Osteogenesis Imperfecta

Osteogenesi s Imperfecta (OI)

Introduction Osteogenesis 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

Penetrance and expressivity in type I OI

 OI is mainly an

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

• 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 (‘nonsensemediated 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 nontriple-helical extensions at the amino and carboxyl terminals of proα chains.

Pathogenesis  OI is a disease of type I

Molecular assembly of Type I procollagen in the Endoplasmic Reticulum

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

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.

 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 posttranslational action of prolyl hydroxylase starts. Increased levels of hydroxylation result in a

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

Procollagen chains molecules

Collagen

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.

Types I Osteogenesis Imperfecta

Procollagen chains molecules

Collagen

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.

Types II Osteogenesis Imperfecta

• In type II OI, mutation causes substitution of glycine to bulkier amino acids in Procollagen chains Collagen the collagen triple molecules 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

Types III and Type IV Osteogenesis 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

Types Type

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 Progressi

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

ve deforming

Deformin Structural mutation in the proα2 (I), or, less frequently, proα1(I) chain that has little or no effect g with on heterotrimer assembly; quality of collagen is normal usually abnormal; quantity can be normal scleras 1 Sporadic (autosomal dominant) 2 Autosomal recessive in rare cases.

Type IV

Clinical Symptoms Type I  Collagen is of normal quality but is

produced in insufficient quantities:  Bones fracture easily, loose joints, poor muscle tone  Slight tendency toward spinal curvature  Discolouration of the sclera (whites of the eyes), usually giving them a blue-gray color.  Triangular face  Early loss of hearing in some children  Slight protrusion of the eyes  Most fractures occur before puberty; occasionally women will have fractures after menopause  IA and IB are defined by the

Type II  Collagen is not of a sufficient quality or

quantity  Most cases die within the first year of life due to respiratory failure or intracerebral hemorrhage  Very small stature with under developed lungs and extremely severe respiratory problems  Severe bone deformity and small stature  Type 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

Type III  Collagen quantity is sufficient but is not of a high

enough quality  Bones fracture easily, sometimes even before birth  Bone deformity, often severe  Respiratory problems possible  Short stature, spinal curvature and sometimes barrel-shaped rib cage  Loose joints  Poor muscle tone in arms and legs  Discolouration of the sclera (the 'whites' of the eyes)  Early loss of hearing possible  Type 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.

Type IV  Collagen quantity is sufficient but is not of a high

enough quality  Bones fracture easily, especially before puberty  Short stature, spinal curvature and barrel-shaped rib cage  Bone deformity is mild to moderate  Early loss of hearing  Similar 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

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).

Diagnosis 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-ray  Examination of the ear, nose, and throat (to detect

hearing loss)  Bone mineral density, as measured with dual-energy xray absorptiometry (DEXA)  Prenatal ultrasonography  Biochemical (collagen) or molecular (DNA) tests

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  Differentiating between OI and child abuse. Mild OI is most mineralization of likely to be confused with child abuse. The sclera and teeth are normal in calvaria (also calvarial compressibility), many patients with OI. A family history is often not present. bowing of the  Some key differentiations no other long bones, decreased (if bone lengthstigmata of OI are present):  Considerof the types of fractures. Although any type of long bone (especially fracture canand occur in OI, certain types are rare. Metaphyseal corner the femur), multiple rib fractures. 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.

Treatment  At present there is no cure for OI.

Bisphosphonates  e.g. alendronate (Fosamax),

pamidronate (Aredia), zoledronic acid (Reclast)).

Calcitonin (CT) Increased vitamin D

intake Growth hormone (GH) Physiotherapy Physical aids Potential for gene

Treatment  At present there is no cure for OI.

Bisphosphonates  e.g. alendronate (Fosamax),

pamidronate (Aredia), zoledronic acid (Reclast)).

Pamidronate last about three hours therapy and is repeated every 3 to Calcitonin (CT) 6 months, and lasts for the life of Increased vitamin D the patient. Common side effects intake include bone pain, low calcium levels, nausea, and dizziness. Growth hormone (GH) According to recent results, extended periods of pamidronate, Physiotherapy (i.e.; 6 years) can actually weaken Physical bones, so patientsaids are recommended to get bone Potential for gene

Surgery  Surgery is done only when

there are:  fractures  bowing of bone  scoliosis  heart problems  Surgery 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 may also be considered to maintain the ability to sit or stand.

Potential for cell and gene therapy

Potenti al for stem cell therap y

Prevention  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,