Syndromic vs non syndromic deafness short note
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Syndromic vs Non-Syndromic Deafness
Overview
Hearing loss with a genetic basis can be broadly divided into two categories based on whether the deafness occurs in isolation or as part of a larger clinical syndrome.
Non-Syndromic Hearing Loss (NSHL)
Definition: Sensorineural hearing loss (SNHL) that occurs without any additional manifestations in at least one other body system. It accounts for approximately 70% of all genetic SNHL, making it by far the more common category.
- Scott-Brown's Otorhinolaryngology, Vol 2
Inheritance Patterns
| Mode | Proportion of NSHL |
|---|---|
| Autosomal Recessive (AR) | ~80% |
| Autosomal Dominant (AD) | ~15-18% |
| X-linked | ~1% |
| Mitochondrial | ~1% |
Gene Nomenclature (DFN Loci)
Gene loci for non-syndromic deafness are designated DFN (DeaFNess):
- DFNA - Autosomal Dominant
- DFNB - Autosomal Recessive
- DFNX - X-linked
The number after the prefix reflects the order of gene discovery (e.g., DFNB1, DFNA2, etc.).
Key Genes
1. GJB2 (Connexin 26) - DFNB1:
- The single most important hearing impairment gene
- Located at the DFNB1 locus
- Responsible for >50% of recessive NSHL and approximately 30-50% of all innate (congenital) hearing loss
- The 35delG mutation accounts for ~70% of all GJB2 mutations worldwide
- 167delT is the most frequent mutation in Ashkenazi Jews
- Over 300 mutations documented; nearly 50% of all non-syndromic hearing loss traces back to connexin 26
2. Other Connexin Genes: CX30 (GJB6), CX31 (GJB3)
3. Myosin genes: MYO1A, MYO3A, MYO6, MYO7A, MYO15A (unconventional myosins expressed in hair cells)
4. Other protein families: Adhesion proteins, ion channels, transcription factors (>100 NSHI loci identified so far)
Clinical Features of AR vs AD NSHL
| Feature | AR NSHL (DFNB) | AD NSHL (DFNA) |
|---|---|---|
| Onset | Prelingual (congenital/early childhood) | Usually postlingual |
| Progression | Stable or slowly progressive | Usually progressive |
| Severity | Severe to profound | Moderate, progressive |
| Family history | Horizontal (affected siblings) | Vertical (multiple generations) |
Note: Exceptions exist - some AD loci (e.g., TECTA - DFNA8/12) cause prelingual loss.
- Scott-Brown's, Vol 2; Scott-Brown's, Vol 1
Syndromic Hearing Loss
Definition: Hearing loss that occurs as part of a recognizable syndrome with features in at least one other organ system. Accounts for approximately 30% of all genetic hearing loss, with over 400 syndromes known to be associated.
- Scott-Brown's Otorhinolaryngology, Vol 2
Common Syndromes - Summary Table
| Syndrome | Inheritance | Hearing Loss Type | Associated Features |
|---|---|---|---|
| Pendred | AR | SNHL (progressive, high-frequency) | Goitre (develops in early puberty/adulthood), widened vestibular aqueducts, enlarged endolymphatic sac; gene: SLC26A4 (pendrin) |
| Usher | AR | SNHL (severe-profound) | Retinitis pigmentosa, vestibular dysfunction; MYO7A mutation in type 1B |
| Jervell and Lange-Nielsen | AR | Profound bilateral SNHL | Long QT syndrome, risk of sudden cardiac death |
| Waardenburg | AD | SNHL (congenital) | White forelock, heterochromia iridis, dystopia canthorum, patches of depigmented skin; PAX3 mutations (WS1/2); MITF mutations (WS2/Tietz) |
| Branchio-Oto-Renal (BOR) | AD | Mixed or SNHL | Branchial cleft anomalies, preauricular pits, renal anomalies |
| Stickler | AD | SNHL + conductive | Cleft palate, myopia, retinal detachment, arthropathy |
| Neurofibromatosis Type 2 (NF2) | AD | Progressive SNHL | Bilateral vestibular schwannomas (presents in childhood/young adult) |
| Treacher Collins | AD | Conductive | Mandibulofacial dysostosis, malar hypoplasia, microtia, choanal atresia |
| CHARGE | Sporadic/AD | Mixed | Coloboma, Heart defects, Atresia choanae, Restricted growth, Genital anomalies, Ear anomalies |
- Scott-Brown's ORL, Vol 1 & Vol 2; Fitzpatrick's Dermatology
Key Differences at a Glance
| Feature | Non-Syndromic | Syndromic |
|---|---|---|
| Proportion of genetic deafness | ~70% | ~30% |
| Other organ involvement | None | Yes (defining feature) |
| Number of syndromes/loci | >100 loci | >400 syndromes |
| Most common gene | GJB2 (Connexin 26) | Varies (SLC26A4, MYO7A, PAX3, etc.) |
| Most common inheritance | AR | Both AR and AD, depends on syndrome |
| Diagnosis | Molecular genetics / gene panel | Clinical + molecular |
Clinical Approach
- History and clinical exam - look for features in other systems (eyes, skin, thyroid, cardiac, renal, skeletal)
- Audiogram - type (SNHL vs conductive vs mixed), onset, progression
- Imaging - CT/MRI temporal bones (enlarged vestibular aqueduct in Pendred, cochlear aplasia/hypoplasia)
- ECG - rule out Jervell-Lange-Nielsen (prolonged QT)
- Ophthalmology - rule out Usher (retinitis pigmentosa) and Stickler (myopia, retinal detachment)
- Genetic testing - GJB2/GJB6 sequencing first (most common), then hearing loss gene panel if negative
- Thyroid function - for Pendred syndrome
A multidisciplinary team including audiologist, otolaryngologist, and clinical geneticist is recommended for evaluation.
- Scott-Brown's Otorhinolaryngology, Vol 2
Recent evidence note: A 2025 meta-analysis (PMID: 39970981) examined the global prevalence of mitochondrial MT-RNR1 A1555G variant in non-syndromic hearing loss, and a 2025 systematic review (PMID: 39862573) analyzed pathogenic GJB2 variants in the Asian population - both confirming continued genetic heterogeneity in NSHL. Waardenburg syndrome genetics in Africa were also systematically reviewed in 2025 (PMID: 41516007), reaffirming the important role of PAX3/MITF mutations.
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