Stickler Syndrome

Stickler Syndrome

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Stickler Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • hereditary arthro-ophthalmopathy

Disorder Subdivisions

  • Stickler syndrome type I
  • Stickler syndrome type II
  • Stickler syndrome type III
  • Stickler syndrome type IV
  • Stickler syndrome type V

General Discussion

Stickler syndrome refers to a group of disorders of connective tissue. Connective tissue, which is distributed throughout the body, multiple organ systems can be affected. 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 philtrum; palatal abnormalities, including cleft palate, bifid uvula or high arched palate; musculoskeletal problems including loose joints, scoliosis, chest deformities, Legg-Calve-Perthe's disease; early onset degenerative osteoarthritis (onset before age 40 years by xray); and mitral valve prolapse. An affected person does not need to have all of these features. In fact, the clinical picture is very variable even among affected people in the same family.



Four distinct forms of Stickler syndrome have been identified in the medical literature based on 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 and 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).

Symptoms

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 COLA21 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. These patients have a milder phenotype with milder facial dysmorphism than Marshall syndrome patients in that the midfacial hypoplasia was less pronounced and the nasal bridge better developed. 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 Stickler type I patients. 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 and 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 one reported kindred with Stickler syndrome type IV or STL4.The inheritance pattern is autosomal recessive.



Stickler syndrome type V: Additional cases of Stickler syndrome have been reported that are not associated with any of the identified Stickler genes suggesting that at least one more as yet unidentified gene may be associated with Stickler syndrome.



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 referred to them.



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).



Individuals with Stickler syndrome often have distinctive facial features including midfacial hypoplasia with abnormally flat cheek bones and nasal bridge, small nose, long 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). Cleft palate may also occur as an isolated finding. The various craniofacial features may give the face a flattened appearance, but they 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 (doublejointedness) 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 and carinatum 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 umbar 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).



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.

Causes

Most cases of Stickler syndrome occur 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) that occurs for no known reason.



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 encodes for collagen type XI.

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.



One family with Stickler syndrome has been reported that showed 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 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).

Affected Populations

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. Stickler syndrome is one of the most common connective tissue disorders in the United States.

Standard Therapies

Diagnosis

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 child'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. 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. 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.



Various anti-inflammatory medications and sometimes pain killers may be used to treat

Various anti-inflammatory medications and sometimes pain killers 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. Corrective lenses (glasses or contact lenses) are used to treat myopia. 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. 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.



Orthodonture may be necessary to correct dental malalignment.

Investigational Therapies

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: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com





For more information on Stickler syndrome, please contact:



Ruth Liberfarb, MD, PhD

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: rliberfarb@partners.org

References

TEXTBOOKS

Cassidy S, Allanson J. Eds. Clinical Management of Common Genetic Syndromes. 3rd ed. Wiley Liss, New York, N.Y. 2010: 787-796.



Traboulsi EI. Ed. A Compendium of Inherited Disorders and the Eye. Oxford University

Press. New York, NY. 2006:173-174.



Castriota-Scanderbeg A, Dallapiccola B, Eds. Abnormal Skeletal Phenotypes: From

Simple Signs to Complex Diagnoses. Springer, New York, NY; 2005:902.



Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th

ed. Oxford University Press, New York, NY; 2001:351-353.



Jones KL. Ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. W. B.

Saunders Co., Philadelphia, PA; 1997:318-319.



JOURNAL ARTICLES

Richards AJ, McNinch A, Martin H, et al. Stickler Syndrome and the Vitreous Phenotype: Mutations in COL2A1 and COL11A1.Human Mutation. 2010; 31:1461-E1471.



Hoornaert KP, Vereecke I, Dewinter C, et al. Stickler Syndrome caused by COL2A1 Mutations: genotype - phenotype correlation in a series of 100 patients.2010; 18:872-881.



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.



Kloeckener - Gruissem B, Bartholdi D, Abdou M, et al., Molecular Vision 2006;12: 350- 5.



Rose PS, Levy HP, Liberfarb RM, et al. Stickler syndrome: clinical characteristics and diagnostic criteria. Am J Med Genet. 2005;138A:199-207.



Poulson AV, Hooymans JMM, Richards AJ, et al. Clinical features of type 2 Stickler syndrome. J Med Genet. 2004;41:3107.



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.



Snead MP, Yates JRW. Clinical and molecular genetics of Stickler syndrome. J Med Genet. 1999; 36: 353-9.



Stickler GB, Pugh DG. Hereditary Progressive Ophthalmopathy. II.Additional Observations, a hearing defect and a report of a similar case. Mayo Clin Proc 1967; 42:495-500.



Stickler GB, Belau PG, Farrell fj, et al. Hereditary Progressive Arthroophthalmopathy. Mayo Clin Proc 1965; 40:433-455.





INTERNET

Robin NH, Moran RT, Warman M, Ala-kokko, L. Updated:November 3, 2011. Stickler Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online).Copyright, University of Washington, Seattle. 1997-2012. Available at

http://www.genetests.org.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The

Johns Hopkins University; Entry No:108300; Last Update:10/07/2011. Available at:

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=108300 . Accessed on:January 18, 2012.



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:

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=604841

Accessed on:January 18, 2012.



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:

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=184840 Accessed on:January 18, 2012.



McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:143299; Last Update:11/16/2010. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=143200 Accessed on:January 18, 2012.



Mayo Clinic for Medical Education and Research. Stickler Syndrome. December 4, 2010.

Available at: http://www.mayoclinic.com/health/stickler-syndrome/DS00831 Accessed

On:January 18, 2012.

Resources

Cleft Palate Foundation

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Stickler Syndrome Support Group

PO Box 3351

Littlehampton, BN16 9GB

United Kingdom

Tel: 01903785771

Email: info@stickler.org.uk

Internet: http://www.stickler.org.uk



Stickler Involved People

15 Angelina

Augusta, KS 67010

Tel: (316)775-2993

Email: sip@sticklers.org

Internet: http://www.sticklers.org



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Genetic and Rare Diseases (GARD) Information Center

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Foundation Fighting Blindness (Canada)

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Fax: 4163600060

Tel: 8004613331

Email: info@ffb.ca

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Madisons Foundation

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Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Let Them Hear Foundation

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Tel: (650)462-3174

Fax: (650)462-3144

Email: info@letthemhear.org

Internet: http://www.letthemhear.org



Perkins School for the Blind

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National Consortium on Deaf-Blindness

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Fax: (503)838-8150

Tel: (800)438-9376

TDD: (800)854-7013

Email: info@nationaldb.org

Internet: http://www.nationaldb.org



European Skeletal Dysplasia Network

Institute of Genetic Medicine

Newcastle University

International Centre for Life

Central Parkway

Newcastle upon Tyne, NE1 3BZ

United Kingdom

Tel: 441612755642

Fax: 441612755082

Email: info@esdn.org

Internet: http://www.esdn.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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