Information on the following diseases can be found in the Related Disorders section of this report:

• Marfan Syndrome
• Marshall Syndrome
• Pierre-Robin Syndrome
• Spondyloepiphyseal Dysplasia Congenita
• Wagner Syndrome

Because Stickler syndrome is a disorder of connective tissue and because connective tissue, in its several forms, is distributed so widely in the body, the symptoms of this multi-system disorder cover a broad array of signs.

Symptoms affecting the eyes may include a high risk of bilateral (or unilateral) detached retinas, and a high degree of shortsightedness (myopia). Less frequently, the lenses of the eye may become cloudy (cataracts) and/or the pressure of the fluid in the eyeball may increase to dangerous levels (glaucoma).

Skeletal symptoms may include both stiffness of the joints, including early onset arthritis, and double-jointedness (over-flexible joints). If rheumatic conditions appear in youth or adolescence, then osteoarthritis is expected at any time from early through middle to late adulthood. Premature degenerative changes in weight bearing joints is one of the most consistent features of Stickler syndrome.

Symptoms involving the mouth include cleft palate or underdeveloped (submucous) palate arising as a result of a very small lower jaw. As the fetus develops, the sides of the palate must come together to close the normal opening in the roof of the mouth. If the lower jaw is very small, there is not enough space to accommodate the tongue, which is then forced upward and interferes with the closing of the palate. These symptoms are similar to those found in the Pierre-Robin sequence.

Facial characteristics include a longish, flat, face with a small nose and a depressed nasal bridge.

Symptoms involving hearing loss are usually progressive and involve the higher frequencies. If the hearing loss is the result of damage to the inner ear, to the auditory nerve or to the hearing centers of the brain, (sensori-neural) it will not likely be recovered as a result of any surgery. If the hearing loss is the result of the failure of the nerves to conduct the signal from the external ear to the inner ear, then surgery will often improve the situation.

The hearing losses associated with Stickler syndrome are similar to those associated with Marshall syndrome. About 80% of people with Stickler syndrome have some degree of hearing loss.

There is some disagreement about whether or not to include mitral valve prolapse among the symptoms of Stickler syndrome. One investigator found the condition to be present in about one-half (50%) of the patients with the disorder. Another study did not find mitral valve prolapse among any of the patients studied. Opinion tends to support its inclusion, even though unanimity is not present. Mitral valve prolapse is a heart condition in which a valve is more flexible (to the point of floppiness) than it should be. The valve gets stuck in the opening on which it acts and prevents the proper flow of blood.

Stickler syndrome has also been related to a Marfan syndrome-like set of symptoms, without the physical height associated with that syndrome (marfanoid habitus). The collection of symptoms includes multiple, deteriorated, joints due to advanced arthritis in these joints, cleft palate, and degeneration of the fluid in the eyeball (vitreous degeneration).
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Stickler syndrome comes about as the result of changes in one of the three or four genes for connective tissue. Three genes have been identified and their sites on a chromosome have been determined. However, studies of some families with Stickler syndrome cannot be linked to any of the three known responsible genes, hence it is proposed that at least one more, as yet unknown gene is implicated.

At least three genes that control collagen production also account for one or another type of Stickler syndrome. These are:

COL2A1. Changes in this gene are responsible for Stickler syndrome
Type I; (STL1). It has been traced to Gene Map Locus 12q13.11-q13.2 and is inherited as an autosomal dominant trait.

COL11A1. Changes in this gene are responsible for Stickler syndrome
Type II; (STL2). It has been traced to Gene Map Locus 1p21 and is also inherited as an autosomal dominant trait.

COL11A2. Changes in this gene are responsible for Stickler syndrome
Type III; (STL3). It has been traced to Gene Map Locus 6p21.3 and is also inherited as an autosomal dominant trait.

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 6p21.3” refers to band 21.3 on the short arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

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, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Stickler syndrome affects males as well as females. Incidence 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.
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Symptoms of the following disorders can be similar to those of Stickler syndrome. Comparisons may be useful for a differential diagnosis:

Marfan syndrome is an inherited disorder that affects the connective tissue of the heart and blood vessels (cardiovascular system). The musculoskeletal system (ligaments and muscles) and ocular system (eyes) are also affected. Major symptoms also include unusual height, large hands and feet, and involvement of the lungs. (For more information choose "Marfan syndrome" 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, nearsightedness, cataracts and hearing loss. Marshall Syndrome is inherited as an autosomal dominant trait. The relationship between Marshall syndrome and Stickler syndrome is not well understood. The site of the gene for Marshall syndrome is the same as the site of the gene for Stickler syndrome, Type II. (For more information choose "Marshall syndrome" as your search term in the Rare Disease Database.)

Pierre Robin syndrome is characterized by a combination of three features, possibly due to the underdevelopment of the lower jaw. The lower jaw is abnormally small (micrognathia), the tongue is displaced downwards (glossoptosis), and there is an abnormal opening in the roof of the mouth (cleft soft palate). (For more information choose "Marshall syndrome" as your search term in the Rare Disease Database.)

Spondyloepiphyseal Dysplasia Congenita (SED Congenita) is a disorder with autosomal dominant inheritance with symptoms which can range from mild to severe. It is characterized by flat facial features, nearsightedness (myopia), retinal detachment, cleft palate, clubfoot, short-trunk dwarfism, a waddling gait and normally sized hands and feet. This disorder is often detectable at birth and may affect males and females in equal numbers. (For more information choose "SED Congenita" as your search term in the Rare Disease Database.)

Wagner syndrome is inherited as an autosomal dominant disorder that can be expressed in mild, moderate or severe form. It is characterized by facial abnormalities, an underdeveloped jaw, saddle nose, cleft palate, and vision abnormalities. Joint hyperextensibility in the fingers, elbows and knees, and hip deformities may also occur.
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Avoidance of excessive physical exertion including contact sports may prevent stiffness and soreness of ankles, knees, and wrists. Detached retinas may be surgically reattached. Genetic counseling will be helpful to families of children with Stickler Syndrome.

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 website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

McKusick VA, Ed. ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). The Johns Hopkins University. Stickler Syndrome, Type I; (STL1) Entry Number; 1083000: Last Edit Date; 3/4/2003.

McKusick VA, Ed. ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). The Johns Hopkins University. Stickler Syndrome, Type II; (STL2) Entry Number; 604841: Last Edit Date; 4/16/2000.

McKusick VA, Ed. ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). The Johns Hopkins University. Stickler Syndrome, Type III; (STL3) Entry Number; 184840: Last Edit Date; 6/16/2000.

TEXTBOOKS
Bennett JC, Plum F. Eds. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., Philadelphia, PA; 1996:161, 1120.

Beighton P. Ed. McKusick’s Heritable Disorders of Connective Tissue. 5th ed. Mosby-Year Book, Inc. St. Louis, MO; 1993:605.

REVIEW ARTICLES
Richards AJ, Scott JD, Snead MP. Molecular genetics of rhegmatogenous retinal detachment. Eye. 2002;16:388-92.

Bowling EL, Brown MD, Trundle TV. The Stickler syndrome: case reports and literature review. Optometry. 2000;71:177-82.

Nowak CB. Genetics and hearing loss: a review of Stickler syndrome. J Commun Disord. 1998;31:437-53; 453-54.

Spranger J. The type XI collagenopathies. Pediatr Radiol. 1998;28:745-50.

JOURNAL ARTICLES
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.

Vu CD, Brown J Jr, Korkko J, et al. Posterior chorioretinal atrophy and vitreous phenotype in a family with Stickler syndrome from a mutation in the COL2A1 gene. Ophthalmology. 2003;110:70-77.

Ahmad N, Richards AJ, Murfett HC, et al. Prevalence of mitral valve prolapse in Stickler syndrome. Am J Med Genet. 2003;116A:234-37.

Keats BJ. Genes and syndromic hearing loss. J Commun Disord. 2002;35:355-66.

Mottes M. Linkage analysis for prenatal diagnosis in a familial case of Stickler syndrome. Genet Couns. 2002;13:163-70.

Webb AC, Markus AF. The diagnosis and consequences of Stickler syndrome. Br J Oral Maxillofac Surg. 2002;40:49-51.

Szymko-Bennett YM, Mastroianni MA, Shotland LI, et al. Auditory dysfunction in stickler syndrome. Arch Otolaryngol Head Neck Surg. 2001;127:657-63.

Stickler GB, Hughes W, Houchin P. Clinical features of hereditary progressive arthro-ophthalmopathy (Stickler syndrome): a survey. Genet Med. 2001;32:192-96.

Soulier M, Sigaudy S, Chau C, et al. Prenatal diagnosis of Pierre-Robin sequence as part of stickler syndrome. Prenat Diagn. 2001;22:567-78.

O’Brien DA, Phillips AJ. Stickler syndrome. Clin Exp Optom. 2000;83:330-32.

FROM THE INTERNET
Robin NH, Warman M. Stickler Syndrome. GeneReviews. Posted: 9 June 2000. 12pp.
www.gneclinics.org/servlet/access?id=8888890&key=3zJZwtBELDHoO&gry

Boys Town National Research Hospital. Information on Hearing Loss. Genetics and Deafness – Stickler Syndrome/Marshall Syndrome. 1990. 3pp.
www.boystownhospital.org/parents/info

UC Davis Children’s Hospital. Craniofacial Anomalies. 2003:2pp.
www.ucdmc.ucdavis.edu/cleft/craniofacial/guide/about/sticklersyndrome.html

Stickler Syndrome Support Group. About Stickler Syndrome. 2000:3pp.
www.stickler.org.uk/info.htm

Pierre Robin Network. Stickler Syndrome. 2001:2pp.
www.pierrerobin.org/sticklersyndrome.html



The National Craniofacial Association. Stickler Syndrome. Last Modified: March 18, 2003:3pp.
www.faces-cranio.org/Disord/Stickler.htm

Snead M. Stickler Syndrome. contact a family. Last Updated: April, 2000:2pp.
www.cafamily.org.uk/cgi-bin/printable.pl

Department of Ophthalmology. University of Iowa. Stickler’s syndrome. nd. 2pp.
www.ophth.uiowa.edu/Stickler.html

Hughes W. Stickler Syndrome. Royal National Institute for the Blind. Last Updated:18/12/2000. 2pp.
www.rnib.org.uk/info/stickler.htm

Bill Houchin for Stickler Involved People (SIP). nd. 3pp.
www.sticklers.org/sip/def.html