Osteogenisis Imperfecta

Presentation by:

Christopher Lim

Central Problem of the Case

Foreground: Excruciating right arm pain in a 5 y/o male status post “fell off the couch” as reported by parents of the child.

Central Problem of Case cont.

Background: Sequelae of fractures shortly after bipedal mobility (from crawling to walking stance). Biological father has also has a history of several broken bones as a child and has recently begun to develop bilateral hearing loss. Patient is 75th percentile for weight and height for his age and has a slight bluish gray tint to the sclera.

Patient Exam ResultsGeneral - WD/WN, 75th percentile for weight and height for his age. Distraught and crying, but appropriately seeking out parents for comfort.

Head - NC/AT

Eyes - PERRLA, slight bluish gray tint to sclera

Mouth - normal dentition

Patient Exam Results cont.Neuro - CNS intact, cerebellar function intact, sensory is intact UE

& LE B/L; DTR are intact (2/4) aside from the right arm reflexes, which were not checked due to the patient’s pain level; motor strength is intact except the right arm, which was again not tested.

Musculoskeletal - reveals his right arm is swollen and his is markedly tender over the right radial head.

Skin - reveals a few bruises in multiple stages on his legs and arms

Differential Diagnosis

Likely Possible, High Stakes (severe)

• Right forearm fracture

• Type I Osteogenesis Imperfecta

Likely Possible, Low Stakes (mild)• Bone fracture, Soft Tissue Injury

• Child Abuse

• Osteomalacia

Differential Diagnosis cont.

Unlikely Possible, High Stakes (severe)

• Type II (OI), stress fracture

Unlikely Possible, Low Stakes (mild)• Ehlers-Danlos Syndrome (collagen effects)

Working Diagnosis

• Bone Fracture: Proximal Radial Head

• Type I Osteogenesis Imperfecta

Physical Manifestation of (OI) and Types

Blue-grey sclera (I) Short stature,small body (I-VIII)

Hearing loss (20-30s) (I-IV)

Brittle teeth (I-VIII)Triangular face (I-VIII)Barrel-shaped rib cage (III)

Curved spine (III-IV)(8)

Acute Fracture observed in OIFrontal radiograph of the leg in a patient with osteogenesis imperfecta (OI)

Hypertrophic callus formation six weeks after femoral shaft fracture at age 9 month A). A radiograph taken 1.5 yr later shows remodeling of the callus

(B).multiple white bands [zebra stripes] parallel to the physis

(11)

Type I Osteogenesis Imperfecta, Acute fracture observed in the radius and ulna. Old healing humeral fracture with callus formation is observed.

Working Diagnosis: (most likely to least likely) 8 Types of Osteogenesis Imperfecta3

Type I - Mild forms, normal quality of collagen but insufficient quantities, Bones fracture easily, blue-gray discoloration of sclera, hearing loss

Type III - considered progressive and deforming

Type IV - deforming, but with normal sclerae

Type V - shares the same clinical features of IV, but has unique histologic findings ("mesh-like")

Working Diagnosis: Types (least likely)

Type VI - shares the same clinical features of IV, but has unique histologic findings ("fish scale bone appearance")

Type VII - related to cartilage associated protein

Type VIII - severe to lethal, associated with the protein leprecan

Type II - severe and usually lethal in the perinatal period (around the time of birth), Severe bone deformity and small stature

Tests to rule out diagnosis• X-Ray of the upper R. extremity (Anterior Posterior/ Lateral),

including Proximal Radius

• Test for blood levels of Vit D, Calcium, and Phosphate

• DNA Test: COL1A1 and COL1A2 specificity for Type I-IV

Osteogenisis Imperfecta (9)

• Collagen Biochemical Test (9,10)

• DNA Test: Gene Specific LEPRE1 to r/o Type VIII (if COL1A1 and

COL1A2 test normal--unlikely) (9)

• EKG, CBC

• CT or MRI (to rule out stress fracture)

Treatment OptionsDiscuss with and obtain agreement (Parental Consent) the following possible plans of treatment:

Treatment of Soft Tissue Injury: (RICE) Rest, Ice, Compression Elevation5

Treatment of Stress Fracture: nonweight-bearing rest of the extremity. Bracing or casting the limb with a hard plastic, air cast or arm splint may also prove beneficial by taking some stress off the stress fracture.

Treatment cont.Treatment of Bone Fracture: Restore fractured pieces of bone to natural positions by aligning bone (reduction). Immobilize with cast or splint. When swelling reduced, fracture may be placed in a removable brace or orthosis.

Pain management: In arm fractures in children, ibuprofen has been found to be equally effective as the combination of acetaminophen and codeine.4

Based on treatment option - follow up with physician in 2 wks to ensure bone has set and for additional complaints

Pathophysiology• People with OI are born with defective connective tissue, or

without the ability to make it, usually because of a deficiency of Type-I collagen.1

• This deficiency arises from an amino acid substitution of glycine to bulkier amino acids in the collagen triple helix structure which compromises interactions with other molecules. The body responds by hydrolyzing the improper collagen structure,however, if this doesnt happen then improper association between collagen fibers and hydroxyapettite crystals ensues resulting in brittle bones. Another theory explains the stress state of collagen fibrils at mutation sites are altered leading to structural failure. These recent findings suggest that the disease is a multi level phenomenon occuring at the genetic, macro, micro and nano levels.

Pathophysiology cont.

• As a genetic disorder, OI has historically been viewed as an autosomal dominant disorder, however, recently autosomal recessive forms have been identified.

• Most cases have been caused by mutations in the COL1A1 and COL1A2 genes. Most people with OI receive it from a parent but in 35% of cases it is an individual (de novo or "sporadic") mutation.

Epidemiology: Bone Fracture

• Bone Fractures are the most common orthopedic injury with over 7 million incidents per year in the United States.

• The average person can expect to sustain 2 fractures over the course of their lifetime.

• 10% of all Bone Fractures incidents are elbow related

• 8% of elbow fractures occur at the proximal end of the Radius in children.

Prognosis: Bone Fracture

• Type I and II are less severe and may heal well without surgical intervention. o (Type I: No displacement & minimal joint involvement, Type II: bone

fragments 2mm displaced)

• Type II and Type III proximal radius fractures, good results obtained with ORIF (Open Reduction Internal Fixation) in over 90% of individuals. o (Type III: Head of Radius broken into many separate fragments)

• Type III fractures receiving radial head arthroplasty, good results are achieved in over 70% of individuals.

Regardless of treatment approach, early mobilization of the elbow is critical.

Epidemiology: Osteogenesis Imperfecta • Osteogenisis Imperfecta is also known as “Brittle Bone

Disease”, “Lobstein Syndrome” or “glass bone disease”

• In the United States, the incidence of osteogenesis imperfecta is estimated to be one per 20,000 live births.2

• Prevalence: An estimated 20,000 to 50,000 people are affected by the disease in the United States.

• Type I is the most Common, mildest form

Prognosis: Osteogenesis Imperfecta

• The lifespan of people with OI types I, III and IV are generally similar to the average lifespan of a healthy individual.

• Type II is more lethal:50% of all babies are stillborn, the other half die within a short time after birth

• Despite severity of the diagnosis and probable disability, individual quality of life is still achievable.

• Many actors, Olympic medalists, journalists, and musicians have been living with this disease and it has not prevented them from achieving personal success.

Notable Persons with Osteogenesis Imperfecta

Actor: Michael J. Anderson (Twin Peaks, HBO film Carnivale, Mullholand Dr) (Type III)

Tarah Lynne Schaeffer actress (Sesame Street)(Type I)

Randy Guss, drummer for “Toad the Wet Sprocket”(Type I)

Patient Education & Counseling

• There is no cure for Osteogenesis Imperfecta

• Treatment is aimed at increasing overall bone strength to prevent fracture and maintain mobility.

• Bisphosphonates can increase bone mass, and reduce bone pain and fracture.

• In severe cases, bones are surgically corrected, and rods are placed inside the bones, particularly to enable infants to learn to walk.

• Promising Clinical Trials

Promising Clinical Trials (current 12 year study) Research sponsored by Eunice Kennedy Shriver of Child Health and Human Development:

• Drug in Phase 3 Clinical trials: GRH Nutropin Study from Nov 1991-Feb 2014 completion date

• current study on children beginning at age 5 with 50% showing growth rate increase.

Prior Clinical Trials (1yr study) Journal of Pediatrics 1996 Sep;129(3):432-9.

Growth hormone treatment in osteogenesis imperfecta with quantitative defect of type I collagen

synthesis. AbstractOBJECTIVES:

We studied growth rate, bone density, and bone metabolism in patients affected by type I osteogenesis imperfecta (OI) with quantitative defect in type I collagen synthesis during treatment with human growth hormone (hGH), being aware of its collagen-stimulating synthesis activity in vitro.

STUDY DESIGN:

Fourteen patients (6 boys; ages 4.8 to 10.8 years) were studied

RESULTS:

After 12 months, linear growth velocity in treated patients increased significantly in comparison with the pretreatment period (from 3.57 +/- 0.55 to 6.04 +/- 0.69 cm/yr; p < 0.05) and with the untreated group (p < 0.05)

Results Clinical Trials (1 yr study)

CONCLUSIONS:

From our results, we conclude that hGH treatment in moderate OI does

not increase the fracture risk in treated patients in the short term,

significantly increases the rate of linear growth velocity, and increases

bone turnover and mineral content in trabecular bone at the lumber

spine. (13)

Patient Education & Counseling• If immobilization of arm is required, offer an

alternative to a Plaster Cast, such as a Arm Splint.

• In children with minimally angulated fractures, a splint may be as effective with less irritation, more comfort and ease of cleaning the area.

Patient Education & Counseling

• Offer some words of encouragement to the young child if he does have this debilitating bone disease.

• for example: “Many actors, Olympic medalists, journalists, and musicians have this brittle bone disease and it has not prevented them from achieving personal success.”

Referrals

• In the case of Osteogenesis Imperfecta a referral to a Physical Therapist would be beneficial.

• Physical Therapy is used to strengthen muscles and improve motility in a gentle manner, while minimizing the risk of fracture.

• Geneticist

• Child Psychologist

Rationale

Susceptibility to fracture, blue-grey discoloration of sclera, hearing loss in biological father, all point to the diagnosis of Type I Osteogenisis Imperfecta. r/o Type II which is severe and usually lethal at time of birth, survivors showing gross bone deformities. Type VIII can be determined by the results of Genetic test specific for protein leprecan.

Treatment for Proximal Radial Bone Fracture or Elbow Stress Fracture (If required), in accordance with standard practice so as to provide reduction and adequate healing of bone fragments. Patient was informed of alternative palliative treatment including Arm Splint, Bisphosphates, surgical correction and Physical Therapy to strengthen bones.7

References1. Rauch F. Glourieux FH (2004) “Osteogenesis imperfect”. Lancet 363 (9418): 1377-1387.

2. Osteogenesis Imperfecta Author: Horacio Plotkin. Updated: March 2, 2010

3. Steiner, RD; Pepin, MG, Byers, PH, Pagon, RA, Bird, TD, Dolan, CR, Stephens, K, Adam, MP (January 28, 2005).

Osteogenesis Imperfecta. PMID 2030147

4. Drendel AL, Gorelick MH, Weisman SJ, Lyon R, Brousseau DC, Kim MK (October 2009). "A randomized clinical trial

of ibuprofen versus acetaminophen with codeine for acute pediatric arm fracture pain". Ann Emerg Med 54 (4):

553–60.

5. "Sports Medicine Advisor 2005.4: RICE: Rest, Ice, Compression, and Elevation for Injuries".

6. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R (1998). "Cyclic administration of pamidronate in

children with severe osteogenesis imperfecta". N. Engl.

7. Steiner RD, MD, Donald Basel MD, Pepin, MG, Byeres PH, Pargon RA, Stephens K.

Adam MP (January 28, 2005). Osteogenisis Imperfecta PMID 20301472

8. www.niams.nih.gov/Health_Info/Bone/Osteogenesis_Imperfecta

9. http://www.pathology.washington.edu/clinical/collagen/index.php/disorders/osteogenesis-imper/

10. http://www.oif.org/site/PageServer?pagename=Testing

11. Lee DY, Cho Tea-Joon, Cho IH, Chung CY, Yoo JY, Kim HJ, Park YK (Augues 2006). “Clinical Manifestations of Osteogenesis Imperfecta.” J Korena Med. Sci doi: 10.3346/jkms.2006.21.4.709

12. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729895/

13. J Pediatr. 1996 Sep;129(3):432-9.

Thank-you for Attendance & Support

Osteogenisis Imperfecta

Presentation by:

Christopher Lim