Syndromes Associated with Sensorineural Hearing Loss (SNHL)

There are over 400 syndromic forms of hearing loss. Below is a systematic classification by inheritance pattern and associated features.

A. Autosomal Recessive Syndromes

1. Usher Syndrome

Most common cause of combined deafness and blindness; 3% of the deaf population.

Gene mutations: MYO7A (USH1), USH2A (USH2), others
Features: SNHL + retinitis pigmentosa + vestibular dysfunction
Three types:
- USH1 (MYO7A mutation, 40%): Profound congenital bilateral SNHL, absent vestibular function, early retinitis pigmentosa (by age 10)
- USH2 (USH2A mutation, 60%): Moderate SNHL, normal vestibular function, later-onset retinitis pigmentosa
- USH3 (3%, mostly Norwegian): Progressive SNHL, variable vestibular function

2. Pendred Syndrome

2% of profound congenital SNHL.

Gene: SLC26A4 (PDS) - defect in iodine-chloride transporter
Features: SNHL (unilateral or bilateral, progressive) + thyroid goiter (euthyroid) + Mondini malformation of the cochlea
May also be associated with thyroid malignancy
Note: Enlarged vestibular aqueduct (EVA) is common; do NOT remove thyroid unless malignancy present

3. Jervell and Lange-Nielsen Syndrome

1/1000 of the profoundly deaf population.

Gene: KV1QT1 - dysregulation of potassium channel
Features: Severe/profound SNHL + prolonged QT interval + large T waves on ECG
Presents as sudden syncope and sudden cardiac death (age 20-30)
Treatment: Beta-blocker; screen first-degree relatives for Romano-Ward syndrome (prolonged QT without hearing loss)

4. Alport Syndrome

Mostly X-linked (COL4A5 mutation); 15% autosomal recessive (COL4A3/COL4A4).

Features: Progressive high-frequency SNHL + glomerulonephritis + hematuria + progressive renal failure
Ocular: Anterior lenticonus, retinal flecks, spherophakia, congenital cataracts

5. Biotinidase Deficiency

1/60,000 births; lack enzyme to recycle biotin
Features: SNHL + hair loss + seizures + hypotonia + coma/death if untreated
Tested in newborn screening - preventable with dietary biotin replacement

B. Autosomal Dominant Syndromes

1. Waardenburg Syndrome

Most common type of autosomal dominant syndromic hearing loss; 2% of congenital deafness.

Pathophysiology: Neural crest cell mutation → defective intermediate layer of stria vascularis
Features: SNHL (unilateral/bilateral) + white forelock + heterochromia iridis + dystopia canthorum (lateral displacement of inner canthi) + synophrys (fused eyebrows) + pinched nose
Four types:
- WS1 (most common): PAX3 mutation, dystopia canthorum, hearing loss in 20%
- WS2A (Tietz): MITF mutation, NO dystopia canthorum, hearing loss in 50%
- WS3 (Klein-Waardenburg): Unilateral ptosis, eyelid and limb anomalies
- WS4 (Shah-Waardenburg): SOX10 mutation + Hirschsprung disease

2. Branchio-Oto-Renal (BOR) Syndrome / Melnick-Fraser

2% of deaf children; gene: EYA1 on chromosome 8q13
Features: Hearing loss (conductive, SNHL, or mixed) + pre-auricular pits + branchial cleft cysts/fistulas + renal dysplasia
Temporal bone: Fused malleoincudal complex, facial nerve on medial side of cochlea, hypoplastic apical cochlear turn

3. Neurofibromatosis Type 2 (NF2)

Incidence 1:40,000-90,000
Features: Bilateral vestibular schwannomas + high-frequency SNHL + tinnitus + vertigo + facial nerve paralysis

4. Stickler Syndrome

Collagen disorder (COL2A1/COL11A1/COL11A2)
Features: SNHL + progressive myopia + vitreoretinal degeneration + cleft palate + arthropathy

C. X-Linked Syndromes

1. Alport Syndrome (X-linked form)

COL4A5 mutation - most common form (see above)

2. Mohr-Tranebjaerg Syndrome (DFN-1)

X-linked recessive; mitochondrial dysfunction
Features: Postlingual SNHL in childhood → progressive dystonia + spasticity + dysphagia + optic atrophy
Resembles Friedreich ataxia but lacks cardiomyopathy

3. X-linked Charcot-Marie-Tooth (CMT)

Connexin 32 gene mutation (Xq13)
Features: Peripheral neuropathy + foot deformities ("champagne bottle" calves) + SNHL in some cases

D. Mitochondrial (Maternal Inheritance) Syndromes

All involve progressive neuromuscular degeneration; hearing loss occurs in all of the following:

Syndrome	Key Features
MELAS	Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes, SNHL
MERRF	Myoclonic epilepsy, ragged red fibers on muscle biopsy, SNHL
Kearns-Sayre	Progressive external ophthalmoplegia, retinopathy, cardiomyopathy, SNHL
LHON (Leber)	Optic neuropathy, SNHL
Mitochondrial A1555G	Maternally inherited 12S rRNA mutation - aminoglycoside-induced SNHL (15% of US aminoglycoside-related SNHL)

E. Chromosomal Syndromes

Syndrome	Key Features
Down Syndrome (Trisomy 21)	SNHL + conductive loss, stenotic EAC, narrow internal auditory canal, cochlear nerve stenosis, large vestibular aqueduct
Turner Syndrome (45,X)	Conductive and SNHL, short stature, webbed neck, shield chest, gonadal dysgenesis - may be first presentation in prepubertal females
Trisomy 13 (Patau)	Significant SNHL among multiple anomalies

F. Other / Multisystem Syndromes

Syndrome	Type of HL	Key Associated Features
CHARGE	Mixed (SNHL + conductive)	Coloboma, heart defects, choanal atresia, retardation of growth, genitourinary anomalies; CHD7 gene
Treacher Collins	Mainly conductive; can have SNHL	Mandibulofacial dysostosis, malar hypoplasia
Friedreich Ataxia	SNHL	Ataxia, cardiomyopathy, optic atrophy
Cogan Syndrome	Bilateral SNHL	Interstitial keratitis, vestibular symptoms, systemic vasculitis
Wildervanck	Mixed hearing loss	Females only; CN6 palsy; fused cervical vertebrae (Klippel-Feil)
Goldenhar (OAVD)	Conductive/mixed	Hemifacial microsomia, epibulbar lipodermoids, vertebral anomalies
Wolfram Syndrome	SNHL (low frequency)	Most common cause of dominantly inherited low-frequency SNHL; progressive

Quick Memory Aid - High-Yield Syndromes

Syndrome	Associated Finding
Usher	Retinitis pigmentosa (most common AR syndromic HL)
Pendred	Thyroid goiter + Mondini malformation
Jervell-Lange-Nielsen	Prolonged QT (cardiac arrest risk)
Alport	Nephritis + lenticonus
Waardenburg	White forelock + heterochromia (most common AD syndromic HL)
NF2	Bilateral acoustic neuromas
BOR	Branchial cysts + renal anomalies
MELAS/MERRF/KSS	Mitochondrial (maternal inheritance)

Sources: Harrison's Principles of Internal Medicine 22E, p. 291 | K.J. Lee's Essential Otolaryngology, pp. 1001-1005 | Quick Compendium of Clinical Pathology 5th Ed., p. 397 | Bailey & Love's Surgery 28th Ed.

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