NORD gratefully acknowledges Paula C. Goldenberg, MD, MSW, MSCE, Director of the Stickler Syndrome Clinic at the Massachusetts General Hospital for Children, for assistance in the preparation of this report.
Stickler syndrome refers to a group of disorders of connective tissue. Connective tissue, which is distributed throughout the body, can affect multiple organ systems. The specific symptoms present in Stickler syndrome often vary greatly from one individual to another. Affected individuals may not have all of the symptoms .The eyes, ears, skeleton and joints are most often affected. Affected individuals may also have distinctive facial features and palate abnormalities.
One of the first signs in Stickler syndrome is nearsightedness (myopia), in which objects close by are seen clearly but objects that are far away appear blurry. Myopia may vary from mild to severe in Stickler syndrome, but generally is not progressive (does not get worse). Myopia may be detectable shortly after birth, but the onset varies and may not develop until adolescence or even adulthood in some cases.
Stickler syndrome is characterized by the following clinical features: vitreoretinal degeneration, myopia, cataracts, retinal holes and detachments, sensorineural hearing loss, a characteristic facial appearance with mid-facial flatness, small chin, long upper lip (philtrum); palatal abnormalities, including cleft palate, bifid uvula or high arched palate; musculoskeletal problems including loose joints, scoliosis, chest deformities, a hip disorder of childhood (Legg-Calve-Perthe’s disease); early onset degenerative osteoarthritis (onset before age 40 years by X-ray); and mitral valve prolapse. An affected person does not need to have all of these features. In fact, the clinical picture is typically variable even among affected people in the same family.
Four distinct forms of Stickler syndrome have been identified in the medical literature based on the location of the mutated gene and inheritance pattern and at least one other form exists with an as yet unknown mutation location.
Stickler syndrome was first described in the medical literature in 1965 by Gunnar Stickler et al., who called the disorder hereditary progressive arthro-ophthalmopathy. Stickler syndrome refers to a group of disorders of connective tissue. Connective tissue, which is the material between cells of the body that gives the tissue form and strength, is found all over the body. Connective tissue is made up of a protein known as collagen of which there are several different varieties found in the body. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor), the specialized tissue that serves as a buffer or cushion for bones at joints (cartilage) and the ends of the bones that make up the joints of the body (epiphysis).
Stickler syndrome type I (STL1) is responsible for approximately 70% of reported cases and presents with a wide variety of symptoms affecting the eye, ear, facial appearance, palate and musculoskeletal system and occurs due to mutations over the entire COL2A1 gene on chromosome 12q13.11. These mutations cause loss of function of the COL2A1 gene. The majority of these mutations are associated with normal stature and early onset osteoarthritis. Only a few non-glycine missense mutations have been reported and among these, the arginine to cysteine substitutions predominate and these mutations cause some unusual disorders which may be described as Stickler-like but have short stature and brachydactyly. The inheritance pattern for Stickler syndrome type I is autosomal dominant.
Stickler syndrome type II (STL2) occurs due to mutations of the COL11A1 gene on chromosome 1p21. Patients with another condition, called Marshall syndrome, can have mutations of COL11A1 also, but patients with Stickler syndrome type II have a milder phenotype with less prominent facial dysmorphism than patients with Marshall syndrome. Patients with Stickler syndrome type II have less pronounced midfacial flattening and the nasal bridge better developed than seen in patients with Marshall syndrome. Myopia and retinal degeneration are not always present. Cataracts and more severe early onset hearing loss are more common in Stickler type II than in patients with Stickler type I. The inheritance pattern is autosomal dominant.
Stickler syndrome type III (STL3) has been described as the non-ocular form of Stickler syndrome, affecting the joints and hearing without involving the eyes. Stickler syndrome type III is caused by mutations of the COL11A2 gene on chromosome 6p21.3. The inheritance pattern is autosomal dominant. This form is now considered the same disorder as heterozygous oto-spondylo-megaepiphyseal dysplasia (OSMED). For more information on heterozygous OSMED see the NORD report on this disorder.
A mutation in a fourth gene, COL9A1, located on chromosome 6q13, has been identified in three reported intermarried families in Turkey and Morocco with Stickler syndrome type IV or STL4.The inheritance pattern is autosomal recessive.
Stickler syndrome type V (STL5) is thought to be caused by COL9A2, located on chromosome 1p33. This has been described in one intermarried family in India. The inheritance pattern is autosomal recessive.
Mutations of COL9A3 have recently been reported in three brothers in an intermarried Moroccan family with features of Stickler syndrome and intellectual disability.
Stickler syndrome has also been subdivided based on the vitreous phenotype resulting from mutations in the various loci. However, it has been reported that it is difficult for most ophthalmologists to classify the type of vitreous anomalies in the patients with Stickler syndrome.
Clinical Features of Stickler Syndrome
Affected individuals may also develop degeneration of the thick, jelly-like fluid (vitreous) that fills the center of the eyes and the thin layer of nerve cells (retina) that lines the back of the eye (vitreoretinal degeneration). The retina senses light and converts it into nerve signals, which are then relayed to brain through the optic nerve. Vitreoretinal degeneration may cause tiny specks (floaters) that seem to float around obstructing a person’s field of vision. Vitreoretinal degeneration also places individuals with Stickler syndrome at risk for retinal detachment, which can affect one or both eyes.
Retinal detachment occurs when the retina pulls away or is separated (detaches) from the underlying tissue. In some cases, small tears may occur in the retina as well. Symptoms of retinal detachment include an increase in the number of floaters in the eye, increased blurriness of vision, sudden flashes of light and a sudden decrease in vision as if a curtain or veil is pulled over a portion of a person’s field of vision. Retinal detachment can cause significant loss of vision or blindness if left untreated. Retinal detachment can occur at any age.
Additional eye abnormalities associated with Stickler syndrome include clouding (opacity) of the lenses of the eyes (cataracts), crossed eyes (strabismus), and abnormal curvature to the cornea (the clear portion of the eye through which light passes) or lens of the eye (astigmatism), which can contribute to blurred vision. A small percentage of individuals with Stickler syndrome, approximately 5-10 percent, may develop glaucoma, a condition in which increased pressure within the eye causes characteristic damage to the optic nerve, which relays signals from the retina to the brain.
Hearing loss may also occur in Stickler syndrome and may be progressive. The degree of hearing loss may vary greatly from one individual to another and can range from mild to significant. Hearing loss can occur due to failure of sound waves to be conducted through the middle ear (conductive hearing loss) or the impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss) or from both (mixed hearing loss). Hearing loss is usually less severe and minimally progressive in Stickler syndrome type I as opposed to type II. Chronic (recurrent) infection of the middle ear (otitis media) may occur and can contribute to conductive hearing loss. Some individuals may develop the accumulation of thick, sticky fluid behind the eardrum (glue ear). People with Stickler syndrome can have hypermobility of the middle ear bones.
Individuals with Stickler syndrome often have distinctive facial features including mid-facial hypoplasia with abnormally flat cheek bones and nasal bridge, small nose, long upper lip (philtrum), prominent eyes, and small chin.
Affected individuals may also have Pierre-Robin sequence, an assortment of abnormalities that may occur as a distinct syndrome or as part of another underlying disorder. Pierre-Robin sequence is characterized by an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and incomplete closure of the roof of the mouth (cleft palate, sub-mucous cleft palate or bifid uvula). Often babies with Pierre-Robin sequence and glossoptosis obstruct their airway when placed on their backs, and it may be recommended that they sleep prone due to this risk. Patients with very small jaws might be recommended to have surgery to extend their jaw forward.
Cleft palate may also occur as an isolated finding. The various craniofacial features may give the face a flattened appearance, but these features usually become less distinctive as affected children grow older. Certain facial features such as cleft palate can cause feeding or breathing difficulties in some children.
Dental anomalies such as failure of the upper and lower teeth to meet when biting down (malocclusion) may also occur.
Skeletal malformations are a common finding in individuals with Stickler syndrome. Affected individuals may have abnormally flexible or lax (hypermobile) joints (double jointedness) that may make them prone to joint dislocation. As affected individuals age, such flexibility becomes reduced. Joint pain and stiffness upon rest are frequent findings, and many individuals develop inflammation of the joints during the third or fourth decade of life (early-onset osteoarthritis).
Chest deformities such as pectus excavatum (depression of the chest bone) and carinatum (prominent chest bone) can occur. Spinal abnormalities are also common in individuals with Stickler syndrome including abnormal sideways curvature of the spine (scoliosis), front-to-back curvature of the spine (kyphosis), and forward displacement of one vertebra over another, usually the 4th lumbar vertebra over the 5th or the 5th over the sacrum (spondylolisthesis). Spinal abnormalities associated with Stickler may become progressively worse and may be associated with back pain.
Additional findings may occur in some cases including diminished muscle tone
(hypotonia), abnormally long, slender fingers (arachnodactyly), flat feet (pes planus), and osteochondritis deformans of the hips (Legg-Calve-Perthes disease), a degenerative hip disorder with childhood onset.
Other Features of Stickler syndrome
Intelligence is unaffected in children with Stickler syndrome, but some children may develop learning disabilities because of hearing and vision abnormalities.
Some studies have seemed to indicate that the prevalence of mitral valve prolapse (MVP) is greater in individuals with Stickler syndrome (4%) than in the general population (2%). However, other studies seem to show that this is not the case.
The mitral valve is located between the left upper and left lower chambers (left atrium and left ventricle) of the heart. Mitral valve prolapse occurs when one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left upper chamber (atrium) of the heart. In some cases, this may allow leakage or the backward flow of blood from the left lower chamber of the heart (ventricle) back into the left atrium (mitral regurgitation). In some cases, no associated symptoms are apparent (asymptomatic). However, in other cases, mitral valve prolapse can result in chest pain, abnormal heart rhythms (arrhythmias), fatigue, and dizziness.
Most cases of Stickler syndrome occur in families with other members that also have Stickler syndrome, due to a familial mutation of a gene inherited as an autosomal dominant trait. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
In some cases, Stickler syndrome occurs randomly as a result of a de novo genetic change (i.e., new mutation in the affected individual) that occurs for no known reason. The affected individual with Stickler syndrome would have 50% risk of having an affected pregnancy due to autosomal dominant inheritance (see above). Parents of a child with a de novo mutation causing Stickler syndrome would have a slightly increased risk of having another child with Stickler syndrome than the general population due to the possibility of gonadal mosaicism, which means carrying the mutation in the ovaries or testes but not in the blood.
Very, very rarely in a few families where both parents are relatives of each other, Stickler syndrome is due to an autosomal recessive pattern of inheritance. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child with Stickler syndrome is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females. The researchers were able to determine that Stickler syndrome in this family occurred due to mutations of the COL9A1 gene located on the long arm (q) of chromosome 6 (6q13), COL9A2 on the short arm (p) of chromosome 1 (1p33), and possibly COL9A3 on the long (q) arm of chromosome 20 (20q13).
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, chromosome 12q13.11 refers to band 13.11 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The genes involved in Stickler syndrome contain instructions for creating (encoding) proteins that are essential for the proper development and function of collagen, one of the most abundant proteins in the body and a major building block of connective tissue, which is the material between cells of the body that gives the tissue form and strength.
There are many different types of collagen, which are indicated by Roman numerals. The COL2A1 gene encodes for collagen type II; the COL11A1 and COL11A2 genes encode for collagen type XI; the COL9A1, COL9A2 and COL9A3 genes encode collagen IX.
These specific collagens are most prevalent in the specialized tissue that serves as a buffer or cushion for bones at joints (cartilage) and the jelly-like fluid that fills the center of the eye (vitreous). Collagen is also found in bone.
Stickler syndrome affects males as well as females. Prevalence rates have been estimated at 1-3 per 10,000 births and at 1 per 7,500 births. Most investigators believe that the disorder is highly under-diagnosed, making it difficult to determine the true prevalence of Stickler syndrome in the general population. Stickler syndrome is one of the most common connective tissue disorders in the United States.
Symptoms of the following disorders can be similar to those of Stickler syndrome.
COL2A1-related disorders are a group of disorders (including Stickler syndrome type I) which are due to mutations of the COL2A1 gene (allelic disorders). This group of disorders includes spondyloepiphyseal dysplasia congenital (SEDC), achondrogenesis type II, spondyloepimetaphyseal dysplasia, and Kneist dysplasia. These disorders are characterized by distinctive facial features, skeletal malformations, abnormal curvature of the spine (kyphoscoliosis), nearsightedness (myopia), and degeneration of the thick, jellylike fluid (vitreous) that fills the center of the eyes and the thin layer of nerve cells (retina) that lines the back of the eye (vitreoretinal degeneration). (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
OSMED (oto-spondyl-megaepiphyseal dysplasia) is a rare genetic disorder characterized by skeletal malformations resulting in shortening of the upper limbs and thighs and short stature (rhizomelic dwarfism). Additional symptoms include distinctive facial features and delays in psychomotor development. After the initial period of growth deficiency, affected individuals experience gradual improvement in bone growth that leads to normal physical development by early childhood. Mental and motor development is also normal by early childhood. In some cases, affected individuals develop hearing loss.
Heterozygous OSMED occurs because of disruptions or changes (mutations) to the
COL11A2 gene, the same gene that causes Weissenbacher-Zweymuller syndrome and non-ocular Stickler syndrome or Stickler syndrome type III. Some researchers consider these three disorders separate entities; others believe that they are the same disorder or different manifestations of the same disorder. Recently, some researchers have suggested that the name OSMED be used as a general heading to consist of “heterozygous OSMED,” which encompasses Weissenbacher-Zweymuller syndrome and Stickler syndrome type III and is inherited as an autosomal dominant trait and “homozygous OSMED,” which encompasses autosomal recessive cases of oto-spondylo-megaepiphyseal dysplasia. (For more information on this disorder, choose “OSMED” as your search term in the Rare Disease Database.)
Marshall syndrome is a rare genetic disorder. Major symptoms may include a distinctive face with a flattened nasal bridge and nostrils that are tilted upward, widely spaced eyes (hyperterlorism), nearsightedness, cataracts and moderate to severe hearing loss. Affected individuals may experience degeneration of the thick fluid that fills the center of the eye and the membrane (retina) that lines the back of the eye (vitreoretinal degeneration). Malformation of certain bones of the arms (e.g., bowing of the arm bones) may also occur. Affected individuals may also have Pierre-Robin sequence. Pierre-Robin sequence consists of an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and, in some cases, incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding. Marshall syndrome is inherited as an autosomal dominant trait. The gene that causes Marshall syndrome (i.e., COL11A1) is the same gene that causes Stickler syndrome type II. Some researchers believe these two disorders are the same disorder or different expressions of the same disorder. Others believe that the two disorders are distinct. Most recent studies show that the mutations in COL11A1 associated with the Marshall Syndrome phenotype are splicing mutations in the exons in the c-terminal region of COL11A1, with a hot spot in exon 50. (For more information choose “Marshall syndrome” as your search term in the Rare Disease Database).
Wagner syndrome is a rare progressive genetic disorder characterized by mild nearsightedness (myopia), degeneration of the thick, jelly-like fluid (vitreous) that fills the center of the eyes and the thin layer of nerve cells (retina) that lines the back of the eye (vitreoretinal degeneration), and distinctive facial features. Retinal detachment, cataracts and glaucoma have also been reported in individuals with Wagner syndrome. For years, some researchers believed that Wagner and Stickler syndromes were the same disorder. However, it has now been determined that Wagner syndrome is caused by mutations to a gene on the long arm (q) on chromosome 5 (5q13-q14). Wagner syndrome is inherited as an autosomal dominant trait.
A diagnosis of Stickler syndrome is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. As yet, no universally agreed upon criteria for the diagnosis of Stickler syndrome exists. A variety of tests such as x-ray studies and eye examinations may be used to detect the presence or evaluate the severity of certain abnormalities potentially associated with Stickler syndrome.
Treatment
The treatment of Stickler syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including: geneticist, pediatrician and/or internist, orthopedic surgeon, rheumatologist, ophthalmologist and retina specialist, otolaryngologist, audiologist, plastic surgeon, orthodontist and other healthcare professionals may need to systematically and comprehensively plan an affected patient’s treatment.
Early identification of Stickler syndrome is important because it allows for surveillance and prompt treatment of associated abnormalities such as retinal detachment or skeletal malformations. Patients with ocular forms of Stickler syndrome are restricted from contact sports due to the risk of retinal detachment. Retinal detachment requires prompt surgery to preserve vision. Retinal detachment can recur even after successful surgery. Some physicians recommend prophylactic cryotherapy in certain cases to reduce the risk of developing retinal detachment.
Affected individuals should be made aware of the symptoms of retinal detachment so they can immediately have their eyes evaluated (ophthalmologic assessment) and treated if necessary. Surgery may also be necessary to remove cataracts.
Corrective lenses (glasses or contact lenses) are used to treat myopia.
Individuals with Stickler syndrome and Pierre-Robin sequence may require a tracheostomy (a procedure in which a tube is placed through a surgical opening in the neck) to prevent breathing (respiratory) difficulties. Surgery may also be required to fix various craniofacial abnormalities (e.g., cleft palate. micrognathia) that can contribute to breathing difficulties.
Orthodonture may be necessary to correct dental malalignment.
Patients with sensorineural or mixed hearing loss may require hearing aids. Hearing aids may be of benefit for certain individuals. A myringotomy, a surgical procedure in which a small incision is made in the eardrum and small tubes are inserted, may be used to treat glue ear. Various anti-inflammatory medications and sometimes prescription pain medications may be used to treat joint disease in individuals with Stickler syndrome. In mild cases, short-term relief may be provided from cortisone injections. Surgical correction of joint abnormalities may be necessary including joint replacement surgery such as a total hip or knee replacement. Surgery may also be necessary for skeletal malformations including abnormal curvature of the spine.
Physical therapy may prove beneficial in some cases.
Special education and other services may be helpful for children with learning disabilities due to hearing or vision problems.
Genetic counseling may be of benefit for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
For more information on Stickler syndrome, please contact:
Paula Goldenberg, MD, MSW, MSCE
Stickler Syndrome Clinic/ Genetics Clinic-Yawkey 6, MGH
Genetics Unit, Massachusetts General Hospital for Children
175 Cambridge Street-5th floor
Boston, MA 02114
Phone: 617-726-1561
Email: [email protected]
TEXTBOOKS
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JOURNAL ARTICLES
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Hoornaert KP, Dewinter C, Vereecke I, et al. The Phenotypic Spectrum in Patients with Arginine to Cyseine mutations in the COL2A1 Gene. J Med Genet. 2009; 43:406-413.
Ang A, Poulson AV, Goodburn SF, et al. Retinal Detachment and Prophylaxis in Type 1 Stickler Syndrome.Ophthalmol. 2008; 115:164-168.
Majava M, Hoornaert K, Bartholdi D, et al. A report on 10 new patients with
Heterozygous mutations in the COL11A1 Gene and a review of Genotype-Phenotype Correlations in Type XI collagenopathies. Am J Med Genet. 2007; 143 A: 258-264.
Van Camp G, Snoeckx RL, Hilgert N, et al. A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Am J Med Genet. 2006;79:449-456.
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Liberfarb RM, Levy HP, Rose PS, et al. The Stickler syndrome: genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genet Med. 2003;5:21-27
Annunen s, Korkko J, Czarny M et al. Splicing Mutations of 54 – bp Exons in the
COL11A1 Gene Cause Marshall Syndrome but Other Mutations Cause Overlapping Marshall/ Stickler Phenotypes. Am J Med Genet. 1999; 65: 974-983.
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INTERNET
Robin NH, Moran RT, Ala-Kokko L. Stickler Syndrome. 2000 Jun 9 [Updated 2014 Nov 26]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1302/ Accessed August 10, 2015.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:108300; Last Update:2/15/13. Available at https://omim.org/entry/108300 Accessed August 10, 2015.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:604841; Last Update:8/4/11. Available at: https://omim.org/entry/604841 Accessed August 10, 2015.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:184840; Last Update:8/3/11. Available at: https://omim.org/entry/184840 Accessed August 10, 2015.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:143200; Last Update:3/31/14. Available at: https://omim.org/entry/143200 Accessed August 10, 2015.
Mayo Clinic for Medical Education and Research. Stickler Syndrome. January 28, 2014. Available at: https://www.mayoclinic.org/diseases-conditions/stickler-syndrome/basics/definition/con-20027976 Accessed August 10, 2015.
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