# Handbook of Genetic Counseling/Osteogenesis Imperfecta (OI)

Osteogenesis Imperfecta (OI)

## Contracting

* What questions or concerns would you like us to address today?
* What has your experience been like with OI?
* Explanation of what will occur during the session
** Confirm family history
** We have some medical records, but will want to confirm some of his med history
** Dr. will come in to examine him
** And we will discuss what we think regarding whether we think he has OI and why we have come to the conclusions we have
** We will then answer any questions you might have

## Overview of OI

* OI is a genetic disorder. Eight types of OI can be distinguished. Most cases are caused by dominant mutations in the COL1A1 and COL1A2 genes. Some are caused by recessive mutations.
* It is due to a lack of or poor quality of type 1 collagen (Collagen is the major protein of the body's connective tissue)
* Extreme variations in severity from one individual to another
* Clinical diagnosis is often grouped into four types based on severity and characteristics

## Inheritance

* As a genetic disorder, OI has historically been viewed as an autosomal dominant disorder of type I collagen. Most cases have been caused by mutations in the COL1A1 and COL1A2 genes. In the past several years, there has been the identification of autosomal recessive forms.
* Most cases of OI are caused by new mutation (especially type II)
** If spontaneous (parents unaffected) then empiric recurrence is 6-7% (Marini JC and Chernoff EJ)
** Empiric recurrence increases to 28% if more than one affected child has been born to unaffected parent
** Recurrence is caused by gonadal mosaicism (or even somatic mosaicism in a parent where parent is only mildly affected)
** 18 cases of mosaicism in literature (12 paternal and 6 maternal)
** approximately 1/3 of these parents were mildly affected
** determining proportion of mutation in sperm can be most accurate way to obtain recurrence risk for mosaic fathers
* Affected individual has 50% chance of passing mutation on to each child (if dominant form)

## Genetics

* Caused by an alteration in COL1A1 gene on chromosome 17 or COL1A2 gene on chromosome 7
* Over 200 mutations recognized (most unique to an individual family)
Geneotype Phenotype correlation (Not well understood)
* Even in families there is considerable phenotypic heterogeneity
* Unrelated individuals with identical mutations may have similar or distinct phenotype
* Individuals with near identical phenotypes often have different mutations
* Lethal and nonlethal mutations are both represented about equally on alpha1 and alpha2 chains
* Type I caused by inactivation of one copy of gene resulting in underproduction of collagen
* More severe forms of OI generally result from structural mutations in gene that cause collagen fibers to become unstable
* Type I collagen is a primary component of bone
* Fibroblasts of patients show decrease in secretion of type I collagen into matrix
* Since the proportions of the components are important for mineralization of bone lack of enough type I results in poor matrix deposition
* Tissue specific difference in metabolism of mutant type I collagen may explain why mostly bone is affected

## Incidence

(Marini JC and Chernoff EJ)
* Between 1 in 20,000 and 1 in 30,000
* Incidence in US is 1 in 20,000 if all diagnosed within 1 year of birth included
* No preferential distribution by gender, race or ethnic group.
* Brittle bone disease is un-cureable for the time being.

## Clinical Features

(Vary widely within types and between types) (There are 4 types according to current classification, but an individual may not fit one category clearly)
* Type I
** Mildest type of OI
** Bones predisposed to fracture, especially before puberty (postnatal onset of fractures usually without bony deformity)
** Normal or near normal stature
** Loose joints (hyperextensible)
** Blue sclera
** Triangular face
** Spinal curvature
** Teeth possibly brittle (dentinogenesis imperfecta)
** Hearing loss in 20s or 30s
* Type II
** Most severe form
** Usually fetal demise or death in the perinatal period
** Numerous fractures and severe bone deformity
** Length and weight SGA
** Head large for body size
** Usually blue-gray sclera
** Markedly reduced ossification
** Underdeveloped lungs
* Type III (progressive deforming form)
** Bones fracture easily - fractures present at birth
** Bone deformity sometimes severe
** Short stature
** Blue sclera (thought to be due to differential scattering of light because of differences in the connective tissue) tends to whiten with age
** Loose joints and poor muscle development
** Barrel-shaped rib cage
** Triangular face
** Relative macrocephaly
** intellectually normal
** most are severely physically handicapped
** Spinal curvature
** Respiratory problems sometimes
** Teeth brittle possibly
** Hearing loss possible
* Type IV
** Between Type I and Type III in severity
** Bones fracture easily, most before puberty
** Mild to moderate bone deformity
** Moderate osteoporosis and modeling abnormalities of the long bones
** Shorter than average stature (moderately short)
** Normal sclera (but some cases reported of blue sclerae that seem to fit this type better than type I)
** Tendency toward spinal curvature
** Barrel-shaped rib cage
** Triangular face
** Brittle teeth possible
** Hearing loss possible

## Management

* Hearing loss
* characteristic in type I OI and also occurs in types III and IV
* Combined sensorineural and conductive deficits
* Hearing aids help with conductive hearing loss more than sensorineural
* Referral to center with experience in OI when hearing aid no longer enough
* Surgical intervention with stapedectomy gives satisfactory long-term results in OI with severe loss (not routine) because won't relieve sensorineural component
* Dental
* May need orthodontic work for maloculsion
* Other dental considerations for dentinogenesis imperfecta
* Cardiovascular
* Aortic root dilatation (12% of all affected individuals 28% in type III)
* No standard regimen for evaluation
* Aortic and mitral regurgitation occasionally noted
* Respiratory
* Pulmonary function evaluated by cardiology or pulmonology initially at young age (4-6 years) then reassessed every 2-3 if normal

## Natural History

* Type II
** Frequently lethal at or shortly after birth due to respiratory problems
** Those that survive perinatal period generally die from pneumonia or respiratory insufficiency
** Some have lived for months or years, but bones are very porotic and no evidence of haversian canals or lamellar bone
* Type I
** rarely diagnosed at birth because it is mildest form
* Type III
** often causes fractures at birth, and fractures may occur in utero
** Compatible with long life, but many die in infancy of respiratory difficulties or in childhood of pneumonia
** Early intervention and rehab have improved prognosis

## Development and behavior

* Minimal delay in fine motor development
* Significant delay in gross motor
* Intelligence and language unaffected

## Diagnosis/Testing

* Can be diagnosed based on fractures, clinical features, and family history
* Collagen testing
** Study cells making type I collagen
** Biopsy 1/8 to 1/16 of an inch of skin
** Radiolabel and run on gel
** In people with OI, also bands that migrate more slowly - abnormal collagen molecules
** Does not identify 10-15% of individuals with mild OI
** May not be possible to distinguish between types of OI
** Usually used before molecular testing
* Molecular testing
** DNA sequencing
** Most families have unique mutation
** Does not identify mutation in about 5% of those with OI
* Prenatal diagnosis
** Ultrasound can often detect fractures, bowing, or other bone deformities in severe cases of OI (milder forms may be missed)
*** Type II OI identifiable as early as 15 weeks gestation
*** Type III OI not reliable until after 20 weeks (limb shortness may not be apparent until then)
*** Findings on U/S may include
** CVS
*** Cells analyzed for abnormal collagen
*** DNA test for mutation if it has been identified in family
** Amniocentesis
*** can identify genetic mutation (useful only if mutation has already been identified)

## Management and Treatment Options

* Currently is no cure
* Management of fractures
** Usually treated with short-term immobilization in lightweight casts, splints, or braces to allow movement as soon as possible
* Physical therapy
** Should begin as soon as muscle weakness identified
** Goal is to give independence in life functions
** Swimming, water therapy, and walking safe exercises to maintain bone and muscle mass
* Rodding surgery
** Metal rods inserted in long bones to control fractures and improve deformities
** Two types of rods
*** Nonexpandable versatile but must be replaced when child grows
*** Expandable rods grow with child but only appropriate for longer bones
** Very thick
** Must be firmly anchored at both ends
** Spinal rodding for severe scoliosis
** If bones strong enough to support rods
* Bisphosphonate drugs
** Currently used to treat osteoporosis and bone complications in cancer
** Study at Montreal Shriners Hospital
** Administered pamindronate intravenously
** Treatment cycle is 4 hour infusion for 3 successive days
** Received cycle every 4 - 6 months
** Prevents breakdown of bones by osteoclasts
** Normally osteoblasts create new bone to replace older bone that is resorbed by osteoclasts
** In OI bone is resorbed by osteoclasts more quickly because it is imperfect and osteoblasts become less efficient (produce less bone) because collagen is abnormal
** Slowing down resorption of bone may strengthen skeleton
** Study included 30 children with severe OI
** Results showed increased bone density, reduction in bone pain, increased motility and decreased incidence of fractures
** Only side effect was mild fever in 87% of children on second day of first treatment - did not occur again
** Small study, no controls, and did not include patients with mild OI
* Growth hormone (still under investigation)
** Administration to those with type III and IV significantly increases linear growth rate in about half of individuals (type IV compose majority of responders)
** Individuals with type I also usually are responsive to GH.
** GH also increases muscle mass and strength.
** GH does not worsen skeletal deformities, but there is increase in blood levels of all components of bone turnover due to an increased rate of whole body remodeling associated with rapid bone gain

## Health tips for individuals with OI

* Safe exercise
* Nutritious diet
* Calcium maintains bone density
* Vitamin C promotes healing
* Avoid smoking, excessive alcohol or caffeine, and steroid medications

## Precautions to take when caring for someone with OI

* Never pull or push on limb or bend it in awkward position
* Don't lift baby under armpits or by ankles - put one hand under buttocks and other under shoulders and head
* Covered foam or a pillow may be used to transport baby but be sure to hold and touch babies
* Support infants in a variety of positions to develop muscles
* Use caution when performing medical procedures
* Minimize handling of limb when fracture suspected
* Respect opinions or instructions of family members

## Differentials

An important differential diagnosis of OI is child abuse, as both may present with multiple fractures in various stages of healing. Differentiating them can be difficult, especially when no other characteristic features of OI are present. Other differential diagnoses include rickets, osteomalacia, and other rare skeletal syndromes.

## Psychosocial issues

* Family attitudes depend on previous experience with OI
* Surprise, shock, anger, guilt, depression, and mourning common in parents with new diagnosis
** Families with a previous child may have already developed coping strategies and acceptance
** May be overprotective and overindulgent with affected children
** Frustration with medical personnel who don't handle child carefully
** Anxiety, frustration if unexplained fractures and child abuse suspected
* Affected individuals
** Frustration with inaccessibility of school, work, social environments
** Concerns about physical appearance, sexual development, and peer acceptance
** Feelings of isolation, discrimination, frustration

## Resources

* Osteogenesis Imperfecta Foundation
    804 West Diamond Avenue, Suite 210
    Gaithersburg, MD 20878
    (800) 947-0456
    Email: bonelink@oif.org
    Internet: www.oif.org

## Facts for me

* Approximately 19 collagen types
* Type I is most abundant and major constituent of most connective tissues, bone, tendon, skin, dentin, ligament, fascia, and many blood vessels
* Composed of 3 alpha chains to form triple helix

## References

* Glauser HC, ed. Living with Osteogenesis Imperfecta: A Guidebook for Families (1994) Osteogenesis Imperfecta Foundation.
* Osteogenesis Imperfecta Foundation website (2002). www.oif.org
* Taybi H, and Lachman RS. Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias (1990): Year Book Medical Publishers, Inc.
* Management of Genetic Syndromes. Suzanne B. Cassidy and Judith E. Allanson ed. Chaper 17 Osteogenesis Imperfecta. 2001.

## Notes

The information in this outline was last updated in 2008.