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

• None

Heterozygous OSMED is characterized by skeletal malformations, distinct facial features and delayed psychomotor development. The specific symptoms affecting each child vary from case to case.

Affected children have abnormally short bones of the upper arms and thighs (rhizomelia) resulting in short stature during infancy and early childhood (rhizomelic dwarfism). The long bones of the upper arm (humeri) and thigh (femora) are short with broad heads (dumbbell-shaped). Affected individuals may also have clefts that resemble fractures in certain bones of the vertebrae (vertebral coronal clefts).

Affected infants may also exhibit a delay in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor delays). As affected individuals age, they experience an increase in growth rate eventually reaching normal height by 5 or 6 years of age. Mental and motor development also becomes normal by this age.

Distinctive facial features associated with heterozygous OSMED include an abnormally small jaw (micrognathia), widely spaced eyes (hypertelorism), depressed nasal bridge, a small upturned nose, and underdevelopment of the bones of the middle portion of the face (midface hypoplasia) giving the face a flat appearance. 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). Cleft palate may also occur as an isolated finding.

Some individuals develop hearing loss because of an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss). Such hearing loss may become progressively more pronounced.

Heterozygous OSMED is inherited as an autosomal dominant trait. Some cases occur randomly as the result of a spontaneous genetic change (i.e., new mutation). 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.

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.

Investigators have determined that some cases of heterozygous OSMED occur due to changes or disruptions (mutations) of the collagen XI, apha-2 polypeptide (COL11A2) gene located on the short arm (p) of chromosome 6 (6p21.3). 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.

The COL11A2 gene is involved in the formation (synthesis) of collagen, specifically type XI collagen. Collagen is the body's major structural protein forming an essential part of connective tissues and is the main component of ligaments, tendons and cartilage. Collagen is also found in bone. Type XI collagen is usually found in cartilage, the specialized tissue that serves as a buffer or cushion for bones at joints. The COL11A2 gene encodes for proteins that are essential to the development and function of type XI collagen. Mutations to this gene result in abnormalities in the production of collagen XI, which in turn affects the proper formation and development cartilage and bone.

Heterozygous OSMED affects males and females in equal numbers. Both heterozygous and homozygous OSMED are extremely rare; approximately 30 cases have been reported in the medical literature. The exact incidence of this disorder is unknown. These disorders may be underdiagnosed making it difficult to determine their true frequency in the general population.

Heterozygous OSMED may be referred to as a type XI collagen disorder (collagenopathy). Type XI collagenopathies are disorders that involve abnormalities affecting type XI collagen and include homozygous OSMED and Stickler syndrome type II.

Symptoms of the following disorders can be similar to those of heterozygous OSMED. Comparisons may be useful for a differential diagnosis.

Homozygous OSMED is an extremely rare genetic disorder characterized by malformation (dysplasia) of certain bones, hearing loss and distinct facial features. Skeletal malformations affect the bones of the arms, legs and spines eventually resulting in disproportionate short stature. Hearing loss is often progressive and severe. Intelligence is normal. Homozygous OSMED occurs because of disruptions or changes (mutations) to the COL11A2 gene and is inherited as an autosomal recessive trait. (For more information on this disorder, choose "OSMED, homozygous" as your search term in the Rare Disease Database.)

Stickler syndrome refers to a group of disorders of the connective tissue that involves several of the body's organ systems such as the eye, skeleton, inner ear, and/or the head and face. Connective tissue is made up of a protein known as collagen that develops into the several varieties found in the body. It is the tissue that physically supports many organs in the body and may act like glue or an elastic band that allows muscles to stretch and contract. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor), and the ends of the bones that make up the joints of the body (epiphysis). Most authorities agree that there are four types of Stickler syndrome, of which three are reasonably well differentiated and a fourth remains not well understood. Stickler syndrome type I (STL1) is responsible for about 75% of reported cases and presents with a full array of symptoms (eye, ear, jaw and cleft, joints); Stickler syndrome type II; (STL2) also presents with a full array of symptoms; Stickler syndrome type III (STL3) presents with a "Stickler-like" syndrome that affects the joints and hearing without involving the eyes. Some researchers believe that this form is the same disorder as heterozygous oto-spondylo-megaepiphyseal dysplasia (OSMED). (For more information on this disorder, choose "Stickler syndrome" as your search term in the Rare Disease Database.)

Kniest dysplasia is one of several forms of dwarfism that is caused by a change (mutation) in a gene known as COL2A1. This gene is involved in the production of a particular protein that forms type II collagen, which is essential for the normal development of bones and other connective tissue.

Changes in the composition of type 2 collagen lead to abnormal skeletal growth and, thus, to a variety of dwarfing conditions known as skeletal dysplasias. Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other characteristics may not appear for two or three years. (For more information on this disorder, choose "Kniest dysplasia" 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 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 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.)

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 thighbone 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" as your search term in the Rare Disease Database.)

Diagnosis
A diagnosis of heterozygous OSMED is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests including x-rays. X-ray studies reveal characteristic skeletal malformations associated with heterozygous OSMED.

Treatment
The treatment of heterozygous OSMED is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists), orthopedic surgeons, specialists who asses and treat hearing problems (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.

Hearing aids may be used to treat hearing loss. Surgery may be necessary to correct certain skeletal malformations and abnormalities such as cleft palate. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

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

TEXTBOOKS
Gorlin RJ, Cohen MMJr, Hennekam RCM, eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:354-6.

Rimoin D, Connor JM, Pyeritz RP, Korf BR, eds. Emory and Rimoin's Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:4082.

JOURNAL ARTICLES
Harel T, Rabinowitz R, Hendler N, et al. COL11A2 mutation associated with autosomal recessive Weissenbacher-Zweymuller syndrome: molecular and clinical overlap with otospondylomegaepiphyseal dysplasia (OSMED). Am J Med Genet. 2005;132:33-5.

Rabinowitz R, Gradstein L, Galil A, Levy J, Lifshitz T. The ocular manifestations of Weissenbacher-Zweymuller syndrome. Eye. 2004;18:1258-63.

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

Pihlajamaa T, Prockop DJ, Faber J, et al. Heterozygous glycine substation in the COL11A2 gene in the original patient with Weissenbacher-Zweymuller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome). Am J Med Genet. 1998;80:115-20.

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

Ramer JC, Eggli K, Rogan PK, Ladda RL. Identical twins with Weissenbacher-Zweymuller syndrome and neural tube defect. Am J Med Genet. 1993;45:614-8.

Chemke J, Carmi R, Galil A, et al. Weissenbacher-Zweymuller syndrome: a distinct autosomal recessive skeletal dysplasia. Am J Med Genet. 1992;42:989-95.

Galil A, Carmi R, Goldstein E, et al, Weissenbacher-Zweymuller syndrome: long-term follow-up of growth and psychomotor development. Dev Med Child Neurol. 1991;33:1104-9.

FROM THE INTERNET
Robin NH, Moran RT, Warman W. Updated:08/05/2005. Stickler Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:277610; Last Update:06/16/2000. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=277610 Accessed on: May 26, 2006.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:184840; Last Update:06/16/2000. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=184840 Accessed on: May 26, 2006.