This article is written for both the public and professionals interested in learning more about Osteogenesis Imperfecta. It was first published in our 2014 autumn journal.
Osteogenesis Imperfecta (OI) is a group of inherited conditions characterised by fragile bones and fractures that arise spontaneously or after minimal trauma. It is also associated with weak teeth due to poor dentine, blue sclerae (a bluish tint to the whites of the eyes), kyphosis (forward curvature) and scoliosis (sideways curvature) of the spine, easy bruising and bleeding, hypermobility, weak muscles, and progressive hearing loss. Bone deformities may lead to chronic pain.
A person is born with this disorder and is affected throughout their life. Males, females and all racial groups are affected equally. Over all OI is rare, being found in about 6 per 100,000 people; which means there are likely 3,000-4,000 people in the UK with the condition. The term ‘brittle bone disease’ is often used to describe OI. The reader should be aware that the same term is used when writing about the condition osteoporosis. Both conditions are associated with fractures but osteoporosis is a very different disorder that is very common, and is not an HDCT. Readers who enjoy film may recall ‘Unbreakable’ starring Samuel L. Jackson as Elijah Price (nicknamed Mr Glass), or the character Raymond Dufayel in the French film Amelie; both characters had OI. For a very real insight in to living with and coping with the condition, many hundreds of thousands of people have watched the inspirational YouTube presentations by Robbie (a.k.a ‘Kid President’).
Classification of OI, clinical findings, and genetics
If you research the most up to date genetics literature you find that currently there are 15 genetically identifiable subtypes of OI. A number are rare autosomal recessive genetic disorders. The most up to date textbooks and reviews however describe the 8 main types of OI that range from the mild with slight increased risk of fractures, normal height, body shape, and lifespan, to severe bone deformities and major mobility problems. There are also rare types that are lethal to the unborn or newly born child, or may lead to premature death in adulthood.
More than 90% of individuals with OI have either the subgroup type I or type IV of the condition. These are the milder variants and are associated with abnormalities of the Collagen 1 (COL1) gene. Two thirds of these individuals will come from families with the condition; the gene abnormality has ‘autosomal dominant’ inheritance meaning there is a 50:50 chance of each affected parent passing on the faulty gene to each of their offspring. In about 1/3rd of individuals the gene defect arises spontaneously for the first time i.e. there is no family history.
Table 1 shows the most common and the least severe of the subtypes, type 1 and IV. Table 2 shows a less common but more severe group that are like type IV but with specific findings and different gene abnormalities. Life expectancy is not usually affected in these groups, though many functional problems may arise. Table 3 shows the very severe types that lead to death very early in infancy / childhood, and type III which can lead to problems with breathing. Breathing problems arise due a compression of the chest from curvature of the spine. This is the most common cause of death in people with OI, followed by accidental trauma.
Table 1. Between type I and type IV the clinical features can range from being so mild as to be barely noticeable to multiple fractures, bone deformities and disability.
Type I:– This group account for 60% of all cases. Fractures can occur at any time from early childhood onward but very rarely lead to deformities of bone shape.
– The teeth can crack easily leading to rapid dental decay in both the ‘milk’ teeth and adult teeth.
– The sclera (the ‘white of the eye’) appears blue because it is thin allowing the pigmented coat of the structures underneath to become visible though it.
– Joints are often hypermobile, with flat feet, and dislocations.
– Hearing can be affected.
– As with variants of Ehlers-Danlos syndrome and Marfan syndrome, heart complications can arise such as weakness of the aortic valve, widening of the aortic root (the first point of the aorta as it leaves the heart) and prolapse of the mitral valve.
– The majority of cases are caused by dominant mutations of the Collagen 1 gene.
– This may be apparent from birth, the infant fracturing bones easily, and the leg bones may become bowed.
– Different from type 1, the sclera is a normal in colour in childhood.
– Growth may be stunted leading to a short stature and various deformities of the long bones of the arms, legs and of the spine. These deformities may cause disability.
– Like Type I, it is also an autosomal dominant defect of the Collagen 1 gene.
Table 2. Type V, VI, and VII are moderate to severe deforming conditions that have specific problems alongside the same features as type IV.
– Individuals experience moderate to severe fragility and fractures of the long bones and the vertebral bodies of the spine.
– Like type IV the sclerae are normal-coloured.
– Abnormal bone formations and dislocations at the wrists separate type V from type IVy.
– The gene abnormality is autosomal dominant and occurs in a protein called IFITM5 – not a Collagen 1.
– Often apparent from infancy and young childhood.
– Individuals tend to fracture more easily than those with type IV. • Most patients seem to get fractures of the spine.
– Teeth are normal.
– The gene defect in this group is autosomal recessive and arises from the protein called SERPINF1.
– Infants fracture from birth.
– Deformities of the legs tend to arise early in life.
– This is an autosomal recessive gene disorder of a protein called CRATP.
– This is often diagnosed by ultrasound during pregnancy and at around 20-weeks in to foetal development. The bones appear to be very poorly formed and disorganised in structure.
– Some infants die at or around birth with multiple fractures. Most do not live beyond infancy and for this reason the subtype is often described as ‘lethal’.
– The infant is short, the limbs are short and deformed, and the skull is soft and deformed.
– The sclerae are deep grey-blue.
– Long bones of the arms and legs are described as crumpled.
– A child may be born with fractures.
– From early infancy through early childhood there is progressive deformity of the skull, the long bones of the arms and legs, spine, chest and pelvis, lead to complications in childhood and adulthood.
– The joints may be hypermobile
– Stature is short and the face appears triangular with a large skull, prominent eyes, and a small jaw with misshapen teeth.
– The sclera is blue in infancy but becomes normal in colour in childhood.
– Because of severe curvature of the spine the breathing can be compromised leading to increased risk of chest infections. Such infections can be life threatening
– This is a lethal condition associated with a gene abnormality of a protein called Leprecan (LEPRI1).
In most cases the diagnosis is made based on the pattern of fractures and other associated clinical features. However, sometimes it can be difficult to diagnose, as few, or mild, signs may be present. When there is uncertainty about the diagnosis, testing is available by taking skin or blood samples to study the amount of Collagen 1 and under-take genetic analysis. A prenatal diagnosis is possible by DNA testing if gene mutations have already been identified in affected family members. Also ultrasonography at 20 weeks in to the pregnancy may help identify the most severe forms of OI. Occasionally milder forms may be detected later in pregnancy if fractures or deformities occur.
In about 50% of children with mild OI, one sign that might be helpful in making a diagnosis is seen on X-rays of the back of the skull. Here one may see additional small bones known as wormian bones that appear to fill in the gaps (sutures) between the normal bony plates that fuse to make the skull. In those that have been affected by bone deformities, X-rays may show abnormalities that are characteristic of a particular subtype.
Other conditions & concerns that may present like OI
There are other conditions that doctors and health and social care workers should be aware of. The first is various forms of dwarfism, the most common of which is Achondroplasia. The second is conditions where bones may bow (Ricketts and Osteomalacia, which are disorders of vitamin D and bone biochemistry), and conditions where bones may fracture such as early onset of Osteoporosis – called ‘Idiopathic Juvenile Osteoporosis’. These need careful assessment and investigation by a doctor in order to make the diagnosis. It is also fundamentally important not to miss deliberate harm – so- called non-accidental injury, or physical abuse. Equally it is fundamentally important not to inadvertently make accusation of physical abuse where OI has been missed and fractures and bruising may be arising with ease in the absence of deliberate injury.
Like all the HDCT a number of different specialists, allied health professionals, and social care teams are likely to make up the multidisciplinary group managing the more complex cases. There is no cure for OI, but, in the future, gene therapy (where there is a specific gene problem identified) may become a reality. Advice focuses on preventing or minimising the physical risks of fractures, and treatments on assisting individuals to achieve as much mobility as possible, maximising their independence and general health.
– Physiotherapy can help improve muscle tone and fitness (see P.E. and sports advice below). Respiratory exercises are important for those with reduced chest movement.
– Occupational therapy. Advising on the practicalities of day to day living both before and after fractures. Good quality and properly assessed and fitted equipment is important. A good example is poor seating and poor posture e.g. at a school desk or in the office.
– Safe exercise such as swimming (see below)
– Teaching parents and other carers techniques for safe handling, protective positioning, and safe movement of kids.
– Mental-health counseling may be helpful for those having difficulty coping with pain and disability.
– Pain management. Standard pain medication might be need either short term (‘acute’) following a fracture, or long term (‘chronic’) because of bone, limb, rib or spinal deformity.
– Splints, supports, and mobility aids. Casts, splints or wraps are used for broken bones. Braces may be required to support wrists, knees or ankles for example. Mobility aids such as canes, walkers, or wheelchairs and other equipment or aids for independence may be needed to compensate for muscle weakness and bony deformities.
– Bisphosphonate medication may be helpful in patients with OI. These bind to, and stabilise bone. These are commonly used first line in the treatment of Osteoporosis too.
– Orthopaedic surgery is often required in both children and adults. This may be, for example, the treatment of individual fractures, deformities of the long bones of arms and legs, or curvature of the spine.
– Physical education and exercise. This is often an area of concern for individuals, parents and schools. Playing certain sports and undertaking certain exercises may increase the risk of fracture. There are, however, many activities that children and adults with OI can participate in safely. There are also recommendations that make playing sport safer. These include:
- Encouraging swimming and water-based exercises as non-contact activities that are a great way to improve muscle strength and fitness.
- Racket sports. Some individuals may need a lighter racket or use a softer ball and play using both hands etc.
- Types of dance are safe activity. But, high impact moves, tugging, pulling or lifting should be avoided.
- As with any hypermobility condition individuals may be more prone to sprains etc.
- The wearing of supportive training shoes rather than plimsolls, and the use of support straps or taping is recommended when exercising.
- Some gym activities at school can be adapted by, for example, using lighter weight apparatus, supervised use of frames etc when exercising off the ground, and balance / strengthening exercises such as walking along a line on the floor instead of walking along a gym bench.
- Wearing a bright or different coloured top may make children/young people more visible to their teacher / trainer and others both assisting supervision and helping to avoid collisions between people.
- Many sports have been adapted for wheelchair users.
– Examples of the higher risk activities that one would recommend should be avoided or undertaken cautiously by individuals with OI include:
- Contact sports where there will be collisions or falls e.g., football, rugby, judo and other contact marshal arts, basketball, hockey etc.
- Trampoline, jumping, or forceful twisting in, for example gymnastics etc.
- Riding – this might cause repetitive stress though the spine.
Individuals with OI are born with the condition. The clinical features range from mild to severe to, sadly, lethal, but for the majority of cases the milder features are the most common and the greatest concern is the increased risk of fractures. Much can be done to support OI. Despite the challenges for some individuals and families, most children and adults lead productive and as normal a life as possible: school, friendships, careers, relationships, families, and participate in non / low contact sports and other recreational activities.
Dr A J Hakim MA FRCP Consultant in Rheumatology and Acute Medicine
Barts Health NHS Trust
Chief Medical Advisor and Trustee, HMSA
First published Autumn 2014, HMSA Journal. Online publication of same article, May 2015. Review date 2017.
Balkefors V, Mattsson E, Pernow Y, Sa?a?f M. Functioning and quality of life in adults with mild-to- moderate osteogenesis imperfecta. Physiother Res Int. 2013 Dec;18(4):203-11.
Ben Amor M, Rauch F, Monti E, Antoniazzi F. Osteogenesis imperfecta. Pediatr Endocrinol Rev. 2013 Jun;10 Suppl 2:397-405. Review.
Bianchi ML, Leonard MB, Bechtold S, et al. International Society for Clinical Densitometry. Bone health in children and adolescents with chronic diseases that may affect the skeleton: the 2013 ISCD Pediatric Official Positions. J Clin Densitom. 2014 Apr-Jun;17(2):281-94.
Dogba MJ, Bedos C, Durigova M, et al. The impact of severe osteogenesis imperfecta on the lives of young patients and their parents – a qualitative analysis. BMC Pediatr. 2013 Sep 30;13:153.
Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. 2014 Jul 23;7:CD005088. doi: 10.1002/14651858.CD005088.pub 3.
Laron D, Pandya NK. Advances in the orthopedic management of osteogenesis imperfecta. Orthop Clin North Am. 2013 Oct;44(4): 565-73.
Lindahl K, Langdahl B, Ljunggren O?, Kindmark A. Treatment of osteogenesis imperfecta in adults. Eur J Endocrinol. 2014 Aug; 171(2):R79-90.
Monti E, Mottes M, Fraschini P, et al. Current and emerging treatments for the management of osteogenesis imperfecta. Ther Clin Risk Manag. 2010 Sep 7;6:367-81.
Valadares ER, Carneiro TB, Santos PM, Oliveira AC, Zabel B. What is new in genetics and osteogenesis imperfecta classification? J Pediatr (Rio J). 2014 Jul 18. pii: S0021-7557(14)00101-6. doi: 10.1016/j.jped.2014.05.003. [Epub ahead of print].
Van Brussel M, Takken T, Uiterwaal CS, et al. Physical training in children with osteogenesis imperfecta. J Pediatr. 2008 Jan;152(1):111-6, 116.e1.
Van Dijk FS, Sillence DO. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A. 2014 Jun;164A(6):1470-81.