hearing loss

Usher Syndrome Type III

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa is a cardinal feature with onset of severe symptoms of nightblindness and tunnel vision by the second decade of life.  The ERG shows depressed responses.  Central vision may also be lost in young adults.  Hypermetropic astigmatism has been reported as the most typical refractive error for type III in the presence of nightblindness and hearing loss, at least in Finnish patients.

Systemic Features: 

Hearing loss is progressive but later in onset than in type I and type II.  Infants are usually born with normal hearing and often experience some loss of hearing by the end of the first decade of life.  Speech can develop normally because of the late onset of the hearing deficit.  Hearing loss is progressive early with older patients having a profound and eventually more stable hearing deficit.  The amount of vestibular dysfunction is variable but usually is severe enough to cause significant unsteadiness.  The mental changes associated with type I are absent.

Genetics

Usher syndrome is a clinically and genetically heterogeneous condition.   Type IIIA is caused by a mutation in the CLRN1 gene (3q21-q25).  It is inherited in an autosomal recessive pattern.  Type IIIB (614505) is the result of homozygous mutations in HARS (5q31.3).

There is also a disorder resembling Usher that results from homozygous mutations in ABHD12 (20p11.21) that also causes PHARC (612674) (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early onset cataract).

This is the least common type of Usher syndrome.  Three additional types of Usher syndrome are recognized:  type I (276900) results from mutations in at least 7 different genes, type II (276901) from mutations in 4 genes, and Type IV resulting from mutations in the ARSG gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Hearing aids might be helpful early but cochlear implants may be needed in older patients with severe deafness.  Low vision aids are often helpful.

References
Article Title: 

Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3

Eisenberger T, Slim R, Mansour A, Nauck M, N?ornberg G, N?ornberg P, Decker C, Dafinger C, Ebermann I, Bergmann C, Bolz HJ. Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3. Orphanet J Rare Dis. 2012 Sep 2;7(1):59. [Epub ahead of print]

PubMed ID: 
22938382

Usher Syndrome Type II

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa is clinically similar to that of nonsyndromal RP and produces symptoms of nightblindness by adolescence.  The ERG is severely reduced and visual fields are constricted.  Rods seem to be more severely affected than cones.  A loss of thickness in the outer nuclear layer in USH2C and USH2A types has been described.  The fundus often contains patches of hyperfluorescence which become larger and often coalesce in older patients.  The retinal disease is progressive but more slowly than in type I.  Eventually by the 4th to 5th decades the visual field is constricted to 5-10 degrees.  It can result in blindness.  Cataracts are common and some patients have cystic changes in the macula.

Systemic Features: 

The hearing deficit in type II can be described as hearing loss rather than deafness as found in type I.  Usually high frequencies are impacted more severely than lower frequencies producing a characteristic 'sloping' audiogram.  The hearing loss is present at birth and progressive, at least in some individuals.  Speech usually develops.  Vestibular dysfunction is not a feature of type II Usher syndrome.  The mental changes observed in type I do not occur in type II.

Genetics

Like other forms of Usher syndrome, type II is inherited in an autosomal recessive pattern.  Like type I, it is genetically heterogeneous and mutations in at least 4 genes seem to be responsible.  Three have been identified: type IIA (USH2A; 276901) results from mutations in the USH2A gene on chromosome 4 (1q41), type IIC (USH2D; 605472) from mutations in GPR98 (5q14), and type IID (USH2D; 611383) is caused by mutations in the DFNB31 gene (9q32-q34).  Type IIB (USH2B) results from mutations in a locus mapped to 3p24.2-p23 but the gene has not been identified.  Clinical features are sufficiently similar so that these are discussed here as a single entity.

This is the most common of the three types of Usher syndrome.  Type I Usher syndrome (276900) results from mutations in at least 7 genes and type III (276902) is caused by a mutations in the CLRN1 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Hearing aids can be helpful and speech therapy may be highly beneficial for the development of speech.  Cochlear implants have been suggested for older persons who have the more severe hearing loss.  Auditory testing should be done shortly after birth and the hearing loss monitored periodically.

An investigational drug (QRX-411) developed by ProQR has been approved as an orphan drug by the FDA and the EMA for patients with the USH2A mutation. 

References
Article Title: 

Kinetics of visual field loss in Usher syndrome Type II

Iannaccone A, Kritchevsky SB, Ciccarelli ML, Tedesco SA, Macaluso C, Kimberling WJ, Somes GW. Kinetics of visual field loss in Usher syndrome Type II. Invest Ophthalmol Vis Sci. 2004 Mar;45(3):784-92.

PubMed ID: 
14985291

Usher Syndrome Type I

Clinical Characteristics
Ocular Features: 

The fundus dystrophy of retinitis pigmentosa in Usher syndrome is indistinguishable from isolated retinitis pigmentosa.   Night blindness begins by about 10 years of age and the ERG by that time is often markedly diminished or absent.  Patches of hyperfluorescence are seen in younger individuals and these enlarge and coalesce with age.  Tunnel vision occurs early as the peripheral visual field is constricted to 5-10 degrees by midlife.  The retinal disease is progressive and blindness may be the final result.

Systemic Features: 

Type I Usher syndrome is characterized by profound hearing impairment beginning at birth, vestibular dysfunction, and unintelligible speech in addition to retinitis pigmentosa.  Vestibular areflexia is virtually complete and constitutes a defining feature.  Ataxic gait disturbances are common secondary to labyrinthine dysfunction and many children do not walk until 18-24 months of age.  Sitting alone may also be delayed.  Sperm motility is abnormal which is likely the basis for reduced fertility in male patients.  An abnormal exoneme morphology from ciliated progenitors is likely the common basis for these clinical findings.  MRI imaging has found a significant decrease in intracranial volume and brain size.  About 1 in 4 children have behavioral problems or psychosocial difficulties.

Genetics

Type I Usher syndrome is an autosomal recessive genetically heterogeneous disorder as mutations in at least 8 genes produce a similar disease.  These are: MYO7A (276900) at 11q13.5 causing USH1B (USH1A is now considered to be the same), USH1C at 11p15.1 causing USH1C (276904), CDH23 at 10q21-q22, causing USH1D (601067), PCDH15 at 10q21.1 causing USH1F (602083), and USH1G at 17q24-25 causing USH1G (606943).  Mutations in as yet unnamed genes in loci at 21q21 (USH1E; 602097), 10p11.21-q21.1 (USH1K), and 15q22-q23 (USH1H; 612632) may also cause this type I phenotype. They are discussed here as a single entity designated type I since the clinical features of each are indistinguishable.'

A varant of USH1C resulting from homozygous deletions in 11p15-p14, known as homozygous 11p15-p14 deletion syndrome, has the additional feature of severe hyperinsulinemia due to the involvement of ABCC8 and KCNJ11 genes (606528).

Clinical differences have led to the categorization of three types of Usher syndrome:  type I described here, type II (276901) caused by mutations in at least 4 genes, and type III (276902) caused by mutations in CLRN1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

At-risk infants should have hearing evaluations as soon as possible after birth.  Assistive hearing devices are of little benefit.  Unless cochlear implants are placed in young children, speech may not develop.  Extra precautions during physical activities such as swimming, bicycling, and night-time driving are highly recommended. Speech therapy and low vision aids can be beneficial.

References
Article Title: 

Targeted exon sequencing in Usher syndrome type I

Bujakowska KM, Consugar MB, Place E, Harper S, Lena J, Taub DG, White J, Navarro-Gomez D, Weigel-DiFranco C, Farkas MH, Gai X, Berson EL, Pierce EA. Targeted exon sequencing in Usher syndrome type I. Invest Ophthalmol Vis Sci. 2014 Dec 2.  [Epub ahead of print].

PubMed ID: 
25468891

Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing Loss, Retinitis Pigmentosa, and Hyperinsulinemic Hypoglycemia Ranging from Severe to Mild with Conversion to Diabetes

Al Mutair AN, Brusgaard K, Bin-Abbas B, Hussain K, Felimban N, Al Shaikh A, Christesen HT. Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing Loss, Retinitis Pigmentosa, and Hyperinsulinemic Hypoglycemia Ranging from Severe to Mild with Conversion to Diabetes. Diabetes Care. 2012 Nov 12. [Epub ahead of print].

PubMed ID: 
23150283

Treacher Collins-Franceschetti Syndrome

Clinical Characteristics
Ocular Features: 

Lid fissures often have an antimongoloid slant.  Many patients (69%) have a coloboma of the lower eyelid (in contradistinction to Goldenhar spectrum syndrome [164210] in which the lid colobomas involve the upper eyelid) with a paucity of lashes and meibomian glands medially.  Colobomas may also involve the iris, choroid and optic nerve.  Other ocular features include blepharoptosis, hypoplasia of the supraorbital ridges, absent lacrimal puncti, underdevelopment of the orbicularis oculi muscle, absence of the tarsal plate, and abnormalities of the lateral canthal tendons.  Strabismus and amblyopia have been reported in a significant number of individuals.

Systemic Features: 

A variety of defects in facial development have been reported, most involving the ears, eyelids, lower jaw, and zygomatic arch.  The characteristic facial phenotype is usually evident at birth.  One-third of patients have a cleft palate.  Microtia or even anotia may be present and a conductive hearing loss can result, especially when the ossicles are malformed or absent.  The pinnae are often malformed, appearing 'crumpled', low-set, and rotated posteriorly.  There may be ear tags and blind fistulas anywhere between the tragus and angle of the mouth.  The mandible and its rami may be hypoplastic causing severe micrognathia that can result in feeding and speaking difficulties, especially when pharyngeal hypoplasia is also present.  The zygomatic arches are often underdeveloped (or even absent) and the midface is flattened.  Arhinia and cleft palate are sometimes seen.  A low hairline may be present.  Intelligence is usually normal.

Genetics

This is an autosomal dominant syndrome secondary to mutations in the TCOF1 gene located at 5q32-q33.1.  A parental gender influence is suggested by at least one study which found an increase in the number of affected offspring from affected mothers compared with those from affected fathers.  Many cases (60%) result from new mutations but a paternal age effect has not been established.  Inter- and intrafamilial clinical variation is wide.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Auditory testing should be done early since corrective action is important in the prevention of developmental delays.  Reconstructive facial surgery can be of great benefit to both cosmesis and function.  Lid reconstruction may be required for corneal protection.

References
Article Title: 

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

Teber OA, Gillessen-Kaesbach G, Fischer S, Bohringer S, Albrecht B, Albert A, Arslan-Kirchner M, Haan E, Hagedorn-Greiwe M, Hammans C, Henn W, Hinkel GK, Konig R, Kunstmann E, Kunze J, Neumann LM, Prott EC, Rauch A, Rott HD, Seidel H, Spranger S, Sprengel M, Zoll B, Lohmann DR, Wieczorek D. Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation. Eur J Hum Genet. 2004 Nov;12(11):879-90.

PubMed ID: 
15340364

Neurofibromatosis Type II

Clinical Characteristics
Ocular Features: 

It is not uncommon for children to present with visual complaints secondary to cataracts, retinal hamartomas, or optic nerve damage from a schwannoma.  The most common eye findings are juvenile cataracts (up to 80% of patients), followed by epiretinal membranes in 12-40%, and retinal tumors in 6-22%.  Lens opacities may be located in the posterior subcapsular region or as cortical wedge-shaped opacities in the periphery where they are easily missed if the pupil is not fully dilated.  Translucent, grayish epiretinal membranes with white edges are present in a significant number of patients, including children.  Elevated retinal hemartomas in the macula are often associated with pigmentary changes.  Lisch nodules characteristic of type I neurofibromatosis (162200) are generally not found in type II.  Corneal damage may occur as a complication of hypesthesia resulting from damage to the fifth cranial nerve.

CT scans reveal calcification along the optic nerve in a "tram-track" configuration which occurs in 20-30% of patients with NF type II.

Systemic Features: 

Type II neurofibromatosis often presents in the third or fourth decade of life as hearing loss accompanied by tinnitus and dizziness. A significant proportion of children (30%) present with the same symptoms although they are more likely to complain of visual disturbances. Type II accounts for about 10% of neurofibromatosis cases.  Acoustic neurinomas, usually bilateral, are far more common in type II (95%) and are considered diagnostically distinctive by some.  Such schwannomas also occur in other cranial and peripheral nerves.  Neurofibromas are uncommon but meningiomas, ependymomas, and astrocytomas are seen frequently. Schwannomas can form anywhere along peripheral nerves and at least a third of patients require surgical excision of one or more of these lesions.  These account for the majority of skin plaques and lumps and are found in more than half of patients.  Caf√©-au-lait spots are uncommon or even absent in many patients with type II.  Patients with type II neurofibromatosis do not have the cognitive problems sometimes seen in those with type I.

Longevity overall is reduced.  The average patient lives about 15 years after diagnosis and the average age of death is 36 years.

Genetics

Type II neurofibromatosis is an autosomal dominant disorder caused by mutations in the NF2 gene (22q12.2) which encodes neurofibromin-2, sometimes called merlin or schwannomin.  This protein product, like neurofibromin in type I (162200), functions as a tumor suppressor.  New mutations are responsible for approximately half of cases.

Cognitive deficits and Lisch nodules on the iris are more commonly found in neurofibromatosis type I (162200) but acoustic neuromas are less common.  Type I results from mutations in NF1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Early surgical treatment of small acoustic and facial schwannomas can preserve nerve function in many cases.  This is a progressive disease requiring lifelong monitoring for disease progression.  The peripheral lens opacities usually do not progress and therefore cause little visual morbidity.

References
Article Title: 

Neurofibromatosis type 2. Review

Asthagiri AR, Parry DM, Butman JA, Kim HJ, Tsilou ET, Zhuang Z, Lonser RR. Neurofibromatosis type 2. Review. Lancet. 2009 Jun 6;373(9679):1974-86.

PubMed ID: 
19476995

Maroteaux-Lamy Syndrome (MPS VI)

Clinical Characteristics
Ocular Features: 

Corneal clouding is the cardinal ocular feature and is often visible by 5 years of age.  Several adult patients have had glaucoma with both open and closed angles.  The mechanism is unknown.  Optic nerve compression or secondary edema can cause a relatively sudden loss of vision.

Systemic Features: 

The lysosomal accumulation of glycosaminoglycans is responsible for the widespread signs and symptoms found in this disease.  Bone destruction in shoulders, hips and skull is often seen by the second decade of life and may become evident later in the knees and spine.  Early growth may be normal but eventually slows resulting in short stature.  Dysplasia of bones comprising these joints leads to stiffness and restricted movement.  The face is dysmorphic with coarse features.  Bone dysplasia and facial dysmorphism may be seen at birth.  Myelopathy and even tetraplegia can result from vertebral compression.  Intelligence is often normal although more severely affected individuals may have some cognitive defects.  Hepatosplenomegaly is common and compromised respiratory function can result in reduced physical stamina.  The tongue is usually enlarged.  Accumulation of dermatan sulfate in heart valves may produce insufficiency or restriction of outflow.

Genetics

MPS VI is a lysosomal storage disease inherited in an autosomal recessive pattern.  The responsible mutations lie in ARSB (5q11-q13), the gene that encodes the enzyme arylsulfatase B.  The phenotype results from defective dermatan sulfate breakdown with lysosomal accumulation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Enzyme replacement therapy with galsulfase (Naglazyme®) is beneficial in alleviating some of the manifestations of this disease.  Orthopedic surgery for specific deformities may be necessary.  Visually significant corneal opacification may require corneal transplantation.

References
Article Title: 

Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)

Swiedler SJ, Beck M, Bajbouj M, Giugliani R, Schwartz I, Harmatz P, Wraith JE, Roberts J, Ketteridge D, Hopwood JJ, Guffon N, S?deg Miranda MC, Teles EL, Berger KI, Piscia-Nichols C. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005 Apr 15;134A(2):144-50.

PubMed ID: 
15690405

Morquio Syndrome (MPS IVB)

Clinical Characteristics
Ocular Features: 

Corneal clouding may not be seen until 10 years of age and is sometimes associated with photophobia.  The stroma has fine dust-like particles most dense centrally.  Penetrating keratoplasty is rarely indicated. There is little retinal degeneration unlike that often seen in other mucopolysaccharidoses but the corneal clouding often precludes detailed examination.

Systemic Features: 

This form of mucopolysaccharidosis is characterized by the urinary excretion of keratin sulfate.  Age of onset is highly variable but most children are diagnosed by 6 years of age.  It is a milder disease than the somewhat similar but genetically distinct Morquio type A (253000)  disorder.  Intelligence is normal and there is no central nervous system involvement.  Hip joints are dysplastic and frequently painful.  Vertebral malformations lead to kyphoscoliosis and short trunk dwarfism.  Odontoid hypoplasia can cause cervical instability and increases the risk of myelopathy with secondary bowel and bladder dysfunction.  Coxa valgum, and narrow phalanges are common.  Many individuals have a characteristic gait secondary to genu valgum.  Patients with MPS IVB initially do not have the coarse facies seen in some other forms of MPS.  Further accumulation of cellular keratin sulfate may lead to some coarsening of facial features, increased corneal clouding, and hepatomegaly.  Some form of hearing loss is common.

Genetics

This is an autosomal recessive lysosomal storage disease caused by a mutation in the GLB1 gene (3p21.33) encoding beta-galactosidase.  It is allelic to GM1 gangliosidosis (230500).  Type A Morquio syndrome (253000) is a separate disorder secondary to a mutation in a different gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A variety of treatments are under investigation including enzyme replacement, gene therapy, and bone marrow transplantation.  Supportive and palliative measures for respiratory difficulties and skeletal deformities can be used.  Atlantoaxial subluxation is a constant risk and some physicians recommend prophylactic vertebral fusion.  Intubation for general anesthesia carries special risks.

References
Article Title: 

Mucopolysaccharidoses and the eye

Ashworth JL, Biswas S, Wraith E, Lloyd IC. Mucopolysaccharidoses and the eye. Surv Ophthalmol. 2006 Jan-Feb;51(1):1-17. Review.

PubMed ID: 
16414358

Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B

Paschke E, Milos I, Kreimer-Erlacher H, Hoefler G, Beck M, Hoeltzenbein M, Kleijer W, Levade T, Michelakakis H, Radeva B. Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B. Hum Genet. 2001 Aug;109(2):159-66.

PubMed ID: 
11511921

Morquio Syndrome (MPS IVA)

Clinical Characteristics
Ocular Features: 

Corneal clouding in the form of fine deposits in the stroma is the major ocular manifestation but it may not be noted for several years after birth.  Penetrating keratoplasty is rarely needed.  Glaucoma occurs rarely.

Systemic Features: 

There is wide variation in the clinical disease in this disorder and some have grouped cases into severe, intermediate and mild categories.   Onset is about 2 years of age and three-quarters of patients are diagnosed by the age of 6 years.  Intelligence is usually normal and the central nervous system is spared similar to MPS IVB. However, the skeletal dysplasia can lead to neurologic complications.  In particular, odontoid hypoplasia raises the risk of atlantoaxial dislocation and spinal cord damage. The maxillary teeth are often abnormal with wide spacing and a flared appearance.  Truncal dwarfism is characteristic but the facies are often more fine-featured than in other mucopolysaccharidoses.  Lifespan is shortened in most patients.

Genetics

This is an autosomal recessive disorder resulting from mutations in the GALNS gene (16q24.3) encoding galactosamine-6-sulfate sulfatase.  Keratan sulfate and chondroitin-5-sulfate accumulates in lysosomes.  Urinary keratin sulfate excretion is increased.

A clinically similar disease, Morquio syndrome B (253010), is caused by a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for this disease.  Some have recommended cervical spine fusion to stabilize the atlantoaxial joint. Orthopedic surgery may be indicated for joint and spine deformities.  Special precautions should be taken during intubation for general anesthesia.

Enzyme replacement therapies and hematopoietic stem cell transplantation techniques now being developed hold promise for more specific treatment for the underlying enzyme deficiencies in mucopolysaccharidoses.

References
Article Title: 

Mucopolysaccharidoses and the eye

Ashworth JL, Biswas S, Wraith E, Lloyd IC. Mucopolysaccharidoses and the eye. Surv Ophthalmol. 2006 Jan-Feb;51(1):1-17. Review.

PubMed ID: 
16414358

Optic Atrophy 1

Clinical Characteristics
Ocular Features: 

This form of bilateral optic atrophy may have its onset in early childhood with optic disc pallor, loss of acuity, loss of color vision, and centrocecal scotomas.  However, it is often not manifest until the second decade of life.  Moderate to severe temporal or diffuse pallor can be seen.  The optic disc has been described as normal in 29% of documented carriers and 20% have no visual field defect.  Pallor of the complete disc is found in only 10%.  Consequently, the phenotype is variable, with some individuals having minimal symptoms while others have severe vision loss.  The disease is progressive in some but not all families.  The median visual acutity is 20/70 but ranges from normal to hand motions.  

Histologic studies show atrophy of ganglion cells in the retina and loss of myelin sheaths in the optic nerve.   VEPs are absent or subnormal.  Optical coherence tomography reveals a significant reduction in retinal nerve fiber layer and ganglion cell layer thickness, most marked in the temporal quadrants.

Systemic Features: 

OPA1 is generally not associated with systemic disease.  However, some have sensorineural deafness, ataxia, ptosis, and ophthalmoplegia.  Families with both early and late onset have been reported.  Some (~20%) individuals have a myopathy as well.

Genetics

This is an autosomal dominant disorder resulting from mutations in a nuclear gene, OPA1 (3q28-q29).  The gene product is attached to the mitochondrial cristae of the inner membrane and metabolic studies have implicated the oxidative phosphorylation pathway which seems to be defective with reduced efficiency of ATP synthesis.  Penetrance approaches 90% but this is, of course, age dependent to some extent.

An allelic disorder (125250) is associated with sensorineural deafness, ataxia, and ophthalmoplegia but its uniqueness remains to be established since the same mutations in OPA1 have been found in both conditions.

Other autosomal dominant optic atrophy disorders include OPA5 (610708) and OPA4 (605293).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

OPA1 in multiple mitochondrial DNA deletion disorders

Stewart JD, Hudson G, Yu-Wai-Man P, Blakeley EL, He L, Horvath R, Maddison P, Wright A, Griffiths PG, Turnbull DM, Taylor RW, Chinnery PF. OPA1 in multiple mitochondrial DNA deletion disorders. Neurology. 2008 Nov 25;71(22):1829-31.

PubMed ID: 
19029523

Goldenhar Syndrome Spectrum

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity in this syndrome.  Upper eyelid colobomas and ocular dermoids or lipdermoids are the primary ocular signs (lower lid colobomas are more common in Treacher Collins-Franceschetti syndrome [154500]).  The caruncles may be dysplastic, displaced or even bilobed.  Iris, optic nerve and chorioretinal colobomas also occur.  Microphthalmia is uncommon.  All ocular features are usually unilateral but are bilateral in a minority of cases.

Systemic Features: 

The facial asymmetry (hemifacial microsomia) can be a striking feature.  The side with microsomia may have a malformed external auricle, preauricular tags, pretragal fistulas, and microtia or even atresia of the external auditory canal.  A wide variety of other anomalies are often found including left lip and palate, mandibular hypoplasia, vertebral anomalies, facial nerve paralysis, congenital heart defects, and conductive hearing loss.  Mental deficits are often present along with features of the autism spectrum in 11%.

Genetics

Most cases are sporadic but other family patterns support autosomal recessive and autosomal dominant inheritance with the latter being the most common.  A locus at 14q32 has been associated with OAVS but so far no mutant gene has been identified.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Some patients benefit from scoliosis and cosmetic surgery.  Assistive hearing devices can be helpful and children especially should be monitored for physical and cognitive development.

References
Article Title: 

Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients

Beleza-Meireles A, Hart R, Clayton-Smith J, Oliveira R, Reis CF, Venancio M, Ramos F, Sa J, Ramos L, Cunha E, Pires LM, Carreira IM, Scholey R, Wright R, Urquhart JE, Briggs TA, Kerr B, Kingston H, Metcalfe K, Donnai D, Newman WG, Saraiva JM, Tassabehji M. Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients. Eur J Med Genet. 2015 Sep;58(9):455-65.

PubMed ID: 
26206081

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