Differential Diagnosis
Nonsyndromic hearing loss (NSHL). Often, a family with more than one affected sib is thought to have NSHL (see Hereditary Hearing Loss and Deafness Overview) until the oldest affected sib manifests signs of retinal degeneration (e.g., night blindness, dark adaptation impairment, contrast vision difficulties, visual acuity changes, and visual field narrowing) and is diagnosed with retinitis pigmentosa (RP). Subsequent visual evaluation often reveals the presymptomatic signs of RP in younger affected sibs. While the timing and extent of vestibulopathy related to Usher syndrome is not fully defined, vestibular symptoms in young children thought to have NSHL may also prompt visual evaluation and subsequent genetic testing. Coinheritance of NSHL and RP. Pathogenic variants associated with separate NSHL and RP (e.g., OTOA-NSHL and NR2E3-RP ) can be inherited independently by a single individual whose symptoms can then mimic those of Usher syndrome . 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 (or inherited retinal degeneration) are both relatively common, with frequencies of 1:1,000 and 1:3,000, respectively, and are both characterized by extreme genetic heterogeneity (to date, 110 genes have been associated with NSHL, 60 genes have been associated with RP, and 172 genes have been associated with inherited retinal degeneration) . See also Hereditary Hearing Loss and Deafness Overview and RetNet: Retinal Information Network. Hereditary disorders characterized by both sensorineural hearing impairment (SNHI) and decreased visual acuity to consider in the differential diagnosis of Usher syndrome type I (USH1) are summarized in . Table 3. Genes of Interest in the Differential Diagnosis of Usher Syndrome Type I
Gene(s) | Disorder | MOI | Clinical Characteristics | Comment |
|---|
USH2 | ARDigenic1 | Congenital bilateral SNHL (predominantly in the higher frequencies); ranges from mild to severe; Adolescent- to adult-onset RP | Children w/USH1 are usually delayed in walking until age 18 mos to 2 yrs because of vestibular involvement, whereas children w/USH2 usually begin walking at ~1 yr. ALMS1 | — |
Alstrm syndrome | AR | SNHI; Progressive cone-rod dystrophy leading to blindness; Childhood obesity associated w/hyperinsulinemia, type 2 diabetes | Cardiomyopathy occurs in ~70% of affected persons in infancy or adolescence.; Kidney failure pulmonary, hepatic, urologic dysfunction are frequent.; Systemic fibrosis develops w/age. | — |
CEP250 | Cone-rod dystrophy and hearing loss 2 (OMIM 618358) | AR | Variable onset severity of hearing loss; Variable onset severity of visual loss | Can be diagnosed as atypical USH12 |
CEP78 | Cone-rod dystrophy hearing loss 1 (OMIM 617236) | AR | Late-onset hearing... | — |
Source: GeneReviews — "Usher Syndrome Type I"
