What is the differential diagnosis and evaluation approach for a patient presenting with hearing loss?

Differential Diagnosis of Hearing Loss by Etiologic Category

The differential diagnosis of hearing loss should be systematically organized into conductive, sensorineural, and mixed categories, with further subdivision into genetic/syndromic, acquired/environmental, and idiopathic causes based on comprehensive history, physical examination, and targeted testing. 1, 2

Primary Classification by Type

Conductive Hearing Loss

Conductive hearing loss results from pathology preventing sound transmission through the external or middle ear. 2, 3

• External ear causes: Cerumen impaction (most common and potentially curative with removal), exostoses, foreign bodies, external auditory canal atresia 2, 3
• Middle ear causes: Tympanic membrane perforation, ossicular chain disruption or fixation, chronic otitis media, cholesteatoma, otosclerosis 2, 4

Sensorineural Hearing Loss

Sensorineural hearing loss involves pathology of the cochlea, auditory nerve, or central auditory pathways. 2, 3

• Age-related (presbycusis): Most common type in adults, typically bilateral and progressive 2, 5
• Noise-induced: Occupational or recreational noise exposure 5
• Ototoxic medications: Aminoglycosides (especially with mitochondrial A1555G mutation), loop diuretics, chemotherapy agents 1, 6
• Sudden sensorineural hearing loss: Loss of ≥30 dB within 72 hours, requires urgent otolaryngology referral 2, 3

Mixed Hearing Loss

Mixed hearing loss combines both conductive and sensorineural components. 2, 4

Differential Diagnosis by Etiologic Category

I. Genetic/Syndromic Causes

A. Nonsyndromic Genetic Hearing Loss

GJB2 (connexin 26) mutations are the most common genetic cause of congenital hearing loss in the United States and should be tested first in nonsyndromic cases. 1

• Autosomal recessive nonsyndromic hearing loss: GJB2 mutations account for majority; simplex cases (no family history) can still have 25% recurrence risk 1
• Autosomal dominant nonsyndromic hearing loss: Various loci, often progressive 1
• X-linked nonsyndromic hearing loss: Less common 1
• Mitochondrial inheritance: A1555G mutation (aminoglycoside-induced), A7445G mutation 1

B. Syndromic Genetic Hearing Loss

Physical examination findings suggesting syndromic hearing loss mandate syndrome-specific evaluation and genetic testing to identify life-threatening associated conditions. 1

Visual system syndromes:

• Usher syndrome: Retinitis pigmentosa with hearing loss 1
• Waardenburg syndrome: Heterochromia irides, dystopia canthorum, white forelock 1
• Stickler syndrome: Myopia, retinal detachment, early cataracts 1

Craniofacial/structural syndromes:

• Branchio-oto-renal (BOR) syndrome: Preauricular pits, branchial cysts, renal anomalies 1
• Treacher Collins syndrome: Facial dysmorphology, aural atresia 1
• CHARGE syndrome: Cleft palate, multiple congenital anomalies 1

Cardiac syndromes:

• Jervell and Lange-Nielsen syndrome: Prolonged QT interval, syncope, sudden death risk 1
• Other cardiac conduction abnormalities with hearing loss 1

Renal syndromes:

• Alport syndrome: Hematuria, proteinuria, progressive renal failure 1
• BOR syndrome: Structural renal defects 1

Endocrine syndromes:

• Pendred syndrome: Thyromegaly, goiter 1
• Diabetes with hearing loss 1

Integumentary syndromes:

• Waardenburg syndrome: Premature graying, abnormal pigmentation 1
• Keratopachyderma with hearing loss: Dry skin, keratoderma 1

Metabolic syndromes:

• Biotinidase deficiency: Preventable hearing loss with early treatment 1

II. Acquired/Environmental Causes

A. Infectious Causes

Intrauterine and postnatal infections are critical acquired causes requiring specific testing in congenital hearing loss. 1, 6

Prenatal infections (TORCH):

• Congenital CMV: Most common infectious cause; CMV testing should be performed in simplex nonsyndromic cases 1, 6
• Congenital rubella 1, 6
• Congenital toxoplasmosis 1, 6
• Congenital syphilis 1, 6
• Herpes simplex 1

Postnatal infections:

• Bacterial meningitis: Major cause of acquired hearing loss 1, 6
• Viral labyrinthitis 2

B. Perinatal/Neonatal Risk Factors

Neonatal intensive care unit exposures significantly increase hearing loss risk. 1, 6

• Prematurity and low birth weight 1, 6
• Birth hypoxia and asphyxia 1, 6
• Hyperbilirubinemia requiring exchange transfusion 1, 6
• Extracorporeal membrane oxygenation (ECMO) 1, 6
• Neonatal sepsis 1

C. Ototoxic Exposures

Aminoglycoside exposure in patients with mitochondrial mutations can cause preventable hearing loss. 1

• Aminoglycosides (especially with A1555G mutation) 1, 6
• Loop diuretics 6, 5
• Chemotherapy agents (cisplatin, carboplatin) 6, 5
• Chronic vestibular suppressive medications 6

D. Trauma and Physical Causes

• Head trauma with temporal bone fracture 1, 2
• Noise exposure (occupational or recreational) 6, 5
• Barotrauma 2

E. Teratogenic Exposures

• Prenatal alcohol exposure 1, 6
• Thalidomide 1
• Retinoic acid 1

III. Idiopathic and Age-Related Causes

Age-related sensorineural hearing loss (presbycusis) is the most common type in adults and increases markedly with age. 2, 5

• Presbycusis: Affects one-third of adults 61-70 years, over 80% of those >85 years 5
• Sudden idiopathic sensorineural hearing loss: Requires urgent referral even without identified cause 2, 3
• Ménière's disease: Fluctuating hearing loss, vertigo, tinnitus, aural fullness 6

Critical Evaluation Approach

History Components That Narrow the Differential

A detailed three-to-four generation pedigree is essential to identify inheritance patterns and distinguish genetic from environmental causes. 1

Family history red flags:

• Consanguinity (increases autosomal recessive risk) 1
• Multiple affected family members (suggests genetic etiology) 1
• Ethnicity and country of origin (certain populations have higher carrier rates) 1
• Sudden cardiac death in relatives (Jervell and Lange-Nielsen syndrome) 1

Audiometric characteristics that guide diagnosis:

• Age of onset (congenital vs. acquired) 1, 6
• Progression pattern (stable, progressive, fluctuating) 1, 6
• Laterality and symmetry (asymmetric suggests acoustic neuroma or other structural lesion) 2
• Severity and frequency configuration 1
• Presence of auditory neuropathy 1

Physical Examination Findings That Establish Diagnosis

Systematic examination for syndromic features is mandatory as approximately 30% of genetic hearing loss is syndromic. 1

Otologic examination:

• External auditory canal: Cerumen, exostoses, atresia 1, 2
• Tympanic membrane: Perforation, retraction, effusion 2
• Airway examination 1

Dysmorphology assessment:

• Facial asymmetry or unusual appearance 1
• Pigmentary anomalies (heterochromia, white forelock, abnormal skin pigmentation) 1
• Craniofacial features (synophrys, dystopia canthorum, preauricular pits, branchial cysts, cleft palate) 1

Neurologic examination:

• Vestibular function assessment (especially in older patients) 1
• Balance disturbances 1
• Other neurological abnormalities 1

Skeletal abnormalities 1

Diagnostic Testing Algorithm

For syndromic hearing loss with identifiable features, proceed directly to syndrome-specific genetic testing and organ system evaluation. 1

For nonsyndromic hearing loss in simplex cases (no family history):

1. CMV testing in early infancy (negative test may exclude CMV-related hearing loss) 1
2. Comprehensive hearing loss gene panel testing (should include genes recommended by Hearing Loss Gene Curation Expert Panel) 1
3. If panel negative, consider exome or genome sequencing 1

For nonsyndromic hearing loss in multiplex cases (affected first-degree relatives):

• Proceed directly to connexin 26 (GJB2) testing 1

For suspected mitochondrial inheritance:

• Test for A1555G and A7445G mutations after excluding common GJB2 mutations 1

For sudden sensorineural hearing loss (≥30 dB loss within 72 hours):

• Urgent otolaryngology referral 2, 3
• MRI or CT imaging to exclude structural lesions 2

For asymmetric hearing loss:

• CT or MRI imaging to exclude acoustic neuroma, temporal bone pathology 2

Common Pitfalls to Avoid

Do not assume absence of family history excludes genetic causes—autosomal recessive nonsyndromic hearing loss commonly presents as simplex cases with 25% recurrence risk. 1

Do not delay genetic testing in congenital hearing loss—early diagnosis of certain syndromes (biotinidase deficiency, aminoglycoside sensitivity, cardiac syndromes) can prevent complications or additional hearing loss. 1

Do not overlook cerumen impaction as it is the most common and easily treatable cause of conductive hearing loss. 2, 3

Do not fail to screen for aminoglycoside sensitivity (A1555G mutation) in families with hearing loss before NICU aminoglycoside exposure. 1

Do not miss life-threatening associated conditions in syndromic hearing loss—cardiac arrhythmias (Jervell and Lange-Nielsen), renal failure (Alport), and other organ involvement require immediate evaluation. 1