Homozygous OSMED (oto-spondylo-megaepiphyseal dysplasia) 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 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.
Two additional disorders, Weissenbacher-Zweymuller syndrome and Stickler syndrome III, more commonly known as non-ocular Stickler syndrome, are also caused by mutations to this gene (allelic disorders). Some clinical researchers believe that each of these three disorders is a separate and distinct entity. Others believe that the three represent a range of severity of one syndrome. Regardless, these disorders involve alterations (mutations) of the collagen gene, COL11A2. Some researchers have suggested that the name OSMED be used as a general heading to consist of "heterozygous OSMED," which encompasses Weissenbacher-Zweymuller syndrome and Stickler syndrome type III and is inherited as an autosomal dominant trait, and "homozygous OSMED," which encompasses autosomal recessive cases of oto-spondylo-megaepiphyseal 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.
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.
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.
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