Osteogenesis imperfecta (OI and sometimes known as brittle bone disease, or "Lobstein syndrome") is a congenital bone disorder characterized by brittle bones that are prone to fracture. 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. Eight types of OI can be distinguished. Most cases are caused by mutations in the COL1A1 and COL1A2 genes.
Diagnosis of OI is based on the clinical features and may be confirmed by collagen or DNA testing. There is no cure for OI. Treatment is aimed at increasing overall bone strength to prevent fracture and maintain mobility. The incidence of OI is estimated to be one per 20,000 live births.
Collagen is of normal quality but is produced in insufficient quantities:
Bones fracture easily
Slight spinal curvature
Poor muscle tone
Discoloration of the sclera (whites of the eyes), usually giving them a blue-gray color. The blue-gray color of the sclera is due to the underlying choroidal veins which show through. This is due to the sclera being thinner than normal because of the defective Type I collagen not forming correctly.
IA and IB are defined to be distinguished by the absence/presence of dentinogenesis imperfecta (characterized by opalescent teeth; absent in IA, present in IB). Life expectancy is slightly reduced compared to the general population due to the possibility of fatal bone fractures and complications related to OI Type I such as basilar invagination.
Severe respiratory problems due to underdeveloped lungs
Severe bone deformity and small stature
Type II can be further subclassified into groups A, B, and 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.
Discolouration of the sclera (the 'whites' of the eyes are blue)
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. Lifespans may be normal, albeit with severe physical handicapping.
Having the same clinical features as Type IV, it is 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-ulnarinterosseous 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. Other features of this condition include radial head dislocation, long bone bowing and mixed hearing loss.
With the same clinical features as Type IV, it is distinguished histologically by "fish-scale" bone appearance. Type VI has recently been found to be caused by a loss of function mutation in the SERPINF1 gene. SERPINF1, a member of the serpin family, is also known as pigment epithelium derived factor (PEDF), the most powerful endogenous antiangiogenic factor in mammals.
In 2006, a recessive form called "Type VII" was discovered (phenotype severe to lethal). Thus far it seems to be limited to a First Nations people in Quebec. Mutations in the gene CRTAP causes this type.
A family with recessive osteogenesis imperfecta has been reported to have a mutation in the TMEM38B gene on chromosome 9. This gene encodes TRIC-B, a component of TRIC, a monovalent cation-specific channel involved in calcium release from intracellular stores.
It is extremely likely that there are other genes associated with this disease that have yet to be reported.
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. This deficiency arises from an amino acid substitution of glycine to bulkier amino acids in the collagentriple helix structure. The larger amino acid side-chains create steric hindrance that creates a bulge in the collagen complex, which in turn influences both the molecular nanomechanics and the interaction between molecules, which are both compromised. As a result, the body may respond by hydrolyzing the improper collagen structure. 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. Another suggested disease mechanism is that the stress state within collagen fibrils is altered at the locations of mutations, where locally larger shear forces lead to rapid failure of fibrils even at moderate loads as the homogeneous stress state found in healthy collagen fibrils is lost. These recent works suggest that OI must be understood as a multi-scale phenomenon, which involves mechanisms at the genetic, nano-, micro- and macro-level of tissues.
As a genetic disorder, OI has historically been viewed as an autosomal dominant disorder of type I collagen. Most cases have been caused by mutations in the COL1A1 and COL1A2 genes. In the past several years, there has been the identification of autosomal recessive forms. Most people with OI receive it from a parent but in 35% of cases it is an individual (de novo or "sporadic") mutation.
There is no definitive test for OI. The diagnosis is usually suggested by the occurrence of bone fractures with little trauma and the presence of other clinical features. Skin biopsy can be performed to determine the structure and quantity of type I collagen. DNA testing can confirm the diagnosis, however it cannot exclude it, because not all mutations causing OI are known and/or tested for. OI type II is often diagnosed by ultrasound during pregnancy, where already multiple fractures and other characteristic features may be present.
An important differential diagnosis of OI is child abuse, as both may present with multiple fractures in various stages of healing. Differentiating them can be difficult, especially when no other characteristic features of OI are present. Other differential diagnoses include rickets, osteomalacia, and other rare skeletal syndromes.
There is no cure for OI. Treatment is aimed at increasing overall bone strength to prevent fracture and maintain mobility. Bisphosphonates can increase bone mass, and reduce bone pain and fracture. In severe cases, bones are surgically corrected, and rods are placed inside the bones, particularly to enable infants to learn to walk.
In 1998, a clinical trial demonstrated the effectiveness of intravenous pamidronate, a bisphosphonate which had previously been used in adults to treat osteoporosis. In severe OI, pamidronate reduced bone pain, prevented new vertebral fractures, reshaped previously fractured vertebral bodies, and reduced the number of long-bone fractures.
Although oral bisphosphonates are more convenient and cheaper, they are not absorbed as well, and intravenous bisphosphonates are generally more effective, although this is under study. Some studies have found oral and intravenous bisphosphonates, such as oral alendronate and intravenous pamidronate, equivalent. In a trial of children with mild OI, oral risedronate increased bone mineral densities, and reduced nonvertebral fractures. However, it did not decrease new vertebral fractures.
Bisphosphonates are less effective for OI in adults.
Metal rods can be surgically inserted in the long bones to improve strength, a procedure developed by Harold A. Sofield, MD, at Shriners Hospitals for Children in Chicago. During the late 1940s, Sofield, Chief of Staff at Shriners Hospitals in Chicago, worked there with large numbers of children with OI and experimented with various methods to strengthen the bones in these children. In 1959, with Edward A. Miller, MD, Sofield wrote a seminal article describing a solution that seemed radical at the time: the placement of stainless steel rods into the intramedullary canals of the long bones to stabilize and strengthen them. His treatment proved extremely useful in the rehabilitation and prevention of fractures; it was adopted throughout the world and still forms the basis for orthopedic treatment of OI.
Spinal fusion can be performed to correct scoliosis, although the inherent bone fragility makes this operation more complex in OI patients. Surgery for basilar impressions can be carried out if pressure being exerted on the spinal cord and brain stem is causing neurological problems.
Physiotherapy is used to strengthen muscles and improve motility in a gentle manner, while minimizing the risk of fracture. This often involves hydrotherapy and the use of support cushions to improve posture. Individuals are encouraged to change positions regularly throughout the day to balance the muscles being used and the bones under pressure.
Children often develop a fear of trying new ways of moving due to movement being associated with pain. This can make physiotherapy difficult to administer to young children.
The condition, or types of it, has had various other names over the years and in different nations. Among some of the most common alternatives are Ekman-Lobstein syndrome, Vrolik syndrome, and the colloquial glass-bone disease. The name osteogenesis imperfecta dates to at least 1895 and has been the usual medical term in the 20th century to present. The current four type system began with Sillence in 1979. An older system deemed less severe types "osteogenesis imperfecta tarda" while more severe forms were deemed "osteogenesis imperfecta congenita." As this did not differentiate well, and all forms are congenital, this has since fallen out of favour.
The condition has been found in an ancient Egyptianmummy from 1000 BC. The Norse king Ivar the Boneless may have had this condition, as well. The earliest studies of it began in 1788 with the Swede Olof Jakob Ekman. He described the condition in his doctoral thesis and mentioned cases of it going back to 1678. In 1831, Edmund Axmann described it in himself and two brothers. Jean Lobstein dealt with it in adults in 1833. Willem Vrolik did work on the condition in the 1850s. The idea that the adult and newborn forms were the same came in 1897 with Martin Benno Schmidt.
In the United States, the incidence of osteogenesis imperfecta is estimated to be one per 20,000 live births. An estimated 20,000 to 50,000 people are affected by OI in the United States.
Frequency is approximately the same across groups, but for unknown reasons, the Shona and Ndebele of Zimbabwe seem to have a higher proportion of Type III to Type I than other groups. However, a similar pattern was found in segments of the Nigerian and South African populations. In these varied cases, the total number of OIs of all four types was roughly the same as any other ethnicity.
Figures in film, television, video games and novels depicted as having osteogenesis imperfecta include:
(1998) British actor and writer Firdaus Kanga, who wrote and starred in the 1998 BBC film Sixth Happiness partially based on his own life. Kanga wrote Trying to Grow exploring the life of adolescents with this condition. Kanga featured on Channel 4 documentaries 'Taboo' and 'Double the Trouble, Twice the Fun,' exploring religion, sexuality and disability.
(2000) The film Unbreakable features a character played by Samuel L. Jackson named Elijah Price who suffers from OI Type I and is nicknamed "Mr. Glass" due to the brittleness of his bones.
(2001) Raymond Dufayel (sometimes simply called "the glass man" by his neighbors) in the French filmAmélie; Dufayel is depicted as being confined to his house (the interior of which is heavily padded) by the condition.
(2005) The movie Fragile features a child with this condition.
(2005) Dean Koontz's novel Forever Odd features a character named Danny Jessup who has OI and has been Odd Thomas's close friend since boyhood. Odd combs Pico Mundo and its environs searching for Danny after he has been abducted by his stepfather's killer.
(2006) The fifth season of the series Scrubs saw Elliot Reid doing research into the various types of therapy available to O.I. patients. Her co-fellow Charlie then developed a new "gene therapy" cure, putting Elliot out of work.
(2007) Jeff "Joker" Moreau, a frigate pilot in the popular video game series Mass Effect is depicted as suffering from Vrolik's Syndrome, requiring crutches or medical enhancements to perform simple tasks such as walking, but thanks to the Pro-Human organization Cerberus operating on his legs between Mass Effect and Mass Effect 2, Joker was able to walk, though with a noticeable limp. He still requires assistance, as he periodically joked about in Mass Effect 3.
(2009) Jodi Picoult wrote Handle with Care, a story about a little girl named Willow who has type III OI. The book shows how her disease has affected her life and the lives of those around her. It also deals with the moral dilemma faced by her Mother when, with mounting medical bills, she makes the decision to sue the hospital for a "wrongful birth".
In dogs, OI is an autosomal-recessive condition. In Golden Retrievers, it is caused by a mutation in the COL1A1, and in Beagles, the COL1A2. A separate mutation in the SERPINH1 gene has been found to cause the condition in Dachshunds. Several mouse models of OI have been described, whereby the abnormal gait 2 (AGA2) mouse line exhibits severe skeletal  and cardio-pulmonary  phenotypes due to a carboxy-terminus mutation in the COL1A1 gene in the mouse.
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