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Marshall Syndrome

NORD is very grateful to Ruth M. Liberfarb, MD, PhD, Massachusetts General Hospital for Children, for assistance in the preparation of this report.

Synonyms of Marshall Syndrome

  • deafness-myopia-cataract-saddle nose, Marshall type

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Marshall syndrome is a rare autosomal dominant genetic disorder caused by mutations in the COL11A1 gene. 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.

Symptoms

Patients with Marshall Syndrome have a distinctive flat sunken midface with a flattened nasal bridge (saddle nose), nostrils that turn upward, and a wide space between the eyes (hypertelorism). The domelike upper portion of the skull (calvaria) is thicker than normal and calcium deposits can be found in the skull (cranium). Eye defects found in patients with Marshall Syndrome are nearsightedness, a disease of the eye in which the lens loses its clarity (cataract), and a wide space between the eyes making the eyeballs appear to be larger than normal. Hearing loss may range from slight to severe; the distortion of the sound is a consequence of the nerve damage (sensorineural). Other symptoms exhibited by some patients with Marshall Syndrome are: crossed eyes (esotropia), a condition in which the line of vision is higher in one eye than the other (hypertropia), retinal detachment, glaucoma, protruding upper incisors (teeth) and a smaller than normal or missing nasal bone.

Causes

Marshall syndrome is a rare autosomal dominant genetic disorder caused by mutations in the collagen XI, alpha-1 polypeptide (COL11A1) gene located on chromosome 1p21.1. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular 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. The risk is the same for males and females.

Affected Populations

Marshall Syndrome affects males and females in equal numbers.

Related Disorders

Symptoms of the following disorders can be similar to those of Marshall Syndrome.

Comparisons may be useful for a differential diagnosis:

Congenital spondyloepiphyseal dysplasia is a rare genetic disorder characterized by growth deficiency before birth (prenatally), spinal malformations, and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency eventually results in short stature (dwarfism) due, in part, to a disproportionately short neck and trunk, and a hip deformity in which the thigh bone is angled toward the center of the body (coxa vara). In most cases, affected individuals may have diminished muscle tone (hypotonia), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), abnormal inward curvature of the spine (lumbar lordosis), and/or unusual protrusion of the breast bone (sternum), a condition known as pectus carinatum. Affected individuals also have abnormalities affecting the eyes including nearsightedness (myopia) and, in approximately 50 percent of cases, detachment of the nerve-rich membrane lining the eye (retina). Congenital spondyloepiphyseal dysplasia is inherited as an autosomal dominant trait. (For more information on this disorder, choose "spondyloepiphyseal dysplasia congenita" as your search term in the Rare Disease Database.)

Congenital syphilis is a chronic infectious disease caused by a spirochete (treponema pallidum) acquired by the fetus in the uterus. Symptoms of this disease may not show up until several weeks or months after birth and in some cases they may take years to appear. Congenital syphilis is passed on to the child from the mother who acquired the disease prior to or during pregnancy. Symptoms of early congenital syphilis include fever, skin problems and low birth weight. In late congenital syphilis the symptoms of the disease do not usually become apparent until two to five years of age. Symptoms of late congenital syphilis may be bone pain, peg-shaped upper central incisors (teeth), blurred vision, eye pain and insensitivity to light, saddle nose, bony prominence of the forehead, short upper jaw bone and deafness. In rare cases the disease may remain latent for years with symptoms not being diagnosed until well into adulthood. (For more information on this disorder, choose "congenital syphilis" as your search term in the Rare Disease Database.)

Stickler syndrome refers to a group of disorders of the connective tissue that affect multiple organ systems of the body such as the eyes, skeleton, inner ear, and/or the head and face. 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). Five distinct forms of Stickler syndrome have been identified in the medical literature based on location of the mutated gene, clinical symptoms and inheritance pattern. Type I with the membraneous vitreous caused by mutations in the COL2A1 gene; type II with the beaded vitreous is caused by mutations in the COL11A1 gene; type III is the non-ocular type caused by mutations in COL11A2, type IV has a degenerated vitreous with progressive liquefaction and has autosomal recessive inheritance with mutations in COL9A1, type V has the same clinical symptoms as types I and II but the location of the mutation has not yet been found.

Stickler syndrome type II is caused by mutations in the same gene COL11A1 as Marshall syndrome. Some researchers believe that the two disorders are the same or different expressions of the same disorder. Others believe that the two disorders are distinct. Recent studies show that the mutations in COL11A1 associated with Marshall syndrome are splicing mutations in the exons in the c-terminal regions of COL11A1, with a "hot spot" in exon 50. (For more information on this disorder, choose Stickler Syndrome as your search term in the Rare Diseases Database.)

Wagner Syndrome is a very rare genetic disorder inherited as an autosomal dominant trait and caused by a mutation in the CSPG2 gene on chromosome 5q13-14. The gene CSPG2 encodes for versican, a structural component of vitreous. It has been reported in one Swiss family. The ocular problems include vitreoretinal degeneration and cataracts. Retinal detachments occur only rarely. Extraocular problems have not been reported.

Standard Therapies

Plastic surgery can improve saddle nose in Marshall syndrome. Other surgical procedures are used to remove the lenses of eyes affected by cataracts, after which lens implants are used as replacements. Subsequently, contact lenses may help improve sharpness of vision. Laser techniques are used to loosen any material, such as the cornea or the lens capsule that may adhere to the lens. The use of a hearing aid may be beneficial in some cases. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

After the removal of the affected lens in children with congenital cataracts, an intraocular lens (IOL) may be implanted. If technically feasible, the IOL is implanted in the lens capsule. More research is needed before this implantation can be used more generally to preserve vision and reduce double vision. 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


Contact for additional information about Marshall syndrome:

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

Organizations related to Marshall Syndrome

References

TEXTBOOKS
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.

Cassidy S, Allanson J. Eds. Clinical Management of Common Genetic Syndromes. 2nd ed. Wiley Liss, New York, N.Y. 2005:539-541.

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
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.

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.

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:154780; Last Update:10/7/11. Available at:
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=108300 . Accessed on: January 18, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/01/19 00:00:00 GMT+0

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