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Case ReportA Start Codon Variant in NOG UnderliesSymphalangism and Ossicular Chain Malformations AffectingBoth the Incus and the Stapes
Nathan R Lindquist 1 Eric N Appelbaum1 Anushree Acharya2 Jeffrey T Vrabec3
Suzanne M Leal2 and Isabelle Schrauwen 2
1Department of Otolaryngology Head and Neck Surgery Baylor College of Medicine Houston Texas USA2Center for Statistical Genetics Department of Neurology Gertrude H Sergievsky Center Columbia University Medical CenterNew York NY USA3Department of Otolaryngology Houston Methodist Hospital Houston Texas USA
Correspondence should be addressed to Isabelle Schrauwen isabelleschrauwengmailcom
Received 5 April 2019 Accepted 11 July 2019 Published 22 July 2019
Academic Editor Silvia Paracchini
Copyright copy 2019 Nathan R Lindquist et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited
We performed exome sequencing to evaluate the underlying molecular cause of a patient with bilateral conductive hearing lossdue to multiple ossicular abnormalities as well as symphalangism of the fifth digits This leads to the identification of a novelheterozygous start codon variant in the NOG gene (c2TgtCpMet1) that hinders normal translation of the noggin proteinVariants in NOG lead to a spectrum of otologic digit and joint abnormalities a combination suggested to be referred to asNOG-related-symphalangism spectrum disorder (NOG-SSD) Conductive hearing loss from such variants may stem from stapesfootplate ankylosis fixation of the malleoincudal joint or fixation of the incus short process In this case the constellation ofboth stapes and incus fixation an exceptionally tall stapes suprastructure thickened long process of the incus and enlarged incusbody was encountered leading to distinct challenges during otologic surgery to improve hearing thresholds This case highlightsmultiple abnormalities to the ossicular chain in a patient with a start codon variant in NOG We provide detailed imaging data onthese malformations as well as surgical considerations and outcomes
1 Introduction
The NOG gene encodes for the secreted protein nogginwhich is crucial in normal bone and joint developmentNoggin antagonizes bone morphogenetic proteins (BMPs)signaling which are multifunctional growth factors thatbelong to the transforming growth factor beta (TGFbeta)superfamily and are important in the development of varioustissues including bone and cartilage [1]
Autosomal dominantly inherited or de novo variants inNOG lead to a spectrum of jointdigit abnormality disorderswith or without conductive hearing loss including Type B2brachydactyly (BDB2) multiple synostoses syndrome 1(SYN1) stapes ankylosis with broad thumbs and toes
(TeunissenndashCremers syndrome) proximal symphalangism1A (SYM1A) and tarsal-carpal coalition syndrome (TCC)Overall this can be referred to as NOG-related-sympha-langism spectrum disorder (NOG-SSD) in a single unifieddiagnostic term [2] The conductive hearing loss is usuallydue to ankylosis of the stapes Other abnormalities of theossicular chain can also occur but are less frequent [2]Heterozygous Nog+minusmice display mild conductive hearingloss due to stapes fixation [3]
Herein we describe a novel variant in theNOG gene caus-ing NOG symphalangism syndrome (NOG-SSD) includingincus malformations and report its clinical and molecularphenotype as well as surgical considerations and results forthe patientrsquos conductive hearing loss
HindawiCase Reports in GeneticsVolume 2019 Article ID 2836263 5 pageshttpsdoiorg10115520192836263
2 Case Reports in Genetics
125
010203040506070
Frequency -- Hz
8090
100110120
250 500 1K 2K15K750
4K 8K6K3Kminus10
(a)
Frequency -- Hz
125 250 500 1K 2K15K750
4K 8K6K3K
0102030405060708090
100110120
minus10
(b)
Figure 1 Preoperative pure tone audiometry revealed bilateral moderate rising to mild conductive hearing loss on the right (a) and left (b)Ipsilateral and contralateral stapedial reflexes were absent bilaterally
2 Materials and Methods
21 Patient After IRB approval (H-17566) at the BaylorCollege of Medicine the patientrsquos complete medical andfamily history was reviewedwith attention to symphalangismand conductive hearing loss Study participants providedwritten informed consent Pre- and postoperative audiom-etry included pure tone audiometry and tympanometry aswell as ipsilateral and contralateral stapedial reflex testingHigh-resolution computed tomography (CT) of the temporalbone without contrast was performed utilizing axial sliceswith coronal and sagittal reconstructions to evaluate themiddle and inner ears
22 Exome Sequencing A saliva sample was obtained fromthe patient using the Oragene OG-500 collection kit andDNA was extracted via the prepIT purification kit (DNAGenotek Ontario Canada) Exomic libraries were preparedusing the SureSelect Human All Exon V6 kit and sequencingwas performed on a HiSeq (25004000) instrument Readswere aligned to the human reference genome using Burrows-Wheeler Aligner (BWAv0715) [4] Local realignment aroundInsertionDeletions (InDels) base quality score recalibrationduplicate reads removal and single nucleotide and InDelvariant calling were performed by the Genome AnalysisToolkit (GATKv37) and Picard tools [5] Next annotationwas performed using ANNOVAR (v2018Apr16) and variantswere filtered based on frequency in databases [GenomeAggregation Database (gnomAD) minor allele frequencylt0005] [6] Various bioinformatic predictions were used toevaluate variants (obtained from dbnsfp33a andANNOVAR)[7] Sanger sequencing was performed to verify a variantidentified inNOG In short purified PCR products (PrimersForward 51015840-GCCAACTTGTGTGCCTTTCT-31015840 Reverse 51015840-GTCTGGGTGTTCGATGAGGT-31015840) were sequenced using
the BigDye Terminator v31 Cycle Sequencing Kit followedby capillary electrophoresis on an ABI 3730 DNA Analyzer(Applied Biosystems Inc Foster City CA)
3 Results
31 Clinical Features Our patient is a 35-year-old Caucasianmale referred for bilateral progressive conductive hearing losssince early childhood Evaluation at the age of ten includedaudiometry but no imaging Reportedly this demonstratedsome degree of hearing loss but was not available for reviewMedical history included an abdominal lipoma open heartsurgery for aortic valve anomaly at the age of 5 and multipleorthopedic surgeries including excision of a ganglion cyst ofthe wrist as well as repair of shoulder and ankle fracturesfrom injury-appropriate sports-related trauma not thoughtto be related to his phenotype Notably the patient deniedophthalmologic history He had a family history of hearingloss in his father and paternal grandfather Reportedly hisgrandfather had similar symphalangism of both fifth digitswhile his father did not Neither were available for genetictesting or examination Physical examination of the handsdemonstrated symphalangism of both fifth digits only He didnot have proximal symphalangismof the other digits or notedbrachydactyly Imaging of the hands was not performed atour institution due to prior work-up with his primary physi-cians Binocular microscopy demonstrated bilateral normaltympanic membranes and well-aerated middle ear spacesand pneumatic otoscopy displayed mobility of the malleusbilaterally Pure tone audiometry revealed bilateral moderaterising to mild conductive hearing loss bilaterally (Figure 1)Speech recognition threshold was 45 dB in the right ear and40 dB in the left with word recognition scores for singleword understanding in quiet of 90 and 100 at 70 dB HLrespectively Acoustic immittance results revealed normal
Case Reports in Genetics 3
(a) (b)
(c) (d)
Figure 2 Axial CT bone windows of the temporal bones revealed a markedly enlarged incus with possible fixation in both the right (a)and the left ears (a) Coronal reformats on the left (c) demonstrated an elongated stapes superstructure of approximately 48 mm (dashedline) with thickening of the incus long process (arrowhead) On the right (d) this measurement was 45 mm Coronal views of the right eardemonstrated bony dehiscence or thinning in the tegmen mastoideum without meningoencephalic herniation Similar findings were notedon the left
eardrum mobility and ipsilateral and contralateral stapedialreflexes were absent bilaterally CT imaging of the temporalbones revealed an enlarged incus with possible fixationin both the right (Figure 2(a)) and the left (Figure 2(b))ears Coronal reformats demonstrated an elongated stapessuperstructure of approximately 45 mm on the right and 48mm on the left with thickening of the incus long processbilaterally (Figure 2(c)) Tegmen dehiscence or thinning wasnoted bilaterally in the tegmen mastoideum without menin-goencephalic herniation (Figure 2(d))
32 Surgical Interventions After appropriate counselling thepatient underwent surgical management to address his rightconductive hearing loss Intraoperatively ossicular abnor-malities including an enlarged fixed incus as well as fixedstapes were confirmed The incus was mildly fixed and wasmobilized using gentle traction between the body and thescutumThe patient underwent right stapedotomy with CO2
laser and reconstruction with a 5 mm Richards piston overfascia seal of the oval window His postoperative coursewas unremarkable The patientrsquos postoperative pure toneand speech recognition thresholds improved significantlyafter surgery (Figure 3) He underwent interval surgery forthe left ear five months later Intraoperative findings wereidentical and included exceptionally tall stapes and thickenedlong process of the incus Initially a Robinson prosthesiswas selected however it would not seat properly on theenlarged lenticular process Therefore a 55 mm Caussepiston was selected for reconstruction with good resultsUnfortunately the patient has not obtained a postoperativeaudiogramafter his second surgery but does report improvedsymmetric subjective hearing bilaterally at his most recentclinical follow-up
33 Genetic Analysis Exome sequencing revealed a het-erozygous start codon variant in the NOG gene in the
4 Case Reports in Genetics
0102030405060708090
100110120
minus10125 250 500 1K 2K
15K7504K 8K
6K3K
Figure 3 Postoperative pure tone audiometry revealed improve-ment of the air conduction thresholds to a mild conductive hearinglosswith near closure of the air-bone gap on the right Unfortunatelythe patient has not followed up for postoperative audiogram after hissecond operation but reports subjectively improved and symmetrichearing
patient (NM 005450 c2TgtCpMet1) which was verified bySanger sequencing This variant is absent from the gnomADdatabase and is predicted to be deleterious by various bioin-formatic tools included in dbnsfp33a (eg VariantTasterFATHMM SIFT) [7] The variant leads to a loss of the ini-tiation codon (Methionine) hinders translation of the wild-type Noggin protein and was classified as likely pathogenic(according to the American College of Medical Genetics(ACMG) guidelines for the interpretation of sequence vari-ants) [8]
4 Discussion
In patients with NOG variants conductive hearing loss hasmainly been described as a result from stapes ankylosisHowever other ossicular chain abnormalities have also beenobserved in a few cases such as fixation of the malleoincudaljoint fixation of the short process of the incus and elongationof the long process of the incus [2] Preoperative imaging forthis case demonstrated a tall stapes superstructure (increaseddistance from the incus to the vestibule) thickened longprocess of the incus and enlarged incus body Intraoper-atively the stapes and incus were both noted to be fixedAfter the mobilization of the incus stapedotomy and fascialgraft placement at the oval window the main intraoperativechallenge was selection of the appropriate stapes prosthesisgiven these anatomic abnormalities The thick incus longprocess makes placement of clip type prosthesis difficult andrenders standard crimping tools less useful Bucket-handleprostheses are also difficult given the girth of the incuslenticular process The CT findings in our case show a verylarge incus not illustrated in other cases of NOG variants
Thus we feel CT imaging is useful in preoperative planningto anticipate difficulties with prosthesis placement
Variable hearing results are reported after stapedectomyforNOG variants [9ndash11] Brown et al noted a high prevalenceof bone regrowth over the footplate resulting in recur-rent conductive loss [9] All authors recognize the needfor prosthesis that is longer than average Temporal bonehistopathology does not demonstrate inner ear anomalies [8]
In conclusion exome sequencing was utilized to identifya novel variant in the NOG gene (c2TgtCpMet1) in apatient with bilateral progressive conductive hearing andsymphalangism in the fifth digits This variant leads to a lossof the translation start site of the NOG gene and is predictedto lead to a complete loss of function of the noggin proteinWe highlight that multiple malformations in the middle earossicular chain can exist with NOG variants
Conflicts of Interest
The authors have no financial interests or disclosures todeclare
Acknowledgments
This study was supported by the American Hearing ResearchFoundation to Isabelle Schrauwen (httpamerican-hearingorg) and National Institute of Deafness and otherCommunication Disorders grants R01 DC011651 andDC003594 to Suzanne M Leal
References
[1] D Chen M Zhao and G R Mundy ldquoBone morphogeneticproteinsrdquo Growth Factors vol 22 no 4 pp 233ndash241 2004
[2] TA Potti EM Petty andMM Lesperance ldquoA comprehensivereview of reported heritable noggin-associated syndromes andproposed clinical utility of one broadly inclusive diagnosticterm NOG-related-symphalangism spectrum disorder (NOG-SSD)rdquo Human Mutation vol 32 no 8 pp 877ndash886 2011
[3] C H Hwang and D K Wu ldquoNoggin heterozygous micean animal model for congenital conductive hearing loss inhumansrdquoHumanMolecular Genetics vol 17 no 6 pp 844ndash8532008
[4] H Li and R Durbin ldquoFast and accurate long-read alignmentwith Burrows-Wheeler transformrdquo Bioinformatics vol 26 no5 pp 589ndash595 2010
[5] A McKenna M Hanna E Banks et al ldquoThe genome analysistoolkit a MapReduce framework for analyzing next-generationDNA sequencing datardquo Genome Research vol 20 no 9 pp1297ndash1303 2010
[6] K Wang M Li and H Hakonarson ldquoANNOVAR functionalannotation of genetic variants from high-throughput sequenc-ing datardquo Nucleic Acids Research vol 38 no 16 article e1642010
[7] X Liu C Wu C Li and E Boerwinkle ldquodbNSFP v30 aone-stop database of functional predictions and annotationsfor human nonsynonymous and splice-site SNVsrdquo HumanMutation vol 37 no 3 pp 235ndash241 2016
Case Reports in Genetics 5
[8] A M Quesnel J B Nadol G P Nielsen H D Curtin andM M Lesperance ldquoTemporal bone histopathology in NOG-symphalangism spectrumdisorderrdquoOtologyampNeurotology vol36 no 10 pp 1651ndash1656 2015
[9] D J Brown T B Kim E M Petty et al ldquoCharacterizationof a stapes ankylosis family with a nog mutationrdquo Otology ampNeurotology vol 24 no 2 pp 210ndash215 2003
[10] A C Coombs and P A Bird ldquoStapedectomy in teunissenndashcremers syndromerdquo Otology amp Neurotology vol 37 no 9 pp1332ndash1334 2016
[11] H H Weekamp H Kremer L H Hoefsloot et al ldquoTeunissen-Cremers syndrome a clinical surgical and genetic reportrdquoOtology amp Neurotology vol 26 pp 38ndash51 2005
Stem Cells International
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
MEDIATORSINFLAMMATION
of
EndocrinologyInternational Journal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Disease Markers
Hindawiwwwhindawicom Volume 2018
BioMed Research International
OncologyJournal of
Hindawiwwwhindawicom Volume 2013
Hindawiwwwhindawicom Volume 2018
Oxidative Medicine and Cellular Longevity
Hindawiwwwhindawicom Volume 2018
PPAR Research
Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom
The Scientific World Journal
Volume 2018
Immunology ResearchHindawiwwwhindawicom Volume 2018
Journal of
ObesityJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
2 Case Reports in Genetics
125
010203040506070
Frequency -- Hz
8090
100110120
250 500 1K 2K15K750
4K 8K6K3Kminus10
(a)
Frequency -- Hz
125 250 500 1K 2K15K750
4K 8K6K3K
0102030405060708090
100110120
minus10
(b)
Figure 1 Preoperative pure tone audiometry revealed bilateral moderate rising to mild conductive hearing loss on the right (a) and left (b)Ipsilateral and contralateral stapedial reflexes were absent bilaterally
2 Materials and Methods
21 Patient After IRB approval (H-17566) at the BaylorCollege of Medicine the patientrsquos complete medical andfamily history was reviewedwith attention to symphalangismand conductive hearing loss Study participants providedwritten informed consent Pre- and postoperative audiom-etry included pure tone audiometry and tympanometry aswell as ipsilateral and contralateral stapedial reflex testingHigh-resolution computed tomography (CT) of the temporalbone without contrast was performed utilizing axial sliceswith coronal and sagittal reconstructions to evaluate themiddle and inner ears
22 Exome Sequencing A saliva sample was obtained fromthe patient using the Oragene OG-500 collection kit andDNA was extracted via the prepIT purification kit (DNAGenotek Ontario Canada) Exomic libraries were preparedusing the SureSelect Human All Exon V6 kit and sequencingwas performed on a HiSeq (25004000) instrument Readswere aligned to the human reference genome using Burrows-Wheeler Aligner (BWAv0715) [4] Local realignment aroundInsertionDeletions (InDels) base quality score recalibrationduplicate reads removal and single nucleotide and InDelvariant calling were performed by the Genome AnalysisToolkit (GATKv37) and Picard tools [5] Next annotationwas performed using ANNOVAR (v2018Apr16) and variantswere filtered based on frequency in databases [GenomeAggregation Database (gnomAD) minor allele frequencylt0005] [6] Various bioinformatic predictions were used toevaluate variants (obtained from dbnsfp33a andANNOVAR)[7] Sanger sequencing was performed to verify a variantidentified inNOG In short purified PCR products (PrimersForward 51015840-GCCAACTTGTGTGCCTTTCT-31015840 Reverse 51015840-GTCTGGGTGTTCGATGAGGT-31015840) were sequenced using
the BigDye Terminator v31 Cycle Sequencing Kit followedby capillary electrophoresis on an ABI 3730 DNA Analyzer(Applied Biosystems Inc Foster City CA)
3 Results
31 Clinical Features Our patient is a 35-year-old Caucasianmale referred for bilateral progressive conductive hearing losssince early childhood Evaluation at the age of ten includedaudiometry but no imaging Reportedly this demonstratedsome degree of hearing loss but was not available for reviewMedical history included an abdominal lipoma open heartsurgery for aortic valve anomaly at the age of 5 and multipleorthopedic surgeries including excision of a ganglion cyst ofthe wrist as well as repair of shoulder and ankle fracturesfrom injury-appropriate sports-related trauma not thoughtto be related to his phenotype Notably the patient deniedophthalmologic history He had a family history of hearingloss in his father and paternal grandfather Reportedly hisgrandfather had similar symphalangism of both fifth digitswhile his father did not Neither were available for genetictesting or examination Physical examination of the handsdemonstrated symphalangism of both fifth digits only He didnot have proximal symphalangismof the other digits or notedbrachydactyly Imaging of the hands was not performed atour institution due to prior work-up with his primary physi-cians Binocular microscopy demonstrated bilateral normaltympanic membranes and well-aerated middle ear spacesand pneumatic otoscopy displayed mobility of the malleusbilaterally Pure tone audiometry revealed bilateral moderaterising to mild conductive hearing loss bilaterally (Figure 1)Speech recognition threshold was 45 dB in the right ear and40 dB in the left with word recognition scores for singleword understanding in quiet of 90 and 100 at 70 dB HLrespectively Acoustic immittance results revealed normal
Case Reports in Genetics 3
(a) (b)
(c) (d)
Figure 2 Axial CT bone windows of the temporal bones revealed a markedly enlarged incus with possible fixation in both the right (a)and the left ears (a) Coronal reformats on the left (c) demonstrated an elongated stapes superstructure of approximately 48 mm (dashedline) with thickening of the incus long process (arrowhead) On the right (d) this measurement was 45 mm Coronal views of the right eardemonstrated bony dehiscence or thinning in the tegmen mastoideum without meningoencephalic herniation Similar findings were notedon the left
eardrum mobility and ipsilateral and contralateral stapedialreflexes were absent bilaterally CT imaging of the temporalbones revealed an enlarged incus with possible fixationin both the right (Figure 2(a)) and the left (Figure 2(b))ears Coronal reformats demonstrated an elongated stapessuperstructure of approximately 45 mm on the right and 48mm on the left with thickening of the incus long processbilaterally (Figure 2(c)) Tegmen dehiscence or thinning wasnoted bilaterally in the tegmen mastoideum without menin-goencephalic herniation (Figure 2(d))
32 Surgical Interventions After appropriate counselling thepatient underwent surgical management to address his rightconductive hearing loss Intraoperatively ossicular abnor-malities including an enlarged fixed incus as well as fixedstapes were confirmed The incus was mildly fixed and wasmobilized using gentle traction between the body and thescutumThe patient underwent right stapedotomy with CO2
laser and reconstruction with a 5 mm Richards piston overfascia seal of the oval window His postoperative coursewas unremarkable The patientrsquos postoperative pure toneand speech recognition thresholds improved significantlyafter surgery (Figure 3) He underwent interval surgery forthe left ear five months later Intraoperative findings wereidentical and included exceptionally tall stapes and thickenedlong process of the incus Initially a Robinson prosthesiswas selected however it would not seat properly on theenlarged lenticular process Therefore a 55 mm Caussepiston was selected for reconstruction with good resultsUnfortunately the patient has not obtained a postoperativeaudiogramafter his second surgery but does report improvedsymmetric subjective hearing bilaterally at his most recentclinical follow-up
33 Genetic Analysis Exome sequencing revealed a het-erozygous start codon variant in the NOG gene in the
4 Case Reports in Genetics
0102030405060708090
100110120
minus10125 250 500 1K 2K
15K7504K 8K
6K3K
Figure 3 Postoperative pure tone audiometry revealed improve-ment of the air conduction thresholds to a mild conductive hearinglosswith near closure of the air-bone gap on the right Unfortunatelythe patient has not followed up for postoperative audiogram after hissecond operation but reports subjectively improved and symmetrichearing
patient (NM 005450 c2TgtCpMet1) which was verified bySanger sequencing This variant is absent from the gnomADdatabase and is predicted to be deleterious by various bioin-formatic tools included in dbnsfp33a (eg VariantTasterFATHMM SIFT) [7] The variant leads to a loss of the ini-tiation codon (Methionine) hinders translation of the wild-type Noggin protein and was classified as likely pathogenic(according to the American College of Medical Genetics(ACMG) guidelines for the interpretation of sequence vari-ants) [8]
4 Discussion
In patients with NOG variants conductive hearing loss hasmainly been described as a result from stapes ankylosisHowever other ossicular chain abnormalities have also beenobserved in a few cases such as fixation of the malleoincudaljoint fixation of the short process of the incus and elongationof the long process of the incus [2] Preoperative imaging forthis case demonstrated a tall stapes superstructure (increaseddistance from the incus to the vestibule) thickened longprocess of the incus and enlarged incus body Intraoper-atively the stapes and incus were both noted to be fixedAfter the mobilization of the incus stapedotomy and fascialgraft placement at the oval window the main intraoperativechallenge was selection of the appropriate stapes prosthesisgiven these anatomic abnormalities The thick incus longprocess makes placement of clip type prosthesis difficult andrenders standard crimping tools less useful Bucket-handleprostheses are also difficult given the girth of the incuslenticular process The CT findings in our case show a verylarge incus not illustrated in other cases of NOG variants
Thus we feel CT imaging is useful in preoperative planningto anticipate difficulties with prosthesis placement
Variable hearing results are reported after stapedectomyforNOG variants [9ndash11] Brown et al noted a high prevalenceof bone regrowth over the footplate resulting in recur-rent conductive loss [9] All authors recognize the needfor prosthesis that is longer than average Temporal bonehistopathology does not demonstrate inner ear anomalies [8]
In conclusion exome sequencing was utilized to identifya novel variant in the NOG gene (c2TgtCpMet1) in apatient with bilateral progressive conductive hearing andsymphalangism in the fifth digits This variant leads to a lossof the translation start site of the NOG gene and is predictedto lead to a complete loss of function of the noggin proteinWe highlight that multiple malformations in the middle earossicular chain can exist with NOG variants
Conflicts of Interest
The authors have no financial interests or disclosures todeclare
Acknowledgments
This study was supported by the American Hearing ResearchFoundation to Isabelle Schrauwen (httpamerican-hearingorg) and National Institute of Deafness and otherCommunication Disorders grants R01 DC011651 andDC003594 to Suzanne M Leal
References
[1] D Chen M Zhao and G R Mundy ldquoBone morphogeneticproteinsrdquo Growth Factors vol 22 no 4 pp 233ndash241 2004
[2] TA Potti EM Petty andMM Lesperance ldquoA comprehensivereview of reported heritable noggin-associated syndromes andproposed clinical utility of one broadly inclusive diagnosticterm NOG-related-symphalangism spectrum disorder (NOG-SSD)rdquo Human Mutation vol 32 no 8 pp 877ndash886 2011
[3] C H Hwang and D K Wu ldquoNoggin heterozygous micean animal model for congenital conductive hearing loss inhumansrdquoHumanMolecular Genetics vol 17 no 6 pp 844ndash8532008
[4] H Li and R Durbin ldquoFast and accurate long-read alignmentwith Burrows-Wheeler transformrdquo Bioinformatics vol 26 no5 pp 589ndash595 2010
[5] A McKenna M Hanna E Banks et al ldquoThe genome analysistoolkit a MapReduce framework for analyzing next-generationDNA sequencing datardquo Genome Research vol 20 no 9 pp1297ndash1303 2010
[6] K Wang M Li and H Hakonarson ldquoANNOVAR functionalannotation of genetic variants from high-throughput sequenc-ing datardquo Nucleic Acids Research vol 38 no 16 article e1642010
[7] X Liu C Wu C Li and E Boerwinkle ldquodbNSFP v30 aone-stop database of functional predictions and annotationsfor human nonsynonymous and splice-site SNVsrdquo HumanMutation vol 37 no 3 pp 235ndash241 2016
Case Reports in Genetics 5
[8] A M Quesnel J B Nadol G P Nielsen H D Curtin andM M Lesperance ldquoTemporal bone histopathology in NOG-symphalangism spectrumdisorderrdquoOtologyampNeurotology vol36 no 10 pp 1651ndash1656 2015
[9] D J Brown T B Kim E M Petty et al ldquoCharacterizationof a stapes ankylosis family with a nog mutationrdquo Otology ampNeurotology vol 24 no 2 pp 210ndash215 2003
[10] A C Coombs and P A Bird ldquoStapedectomy in teunissenndashcremers syndromerdquo Otology amp Neurotology vol 37 no 9 pp1332ndash1334 2016
[11] H H Weekamp H Kremer L H Hoefsloot et al ldquoTeunissen-Cremers syndrome a clinical surgical and genetic reportrdquoOtology amp Neurotology vol 26 pp 38ndash51 2005
Stem Cells International
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
MEDIATORSINFLAMMATION
of
EndocrinologyInternational Journal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Disease Markers
Hindawiwwwhindawicom Volume 2018
BioMed Research International
OncologyJournal of
Hindawiwwwhindawicom Volume 2013
Hindawiwwwhindawicom Volume 2018
Oxidative Medicine and Cellular Longevity
Hindawiwwwhindawicom Volume 2018
PPAR Research
Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom
The Scientific World Journal
Volume 2018
Immunology ResearchHindawiwwwhindawicom Volume 2018
Journal of
ObesityJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Case Reports in Genetics 3
(a) (b)
(c) (d)
Figure 2 Axial CT bone windows of the temporal bones revealed a markedly enlarged incus with possible fixation in both the right (a)and the left ears (a) Coronal reformats on the left (c) demonstrated an elongated stapes superstructure of approximately 48 mm (dashedline) with thickening of the incus long process (arrowhead) On the right (d) this measurement was 45 mm Coronal views of the right eardemonstrated bony dehiscence or thinning in the tegmen mastoideum without meningoencephalic herniation Similar findings were notedon the left
eardrum mobility and ipsilateral and contralateral stapedialreflexes were absent bilaterally CT imaging of the temporalbones revealed an enlarged incus with possible fixationin both the right (Figure 2(a)) and the left (Figure 2(b))ears Coronal reformats demonstrated an elongated stapessuperstructure of approximately 45 mm on the right and 48mm on the left with thickening of the incus long processbilaterally (Figure 2(c)) Tegmen dehiscence or thinning wasnoted bilaterally in the tegmen mastoideum without menin-goencephalic herniation (Figure 2(d))
32 Surgical Interventions After appropriate counselling thepatient underwent surgical management to address his rightconductive hearing loss Intraoperatively ossicular abnor-malities including an enlarged fixed incus as well as fixedstapes were confirmed The incus was mildly fixed and wasmobilized using gentle traction between the body and thescutumThe patient underwent right stapedotomy with CO2
laser and reconstruction with a 5 mm Richards piston overfascia seal of the oval window His postoperative coursewas unremarkable The patientrsquos postoperative pure toneand speech recognition thresholds improved significantlyafter surgery (Figure 3) He underwent interval surgery forthe left ear five months later Intraoperative findings wereidentical and included exceptionally tall stapes and thickenedlong process of the incus Initially a Robinson prosthesiswas selected however it would not seat properly on theenlarged lenticular process Therefore a 55 mm Caussepiston was selected for reconstruction with good resultsUnfortunately the patient has not obtained a postoperativeaudiogramafter his second surgery but does report improvedsymmetric subjective hearing bilaterally at his most recentclinical follow-up
33 Genetic Analysis Exome sequencing revealed a het-erozygous start codon variant in the NOG gene in the
4 Case Reports in Genetics
0102030405060708090
100110120
minus10125 250 500 1K 2K
15K7504K 8K
6K3K
Figure 3 Postoperative pure tone audiometry revealed improve-ment of the air conduction thresholds to a mild conductive hearinglosswith near closure of the air-bone gap on the right Unfortunatelythe patient has not followed up for postoperative audiogram after hissecond operation but reports subjectively improved and symmetrichearing
patient (NM 005450 c2TgtCpMet1) which was verified bySanger sequencing This variant is absent from the gnomADdatabase and is predicted to be deleterious by various bioin-formatic tools included in dbnsfp33a (eg VariantTasterFATHMM SIFT) [7] The variant leads to a loss of the ini-tiation codon (Methionine) hinders translation of the wild-type Noggin protein and was classified as likely pathogenic(according to the American College of Medical Genetics(ACMG) guidelines for the interpretation of sequence vari-ants) [8]
4 Discussion
In patients with NOG variants conductive hearing loss hasmainly been described as a result from stapes ankylosisHowever other ossicular chain abnormalities have also beenobserved in a few cases such as fixation of the malleoincudaljoint fixation of the short process of the incus and elongationof the long process of the incus [2] Preoperative imaging forthis case demonstrated a tall stapes superstructure (increaseddistance from the incus to the vestibule) thickened longprocess of the incus and enlarged incus body Intraoper-atively the stapes and incus were both noted to be fixedAfter the mobilization of the incus stapedotomy and fascialgraft placement at the oval window the main intraoperativechallenge was selection of the appropriate stapes prosthesisgiven these anatomic abnormalities The thick incus longprocess makes placement of clip type prosthesis difficult andrenders standard crimping tools less useful Bucket-handleprostheses are also difficult given the girth of the incuslenticular process The CT findings in our case show a verylarge incus not illustrated in other cases of NOG variants
Thus we feel CT imaging is useful in preoperative planningto anticipate difficulties with prosthesis placement
Variable hearing results are reported after stapedectomyforNOG variants [9ndash11] Brown et al noted a high prevalenceof bone regrowth over the footplate resulting in recur-rent conductive loss [9] All authors recognize the needfor prosthesis that is longer than average Temporal bonehistopathology does not demonstrate inner ear anomalies [8]
In conclusion exome sequencing was utilized to identifya novel variant in the NOG gene (c2TgtCpMet1) in apatient with bilateral progressive conductive hearing andsymphalangism in the fifth digits This variant leads to a lossof the translation start site of the NOG gene and is predictedto lead to a complete loss of function of the noggin proteinWe highlight that multiple malformations in the middle earossicular chain can exist with NOG variants
Conflicts of Interest
The authors have no financial interests or disclosures todeclare
Acknowledgments
This study was supported by the American Hearing ResearchFoundation to Isabelle Schrauwen (httpamerican-hearingorg) and National Institute of Deafness and otherCommunication Disorders grants R01 DC011651 andDC003594 to Suzanne M Leal
References
[1] D Chen M Zhao and G R Mundy ldquoBone morphogeneticproteinsrdquo Growth Factors vol 22 no 4 pp 233ndash241 2004
[2] TA Potti EM Petty andMM Lesperance ldquoA comprehensivereview of reported heritable noggin-associated syndromes andproposed clinical utility of one broadly inclusive diagnosticterm NOG-related-symphalangism spectrum disorder (NOG-SSD)rdquo Human Mutation vol 32 no 8 pp 877ndash886 2011
[3] C H Hwang and D K Wu ldquoNoggin heterozygous micean animal model for congenital conductive hearing loss inhumansrdquoHumanMolecular Genetics vol 17 no 6 pp 844ndash8532008
[4] H Li and R Durbin ldquoFast and accurate long-read alignmentwith Burrows-Wheeler transformrdquo Bioinformatics vol 26 no5 pp 589ndash595 2010
[5] A McKenna M Hanna E Banks et al ldquoThe genome analysistoolkit a MapReduce framework for analyzing next-generationDNA sequencing datardquo Genome Research vol 20 no 9 pp1297ndash1303 2010
[6] K Wang M Li and H Hakonarson ldquoANNOVAR functionalannotation of genetic variants from high-throughput sequenc-ing datardquo Nucleic Acids Research vol 38 no 16 article e1642010
[7] X Liu C Wu C Li and E Boerwinkle ldquodbNSFP v30 aone-stop database of functional predictions and annotationsfor human nonsynonymous and splice-site SNVsrdquo HumanMutation vol 37 no 3 pp 235ndash241 2016
Case Reports in Genetics 5
[8] A M Quesnel J B Nadol G P Nielsen H D Curtin andM M Lesperance ldquoTemporal bone histopathology in NOG-symphalangism spectrumdisorderrdquoOtologyampNeurotology vol36 no 10 pp 1651ndash1656 2015
[9] D J Brown T B Kim E M Petty et al ldquoCharacterizationof a stapes ankylosis family with a nog mutationrdquo Otology ampNeurotology vol 24 no 2 pp 210ndash215 2003
[10] A C Coombs and P A Bird ldquoStapedectomy in teunissenndashcremers syndromerdquo Otology amp Neurotology vol 37 no 9 pp1332ndash1334 2016
[11] H H Weekamp H Kremer L H Hoefsloot et al ldquoTeunissen-Cremers syndrome a clinical surgical and genetic reportrdquoOtology amp Neurotology vol 26 pp 38ndash51 2005
Stem Cells International
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
MEDIATORSINFLAMMATION
of
EndocrinologyInternational Journal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Disease Markers
Hindawiwwwhindawicom Volume 2018
BioMed Research International
OncologyJournal of
Hindawiwwwhindawicom Volume 2013
Hindawiwwwhindawicom Volume 2018
Oxidative Medicine and Cellular Longevity
Hindawiwwwhindawicom Volume 2018
PPAR Research
Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom
The Scientific World Journal
Volume 2018
Immunology ResearchHindawiwwwhindawicom Volume 2018
Journal of
ObesityJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
4 Case Reports in Genetics
0102030405060708090
100110120
minus10125 250 500 1K 2K
15K7504K 8K
6K3K
Figure 3 Postoperative pure tone audiometry revealed improve-ment of the air conduction thresholds to a mild conductive hearinglosswith near closure of the air-bone gap on the right Unfortunatelythe patient has not followed up for postoperative audiogram after hissecond operation but reports subjectively improved and symmetrichearing
patient (NM 005450 c2TgtCpMet1) which was verified bySanger sequencing This variant is absent from the gnomADdatabase and is predicted to be deleterious by various bioin-formatic tools included in dbnsfp33a (eg VariantTasterFATHMM SIFT) [7] The variant leads to a loss of the ini-tiation codon (Methionine) hinders translation of the wild-type Noggin protein and was classified as likely pathogenic(according to the American College of Medical Genetics(ACMG) guidelines for the interpretation of sequence vari-ants) [8]
4 Discussion
In patients with NOG variants conductive hearing loss hasmainly been described as a result from stapes ankylosisHowever other ossicular chain abnormalities have also beenobserved in a few cases such as fixation of the malleoincudaljoint fixation of the short process of the incus and elongationof the long process of the incus [2] Preoperative imaging forthis case demonstrated a tall stapes superstructure (increaseddistance from the incus to the vestibule) thickened longprocess of the incus and enlarged incus body Intraoper-atively the stapes and incus were both noted to be fixedAfter the mobilization of the incus stapedotomy and fascialgraft placement at the oval window the main intraoperativechallenge was selection of the appropriate stapes prosthesisgiven these anatomic abnormalities The thick incus longprocess makes placement of clip type prosthesis difficult andrenders standard crimping tools less useful Bucket-handleprostheses are also difficult given the girth of the incuslenticular process The CT findings in our case show a verylarge incus not illustrated in other cases of NOG variants
Thus we feel CT imaging is useful in preoperative planningto anticipate difficulties with prosthesis placement
Variable hearing results are reported after stapedectomyforNOG variants [9ndash11] Brown et al noted a high prevalenceof bone regrowth over the footplate resulting in recur-rent conductive loss [9] All authors recognize the needfor prosthesis that is longer than average Temporal bonehistopathology does not demonstrate inner ear anomalies [8]
In conclusion exome sequencing was utilized to identifya novel variant in the NOG gene (c2TgtCpMet1) in apatient with bilateral progressive conductive hearing andsymphalangism in the fifth digits This variant leads to a lossof the translation start site of the NOG gene and is predictedto lead to a complete loss of function of the noggin proteinWe highlight that multiple malformations in the middle earossicular chain can exist with NOG variants
Conflicts of Interest
The authors have no financial interests or disclosures todeclare
Acknowledgments
This study was supported by the American Hearing ResearchFoundation to Isabelle Schrauwen (httpamerican-hearingorg) and National Institute of Deafness and otherCommunication Disorders grants R01 DC011651 andDC003594 to Suzanne M Leal
References
[1] D Chen M Zhao and G R Mundy ldquoBone morphogeneticproteinsrdquo Growth Factors vol 22 no 4 pp 233ndash241 2004
[2] TA Potti EM Petty andMM Lesperance ldquoA comprehensivereview of reported heritable noggin-associated syndromes andproposed clinical utility of one broadly inclusive diagnosticterm NOG-related-symphalangism spectrum disorder (NOG-SSD)rdquo Human Mutation vol 32 no 8 pp 877ndash886 2011
[3] C H Hwang and D K Wu ldquoNoggin heterozygous micean animal model for congenital conductive hearing loss inhumansrdquoHumanMolecular Genetics vol 17 no 6 pp 844ndash8532008
[4] H Li and R Durbin ldquoFast and accurate long-read alignmentwith Burrows-Wheeler transformrdquo Bioinformatics vol 26 no5 pp 589ndash595 2010
[5] A McKenna M Hanna E Banks et al ldquoThe genome analysistoolkit a MapReduce framework for analyzing next-generationDNA sequencing datardquo Genome Research vol 20 no 9 pp1297ndash1303 2010
[6] K Wang M Li and H Hakonarson ldquoANNOVAR functionalannotation of genetic variants from high-throughput sequenc-ing datardquo Nucleic Acids Research vol 38 no 16 article e1642010
[7] X Liu C Wu C Li and E Boerwinkle ldquodbNSFP v30 aone-stop database of functional predictions and annotationsfor human nonsynonymous and splice-site SNVsrdquo HumanMutation vol 37 no 3 pp 235ndash241 2016
Case Reports in Genetics 5
[8] A M Quesnel J B Nadol G P Nielsen H D Curtin andM M Lesperance ldquoTemporal bone histopathology in NOG-symphalangism spectrumdisorderrdquoOtologyampNeurotology vol36 no 10 pp 1651ndash1656 2015
[9] D J Brown T B Kim E M Petty et al ldquoCharacterizationof a stapes ankylosis family with a nog mutationrdquo Otology ampNeurotology vol 24 no 2 pp 210ndash215 2003
[10] A C Coombs and P A Bird ldquoStapedectomy in teunissenndashcremers syndromerdquo Otology amp Neurotology vol 37 no 9 pp1332ndash1334 2016
[11] H H Weekamp H Kremer L H Hoefsloot et al ldquoTeunissen-Cremers syndrome a clinical surgical and genetic reportrdquoOtology amp Neurotology vol 26 pp 38ndash51 2005
Stem Cells International
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
MEDIATORSINFLAMMATION
of
EndocrinologyInternational Journal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Disease Markers
Hindawiwwwhindawicom Volume 2018
BioMed Research International
OncologyJournal of
Hindawiwwwhindawicom Volume 2013
Hindawiwwwhindawicom Volume 2018
Oxidative Medicine and Cellular Longevity
Hindawiwwwhindawicom Volume 2018
PPAR Research
Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom
The Scientific World Journal
Volume 2018
Immunology ResearchHindawiwwwhindawicom Volume 2018
Journal of
ObesityJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Case Reports in Genetics 5
[8] A M Quesnel J B Nadol G P Nielsen H D Curtin andM M Lesperance ldquoTemporal bone histopathology in NOG-symphalangism spectrumdisorderrdquoOtologyampNeurotology vol36 no 10 pp 1651ndash1656 2015
[9] D J Brown T B Kim E M Petty et al ldquoCharacterizationof a stapes ankylosis family with a nog mutationrdquo Otology ampNeurotology vol 24 no 2 pp 210ndash215 2003
[10] A C Coombs and P A Bird ldquoStapedectomy in teunissenndashcremers syndromerdquo Otology amp Neurotology vol 37 no 9 pp1332ndash1334 2016
[11] H H Weekamp H Kremer L H Hoefsloot et al ldquoTeunissen-Cremers syndrome a clinical surgical and genetic reportrdquoOtology amp Neurotology vol 26 pp 38ndash51 2005
Stem Cells International
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
MEDIATORSINFLAMMATION
of
EndocrinologyInternational Journal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Disease Markers
Hindawiwwwhindawicom Volume 2018
BioMed Research International
OncologyJournal of
Hindawiwwwhindawicom Volume 2013
Hindawiwwwhindawicom Volume 2018
Oxidative Medicine and Cellular Longevity
Hindawiwwwhindawicom Volume 2018
PPAR Research
Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom
The Scientific World Journal
Volume 2018
Immunology ResearchHindawiwwwhindawicom Volume 2018
Journal of
ObesityJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
Stem Cells International
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
MEDIATORSINFLAMMATION
of
EndocrinologyInternational Journal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Disease Markers
Hindawiwwwhindawicom Volume 2018
BioMed Research International
OncologyJournal of
Hindawiwwwhindawicom Volume 2013
Hindawiwwwhindawicom Volume 2018
Oxidative Medicine and Cellular Longevity
Hindawiwwwhindawicom Volume 2018
PPAR Research
Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom
The Scientific World Journal
Volume 2018
Immunology ResearchHindawiwwwhindawicom Volume 2018
Journal of
ObesityJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Computational and Mathematical Methods in Medicine
Hindawiwwwhindawicom Volume 2018
Behavioural Neurology
OphthalmologyJournal of
Hindawiwwwhindawicom Volume 2018
Diabetes ResearchJournal of
Hindawiwwwhindawicom Volume 2018
Hindawiwwwhindawicom Volume 2018
Research and TreatmentAIDS
Hindawiwwwhindawicom Volume 2018
Gastroenterology Research and Practice
Hindawiwwwhindawicom Volume 2018
Parkinsonrsquos Disease
Evidence-Based Complementary andAlternative Medicine
Volume 2018Hindawiwwwhindawicom
Submit your manuscripts atwwwhindawicom
