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

• OSMED, Heterozygous
• Stickler Syndrome
• Kniest Dysplasia
• Marshall Syndrome
• Congenital Spondyloepiphyseal Dysplasia

Symptoms associated with homozygous OSMED vary from case to case. Affected individuals have progressive, severe hearing loss, skeletal malformations and distinctive facial features.

Hearing loss in individuals with homozygous OSMED may be progressive and severe and occurs because of an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss). During infancy, affected individuals may also experience feeding difficulties, recurrent pulmonary infections, and inflammation of the main air passages (bronchioles) to the lung (bronchitis), and pneumonia.

Skeletal abnormalities associated with homozygous OSMED include malformation (dysplasia) of the long bones of the arms (humeri) and legs (femora). The “growing portion” or head of the long bones (epiphyses) is abnormally large and broad and the end portion of the shaft of the long bones is abnormally widened (metaphyseal flaring) resulting in a dumbbell shape. Affected individuals may also have joint contractures, abnormally large bones of the ankle (tarsal bones), and short hands with stubby fingers. In some cases, the upper portion (capital) of the thighbone where it meets the hip (capital femoral epiphyses) is abnormally small or absent. As affected individuals age, they may develop progressive front-to-back curvature of the spine (lordosis) and large, painful joints with reduced mobility. Skeletal abnormalities associated with homozygous OSMED eventually result in short stature with disproportionately short limbs.

Affected individuals may also develop osteoarthritis, a condition characterized by the breakdown of cartilage and pain, degeneration, and stiffness of affected joints. Individuals with homozygous OSMED also have flattening of the central regions of bones in the spinal column (platyspondyly) and progressive fusion of the eight small bones of the wrists (carpal bones).

Distinctive facial features associated with homozygous OSMED include an underdeveloped jaw bone (mandibular hypoplasia), a rounded (bulbous) upturned nose with nostrils that are flared forward (anteverted nares), and underdevelopment of the bones of the middle of the face (midface hypoplasia) resulting in a flat facial 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

Homozygous OSMED is inherited as an autosomal recessive trait. 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.

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% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% 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%. The risk is the same for males and females.

Some individuals with homozygous OSMED have parent who were closely related. 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.

Homozygous OSMED appears to occur as a result of 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 of cartilage and bone.

Homozygous OSMED affects males and females in equal numbers. The disorder was first described in the medical literature in 1970.

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

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

Heterozygous OSMED (also known as Weissenbacher-Zweymuller syndrome or Stickler syndrome type III) 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 an 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 and is inherited as an autosomal dominant trait. (For more information on this disorder, choose "heterozygous OSMED" 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 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 homozygous 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 homozygous OSMED. Genetic testing is also available to scan for mutations of genes coding for collagen XI.

Treatment
The treatment of homozygous 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

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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.

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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.

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Van Steensel MA, Buma P, de Waal Malefijt MC, van den Hoogen FH, Brunner HG. Oto-spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene. Am J Med Genet. 1997;70:315-23.

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Rosser EM, Hall CM, Harper J, Lacour M, Baraitser M. Nance-Sweeney chondrodysplasia – a further case? Clin Dysmorphol. 1996;5:207-12.

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FROM THE INTERNET
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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.