Stickler syndrome (ORPHA:828)
A rare group of genetic connective tissue disorders characterized by ophthalmic, auditory, orofacial and articular manifestations. The two main clinical forms are clinically distinguished by the vitreous phenotype; stickler type 1 by a vestigial vitreous gel in the immediate retrolental space, bordered by a distinct folded membrane, and Stickler type 2 by sparse and irregularly thickened bundles of ﬁbers throughout the vitreous cavity.
Epidemiology
Prevalence at birth has been estimated at around 1/7,500 to 1/9,000.
Clinical description
Ocular manifestations include a high risk of retinal detachment, congenital abnormalities of vitreous development, congenital myopia and congenital cataract. Retinal paravascular lattice degeneration may develop in adulthood. Orofacial features include Pierre Robin sequence (PRS), cleft palate and midfacial hypoplasia. In addition, congenital high-frequency sensorineural deficit is common and variable conductive hearing loss may also occur. Musculoskeletal problems include spinal abnormalities, hypermobility, epiphyseal dysplasia and premature osteoarthritis. Two other forms are characterized by the ocular-only (autosomal dominant rhegmatogenous retinal detachment) or systemic-only (Stickler syndrome type 3) manifestations.
Etiology
Stickler syndrome is an inherited connective tissue disorder most commonly caused by mutations in the genes encoding collagen types II (COL2A1, 12q13.11), IX (COL9A1, 6q13; COL9A2, 1p34.2; COL9A3, 20q13.33), and XI (COL11A1, 1p21.1), but rarer non-collagen gene variants have been reported.
Diagnostic methods
Diagnosis is made on the basis of clinical and ophthalmic examination and confirmed by molecular genetic analysis. Vitreous phenotyping is helpful in segregating sub-types as many of the other shared clinical features are similar.
Differential diagnosis
Differential diagnoses includes spondyloepiphyseal dysplasia congenita, spondyloperipheral dysplasia, Kniest dysplasia, Wagner syndrome, Knobloch syndrome, multiple epiphyseal dysplasia, metatropic dysplasia, Marfan syndrome and Marshall syndrome.
Antenatal diagnosis
Prenatal diagnosis may be possible. First trimester prenatal diagnosis based on the analysis of linked markers may be possible. In second trimester, ultrasound may be helpful in detecting features such as micrognathia or cleft palate, but their absence does not exclude the diagnosis.
Genetic counseling
The pattern of inheritance for Stickler syndrome type 1 and 2 is autosomal dominant; the risk of disease transmission to offspring is 50%. Autosomal recessive inheritance is rarely observed but should be considered if there is a history of consanguinity. However, there is wide variation in clinical expression of the disease. The disease is highly penetrant but with wide variability in its extraocular phenotype. Affected family members in the high risk sub-groups should be offered prophylactic treatment to reduce the risk of retinal detachment and be offered genetic counselling.
Management and treatment
Management should be multidisciplinary and as clinical expression is very variable, treatment needs to be adapted to each case. Patients with PRS or cleft palate will require referral to a specialist multidisciplinary cleft team for assessment and management. This may also include speech therapy for patients with sub-clinical or soft palate cleft. Any refractive error should be corrected and prophylactic retinopexy discussed for the high risk variants. For type 1 Stickler syndrome, retinopexy substantially reduces the risk of giant retinal tear detachment. Patients should be warned of the signs and symptoms of retinal detachment and have rapid access to specialist vitreoretinal expertise in the event of such a development. Cataract is common and the surgical management, particularly in the pediatric sub-group requires specialist care. All affected patients should be referred for specialist audiology assessment if this has not already been undertaken by the cleft team. Patients may be unaware of sub-clinical hearing loss, particularly if present from birth. Although intellect is normal, pre-verbal children may need additional educational support with respect to their auditory and visual impairment. Specialist rheumatology and orthopedic management may be required for the associated arthropathy.
Prognosis
Prognosis of the disease is generally good. There is no direct reduction on life expectancy. The quality of life will differ depending on clinical expression, age of diagnosis and degree (if any) of associated visual loss, deafness, speech impairment and arthropathy.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Dr Martin SNEAD  - Dr Aijing WANG