J Med Genet1984;18:237–47.

47. Hurvitz SA, Goodman RM, Hertz M, Katznelson MB-M, Sack Y.The facio-audio-symphalangism syndrome: report of a case andreview of the literature. Clin Genet 1985;28:61–8.

48. Gaal SA, Doyle JR, Larsen IJ. Symphalangism in Hawaii: a studyof three distinct ethnic pedigrees. J Hand Surg [Am] 1988;13:783–7.

49. Pheiffer RA, Rott HD, Angerstein W. An autosomal dominantfacio-audio symphalangism syndrome with Klippel-Feil anomaly:a new variant of multiple synostoses. Genet Couns 1990;38:133–40.

50. Moumoumi H, Mayelo V, Anthonioz P. Familial symphalangismsyndrome transmitted through five generations. Genet Couns 1991;2:139–46.

51. Castle JE, Bass S, Kanat IO. Hereditary symphalangism with as-sociated tarsal synostosis and hypophalangism. J Am Podiatr MedAssoc 1993;83:1–9.

52. Spoendlin H. Congenital stapesankylosis and fusion of tarsal andcarpal bones as a dominant hereditary syndrome. Arch Otorhino-laryngol 1974;206:173–9.

53. Drawbert JP, Stevens DB, Cadle RG, et al. Tarsal and carpalcoalition and symphalangism of the Fuhrmann type. J Bone JointSurg Am 1985;67:884–9.

54. Gorlin RJ, Toriello HV, Cohen MM. Hereditary Hearing Loss andIts Syndromes. Oxford Monographs on Medical Genetics no. 28.New York: Oxford University Press, 1995.

55. Groppe J, Greenwald J, Wiater E, et al. Structural basis of BMPsignalling inhibition by the cystine knot protein Noggin. Nature2002;420:636–42.

56. McMahon JA, Takada S, Zimmerman LB, Fan CM, Harland RM,McMahon AP. Noggin-mediated antagonism of BMP signaling isrequired for growth and patterning of the neural tube and somite.Genes Dev 1998;12:1438–52.

57. Marcelino J, Sciortino CM, Romero MF, et al. Human disease-causing NOG missense mutations: effects on noggin secretion,dimer formation, and bone morphogenetic protein binding. ProcNatl Acad Sci U S A 2001;98:11353–8.

58. Ensink RJH, Sleeckx JP, Cremers CWRJ. Proximal symphalang-ism and congenital conductive hearing loss: otological aspects. AmJ Otol 1999;20:344–9.

59. Brown DJ, Kim TB, Petty EM, et al. Characterization of a stapesankylosis family with a NOG mutation. Otol Neurotol 2003;24:210–5.



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