Stickler syndrome is a rare variant of hereditary collagenopathies, in which there is a violation of the structure of collagen types II, IX, XI. It is inherited by autosomal dominant and autosomal recessive mechanisms. The disease is manifested by progressive myopia with retinal detachment, damage to the osteoarticular apparatus, and characteristic phenotypic features. Diagnosis of the syndrome is carried out using skeletal radiography, ophthalmoscopy, biochemical and molecular genetic testing. Supportive treatment: rehabilitation programs, psychological support, surgical correction of complications.
Stickler syndrome is named after the American pediatrician G.B. Stickler, who in 1965 published an article analyzing his long-term work with patients who had a typical set of symptoms: progressive myopia, degeneration of joints, expansion of the epiphyses. The genetic basis of pathology was discovered only in the 1980s and 1990s. The disease has a second name “congenital arthroophthalmopathy”. The prevalence of Stickler syndrome is 1 case per 7.5-10 thousand adults, there are no sex differences in the structure of morbidity.
In Stickler syndrome, 5 variants of mutations in the genes encoding the synthesis of collagen fibers were identified: COL2A1, COL11A1, COL11A2, COL9A1, COL9A2. The disease of subtypes 1, 2, 3 is characterized by an autosomal dominant variant of inheritance, that is, the probability of having a sick child is 50% if one of the parents is a carrier of a mutant gene. The syndrome of subtypes 4 and 5 is transmitted autosomal recessive, manifests itself only if both parents have a mutant gene.
The disease occurs when the structure of collagen fibers of the 2nd, 9th and 10th types, which are part of bone and cartilage tissue, vitreous of the eyeball, is disrupted. Defective collagen changes the normal structure of connective tissue. At the same time, the formation of joints is disrupted in patients, degenerative processes occur, the bone skeleton is deformed and, as a result, characteristic phenotypic signs become noticeable.
In clinical practice, the systematization of the disease into separate subtypes is rarely used, due to the similarity of their symptoms, common treatment approaches. According to the results of molecular genetic diagnostics, 5 varieties of Stickler syndrome were identified, which differ in the localization of the mutation, the type of defective collagen. In the classification of hereditary collagenopathy, the following variants are distinguished:
- I — mutation of COL2A1 encoding the alpha-1 chain of type 2 collagen.
- II is an anomaly of COL11A1, which is responsible for the synthesis of the alpha-1 chain of type 11 collagen.
- III — pathology of COL11A2, responsible for the formation of α-2 chains of type 11 collagen fibers.
- IV — a change in the sequence of COL9A1, which regulates the synthesis of α-1 collagen chains of type 9.
- V — point mutation of COL9A2, which encodes the alpha-2 chain of type 9 collagen fibers.
Children with congenital arthroophthalmopathy have specific changes in facial features that are noticeable already in the neonatal period. Patients have Robin’s anomaly: a flat face with an underdeveloped lower jaw, cleft palate, tongue sinking. There is also a bulging of the upper lip, deformation of the zygomatic arches, sinking of the bridge of the nose. Occasionally, patients have a typical marfanoid phenotype, which makes it difficult to make a diagnosis.
Articular lesions are initially manifested by hypermobility, excessive flexibility and mobility. Children and adolescents often suffer from curvature of the spine in the form of kyphosis, lordosis, scoliosis. As the syndrome progresses, degenerative changes provoke contractures, pain, enlargement and swelling of the joints. Patients after the age of 30 usually face arthropathy of the hip, knee, and ankle joints.
Damage to the visual apparatus consists in progressive deterioration of vision, the appearance of cataract, degenerative changes of the vitreous body. There are hearing disorders of the type of conductive hearing loss. In some patients, there is a delay in psychomotor development, a decrease in intellectual abilities of mild or moderate severity.
The most dangerous consequence of the syndrome is retinal detachment, which can begin in childhood in the absence of treatment for progressive myopia. As a result, blindness occurs in one or both eyes. Joint damage eventually leads to limited mobility and, without correction, ends with disability of patients. Unaesthetic changes in the facial skeleton become the causes of complexes, problems with socialization.
Involvement of an auditory analyzer in the process is fraught with frequent otitis media, and with an unfavorable course there is a risk of hearing loss up to deafness. Occasionally, connective tissue pathology affects the valvular apparatus of the heart, which causes mitral valve prolapse, circulatory disorders, heart failure. Anomalies of the structure of the oral cavity are accompanied by problems with eating, a high risk of aspiration, difficulty breathing.
Stickler syndrome is characterized by polymorphism of the clinical picture, similarity of symptoms with other hereditary disorders of connective tissue, which complicates the diagnostic search. During the initial examination at the pediatrician, the phenotypic manifestations of collagenopathy are determined, the family history is studied. To confirm congenital arthroophthalmopathy, the following research methods are prescribed:
- Radiography of the skeleton. Pathognomonic symptoms of Stickler syndrome are enlarged bone epiphyses, altered diaphysis structure, joint degeneration. For a more detailed diagnosis, computed tomography of the joints and CT of the facial skull are performed.
- Molecular genetic testing. A genome study is recommended for 100% confirmation of the diagnosis in patients with Stickler’s disease. In genetic laboratories, techniques of fluorescent hybridization, genome sequencing are used to identify the damaged gene, to clarify the subtype of the syndrome.
- Laboratory methods. With the help of thin-layer chromatography, an increase in the level of glycosaminoglycans in the blood is detected, their increased excretion in the urine. The condition of collagen fibers is assessed by immunohistochemical method with the determination of specific antibodies, as well as by analyzing free hydroxyproline in urine.
- Consultations of specialists. An ophthalmologist’s examination with an ophthalmoscopy is necessary to assess the condition of the visual apparatus, examine the fundus, and identify signs of incipient retinal detachment. An otolaryngologist’s appointment with audiometry is used for hearing problems.
There is no etiopathogenetic treatment of Stickler’s disease. The efforts of doctors are aimed at correcting existing health problems, improving the quality of life of patients. An integrated approach to the treatment of such patients includes several directions:
- Physical therapy. Physical therapy is necessary to eliminate joint stiffness that occurs with the progression of the syndrome, correction of spinal curvature and accompanying musculotonic syndrome. Physical therapy, as a rule, is supplemented by massage, kinesiotaping.
- Habilitation. Children with reduced intelligence need training in special schools, classes with speech pathologists, speech therapists, oligophrenopedagogues. Thus, it is possible to increase the learning ability of patients, prepare them for independent life.
- Psychological help. Defects in appearance, combined with a decrease in cognitive abilities, make it difficult for children to socialize, provoke isolation, depression. To correct these problems, regular visits to a child psychologist are required.
Patients often need the help of ophthalmic surgeons who perform laser coagulation or cryotherapy to treat retinal detachment and preserve vision. In case of critical hearing impairment, the issue of setting up a hearing aid is considered. Anomalies in the development of the facial skull require gradual plastic correction to eliminate problems with breathing and eating, to improve the aesthetics of appearance.
Prognosis and prevention
The condition of patients depends on the timeliness of diagnosis, completeness of therapeutic, surgical, rehabilitation measures. With proper treatment, it is possible to maintain a good quality of life for patients, so the prognosis is relatively favorable. Measures for the primary prevention of the syndrome have not been developed. Married couples with burdened heredity are recommended to consult a geneticist when planning conception.