Common Otolaryngological
Congenital Abnormalities
Visual Synopsis of Classic Syndromes and
Features
http://www.explosm.net/comics
Viet Pham, M.D.
Lewis Hutchinson, M.D.
Harold Pine, M.D.
Shraddha Mukerji, M.D.
University of Texas Medical Branch
Grand Rounds Presentations
November 22, 2010
Foreword and Acknowledgements
Special appreciation to Dr. Hutchinson for his
assistance and contribution
Additional gratitude to Drs. Pine and Mukerji
All clinical photos are presented solely for
educational purposes
All other photos were obtained via a Google search
http://www.explosm.net/comics
unless otherwise specified and are used without
permission
Objective


Highlight typical features of congenital abnormalities
evaluated in the otolaryngology practice
Visual emphasis on classical presentation of commonly
encountered syndromes
Down Syndrome
(Trisomy 21)

Extra chromosome 21


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

Meiotic nondisjunction in gamete formation
Mosaicism (1-2%)
Robertsonian translocation (2-3%)
Duplication (rare)
Increased risk with advanced maternal age
Most common cause of intellectual disability
Down Syndrome
Features

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Brachycephaly
Flat nasal bridge and occiput
Small, low-set ears
Macroglossia, glossoptosis
Upslanting palpebral fissures
Epicanthal folds
Brushfield spots
Simian crease
Sandal gap deformity of feet
Excessive nuchal folds
Mental retardation
(courtesy of Dr. Hutchinson via Maria Blazo, M.D.)
Down Syndrome
Features
(Dourmishev, 2009)
Brachycephaly
Brushfield spots
Macroglossia,
glossoptosis
Epicanthus
Flat nasal bridge,
hypoplastic maxilla
(Dourmishev, 2009)
Microtic, low-set ears
(Dourmishev, 2009)
Upslanting palpebral fissure
Sandal deformity
Simian crease
Excessive
nuchal folds
Down Syndrome
Other Features

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Muscular hypotonia
Strabismus
Congenital cataracts
Atrial or ventricular septal
defect
Gastroesophageal reflux
Duodenal stenosis or
atresia
Hirschsprung disease or
celiac disease
Seizures
Down Syndrome
Prenatal Ultrasound

Absent nasal bones



First trimester (60-80%)
Second trimester (37-41%)
Hypoplastic nasal bones


Not useful as single marker in first
trimester
Best used with absent nasal bones in
second trimester (60-100%)
(Gonçalves, 2004)
Down Syndrome
Otolaryngological Considerations


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
Tympanostomy tubes
Esophageal atresia,
tracheoesophageal fistula
Atlantoaxial instability
Obstructive sleep apnea
Hypothyroidism
Increased risk for malignancy

Acute lymphoblastic leukemia

Transient myeloproliferative disorder
Crouzon Syndrome
(Craniofacial Dysostosis)


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Autosomal dominant
Virtually complete penetrance
Mutation of fibroblast growth factor receptor II (FGFR2) on
chromosome 10
Affects first pharyngeal arch


Precursor maxilla
and mandible
Early fusion of face
and skull bones
(courtesy of Dr. Pine)
Crouzon Syndrome
(Jackson, 2009)
Features

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Craniosynostosis
Exophthalmos
Hypertelorism
Strabismus
Psittichorhina
Hypoplastic maxilla
Mandibular
prognathism
Caused by a mutation in the fibroblast growth factor receptor II, located on chromosome 10
this syndrome affects the first branchial (or pharyngeal) arch, which is the precursor of the maxilla and mandible
What occurs in the disease is that an infant's skull and facial bones, while in development, fuse early or are unable to expand.
Thus, normal bone growth cannot occur. Fusion of different sutures leads to different patterns of growth of the skull.
hypoplastic maxilla: insufficient growth of the midface
mandibular prognathism: chin appears to protrude despite normal growth of mandible and gives the effect of the patient having a
concave face
Mental retardation possible if premature closure of the cranial suture lines
Psittichorhina: beak-like nose
Crouzon Syndrome
Features
Strabismus
Exophthalmos
Hypertelorism
(Jackson, 2009)
Cranial synostosis
Mandibular
prognathism
Psittichorhina
Hypoplastic maxilla
Crouzon Syndrome
Otolaryngological Considerations

Hearing loss in 1/3 of cases
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Auricular misalignment
Ossicular fixation
Serous otitis media
Sensorineural and mixed hearing losses
Surgical craniofacial reconstruction
(http://candar.wordpress.com)
Crouzon Syndrome
Otolaryngological Considerations

Surgical craniofacial reconstruction
(Jackson, 2009)
Apert Syndrome
(Acrocephalosyndactyly)

Autosomal dominant

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Craniofacial abnormalities by FGFR2 mutations
Syndactyly by keratinocyte growth factor receptor (KGFR) mutations
Parents pass on to offspring
50% of the time
Sporadic mutation in 98%
Affects first pharyngeal arch
(Shah AR, Danahey DG. Distraction Osteogenesis of the Maxilla.
eMedicine 11 Feb 2009.)
Apert Syndrome
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Craniofacial dysostosis
Hypoplastic maxilla
Frontal prominence
Syndactyly
Exophthalmos
Hypertelorism
Saddle nose, depressed
nasal bridge
Oral cavity


High-arched palate, cleft
palate
Dental abnormalities
(courtesy of Dr. Hutchinson)
Features
Apert Syndrome
(Chen, 2009)
Features
Craniofacial dysostosis
Syndactyly
Frontal
prominence
Malocclusion
Ectopic eruption
Depressed
nasal bridge
Hypoplastic
maxilla
Hypertelorism
Apert Syndrome
Dr. Hutchinson’s mnemonic
Apert = Crouzon + Syndactyly
Apert Syndrome
Otolaryngological Considerations

Conductive hearing loss




Chronic otitis media
Stapes fixation
Patent cochlear aqueduct
Surgical craniofacial reconstruction
(Jackson, 2009)
Treacher Collins Syndrome
(Mandibulofacial Dysostosis)


Also known as Franceschetti-Zwahlen-Klein syndrome
Autosomal dominant




TCOF1 gene on chromosome 5q
New mutation in up to 60%
Complete penetrance, variable expression
First and second pharyngeal arches,
grooves, and pouches
Treacher Collins Syndrome
Features
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Characteristic facial dysmorphia
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Downward slanting palpebral fissures
Hypoplastic supraorbital rims
Malar hypoplasia
Mandibular hypoplasia
Auricular and middle
ear malformations
Lower eyelid coloboma
May have cleft palate
Normal intelligence
(Tolarova, 2009)
Treacher Collins Syndrome
Features
Malar hypoplasia
Lower eyelid colobomas
Hypoplastic supraorbital rims
(courtesy of Dr. Hutchinson)
Downward slanting
palpebral fissures
Mandibular
hypoplasia
Auricular malformation
Treacher Collins Syndrome
Features
Malar hypoplasia
Lower eyelid colobomas
Hypoplastic supraorbital rims
Scant lower eyelashes
Mandibular
hypoplasia
Auricular malformation
(courtesy of Dr. Hutchinson)
Downward slanting
palpebral fissures
Treacher Collins Syndrome
Otolaryngological Considerations
Hearing

Conductive hearing loss in 30%

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Ossicular malformation
Microtia and/or canal atresia
Mastoid hypoplasia
Some sensorineural hearing loss and
vestibular dysfunction
Upper airway obstruction
(Tolarova, 2009)

Treacher Collins Syndrome
Otolaryngological Considerations

Surgical craniofacial reconstruction
(Jackson, 2009)
Goldenhar Syndrome
Oculoauriculovertebral Dysplasia

Diverse etiologies

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
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In utero vascular disruption with hematoma
Disturbed neural crest cells at 30-45 days gestation
No single genetic locus
First and second branchial arch
Hemifacial microsomia
when no internal organ or
vertebral disruption
Goldenhar Syndrome
Features
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Hemifacial microsomia
Mandibular hypoplasia
Microstomia
Epibulbar lipodermoids
Upper eyelid coloboma
Vertebral anomalies
(Bailey, 2006)

Goldenhar Syndrome
Features
Mandibular
hypoplasia
Hemifacial microsomia
Microtia and preauricular tags/pits
Upper eyelid
coloboma
Epibulbar dermoid
Goldenhar Syndrome
Classification Scheme
OMENS
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Orbital distortion
Mandibular hypoplasia
Ear anomaly
Nerve (facial) involvement
Soft-tissue deficiency
“Plus” to include additional anomalies
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Cardiac
Skeletal, limb
Pulmonary
Renal
Gastrointestinal
Anderson PJ, David DJ. Spinal anomalies in Goldenhar
syndrome. Cleft Palate-Craniofacial Journal 2005; 42:477-80.

Goldenhar Syndrome
Classification Scheme: Mandible
(Horgan, 1995)

Normal mandible
Goldenhar Syndrome
Classification Scheme: Mandible
(Horgan, 1995)

Type I
Smaller mandible but identifiable mandible
Goldenhar Syndrome
Classification Scheme: Mandible
(Horgan, 1995)
Type II
Functioning temporomandibular joint (TMJ) but abnormal shape and glenoid
fossa

Type IIA
Glenoid fossa is in an acceptable position
Goldenhar Syndrome
Classification Scheme: Mandible
(Horgan, 1995)
Type II
Functioning temporomandibular joint (TMJ) but abnormal shape and glenoid
fossa

Type IIB
Abnormally placed TMJ cannot be incorporated into surgical
reconstruction
Goldenhar Syndrome
Classification Scheme: Mandible
(Horgan, 1995)

Type III
Absent ramus and nonexistent glenoid fossa
Goldenhar Syndrome
Classification Scheme

Orbits

Ear
(Horgan, 1995)
Goldenhar Syndrome
Classification Scheme
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Facial Nerve

Soft tissue defect
(Horgan, 1995)
Goldenhar Syndrome
Otolaryngological Considerations

Hearing loss
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More conductive than sensorineural
Ossicular abnormalities
Microtia
Aberrant facial nerve course
Surgical craniofacial reconstruction
Pierre Robin Syndrome
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Sequence of micrognathia, glossoptosis, and cleft palate
Syndrome reserved for multiple malformations by a single
etiology
Confusing classification, up to 14 definitions (Breugem 2009)
Possibly due to arrested intrauterine development

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Mechanical
Neurological
Ontogenesis
(Tolarova, 2009)
Pierre Robin Syndrome
(courtesy of Dr. Hutchinson)
Features

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Cleft palate
 Glossoptosis
Retrognathia
Macroglossia and
ankloglossia uncommon
(Jackson, 2009)

Micrognathia
(courtesy of Dr. Hutchinson)

Pierre Robin Syndrome
Sequence
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Mandibular hypoplasia
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Between 7-11 weeks gestation
Mandible gets temporarily “stuck” between
clavicle and sternum
Oligohydramnios
Tongue remains high in oral cavity
Cleft palate results from failed closure of palatal shelves


U-shaped cleft palate (80%), can
have V-shaped (20%)
Typically no cleft lip
Pierre Robin Syndrome
Otolaryngological Considerations

Airway compromise
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Upper airway obstruction
Feeding, aspiration
Subglottic stenosis
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Hearing loss
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Otitis media most common
(60%)
Auricular malformation
Mixed hearing loss
Associated syndromes


Stickler (18-25%)
Velocardiofacial (7-15%)
Treacher Collins (5%)
Hemifacial microsomia (3%)
Mandibular “catch up” if
isolated sequence
(Tolarova, 2009)
Pierre Robin Syndrome
Otolaryngological Considerations
Distraction osteogenesis

Intubation, tracheostomy
(Tolarova, 2009)

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Cleft palate repair
(courtesy of Dr. Hutchinson)
Stickler Syndrome

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Autosomal dominant
Mutations of type II and XI collagen

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
COL2A1 gene on chromosome 12
COL11A1 and COL11A2 genes on chromosome 6
COL9A1 is rare recessive variant
Craniofacial, ocular, and
arthopathic features
Stickler Syndrome

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“Flattened” face
Ocular findings
Musculoskeletal
abnormalities
Cleft palate
(courtesy of Dr. Hutchinson via Maria Blazo, M.D.)
Features
Stickler Syndrome
Features
Midfacial
hypoplasia
Short upturned
nose
Long philtrum
(Tolarova, 2009)
(Poulson, 2004)
Micrognathia
Stickler Syndrome
Features

Ocular
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Myopia
Glaucoma
Retinal detachment
Cataracts
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Musculoskeletal
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Osteoarthritis
Joint hypermobility
Abnormal epiphyseal
development
Vertebral abnormalities
Scoliosis
Stickler Syndrome
Otolaryngological Considerations
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Hearing loss
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Mild to moderate sensorineural hearing loss (SNHL) in 80%
Significant SNHL or mixed hearing loss in 15%
Conductive component secondary to eustachian tube dysfunction from
cleft palate
Ossicular abnormalities may be present
Pierre Robin sequence
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Present in 25% of Stickler syndrome
Cleft palate
Micrognathia
(courtesy of Dr. Hutchinson via Maria Blazo, M.D.)
Waardenburg Syndrome

Autosomal dominant
Multiple genes

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PAX3 (Types 1 and 3)
MITF, SNAI2 (Type 2)
EDN3, EDNRB, SOX10 (Type 4)
Autosomal recessive for Type 4
Variable penetrance
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Hearing loss
Dystopia canthorum
Pigmentary abnormalities
(courtesy of Dr. Hutchinson)

Waardenburg Syndrome
Features
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Dystopia canthorum
Flat nasal root
Hypoplastic nasal alae
Synophyrs
Heterochromia irides
Isohypochromia irides
White forelock
Vitiligo
Cleft lip and palate (10%)
(Schwartz, 2010)
Waardenburg Syndrome
(courtesy of Dr. Hutchinson)
Features
White forelock
Synophyrs
Hypoplastic alae
Short philtrum
Heterochromia irides
Flat nasal
root
Dystopia canthorum
Isohypochromia irides
(Schwartz, 2010)
Waardenburg Syndrome
Features

Major
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Heterochromia irides
White forelock
Dystopia canthorum
Congenital sensorineural
hearing loss
Affected first-degree relative

Minor

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Congenital leucoderma
Synophyrs
Broad high nasal root
Hypoplastic nasal alae
Premature graying hair
Waardenburg Syndrome
Diagnosis

Major





Heterochromia irides
White forelock
Dystopia
canthorum
Diagnosis
Congenital sensorineural
 2 major features
hearing loss
 1 major features +
Affected
first-degree relative

Minor





Congenital leucoderma
Synophyrs
Broad high nasal root
Hypoplastic nasal alae
Premature graying hair
2 minor features
Waardenburg Syndrome
Subtypes

Type 1

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
Type 2

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
No dystopia canthorum, white forelock less common
Sensorineural hearing loss, heterochomia irides
Type 3 (Klein-Waardenburg syndrome)



Full symptomatology
Facial asymmetry, dysmorphic facies
Similar to Type 1 but with skeletal anomalies and mental retardation
Rib aplasia, cystic sacrum, cutaneous syndactyly
Type 4 (Shah-Waardenburg syndrome)

Association with Hirschsprung disease
(courtesy of Dr. Hutchinson)
(Schwartz, 2010)
Waardenburg Syndrome
Subtypes

Type 1



Type 2

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No dystopia canthorum, white forelock less common
Sensorineural hearing loss, heterochomia irides
Type 3 (Klein-Waardenburg syndrome)



Full symptomatology
Facial asymmetry, abnormal facies
Similar to Type 1 but with skeletal anomalies and mental retardation
Rib aplasia, cystic sacrum, cutaneous syndactyly
Type 4 (Shah-Waardenburg syndrome)

Association with Hirschsprung disease
(courtesy of Dr. Hutchinson)
Waardenburg Syndrome
Subtypes

Type 1



Type 2



No dystopia canthorum, white forelock less common
Sensorineural hearing loss, heterochomia irides
Type 3 (Klein-Waardenburg syndrome)



Full symptomatology
Facial asymmetry, abnormal facies
Similar to Type 1 but with skeletal anomalies and mental retardation
Rib aplasia, amyoplasia, cystic sacrum, cutaneous syndactyly
Type 4 (Shah-Waardenburg syndrome)

Association with Hirschsprung disease
Waardenburg Syndrome
Subtypes

Type 1



Type 2



No dystopia canthorum, white forelock less common
Sensorineural hearing loss, heterochomia irides
Type 3 (Klein-Waardenburg syndrome)



Full symptomatology
Facial asymmetry, abnormal facies
Similar to Type 1 but with skeletal anomalies and mental retardation
Rib aplasia, cystic sacrum, cutaneous syndactyly
Type 4 (Shah-Waardenburg syndrome)

Association with Hirschsprung disease
Waardenburg Syndrome
Otolaryngological Considerations

Congenital sensorineural deafness





Typically not progressive
Hearing amplification
Cochlear implantation
Cleft lip or palate repair
Cosmetic considerations
Beckwith-Wiedemann
Syndrome

Imprinting defect at chromosome 11p15




Most cases are sporadic
Autosomal dominant familial inheritance in 15%
Most common overgrowth syndrome in infancy
Five common features





Macroglossia
Macrosomia
Midline abdominal wall defect
Ear pits/creases
Neonatal hypoglycemia
(courtesy of Dr. Hutchinson)
Beckwith-Wiedemann
Syndrome

Imprinting defect at chromosome 11p15




Most cases are sporadic
Autosomal dominant familial inheritance in 15%
Most common overgrowth syndrome in infancy
Five common features





Macroglossia
Macrosomia
Midline abdominal wall defect
Ear pits/creases
Neonatal hypoglycemia
Beckwith-Wiedemann
Features
Macrosomia
Midline abdominal defect
(courtesy of Dr. Hutchinson
via Maria Blazo, M.D.)
Macroglossia
Ear pits/creases
Beckwith-Wiedemann
Features

Major









Midline abdominal defect
Macroglossia
Macrosomia
Ear pits/creases
Adrenocortical cytomegaly
Renal abnormalities
Embryonal tumors
Cleft palate (rare)
Hemihyperplasia
Beckwith-Wiedemann
Features

Major









Midline abdominal defect
Macroglossia
Macrosomia
Ear pits/creases
Adrenocortical cytomegaly
Renal abnormalities
Embryonal tumors
Cleft palate (rare)
Hemihyperplasia

Minor









Neonatal hypoglycemia
Polyhydramnios
Prematurity
Facial nevus flammeus
Hemangioma
Characteristic facies (i.e.
midface hypoplasia)
Cardiac anomalies
Diastasis recti
Advanced bone age
Beckwith-Wiedemann
Diagnosis

Major










Minor
Midline abdominal defect
 Neonatal hypoglycemia
Macroglossia
 Polyhydramnios
Macrosomia
 Prematurity
Diagnosis
Ear pits/creases
 Facial nevus flammeus
 At least 2 common features
Adrenocortical cytomegaly
 Hemangioma
 3 major features
Renal abnormalities
 Characteristic facies (i.e.
 2 major
features
midface
hypoplasia)
Embryonal
tumorsfeatures + 3 minor
 Cardiac anomalies
Cleft palate (rare)
 Diastasis recti
Hemihyperplasia
 Advanced bone age
Beckwith-Wiedemann
Otolaryngological Considerations

Macroglossia



Airway obstruction,
feeding difficulty
Less noticeable with age
Increased risk of malignancy



Wilms’ tumor
Hepatoblastoma
Surveillance


Abdominal ultrasound every 3 months until 8 years
Alpha-fetoprotein every 6 weeks until 4 years
Neurofibromatosis
Type 1 (von Recklinghausen)


Peripheral neurofibromatosis
Autosomal dominant




Neurofibromin gene (NF1) on chromosome 17
Half result from de novo mutation
Variable expression
Better prognosis than Neurofibromatosis
Type 2
(courtesy of Dr. Hutchinson via
Maria Blazo, M.D.)
(Dahl, 2010)
Neurofibromatosis, Type 1
Features







Café au lait spots
Cutaneous neurofibromas
Plexiform neuromas
Lisch nodules
Axillary or perineum
freckling (Crowe sign)
Optic gliomas
Bone abnormalities
Neurofibromatosis, Type 1
Features
Café au lait spots
Plexiform neuroma
Axillary freckling
(Dahl, 2010)
(courtesy of Dr. Hutchinson
via Maria Blazo, M.D.)
Cutaneous neurofibomas
Optic glioma
Lisch nodules
Long bone bowing
Neurofibromatosis, Type 1
Diagnosis
Six or more café au lait macules








Diameter larger than 5mm in prepubescent
Diameter larger than 15mm in adults
Two or more neurofibromas or one
plexiform neurofibroma
Axillary or inguinal freckling
Optic glioma
Two or more Lisch nodules
Distinctive osseous lesion
First-degree relative with condition
(Nazareth, 2010)

Neurofibromatosis
Type 2


Central neurofibromatosis
Autosomal dominant




NF2 (Merlin) gene on chromosome 22
Approximately 10% of all individuals with
neurofibromatosis
Significant morbidity, decreased
lifespan
Paucity of café au lait spots and
Crowe sign
(Pletcher, 2010)




Café au lait spots
Schwannomas



Bilateral acoustic neuromas
Spinal cord
Nonvestibular
Subcapsular cataracts
Meningiomas
Kutz JW Jr, Roland PS, Isaacson B. Skull base, acoustic
neuroma (vestibular schwannoma): multimedia.
eMedicine 24 Sep 2009. Accessed 5 Nov 2010
<http://emedicine.medscape.com/article/882876-media>.
Neurofibromatosis, Type 2
Features
Neurofibromatosis, Type 2
Diagnosis


Bilateral vestibular schwannomas
Presumptive
 Suggestive



Affected first-degree relative
Unilateral vestibular
schwannoma
Or two of the following:




Meningioma
Glioma
Schwannoma
Juvenile posterior subcapsular
or cortical cataract


Unilateral vestibular
schwannoma
Two of the following:





Meningioma
Glioma
Schwannoma
Juvenile posterior subcapsular
or cortical cataract
Or multiple meningiomas
Klippel-Feil Syndrome
(Brevicollis, Wildervanck)

Cervical vertebral fusion






Type I – single level
Type II – multiple, noncontiguous segments
Type III – multiple, contiguous segments
Short, webbed neck and low hairline
Unclear etiology
Associated abnormalities




Sprengel deformity
Scoliosis
Facial asymmetry
Renal abnormalities
(Sullivan, 2009)
Other Syndromes
Without Craniofacial Features

Usher

Hearing loss with defective inner ear





Type I – deafness and vestibular dysfunction
Type II – nonprogressive hearing loss and normal vestibular function
Type III – progressive hearing loss and half vestibular function
Progressive vision loss from retinitis pigmentosa
Pendred



Yeah
Yeah
Yeah
Sensorineural hearing loss
Thyroid goiter
Jervell and Lange-Neilsen


Defective potassium channel from KCNQ1 and KCNE1
mutations
Sensorineural hearing loss and palpitations (long QT syndrome)
Conclusion

Many syndromes will
present to the
otolaryngologist



Warrant otolaryngological
intervention
Attention to coexisting
conditions
Many affected individuals
are aware of the social
stigma related to their
condition
http://www.explosm.net/comics
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