Hypermobility Types of HMS Osteogenesis Imperfecta OI: Classification, clinical findings, and genetics Classification 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 slightly 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 to 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 through 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. Type IV: 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 normal in colour in childhood. Growth may be stunted leading to 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. Type V: 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. Type VI: 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. Type VII: 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. Table 3. Type II: 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. Type III: 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 Type VIII: This is a lethal condition associated with a gene abnormality of a protein called Leprecan (LEPRI1). Diagnosing OI 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 into 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 the 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 an accusation of physical abuse where OI has been missed and fractures and bruising may be arising with ease in the absence of deliberate injury.