Usher Syndrome Type Ii
Summary
Clinical characteristics.
Usher syndrome type II (USH2) is characterized by the following:
- Congenital, bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies
- Intact or variable vestibular responses
- Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity; the rate and degree of vision loss vary within and among families.
Diagnosis/testing.
The diagnosis of USH2 is established in a proband using electrophysiologic and subjective tests of hearing and retinal function. Identification of biallelic pathogenic variants in one of three genes – ADGRV1, USH2A, or WHRN – establishes the diagnosis if clinical features are inconclusive.
Management.
Treatment of manifestations: Early fitting of hearing aids and speech training. Children with incomplete speech and sentence rehabilitation with hearing aids and older individuals with severe-to-profound hearing loss should be considered for cochlear implantation. Standard treatments for retinitis pigmentosa; vestibular rehabilitation.
Surveillance: Annual audiometry and tympanometry with hearing aids or cochlear implant to assure adequate auditory stimulation. Annual ophthalmologic evaluation from age 20 years to detect potentially treatable complications such as cataracts, refractive errors, and cystoid macular edema. Annual fundus photography, visual acuity, visual field, electroretinography, optical coherence tomography, and fundus autofluorescence from age ten years.
Agents/circumstances to avoid: Tunnel vision and night blindness can increase the likelihood of accidental injury. Competition in sports requiring a full range of vision may be difficult and possibly dangerous. Progressive loss of peripheral vision impairs the ability to safely drive a car.
Evaluation of relatives at risk: The hearing of at-risk sibs should be assessed as soon after birth as possible to allow early diagnosis and treatment of hearing loss.
Genetic counseling.
USH2 is inherited in an autosomal recessive manner. Each subsequent pregnancy of a couple who have had a child with Usher syndrome type II has a 25% chance of resulting in an affected child, a 50% chance of resulting in an unaffected child who is a carrier, and a 25% chance of resulting in an unaffected child who is not a carrier. Prenatal testing and preimplantation genetic testing are possible for pregnancies at increased risk if the pathogenic variants have been identified in the family.
Diagnosis
Suggestive Findings
Usher syndrome type II (USH2) should be suspected in individuals with:
- Congenital (i.e., prelingual) sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies (see Hereditary Hearing Loss and Deafness Overview);
- Intact or variable vestibular responses;
- Retinitis pigmentosa (RP);
- Normal general health and intellect; otherwise normal physical examination;
- A family history consistent with autosomal recessive inheritance.
Establishing the Diagnosis
The diagnosis of USH2 is established in a proband with the above clinical features and family history. Identification of biallelic pathogenic variants in one of the genes listed in Table 1 establishes the diagnosis if clinical features are inconclusive.
The phenotype of USH2 is often indistinguishable from many other inherited disorders associated with hearing loss and/or RP, therefore the recommended molecular testing approaches can include use of a multigene panel or comprehensive genomic testing.
Note: Single-gene testing is rarely useful and typically NOT recommended.
- An Usher syndrome multigene panel or a more comprehensive multigene panel (e.g., inherited retinal dystrophy panel, hereditary hearing loss panel) that includes the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Usher Syndrome Type II (USH2)
| Gene 1, 2 | USH2 Subtype | Proportion of USH2 Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detected by Method | |
|---|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | |||
| ADGRV1 | USH2C | 6.6%-19% 6 | >90% 7 | 3/49 individuals 8 |
| USH2A | USH2A | 57%-79% 6 | >90% 7, 9 | 6%-9% 10, 11 |
| WHRN | USH2D | 0%-9.5% 6 | >95% 7 | None reported 7 |
| Unknown 12, 13 | NA | |||
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Bonnet et al [2011], Le Quesne Stabej et al [2012], García-García et al [2013]
- 7.
LOVD Usher Syndrome Database
- 8.
Hilgert et al [2009], Besnard et al [2012], Aparisi et al [2014]
- 9.
Several deep intronic variants outside of the exon and splice junction regions typically included in sequence analysis have been observed [Vaché et al 2012, Liquori et al 2016].
- 10.
Bernal et al [2005], Dreyer et al [2008], Steele-Stallard et al [2013], Aparisi et al [2014], Baux et al [2014], Krawitz et al [2014], Sodi et al [2014], Dad et al [2015]
- 11.
By screening for duplications/deletions, Steele-Stallard et al [2013] found a second USH2A pathogenic variant in 26% (6/23) of individuals for whom only one disease-causing allele had been found by sequencing.
- 12.
A fourth locus associated with Usher syndrome type II has been provisionally mapped to 15q in a consanguineous Tunisian family [Ben Rebeh et al 2008].
- 13.
To date, PDZD7 pathogenic variants have not been shown to cause Usher syndrome but may act as modifiers of the retinal phenotype in individuals with USH2A-related USH2 [Ebermann et al 2010]. Additionally, an individual with USH2 and compound heterozygous pathogenic variants in USH2A and PDZD7 and another affected individual with compound heterozygous variants in ADGRV1 and PDZD7 were reported, leading to the suggestion of digenic inheritance [Ebermann et al 2010].
Clinical Characteristics
Clinical Description
Usher syndrome type II (USH2) is characterized by moderate-to-severe sensorineural hearing loss at birth and retinitis pigmentosa (RP) that begins in late adolescence or early adulthood. Some individuals also have vestibular loss [Yang et al 2012, Blanco-Kelly et al 2015, Magliulo et al 2017].
Table 2.
Select Features of Usher Syndrome Type II
| Feature | % of Persons w/Feature | Comment |
|---|---|---|
| Hearing loss | 100% | High-frequency loss which is usually stable |
| RP | 100% | Variable age of onset & rate of progression |
| Vestibular loss | 40%-80% | Usually asymptomatic but identifiable on specialized testing 1 |
RP = retinitis pigmentosa
- 1.
Magliulo et al [2017]
Hearing Loss
The hearing loss in USH2 is typically congenital and bilateral, occurring predominantly in the higher frequencies and ranging from moderate to severe. The degree of hearing loss varies within and among families; however, the "sloping" audiogram is characteristic of USH2. The hearing loss may be perceived by the affected individual as progressing over time because speech perception decreases, possibly as a result of diminished vision that interferes with subconscious lip reading. Hearing aids are usually adequate in individuals with USH2. Cochlear implants are highly effective if speech and sentence testing indicates inadequate response with hearing aids.
Clinical variability of the hearing phenotype has been observed. In particular, a few individuals with USH2 have a mild but definite progression of hearing loss that is unrelated to presbycusis. A cross-sectional study of 27 persons with USH2A-USH2 confirmed by linkage analysis compared hearing threshold against age; significant progression of hearing impairment was observed but at a much slower rate than reported for Usher syndrome type III (USH3) [Pennings et al 2003]. In contrast, in a large study of 125 individuals with USH2, Reisser et al [2002] found no clinically relevant progression of hearing loss over a span of up to 17 years.
Visual Loss
Children with USH2 are often misdiagnosed as having nonsyndromic hearing impairment until tunnel vision and night blindness (early signs of RP) become severe enough to be noticeable, either by parents and teachers or by the individual. The onset of RP in individuals with USH2 is variable but typically starts in late adolescence or early adulthood and occasionally can start much earlier. RP is progressive, bilateral, symmetric photoreceptor degeneration of the retina that initiates in the mid-periphery; rods (photoreceptors active in the dark-adapted state) are mainly affected first, causing night blindness and constricted visual fields (tunnel vision). Cones (photoreceptors active in the light-adapted state) are affected second and eventually die and cause central blindness. Contrast sensitivities, color vision, and mobility may become severely affected as the retinal degeneration progresses.
Visual fields become progressively constricted with time. The rate and degree of visual field loss show intra- and interfamilial variability. A visual field of 5-10 degrees ("severe tunnel") is common for a person with USH2 at age 30-40 years. Visual impairment worsens significantly each year [Iannaccone et al 2004, Pennings et al 2004]. Individuals with USH2 may become completely blind. Cataracts and/or cystoid macular edema sometimes reduce central vision. These two associated conditions are treatable.
Vestibular Loss
Vestibular loss has been identified in 40%-80% of individuals with USH2 in a small study of specialized vestibular testing [Magliulo et al 2017]. However, these individuals were found to be asymptomatic suggesting that they compensate for the loss of vestibular function.
Heterozygotes
Heterozygotes are asymptomatic; however, they may exhibit audiogram anomalies that are not sensitive or specific enough for carrier detection.
Phenotype Correlations by Gene
Sadeghi et al [2004] compared serial audiograms of individuals with USH2 who had pathogenic variants in USH2A (group 1) with those of individuals diagnosed with USH2 who did not have pathogenic variants in USH2A (group 2). They found significantly worse thresholds in group 1 than in group 2 after the second decade. These results suggested that the USH2A-USH2 auditory phenotype may be different from that of other subtypes of USH2. Abadie et al [2012], however, did not find any significant differences between the audiograms from 88 individuals with pathogenic variants in USH2A and ten individuals with pathogenic variants in ADGRV1.
Schwartz et al [2005] did not observe any genotype-phenotype correlations between individuals with pathogenic variants in USH2A and those with variants in ADGRV1; however, only three sibs with pathogenic variants in ADGRV1 were evaluated. They found a wide spectrum of photoreceptor disease with more rod than cone dysfunction, and both intra- and interfamilial variation for USH2A-USH2.
Frenzel et al [2012] performed two measures of touch sensation (tactile sensation and vibrational detection threshold) on two cohorts of individuals with USH2 from Germany and Spain. USH2A variants were associated with poor touch acuity as well as congenital hearing loss and adult-onset RP.
Genotype-Phenotype Correlations
USH2A. Deleterious null (e.g., nonsense, frameshift, splicing) variants are associated with USH2, whereas homozygous missense variants that generate partially functional proteins typically cause nonsyndromic RP [Lenassi et al 2015b, Hartel et al 2016, Jung 2020]. The visual phenotype in individuals with USH2A-USH2 pathogenic variants is associated with more severe RP compared with nonsyndromic USH2A-RP [Pierrache et al 2016, Sengillo et al 2017, Gao et al 2020]. The hearing phenotype in individuals with USH2A-USH2 is more severe and progressive in individuals with one or more deleterious USH2A variants [Hartel et al 2016, Jung 2020].
Lenassi et al [2015b] designated retinal disease-specific pathogenic variants in USH2A that cause RP with preservation of normal hearing. While these individuals did not report hearing loss, audiometric testing found variable hearing loss in a substantial number. A correlation between severity of hearing loss and severity of RP was not found.
Individuals of Swedish or Dutch origin with biallelic USH2A truncating variants (including homozygous c.2299delG variants) developed significantly more severe and progressive hearing loss than individuals with one truncating USH2A variant combined with one nontruncating variant and individuals with two nontruncating variants. Similar findings were also reported in individuals of Korean ancestry [Hartel et al 2016, Jung 2020].
Penetrance
Penetrance is 100% in USH2.
Nomenclature
The numbering system used in Usher syndrome classification (USH1, USH2, and USH3) corresponds with the associated severity of the clinical presentation (i.e., degree of hearing impairment, the presence or absence of vestibular areflexia, and the age of onset of retinitis pigmentosa). The letter following USH2 indicates the molecular subtype caused by biallelic variants in one of the related genes listed in Table 1.
Prevalence
The prevalence of Usher syndrome in the general US population has been conservatively estimated at 4.4:100,000. However, a study of children with hearing loss in Oregon found that 11% had pathogenic variants in genes associated with Usher syndrome and estimated that the prevalence may be as high as 1:6,000 [Kimberling et al 2010].
Usher syndrome has been estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness. These estimates were made prior to 1989, when Möller et al [1989] subdivided Usher syndrome into USH1 and USH2, and USH3 had not yet been recognized. The specialized educational requirements of the congenitally deaf have historically rendered the population with USH1 more accessible for study by researchers. Persons with USH2 or USH3 communicate orally and are mainstreamed into regular schools; thus, the prevalence of USH2 and USH3 in the general population cannot be estimated as accurately as that of USH1. Often, persons with USH2 are not diagnosed until early adulthood, when progressive RP becomes debilitating.
The prevalence of Usher syndrome in Heidelberg, Germany and its suburbs has been calculated to be 6.2:100,000 [Spandau & Rohrschneider 2002]. In that study, the ratio of USH1 to USH2 was 1:3.
Differential Diagnosis
Often, a family with more than one affected sib is thought to have nonsyndromic hearing loss (NSHL) (see Hereditary Hearing Loss and Deafness Overview) until the oldest is diagnosed with retinitis pigmentosa (RP). Subsequent visual evaluation often reveals the presymptomatic early stages of RP in younger affected sibs.
Pathogenic variants associated with NSHL and RP can be inherited independently by a single individual whose symptoms mimic those of Usher syndrome [Fakin et al 2012]. Larger families lessen the statistical probability of this occurrence because at least one sib is likely to inherit one pathogenic variant without the other. NSHL and RP are both relatively common, with frequencies of 1:1,000 and 1:4,000, respectively, and are characterized by extreme genetic heterogeneity (to date, >110 genes have been associated with NSHL and >80 genes have been associated with RP).
Hereditary disorders characterized by both sensorineural hearing impairment and decreased visual acuity to consider in the differential diagnosis of Usher syndrome type II (USH2) are summarized in Table 4.
Table 4.
Genes of Interest in the Differential Diagnosis of Usher Syndrome Type II
| Gene(s) | Disorder | MOI | Clinical Characteristics | Comment | |
|---|---|---|---|---|---|
| CDH23 CIB2 MYO7A PCDH15 USH1C USH1G | USH1 | AR | Congenital bilateral profound SNHL, vestibular areflexia, adolescent-onset RP | Children w/USH1 are usually do not walk until age 18 mos to 2 yrs due to vestibular involvement (those w/USH2 usually walk at age ~1 yr). | |
| CLRN1 HARS1 | USH3 (OMIM 276902, 614504) | AR | Postlingual progressive SNHL, late-onset RP, variable impairment of vestibular function | Some persons w/USH3 may have profound HL & vestibular disturbance & thus be clinically misdiagnosed w/USH1 or USH2. 1 | |
| PEX1 PEX6 PEX12 (13 genes) 2 | Zellweger spectrum disorder (ZSD) 3 | Intermediate/ milder ZSD | AR (AD) 4 | Mainly sensory deficits &/or mild developmental delay; intellect may be normal. | Milder ZSD & USH2 can both have SNHL & retinal pigmentary abnormalities, but visual impairment in milder ZSD is more variable. Also, those w/milder ZSD typically develop ameliogenesis imperfecta of secondary teeth. |
| Severe ZSD | AR | Severe neurologic dysfunction, craniofacial abnormalities, liver disfunction, absent peroxisomes | Infants w/severe ZSD are significantly impaired & usually die during 1st yr of life, usually having made no developmental progress. | ||
| PEX7 PHYH | Refsum disease | AR | RP, HL, anosmia, polyneuropathy, ataxia | RP is nearly always 1st noticeable feature; anosmia, polyneuropathy, & then mild-to-moderate HL follow. | |
| ABHD12 | Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, & cataract (PHARC) (OMIM 612674) | AR | Polyneuropathy, HL, ataxia, RP, cataract | Persons w/PHARC typically develop polyneuropathy & ataxia in teens or early adulthood; & RP typically later in adulthood. | |
| TIMM8A 5 | Deafness-dystonia-optic neuronopathy syndrome (DDON) | XL | Males: pre- or postlingual SNHL in early childhood; optic atrophy → slowly progressive ↓ visual acuity from age ~20 yrs; dementia from age ~40 yrs; slowly progressive dystonia or ataxia in the teens 6 Females: mild hearing impairment & focal dystonia | In DDON, appearance of the retina, night vision, & ERG are usually normal; in USH, impaired vision results from retinal dystrophy that first manifests as impaired dark adaptation. 7 | |
AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss; MOI = mode of inheritance; RP = retinitis pigmentosa; SNHL = sensorineural hearing loss; USH = Usher syndrome; XL = X-linked
- 1.
Pennings et al [2003]
- 2.
60.5% of Zellweger spectrum disorder (ZSD) is associated with biallelic pathogenic variants in PEX1, 14.5% with pathogenic variant in PEX6, 7.6% with pathogenic variants in PEX12. In total, 13 genes are known to be associated with ZSD.
- 3.
The term "Zellweger spectrum disorder" refers to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype.
- 4.
One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state due to allelic expression imbalance dependent on allelic background.
- 5.
DDON syndrome is caused by either (1) a hemizygous TIMM8A pathogenic variant in a male proband or a heterozygous TIMM8A pathogenic variant in a female proband or (2) a contiguous gene deletion of Xp22.1 involving TIMM8A.
- 6.
In DDON syndrome, hearing impairment appears to be constant in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs (e.g., personality change and paranoia) vary in degree of severity and rate of progression.
- 7.
Sadeghi et al [2004]
Other. Viral infections, diabetic neuropathy, and syndromes involving mitochondrial defects (see Mitochondrial Disorders Overview) can all produce concurrent symptoms of hearing loss and retinal pigmentary changes that suggest Usher syndrome.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Usher syndrome type II (USH2), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 5.
Recommended Evaluations Following Initial Diagnosis in Individuals with Usher Syndrome Type II
| System/Concern | Evaluation | Comment |
|---|---|---|
| Audiology | Otoscopy, puretone audiometry, assessment of speech perception | Consider auditory brain stem response (ABR), electrocochleography (ECOG), and distortion product otoacoustic emission (DPOAE). Speech and sentence tests with hearing aids will determine if cochlear implantation offers better rehabilitation than hearing aids. |
| Vestibular function | Rotary chair, calorics, electronystagmography, ocular & cervical myogenic evoked potentials, video head impulse testing, computerized posturography | Patients describing imbalance or dizziness should undergo comprehensive vestibular testing to guide rehabilitation. |
| Ophthalmology | Fundus photography, VA, VF (Goldmann perimetry, Humphrey perimetry, Dark adapted rod perimetry), ERG, OCT, FAF | Fundus photography documents extent of pigmentation & RPE atrophy; VA is often maintained until late in disease; VF maps extent of functional peripheral vision, retinal sensitivities, & functional rod & cone responses. ERG is often nondetectable at presentation; OCT allows determination of "live" photoreceptors (measuring the ellipsoid zone); FAF can measure the perifoveal hyperfluorescent ring lipofuscin disturbance. |
| Genetic counseling | By genetics professionals 1 | To inform patients & families re nature, MOI, & implications of USH2 in order to facilitate medical & personal decision making |
| Family support/ resources | Assess:
|
ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; RPE = retinal pigment epithelium; VA = visual acuity; VF = visual field; MOI = mode of inheritance
- 1.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations
Table 6.
Treatment of Manifestations in Individuals with Usher Syndrome Type II
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Hearing loss | Hearing aids | Young children benefit from early fitting of hearing aids & speech training. |
| Cochlear implantation | Children w/incomplete speech & sentence rehabilitation w/hearing aids & older persons w/severe-to-profound hearing loss: consider for cochlear implantation. | |
| Retinitis pigmentosa |
| Tunnel vision & night blindness can ↑ likelihood of accidental injury. |
| Imbalance | Vestibular rehabilitation | Neurologically active medications or sedatives can aggravate mild vestibular dysfunction. |
- 1.
Nadal & Iglesias [2018] describe the visual outcomes and rehabilitation of a one individual with USH2 that underwent Argus II prosthesis surgery.
Surveillance
Table 7.
Recommended Surveillance for Individuals with Usher Syndrome Type II
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Hearing loss | Audiometry & tympanometry w/hearing aids or cochlear implant to assure adequate auditory stimulation | Annually, incl testing w/hearing aids in place |
| Cataracts | Ophthalmologic eval | Annually from age 20 yrs or age of diagnosis |
| Cystoid macular edema | Ophthalmologic eval | |
| Retinitis pigmentosa | Fundus photography, VA, VF (Goldmann perimetry, Humphrey perimetry, dark adapted rod perimetry), ERG, OCT, FAF |