Osteogenesis Osteogenesis Imperfecta (OI)Imperfecta (OI)

IntroductionOsteogenesis imperfecta (OI) , also known as Brittle

Bone Disease, "Lobstein syndrome” or Fragilitas ossium.

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.

Occurs in 1:20,000 to 1:60,000 live births. OI can affect males and females of all races.

Etiology OI is mainly an autosomal dominant defect. It can also be an individual (de novo or "sporadic") mutation.

Penetrance and expressivity in type I OIPenetrance and expressivity in type I OI

• Phenotypically normal father (arrow) has had two children by different mates, each of whom is affected with autosomal dominant type II osteogenesis imperfecta (OI). Analysis of the father showed that some of his spermatozoa carried a COL1A1 mutation, indicating that the explanation for this unusual pedigree is germline/gonadal mosaicism.

Researches show that that a mutation of the COL1A1 or COL1A2 genes, which encode the subunits of type I collagen, proα 1(I) and proα 2(I), respectively causes OI.

In type I OI, mutations in COL1A1 allele gives rise to greatly reduced or no function of mRNA. In most cases, nonsense mutation occur. Partially synthesized mRNA precursors that carry the nonsense codon are recognized and degraded by the cell (‘nonsense-mediated decay’). It acts as a protective phenomenon but reduces synthesis of type I collagen.

Type II OI is usually caused by missense mutations of a glycine residue that allow the mutant peptide chain to bind to normal one.

Collagen mutations that cause type III and type IV OI are diverse and include glycine substitutions of the collagen triple helix, a few internal deletions of COL1A1 and COL1A2 that do not significantly disturb triple helix formation, and some unusual alterations in the non-triple-helical extensions at the amino and carboxyl terminals of proα chains.

Pathogenesis OI is a disease of type I

collagen. It is the major collagen in the dermis, the connective tissue capsules of most organs, and the vascular and GI adventitia and is the only collagen in bone.

Each mature type I collagen molecule contains two α1 chains and one α2 chain, encoded by the COL1A1 and COL1A2 genes, respectively. The COL1A1 and COL1A2 genes have 51 and 52 exons, respectively, of which exons 6-49 encode the entire triple-helical domain.

Three proα chains that associate with each other beginning at their carboxyl terminals. An important requirement for proper assembly of the triple helix is the presence of a glycine residue at every third position in each of the proα chains.

Molecular assembly of Type I procollagen in the Endoplasmic Reticulum

The α 1 and α 2 chains are synthesized as larger precursors with amino and carboxyl terminal ‘propeptide’ extensions, assemble with each other inside the cell. Then, they are secreted as a heterotrimer type I procollagen molecule.

During intracellular assembly, the 3 chains wind around each other in a triple helix that is stabilized by interchain interactions between hydroxy proline and adjacent carbonyl residues. Assembly of the triple helix, which begins at the carboxyl terminal end of the molecule and post-translational action of prolyl hydroxylase starts. Increased levels of hydroxylation result in a more stable helix, but helix formation prevents further prolyl hydroxylation.

Molecular assembly of Type I procollagen in the Endoplasmic Reticulum

After secretion, the amino and carboxyl terminal propeptides are proteolytically cleaved, leaving a rigid triple helical collagen molecule with very short non-triple-helical domains at both ends.

Normal Production

The COL1A1 gene normally produces twice as many proα chains as the COL1A2 gene. Therefore, in nonmutant cells, the ratio of proα 1 to proα 2 chains is 2:1, which corresponds to the ratio of α1 and α2 chains in intact collagen molecules.

Procollagen chains Collagen molecules

Types I Osteogenesis Imperfecta

In type I OI, a mutation in one of the COL1A1 alleles results in failure to produce proα 1 chains, leading to a 50% reduction in the total number of proα1 chains, a 50% reduction in the production of intact type I collagen molecules, and an excess of unassembled proα 2 chains, which are degraded inside the cell.

Procollagen chains Collagen molecules

Types II Osteogenesis Imperfecta

• In type II OI, mutation causes substitution of glycine to bulkier amino acids in the collagen triple helix structure. The larger amino acid side-chains creates a "bulge" the collagen complex and secretion of partially assembled collagen molecules (heterotrimers) containing the mutant chain. • If the body does not destroy the improper collagen, the relationship between the collagen fibrils and hydroxyapatite crystals to form bone is altered, causing brittleness.• Type II OI is more severe than type I . 75% reduction of production of intact type I collagen molecules occurred.

Procollagen chains Collagen molecules

Types III and Type IVOsteogenesis Imperfecta

Collagen mutations that cause type III and type IV OI are diverse and include glycine substitutions in the amino terminal portion of the collagen triple helix, a few internal deletions of COL1A1 and COL1A2 that do not significantly disturb triple helix formation, and some unusual alterations in the non-triple-helical extensions at the amino and carboxyl terminals of proα chains.

Type III OI tend to be isolated family incidents Type IV OI can frequently be traced through the family

TypesType Phenotype Molecular Pathology

Type I Mild Loss-of-function mutation in proα (I) chain resulting in decreased amount of mRNA; quality of collagen is normal; quantity is reduced two fold

Type II 1 Perinatal lethal

Structural mutation in proα1(I) or proα2 (I) chain that has mild effect on heterotrimer assembly; quality of collagen is severely abnormal; quantity often reduced also

Type III 2 Progressive deforming

Structural mutation in proα1 (I) or proα2 (I) chain that has mild effect on heterotrimer assembly; quality of collagen is severely abnormal; quantity can be normal

Type IV Deforming with normal scleras

Structural mutation in the proα2 (I), or, less frequently, proα1(I) chain that has little or no effect on heterotrimer assembly; quality of collagen is usually abnormal; quantity can be normal

1 Sporadic (autosomal dominant) 2 Autosomal recessive in rare cases.

Clinical SymptomsType I

Collagen is of normal quality but is produced in insufficient quantities:

Bones fracture easily, loose joints, poor muscle toneSlight tendency toward spinal curvatureDiscolouration of the sclera (whites of the eyes),

usually giving them a blue-gray color. Triangular faceEarly loss of hearing in some childrenSlight protrusion of the eyesMost fractures occur before puberty; occasionally

women will have fractures after menopause IA and IB are defined by the absence/presence of

dentinogenesis imperfecta (characterized by opalescent teeth; absent in IA, present in IB).

Type II

Collagen is not of a sufficient quality or quantityMost cases die within the first year of life due to

respiratory failure or intracerebral hemorrhageVery small stature with under developed lungs and

extremely severe respiratory problems Severe bone deformity and small statureType II can be further subclassified into groups A, B, C,

which are distinguished by radiographic evaluation of the long bones and ribs.Type IIA demonstrates broad and short long bones with broad and beaded ribs. Type IIB demonstrates broad and short long bones with thin ribs that have little or no beading. Type IIC demonstrates thin and longer long bones with thin and beaded ribs.

Type III

Collagen quantity is sufficient but is not of a high enough quality

Bones fracture easily, sometimes even before birthBone deformity, often severeRespiratory problems possibleShort stature, spinal curvature and sometimes barrel-shaped

rib cageLoose jointsPoor muscle tone in arms and legsDiscolouration of the sclera (the 'whites' of the eyes)Early loss of hearing possibleType III is distinguished among the other classifications as

being the "Progressive Deforming" type, wherein a neonate presents with mild symptoms at birth and develops the aforementioned symptoms throughout life. Lifespan may be normal, albeit with severe physical handicapping.

Type IV

Collagen quantity is sufficient but is not of a high enough qualityBones fracture easily, especially before pubertyShort stature, spinal curvature and barrel-shaped rib cageBone deformity is mild to moderateEarly loss of hearingSimilar to Type I, Type IV can be further subclassified into types IVA

and IVB characterized by absence (IVA) or presence (IVB) of dentinogenesis imperfecta.

Under the microscope, investigators noticed that some people who are clinically within the Type IV group had a distinct pattern to their bone. When they reviewed the full medical history of these people, they found that groups had other features in common. They named these groups Types V and VI OI. The mutations causing these forms of OI have not been identified, but people in these two groups do not have mutations in the type I collagen genes.

Type V

Same clinical features as Type IV. Distinguished histologically by "mesh-like" bone appearance. Further characterized by the "V Triad" consisting of: a) radio-opaque band adjacent to growth plates, b) hypertrophic calluses at fracture sites, and c) calcification of the radio-ulnar interosseous membrane.

OI Type V leads to calcification of the membrane between the two forearm bones, making it difficult to turn the wrist. Another symptom is abnormally large amounts of repair tissue (hyperplasic callus) at the site of fractures. At the present time, the cause for Type V is unknown, though doctors have determined that it is inherited.

Type VI

Clinically similar to Type IV in appearance and symptoms of OI.Bone has a distinctive “fish-scale” appearance when viewed under the

microscope.The alkaline phosphatase (an enzyme linked to bone formation)

activity level is slightly elevated in OI Type VI. This can be determined by a blood test.

Diagnosed by bone biopsy.Whether this form is inherited in a dominant or recessive manner is

unknown, but researchers believe the mode of inheritance is most likely recessive.

Eight people with this type of OI have been identified.

Recessive Forms of OI Two forms of OI that are inherited in a recessive manner were discovered in 2006. Both types

are caused by genes that affect collagen formation. These forms provide information for people who have severe or moderately severe OI but who do not have a primary collagen mutation.

Type VII

The first described cases resemble Type IV OI in many aspects of appearance and symptoms.

In other instances the appearance and symptoms are similar to Type II lethal OI, except infants had white sclera, a small head and a round face.

Short stature.Short humerus (arm bone) and short femur (upper leg bone) Coxa vera is common (the acutely angled femur head affects the hip

socket).Results from recessive inheritance of a mutation to the CRTAP (cartilage-

associated protein) gene. Partial function of CRTAP leads to moderate symptoms while total absence of CRTAP was lethal in all 4 identified cases.

Type VIII

Resembles lethal Type II or Type III OI in appearance and symptoms except that infants have white sclera.

Severe growth deficiency.Extreme skeletal under mineralization.Caused by a deficiency of P3H1 (Prolyl 3-hydroxylase 1) due to a

mutation to the LEPRE1 gene (protein leprecan).

In addition to a complete medical history and physical examination, diagnostic procedures for OI may include a skin biopsy to evaluate the amount and structure of collagen or molecular (DNA) tests. However, this test is complicated and not many qualified facilities are available to perform the procedure. It is not unusual for results of the biopsy to take up to six months.

Additional diagnostic tests may include: X-rayExamination of the ear, nose, and throat (to detect hearing loss)Bone mineral density, as measured with dual-energy x-ray

absorptiometry (DEXA) Prenatal ultrasonographyBiochemical (collagen) or molecular (DNA) tests

Diagnosis

Imaging Studies

Obtain a radiographic skeletal survey after birth. In mild (type I) OI:

thinning of the long bones with thin cortices. Several wormian bones may be present. No deformity of long bones is observed.

In extremely severe (type II) OI: beaded ribs, broad bones, and numerous fractures with deformities of the long bones. Platyspondylia may also be revealed.

Moderate and severe (types III and IV) OI: cystic metaphyses, or a popcorn appearance of the growth cartilage. Normal or broad bones are revealed early, with thin bones revealed later. Fractures may cause deformities of the long bones. Old rib fractures may be present. Vertebral fractures are common.

• Prenatal ultrasonography to detect limb-length abnormalities at 15-18 weeks' gestation.

• Mild forms may result in normal sonogram findings.• Features include supervisualization of intracranial contents caused by decreased mineralization of calvaria (also calvarial compressibility), bowing of the long bones, decreased bone length (especially of the femur), and multiple rib fractures.

Differentiating between OI and child abuse. Mild OI is most likely to be confused with child abuse. The sclera and teeth are normal in many patients with OI. A family history is often not present.

Some key differentiations (if no other stigmata of OI are present): Consider the types of fractures. Although any type of long bone fracture can occur in OI, certain

types are rare. Metaphyseal corner fractures (common in child abuse) are rare in OI. In children with OI, fractures may continue to occur while they are in protective custody;

however, this scenario is hard to evaluate. Child abuse can also be differentiated from OI on the basis of nonskeletal manifestations, such

as retinal hemorrhage, visceral intramural hematomas, intracranial bleeds of various ages, pancreatitis, and splenic trauma.

Collagen analysis is useful in difficult cases, but a negative result does not rule out OI. OI and child abuse can coexist.

Treatment At present there is no cure for OI.

Bisphosphonates e.g. alendronate (Fosamax), pamidronate

(Aredia), zoledronic acid (Reclast)).

Calcitonin (CT)Increased vitamin D intakeGrowth hormone (GH)PhysiotherapyPhysical aidsPotential for gene therapy

At present there is no cure for OI.

Bisphosphonates e.g. alendronate (Fosamax), pamidronate

(Aredia), zoledronic acid (Reclast)).

Calcitonin (CT)Increased vitamin D intakeGrowth hormone (GH)PhysiotherapyPhysical aidsPotential for gene therapy

Pamidronate last about three hours and therapy is repeated every 3 to 6 months, and lasts for the life of the patient. Common side effects include bone pain, low calcium levels, nausea, and dizziness. According to recent results, extended periods of pamidronate, (i.e.; 6 years) can actually weaken bones, so patients are recommended to get bone densities every 6 months-1 year, to monitor bone strength.

Treatment

Pamidronate last about three hours and therapy is repeated every 3 to 6 months, and lasts for the life of the patient. Common side effects include bone pain, low calcium levels, nausea, and dizziness. According to recent results, extended periods of pamidronate, (i.e.; 6 years) can actually weaken bones, so patients are recommended to get bone densities every 6 months-1 year, to monitor bone strength.

Surgery

Surgery is done only when there are: fracturesbowing of bone scoliosis heart problemsSurgery may also be

considered to maintain the ability to sit or stand.

Metal rods can be surgically inserted in the long bones to improve strength. “Rodding Surgery” was adopted throughout the world and still forms the basis for orthopedic treatment of OI.

Surgery

X-ray after “Rodding Surgery”

Surgery may also be considered to maintain the ability to sit or stand.

Potential for cell and gene therapy

Potential for stem cell therapy

For both type I and type IV OI, the most important question in the clinical setting often relates to the natural history of the illness.

Reproductive decision making in families at risk for OI – consider the life of the child.

A definitive diagnosis may be made using a skin punch biopsy. Family members may be given a DNA blood test.

If there is a family history of OI, chorionic villus sampling may be done during pregnancy to determine if the baby has the condition. However, because so many different mutations can cause OI, some forms cannot be diagnosed with a genetic test.

On ultrasound from a 16-weeks-fetus, severe form of type II OI can be seen After-birth precautions:

Consultations Lifestyles changes: Avoid smoking and steroid or osteoporosis-causing

medications, Diet, Exercise, Supplements

Prevention