Osteogenesis Imperfecta: The Brittle Bone Syndrome

R. Smith

Introduction

Osteogenesis imperfecta (fragilitas ossium), otherwise known as the Brittle Bone Syndrome, comprises a group of disorders with the common clinical features of bony fragility and the common biochemical cause of mutations in the genes for the major fibrillar collagen, Type I. The transformation of this disorder from an orthopaedic curiosity to a metabolic bone disease has occurred within the last 20 years and is the result of parallel clinical and biochemical advance. Recent reviews deal with this change? 5 This account aims to bring the orthopaedic reader up to date, to outline current problems and to look to the future. It will be necessary to deal with some biochemistry and genetics on the way.

Classification

Osteogenesis imperfecta (OI) occurs in about 1 : 20 000 births, having the approximate frequency of haemo- philia; since a significant number of patients are not diagnosed either because they are mild, or out of ignorance, the true incidence is probably more than this. Previously OI was classified according to the time of onset of the first fracture into OI congenita (fractures at birth) and OI tarda (fractures subse- quently). This has now been superseded by a classi- fication which takes into account genetics and extra- skeletal features, in addition to those of the skeleton (Tables 1 and 2). It turns out that the biochemical features of Type I OI are also distinct from those in the other types. Despite this widely recognised improvement in the identification of different types of

Roger Smith MD PhD FRCP, Nuffield Department of Orthopaedic Surgery, Nuttield Orthopaedic Centre NHS Trust, Headington, Oxford OX3 7LD, UK.

OI a significant number of subjects with OI cannot be put into any of the four groups. Very rarely OI is described in which the inheritance is recessive, and in some collagen gene mutations are excluded; so far most are from South Africa.

Collagen

It is impossible to understand OI without at least a rudimentary knowledge of collagen. 2 Collagen is the major protein in the body and is extracellular. More than half of the body's collagen is within the skeleton and much of the rest in the skin. There is a large family of collagens, all with their own different genes, structure and tissue distribution, and all with re- petitive lengths of Gly X Y (glycine, X often proline, Y often hydroxyproline) wound in a triple helix.

The major fibrillar collagen, and the one whose mutations cause OI, is Type I, a triple helical heteropolymer whose molecules cross link to form fibrils and fibres of considerable length.

For the present purpose there are some important points of which the reader should be aware:

a. Type I collagen is composed of two different chains (e 1 and ~ 2), and. each triple helix consists of two

1 and one c~ 2 chains. b. The sequence of each of these chains involves a

glycine residue in every third position. Glycine has no side chain and fits into the core of the triple helix.

c. The mutations which lead to OI occur in the genes controlling the synthesis of the ~ 1 and ~ 2 chains, COL1A1 on chromosome 17 and COL1A2 on chromosome 7 respectively.

d. The main biochemical abnormalities in OI are either a non-functional allele for the a 1 chain of Type I collagen with the result that the amount of

Current Orthopaedics (1995) 9, 28-33 © Pearson Professional Ltd 1995 28

OSTEOGENESIS IMPERFECTA: THE BRITTLE BONE SYNDROME 29

Table 1--Current classification of osteogenesis imperfecta (for details see ref 1)

OI Type Clinical features Inheritance Main biochemical defects

I Normal stature, little or no AD Decreased production of type deformity, blue sclerae, hearing I procollagen loss in about 50% of individuals, dentinogenesis imperfecta rare

II Lethal in the perinatal period, minimal calvarial mineralisation, beaded ribs, compressed femurs, marked long bone deformity

III Progressively deforming bones, usually with moderate deformity at birth. Sclerae variable in hue, often lighten with age. Dentinogenesis common, hearing loss common. Stature very short

IV Normal sclerae, mild to AD moderate bone deformity and variable short stature, dentinogenesis common, hearing loss in some

AD (new mutation)

Substitutions of glycyl residues in the triple helical domain of alpha I or 2 chain

Some AR As for Type II

As for Type II

Table 2--Extraskeletal features of OI

Blue sclerae (mainly Type I) Dentinogenesis imperfecta Early onset deafness Hypermobility Aortic widening (and incompetence) Tissue fragility Easy bruising

e.

normal collagen is reduced by 50%; or the substitution of glycine in the triple helix by amino acids with side chains which disturb or prevent helix formation. The first produces Type I (mild, dominantly inherited) OI, which is in essence an inherited form of osteoporosis; the second causes lethal OI and also occurs in Type III and IV OI. The phenotypic effect of a glycine substitution depends where it occurs in the alpha chain in relation to the carboxy terminus which is the position where chain alignment and triple helix formation begin; on which chain; and whether or not it is incorporated into the molecule. The effect of a collagen gene mutation is altered by factors in addition to the mutation itself. Particularly important are tissue expression and mosaicism (see below).

Type I OI

This is probably the most frequent form of OI. Typically, affected individuals have increased bony fragility, blue sclerae, and early onset hearing loss. Dentinogenesis imperfecta is rare. Hypermobility, laxity of ligaments and cardiac valve abnormalities demonstrate extraskeletal changes in collagen con- taining tissues. Fractures rarely occur at birth, but bilateral femoral neck fractures can occur when the baby is examined to detect hip dislocation. Fractures of the long bones are most frequent in childhood and may cease in adult life; in contrast vertebral fractures

Fig. 1--The appearance of Wormian bones in an infant with osteogenesis imperfecta; there are numerous small centres of ossification throughout the vault.

(and other fractures) may occur first in the later years around the menopause.

There may be affected members in the family but a significant proportion represent new mutations. The only feature on examination may be the obviously blue sclerae. This may be difficult to be certain of in infancy - where the sclerae are bluer than in adult life - b u t usually there is no difficulty.

Radiographically the skeleton can be normal at birth, but the presence of Wormian bones (Fig. 1) is virtually diagnostic (Wormian bones are also de- scribed in pyknodysostosis and cleidocranial dys- ostosis).

The differential diagnosis depends on age. In early childhood the main problem is to distinguish Type I OI from non-accidental injury (NAI); later from idiopathic juvenile osteoporosis (IJO); and in adult life other causes of early onset osteoporotic fracture.

Features which suggest NAI are the presence of

30 CURRENT ORTHOPAEDICS--MEDICAL REVIEW

several fractures in different places and at apparently different dates. In clinically obvious cases there are signs of neglect and assault and certain fractures such as the posterior ribs, the skull and the metaphyses. Although OI is far less common than NAI it is important to get the diagnosis right. Any type of fracture can occur in OI and the skeletal radiographs may be normal. Failure to establish sufficient cause for the fracture does not distinguish between NAI and OI. In different cases fibroblast culture and investi- gation of collagen synthesis can be helpful)' 7

Features which suggest IJO are onset of long bone or vertebral fractures in pre-adolescence. Typically growth in height slows, walking is difficult due to metaphyseal compression fractures, and kyphosis may develop. Improvement in adolescence can be striking but does not always occur, s

The management of Type I OI is usually not difficult. There is no specific medical treatment to increase bone strength but so far as possible bone mass and strength should be maintained by using the skeleton, by sufficient calcium intake and after the menopause by hormone replacement therapy where appropriate. Fractures should be dealt with appro- priately. Problems may arise more from non-skeletal features, Where it occurs early onset deafness which is mainly conductive (due for instance to fracture of the stapedial crura) can be improved by stapedectomy; replacement of heart valves (as for aortic incom- petence) should not be undertaken lightly, because of the fragility of the tissues. Dentinogenesis imperfecta (more common in Type I I I& IV) may rarely justify extensive restoration.

Type II OI

In this type the mutation causes perinatal death and the skeleton is virtually useless with innumerable fractures. Subdivisions have been described (A, B and C) according to the radiological appearances. In the most frequent form (IIA) the ribs and long bones are broad and grossly abnormal (Fig. 2) and there is defective bone formation in the skull; this may be so marked in utero that the only bone detected radio- logically in the skull is at the base.

Lethal OI is a major cause of short limbed lethal dwarfism; although the diagnosis can be considered clinically at birth (the sclerae are often a deep blue or purple in colour), radiographs of the whole body are essential.

The differential diagnosis is from other causes of lethal short-limbed dwarfism. These include thana- trophic dwarfism, lethal (severe) hypoposphatasia, asphyxiating thoracic dystrophy, campomelic dys- plasia, and various forms of short-rib dwarfism. Since the infants are so severely affected treatment is purely supportive.

The main problem posed by the birth of a Type II OI infant is the likelihood of recurrence. Since the

Fig. 2- -The skeleton in Type II (perinatal lethal) osteogenesis imperfecta. The long bones are short and deformed; there are innumerable fractures in the structureless ribs and there is no visible mineralisation in the skull vault.

great majority are due to new dominant mutations (in which glycine is replaced by a larger amino acid) the likelihood of the parents producing another Type II baby is low. However, this is influenced by the possibility of germline mosaicism) ,1°

Type III Ol

This is the progressive deforming form of OI which requires most attention from orthopaedic surgeons and most specialised rehabilitation. The skeleton is usually (but not always) unusual at birth, and fractures may occur at this time. However, fracture onset may be delayed to later infancy. The sclerae are initially blue but this colour may fade to normal later. Dentinogenesis imperfecta is common. The main orthopaedic problems begin in early childhood and progress rapidly to adolescence. Multiple fractures of the long bones are associated with progressive deformity and severe growth failure. Walking is not

OSTEOGENESIS IMPERFECTA: THE BRITTLE BONE SYNDROME 31

Fig. 3~Severe scoliosis in Type III osteogenesis imperfecta.

Fig. 4~Changes in the bones in a young child with Type III osteogenesis imperfecta. The diaphysis is thin and deformed, and epiphyses and metaphyses show a cystic appearance due to islands of cartilage.

possible and a wheelchair existence is usual. Pro- gressive and severe scoliosis occurs, associated with sternal deformity (Fig. 3). The mortality in Type III OI is significantly increased often due to respiratory

Fig. 5~Demonstrates the position of extensible rods in a child with progressive deforming (Type III) osteogenesis imperfecta,

infection but also resulting from the bony fragility (for instance skull fracture after mild injury).

Radiographic appearances confirm the deformity. The long bones, particularly those of the lower limbs which are not used can take on a bizarre appearance with a very narrow diaphysis and wide expanded metaphyses containing islands of cartilage which give a cystic or popcorn appearance (Fig. 4).

Management of Type III OI can be very difficult. Repeated fracture and deformity can be alleviated by the use of intramedullary rods but it is important to realise their limitations and complications. TM The aim of inserting an intramedullary rod is to correct deformity and to stabilise the bone so that further fractures are less likely and handling of the child less difficult. It is unrealistic to suggest that a badly deformed Type III OI infant can eventually walk with this form of surgery. Available pins or rods may be of fixed length or extensible (Fig. 5); non-extensible rods need to be replaced as the child grows. Internal support of the long bones may be combined with inflatable splints.

Apart from the long bones operations to correct scoliosis are unlikely to be successful, partly because of its severity and partly because of the fragility of the tissues. It is in this type of OI that specialised rehabilitation is most important? ~ The skeleton must

32 CURRENT ORTHOPAEDICS--MEDICAL REVIEW

be used as much as possible and from an early age, and repeated surgery in hospital must not prevent time spent on education. Often the appropriate treatment is provided by electrically driven (and individually constructed) wheelchairs.

Type III OI is most commonly the result of a new dominant mutation, but it is within this group that recessive inheritance can occur, with affected siblings the offspring of consanguineous parents. Accurate genetic advice about recurrence may therefore be difficult, with the likelihood of further affected offspring of up to 25%.

Type IV OI

In any survey of patients with O2 a small number have a bone disease which is intermediate in severity between Type I and Type III, which is dominantly inherited and is associated with normal coloured sclerae. Additional features include conspicuously short stature, multiple fractures and moderate de- formity. Some affected subjects may walk indepen- dently, others require orthoses or wheelchairs. Other associated abnormalities can include hyperplastic callus and severe basilar impression. The cause of hyperplastic callus is unknown, and it is not necess- arily related to fracture. The affected limb becomes swollen, red and painful; infection or sarcoma may be suspected. Radiographs show extensive new bone formation, whose appearance slowly alters.

Severe basilar impression, secondary to alteration in the shape of the skull and particularly sagging of the occipital region, can lead to blockage of CSF drainage and enlargement of the ventricular system which requires surgery.

Type IV OI may present some of the management problems of Type III but they are usually less severe. Since Type IV OI is dominantly inherited the likelihood of an affected infant in the next generation is 50%.

One of the main problems in children with sporadic Type IV OI (i.e. without a family history) is diagnosis, since the absence of blue sclerae removes one of the signs widely thought to be essential to diagnose OI. Distinction from non-accidental injury can then be difficult. The presence of Wormian bones and exam- ination of collagens synthesised by dermal fibroblasts can provide important clues. In most patients with OI Type I the mutation is linked to the 0~ 2 chain of Type I collagen.

Current Problems

Increasing knowledge of OI has not settled all the clinical problems. We have identified the numerous mutations in the collagen genes which appear to be causative. However, there is a large area of ignorance between these mutations (the genotype) and the clinical features (the phenotype)? * Likewise there has been little advance in treatment.

Genotype and Phenotype

The clinical effect of a collagen gene mutation depends on the mutation itself (which alpha chain is affected, the nature of the mutation, the position in the chain, whether the mutation is incorporated in the triple helix) and the degree to which synthesis of normal collagen is reduced. Two other important factors include tissue expression and mosaicism.

It is clear to anyone dealing with OI patients that within the particular Type of OI there is variation in the clinical severity both within the family and between families; and that there is also variation in the extent to which collagen containing tissues are affected. An example of the latter is the observation that dentinogenesis imperfecta does not always occur in the presence of OI, although the collagen in both tissues is Type I and the effects of a mutation should involve dentine and bone equally. This dissociation is an example of the control of gene expression by different tissues. 9" lo

Mosaicism is another cause of phenotypic varia- bility. The importance of this became evident when phenotypically normal men had recurrent Type II lethal offspring by different partners. The recurrence of Type II OI offspring to apparently normal parents used to be explained on the basis of recessive inheritance. However, it is now clear that lethal OI is due to a dominant mutation and one explanation of recurrent Type II OI is that the apparently normal parent is carr~(ing a mutant gene in the germ line. This has now been demonstrated with a proportion of sperm carrying such a mutation. Interestingly there may be a mutation in the somatic cells (hair root bulbs, lymphocytes) without any clinical evidence (or very little) of OI. In those subjects with both germ line and somatic cell mosaicism it is assumed that the mutation occurred very early in development.

Apart from the general importance of mosaicism to genetics it is clear that in certain situations the presence of undetected mosaicism makes accurate genetic counselling difficult.

Treatment and Prevention of OI

Despite the advance in our understanding of OI it is doubtful whether treatment is much improved. Attempts have been made to strengthen the bone and reduce fracture rate with calcitonin, fluoride or bisphosphonates without convincing success. Clearly now that we know the underlying mutations it is possible to prevent OI either in practice (by prenatal diagnosis) or in theory (by gene therapy). It is possible to confirm or exclude OI early in pregnancy using DNA obtained from chorionic villus biopsy either by linkage to a restriction fragment length poly- morphism or direct identification of the causal mutation. In later pregnancy an affected fetus should be detected by ultrasound looking for features such as fracture or deformity or shortening of the limbs or

OSTEOGENESIS IMPERFECTA: THE BRITTLE BONE SYNDROME 33

reduction in mineralisation in the skull of varying severity according to the Type of OI.

Since we now know the causes of OI it is possible to suggest how gene therapy might work. There are two approaches, separately or combined; the first is to stimulate the formation of normal collagen, the second to eliminate the harmful (usually glycine) mutations which disturb helix formation and suppress normal collagen synthesis.

Future

Advances in understanding of OI have biochemical and clinical advantages. Demonstration of the clinical effect of Type I collagen mutations suggested that at least some of the chondrodysplasias could be due to mutations in Type II collagen which is the main protein of cartilage; and such mutations have now been identified in some but not all such dysplasias (such as achondrogenesis and spondyloepiphyseal dysplasia).

Identification of the mutations of OI has proved to be useful where the cause of inexplicable fractures include non-accidental injury; demonstration, for instance, of a mutant collagen chain in an infant with fractures will save much investigation.

Finally, for those interested in osteoporosis, there is the question of how much the heritability of bone density can be explained by abnormalities in the collagen genes. The importance of low bone density derives from its relationship to fracture rate and recently much of its variation has been attributed to allelic changes in the vitamin D receptor gene. :~

Another aspect may be particular collagen gene mutations not sufficiently severe to produce OI.

References

1. Byers P H. Osteogenesis imperfecta. In: Connective tissue and its heritable disorders. Royce P M, Steinmann B (eds) 1st edition. Wiley Liss Inc., 1993

2. Byers P H. Disorders of collagen biosynthesis and structure. In: The metabolic basis of inherited disease. Scriver C R, Beaudet A L, Sly W S, Valle D (eds) 6th edition. McGraw Hill, 1989, 2805-2842

3. Papers presented at the Fourth International Conference on Osteogenesis Imperfecta. Pavia, Italy. 1990. Am J Med Genet 1993; 43:139-283

4. Cole W G. Bone, cartilage and fibrous tissue disorders. In: Children's orthopaedics and fractures. Benson M K D, Fixsen J A, Macnicol M F (eds). Churchill Livingstone, 1994, 35-71

5. Rowe D R, Shapiro J R. Osteogenesis imperfecta. In: Metabolic bone disease. Avioli L V, Krane S M (eds) 2nd edition. W B Saunders, 1990, 659-701

6. Smith R. Osteogenesis imperfecta, non-accidental injury and temporary brittle bone disease. Arch Dis Child 1994 (In press)

7. Carty H M L. Fractures caused by child abuse. J Bone Joint Surg 1993; 75B: 849-857

8. Smith R. Idiopathic juvenile osteoporosis; a review of twenty-one patients. J Paed Rheumatol 1994 (in press)

9. Hall J G. Reviews and hypotheses: Somatic mosaicism: observations related to clinical genetics. Am J Human Genet 1988; 43:355-363

10. Sykes B. Bone disease cracks genetics. Nature 1990; 348: 18-20

11. Cole W G. Early surgical management of severe forms of osteogenesis imperfecta. Am J Med Genet 1993; 45:270-274

12. Binder H, Conway A, Gerber L H. Rehabilitation approaches to children with Osteogenesis Imperfecta: a ten year experience. Arch Phys Med Rehabil 1993; 74:386-390

13. Smith R. Osteogenesis imperfecta. From phenotype to genotype and back again. Int J Exp Pathol 1994 (In press)

14. Morrison N A, Qi J C, Tokita A et al. Prediction of bone density from vitamin D receptor alleles. Nature 1994; 367: 284-287