Stickler Syndrome

Definition and epidemiology

Stickler syndrome is an inherited collagenopathy in which high myopia and vitreous anomalies, a flat midface and small lower jaw, cleft palate, joint hypermobility with early arthropathy, and hearing loss appear in varying combinations. About 80% of cases are caused by autosomal dominant variants in COL2A1 and 20% in COL11A1; COL11A2 and the autosomal recessive COL9A1, COL9A2 and COL9A3 types account for less than 1% each (Mortier, 2023). In the gene-based classification these are called Stickler type 1 (STL1), type 2 (STL2), type 3 (STL3) and the recessive types (STL4-6).

The types differ clinically. Eye findings are prominent in the COL2A1 type; because COL11A2 is not expressed in the vitreous, eye involvement is not expected in type 3, and the picture may be limited to hearing loss with facial and joint features. Conversely, some COL2A1 variants cause eye findings only (Snead et al., 2011). The exact prevalence is unknown (Mortier, 2023). About a third of babies with Pierre Robin sequence (small lower jaw, backward displacement of the tongue and cleft palate) have an underlying syndrome, and Stickler syndrome is the commonest of these (Mortier, 2023).

Symptoms and signs

In a systematic review covering 313 patients, hearing loss was found in 63%. Of these losses 68% were sensorineural, 18% mixed and 14% conductive; a conductive component was significantly more common in children (47%) than in adults (23%). The loss was mild in 45%, moderate in 37% and severe in 19%, and no profound loss was observed (Acke et al., 2012). Frequency varies by type: the same review reported hearing loss in 52% with COL2A1, 83% with COL11A1 and 94% with COL11A2 (Acke et al., 2012). GeneReviews reports hearing loss in 90-95% of the recessive COL9 types, usually moderate to severe and sensorineural (Mortier, 2023).

The pattern also differs by type. In the COL2A1 type the loss is mild, affects high frequencies and does not progress noticeably faster than age-related loss. In the COL11A1 and COL11A2 types the loss starts earlier and is more severe; it may be mild to moderate at low and middle frequencies and moderate to severe at high frequencies, and some audiograms are U-shaped. The recessive COL9 types show a loss sloping towards the high frequencies that can reach severe to profound levels and often needs amplification at a young age (Acke and De Leenheer, 2022).

Myopia occurs in 80-90% of the COL2A1 and COL11A1 types and is often high. Retinal detachment occurs in 40-70% with COL2A1, in less than 40% with COL11A1 and in 13-18% of the recessive types (Mortier, 2023). Detachment usually occurs between the ages of 10 and 30, and in about half of cases both eyes are affected (Boothe et al., 2020). Joint hypermobility, early-onset arthritis and back pain are common (Boothe et al., 2020).

Causes and risk factors

The genes behind Stickler syndrome encode components of type II, IX and XI collagen, which are found in cartilage, the vitreous and the inner ear. Most COL2A1 variants cause premature termination of the protein and halve the amount of normal type II collagen, whereas COL11A1 and COL11A2 variants are more often associated with structurally abnormal collagen. Since type II collagen is the main component of the vitreous, eye involvement is most marked in the COL2A1 type (Mortier, 2023).

Hearing loss has two separate sources. The sensorineural component is attributed to disrupted collagen structure in the inner ear; in the COL2A1 type, DPOAEs are reduced more than the audiogram would predict, suggesting early involvement of outer hair cell function (Acke and De Leenheer, 2022). The conductive component mostly comes from Eustachian tube dysfunction linked to cleft palate and from recurrent middle ear infections, and ossicular anomalies have occasionally been reported (Mortier, 2023). Hearing loss was found in 74% of patients with a palatal defect and in 54% of those without (Acke et al., 2012). In the dominant types an affected person has a 50% chance of passing the variant to each child; the recessive types are more common in consanguineous families.

Audiological and clinical assessment

The authors of the systematic review recommend referring every patient for a hearing assessment at diagnosis and performing regular hearing tests whether or not symptoms are reported, because high-frequency and mild losses may not be picked up from the history (Acke et al., 2012). GeneReviews recommends annual audiological evaluation (Mortier, 2023). As visual loss may coexist, preserving hearing is especially important.

• Pure-tone audiometry: the typical finding in the COL2A1 type is a mild sensorineural loss sloping from 2 to 8 kHz. Speech frequencies may be normal, so 6 and 8 kHz must always be tested. The COL11A1 and COL11A2 types may show losses involving the mid frequencies or a U-shaped configuration (Acke and De Leenheer, 2022).
• Tympanometry: in children with cleft palate a flat (type B) trace indicates effusion. Hypermobile (type AD) tympanograms have been reported in up to 46% of patients with Stickler syndrome, explained by previous otitis, ventilation tubes and altered collagen structure (Acke et al., 2012).
• OAEs: DPOAEs may be reduced more than the audiometric loss suggests (Acke and De Leenheer, 2022), so OAEs can complement audiometry during monitoring.
• In infants: babies with Pierre Robin sequence need diagnostic ABR after newborn screening to establish thresholds and type of loss; bone-conduction ABR separates the conductive component.
• Site of lesion: once a loss is found, separating the conductive and sensorineural components guides the choice between ventilation tubes and hearing aids (Acke et al., 2012).

The diagnosis is based on clinical findings and genetic testing; targeted gene panels identify the cause in about 90% of people with a clinical diagnosis (Boothe et al., 2020). The differential diagnosis includes Marshall syndrome (COL11A1-related, with more marked hearing loss and facial features), Wagner syndrome (VCAN) and other genes that cause high myopia (Mortier, 2023). COL11A2 cases presenting with hearing loss alone and no eye findings can be mistaken for non-syndromic hearing loss.

Treatment and audiological rehabilitation

Hearing loss is treated with standard approaches according to its type (Mortier, 2023). In children with cleft palate, otitis media with effusion is common and prolonged; the decision on ventilation tubes for persistent effusion with hearing loss rests with the ENT surgeon. Eustachian tube dysfunction can persist into adulthood and may need middle ear surgery (Acke and De Leenheer, 2022), and clinicians should bear cholesteatoma in mind (Acke et al., 2012).

Sensorineural loss is managed with hearing aid fitting. For the mild high-frequency loss of the COL2A1 type, an open fitting may be enough to help with speech in noise and listening at school; in the COL11A1 and COL11A2 types the loss is more severe, so the need for amplification arises earlier. The recessive types often need amplification at a young age (Acke and De Leenheer, 2022). Profound loss is not expected in the dominant types (Acke et al., 2012), and recessive types and other causes should be considered when it is found. The high risk of visual loss makes preserving and correcting hearing early even more important (Acke and De Leenheer, 2022).

For the eyes, an annual examination by a vitreoretinal specialist is recommended; prophylactic treatment (retinopexy) to prevent detachment and correction of refractive error are considered, and patients should be taught the symptoms of detachment (Mortier, 2023). In babies with Pierre Robin sequence, airway and feeding problems take priority in the first months, and decisions on palate repair and jaw surgery rest with the team. Joint symptoms are managed with physiotherapy and pain control.

Impact on quality of life and advice

For people with Stickler syndrome the biggest worry is usually the risk of visual loss, while hearing loss often progresses silently and is noticed only when tested. Even a mild high-frequency loss makes it harder to follow speech in a noisy classroom, a meeting or a crowded room, and increases listening effort. Combined visual and hearing loss also makes it harder to rely on visual cues in conversation. Joint pain and early arthritis can affect choices about work and sport.

Practical advice: have a hearing test and an eye examination once a year even if you have no symptoms. Learn the symptoms of retinal detachment (flashing lights, new floaters, a curtain across the vision) and seek help immediately if any occur. Protect your ears from loud sound and avoid long periods of high-volume listening through in-ear headphones. Tell your child’s teacher about their hearing and vision and ask for a seat near the front in good light. Contact sports and sudden blows may carry a risk for the eyes, so discuss suitable sports with your eye doctor. Seek genetic counselling for family planning.