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ODHHS Information
The main problem for someone with Osteogenesis Imperfecta (OI) is broken bones. Because their bones fracture so easily, OI is also known as the "brittle bone disease". It has also been called "van der Hoeve´s syndrome", after one of the first doctors to study it. There is a wide range of severity in OI. In the most serious cases, a baby may actually have broken bones while still in the womb, and rarely lives long after birth. Other people with OI may have many fractures and deformity of their bones. People with the mildest OI may have frequent broken bones in childhood, but have fewer fractures as they get older. Hearing loss is often a part of OI. There are some other more rare complications in OI; we will concentrate only on the most common problems and on the hearing loss.
 

Types of OI

 
OI has been classified into four types based on the severity and the other features that can go along with the condition. The four types of OI are summarized in Table 1. Most families with OI fit into one of these four types, but there is variation within each type. This is a fairly new classification system based on new genetic information, and may be different from older material you might find. As a result, some of the older studies of hearing loss in OI may have included people with different types. Also, it has been found that the hearing loss may not be the same even in people with the same type of OI, so it is impossible to predict exactly how much hearing loss a person with OI will develop. However, some types appear to have more of a tendency toward hearing loss than others.

Table 1 Type % Loss Characteristics------ I >50% blue sclerae, fractures in childhood, rarely deforming, opalescent teeth in some families II unknown fractures at birth, bone deformities, short survival common III unknown very short stature, progressive deformation, normal sclera in adulthood, opalescent teeth IV 30% short stature, milder deformation, opalescent teeth some families.

Type I has also been called the "Tarda" form, meaning that it often isn´t diagnosed at birth, but is noticed later when a baby has fractures as the result of minor trauma. It is the most common form of OI. One characteristic of this type of OI is a blue color to the whites of the eyes (the sclerae). In some people with OI type I, the teeth are discolored with an "opalescent", milky color or a brownish or bluish cast, and are more likely to get cavities or to break. This has sometimes been called type IB. About half of the people with OI type I develop hearing loss in adulthood; some studies have suggested that by old age nearly all of the people have at least some hearing loss. It generally appears as a conductive loss in the late teens or twenties, due to problems with the small bones of the middle ear (ossicles). They may be fragile and malformed, or the footplate of one of the bones, the stapes, may be unable to move, as in otosclerosis. A sensorineural (nerve) loss may also develop. There is much variation in the severity of the hearing loss; some people may be deaf in old age, while others may be hard of hearing. Other people with OI never develop significant hearing problems.
 
Type II has also been called "OI Congenita" or the "Lethal Perinatal" form, because it is readily noticed at birth, and the baby usually does not survive. There are deformities of the ribs, vertebrae and bones, along with fractures. Ultrasound before the baby is born can even show fractures.
 
Type III, or the "Progressively Deforming" form of OI, is more severe than type I but less severe than type II. In some older reports, individuals with type III OI may have also been classified as "congenita", since it can be diagnosed at birth. Babies may be born with fractures, and also have blue sclerae at birth, but they do not die from OI. As they get older, they continue to have fractures and their arms and legs grow poorly and become crooked, and they often develop curvature of the spine as well. It is not clear if hearing loss is common in people with type III, probably because of the way different studies have defined each type. Some studies have said that hearing loss is rare in this type, while others have said it is frequent. When present, the hearing loss is similar to that seen in OI type I, but tends to be more severe3.
 
Type IV is very similar to type I except that the sclerae are not blue. Fractures may be present at birth, but the course of the condition is not as severe as types II or III. There also appear to be two types within type IV, one with opalescent teeth and the other without. Hearing loss is less common than in type I, but is seen in some families. One study estimated that 30% of the people with OI type IV have hearing loss. When present, the hearing loss is similar to that seen in type I.

The Cause of OI

All four types of OI are caused by defects in collagen. Collagen is a protein in the body that is part of the "connective tissue", the tissue that helps to hold the skin, tendons and bones together. It creates strong fibers which serve as a "scaffolding" for the bones. There are several different forms of collagen, each specialized to certain parts of the body. Type I collagen is involved with bone.
 
A collagen fiber is made up of three separate molecules wound together like strands in a rope. This ropelike structure is what gives collagen its strength. There are two "A1" strands and one "A2" in each collagen I fiber. These two types of strands are made by two separate genes, and genetic flaws (mutations) in either of them can cause Osteogenesis Imperfecta. It has been suggested that hearing loss is most often associated with mutations in the A1 strand. Many different mutations have been found in these two strands. The type of OI that results from a given genetic mutation is dependent both on the strand that is involved and the type of mutation.
 
Families with the same type of OI can have defects in different strands, or even different defects in the same strand. For example, in some families with OI type I the mutation is in the gene for the A1 strand, while in others it is in the gene for the A2 strand. On the other hand, families with different types of OI may have defects in the same strand, but in a different place along the strand. That is, one defect in the A2 strand might produce OI type I, but a different defect in the A2 strand may cause OI type IV. With all of this variation in the genes, it is no wonder that there is so much variation within OI. Indeed, in a few cases of OI, the mutation does not appear to be in either the A1 or A2 strand, but must involve the collagen fiber in some other way.
 
There is no cure for OI yet. In addition to treatment for the fractures, there may need to be physical and occupational therapy, dental treatment, and even surgery for curvature of the spine or other problems with the bones. Since the hearing loss usually affects both ears and is often moderate to severe, children with OI should have their hearing tested as soon as possible, and the hearing should be followed throughout life. Hearing aids may be the most effective treatment. Middle ear surgery such as stapedectomy has been used in some people to lessen the conductive component of the hearing loss, although sensorineural loss, if present, will still continue. Since the bones in the middle ear are very fragile, the surgery is very complicated and it is probably best done by surgeons with a lot of experience. It generally is not done in early childhood.

Genetics

It has recently been found that all of the types of OI are caused by autosomal dominant genes, with the possible exception of a few rare autosomal recessive forms of Type II. This means that either a person with OI inherited the gene from one of his or her parents, or that a normal collagen gene changed to become an OI gene. This genetic change is also referred to as a new mutation. Everyone has genes that have mutated, but the change may never be noticed if the change happens in an unimportant part of a gene. The changes are noticed only if they happen to cause a problem.
 
If a person has OI, each of their children has a 50-50 chance of inheriting the OI gene. If neither parent has OI (as in the case of type II), the cause of the OI in the baby is almost always a new mutation, and there is very little chance that the parents would have another child with OI. There are exceptions to this, however. If the baby had a rare autosomal recessive type, the parents would have a 25% (1 in 4) risk of having another baby with OI. Also, occasionally a parent will carry the OI gene in some of the egg or sperm cells, but not in other cells that affect their bones. As a result, the parent would not have any of the symptoms of OI, but could still pass it on to their children. Anyone who has OI or has had a baby with OI should see a genetic counselor to get the correct information for their own situation. Support groups are also available for OI, and are active in providing a newsletter for families and in funding research. Further information can be found at the end of this factsheet.

Other Collagen Disorders and Hearing Loss

There are several other genetic conditions which involve collagen and hearing loss.
 
For example, Stickler syndrome is sometimes caused by mutations in a different type of collagen, Collagen 2. People with the Marshall/ Stickler syndrome have problems with arthritis, vision, and hearing.
 
X-linked Alport syndrome involves kidney problems (nephritis) and progressive hearing loss, and has been reviewed in a previous newsletter as well. It has been found that it is often caused by a mutation in a gene for Collagen 5 on the X chromosome.

References

 
1. Sillence, D. O. (1988). Osteogenesis imperfecta nosology and genetics. Annals of the New York Academy of Science 543: 1-15.
 
2. Riedner, E.D., et al. (1980). Hearing patterns in dominant Osteogenesis Imperfecta. Archives of Otolaryngology 106: 737-740.
 
3. Stewart, E.J., O´Reilly, B.F. (1989). A clinical and audiological investigation of osteogenesis imperfecta. Clinical Otolaryngology 14: 509-14.
 
4. Sykes, B., et al. (1990). Consistent linkage of dominantly inherited osteogenesis imperfecta to the type I collagen loci: COL1A1 and COL1A2. American Journal of Human Genetics 46: 293-307.

Support Groups

Osteogenesis Imperfecta Foundation, Inc.
5005 W. Laurel St., Suite 210
Tampa, FL 33607-8214
(813)282-1161
4 chapters



Date Originally Created: Spring of 1991.
The information presented here first appeared in publications of the Boys Town National Research Register for Hereditary Hearing Loss, the National Institute on Deafness and Other Communication Disorders (NIDCD), Hereditary Hearing Impairment Resource Registry (HHIRR), or the Boys Town Research Registry for Hereditary Hearing Loss.  
 
The Boys Town Research Registry for Hereditary Hearing Loss

The Boys Town Research Registry for Hereditary Hearing Loss (Registry) is designed to foster a partnership between families, clinicians and researchers in the area of hereditary hearing loss/deafness through three primary functions. First, the Registry disseminates information to professionals and families about clinical and research issues related to hereditary deafness/hearing loss. Second, the Registry collects information from individuals interested in supporting and participating in research projects. This information is used to support the third function of the Registry - matching families with collaborating research projects.  
For more information, contact:

Research Registry for Hereditary Hearing Loss
555 N. 30th Street
Omaha, NE 68131
800 320-1171 (V/TDD)
402 498-6331 (FAX)

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