osteogenesis imperfecta osteogenesis imperfecta osteogenesis imperfecta (ipa: /ˌɒstioʊˈdʒɛnəsɪs ˌɪmpɜːrˈfɛktə/; oi), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily.: 85 the range of symptoms—on the skeleton as well as on the body's other organs—may be mild to severe.: 1512 symptoms found in various types of oi include whites of the eye (sclerae) that are blue instead, short stature, loose joints, hearing loss, breathing problems and problems with the teeth (dentinogenesis imperfecta). potentially life-threatening complications, all of which become more common in more severe oi, include: tearing (dissection) of the major arteries, such as the aorta;: 333 pulmonary valve insufficiency secondary to distortion of the ribcage;: 335–341 and basilar invagination.: 106–107 osteogenesis imperfecta(oi)other namesbrittle bone disease, lobstein syndrome,: 5 fragilitas ossium, vrolik disease,: 5 osteopsathyrosis idiopathica: 347 blue sclerae, as in the eyes of the girl above, are a classic non-pathognomonic sign of oi.pronunciation/ˌɒstioʊˈdʒɛnəsɪs ˌɪmpɜːrˈfɛktə/ oss-tee-oh-jen-ə-siss im-pur-fek-tə specialtypediatrics, medical genetics, orthopedicssymptomsbones that break easily, blue tinge to the sclera (whites of the eye), short height, joint hypermobility, hearing lossonsetbirthdurationlong termcausesgenetic (autosomal dominant or de novo mutation)diagnostic methodbased on symptoms, dna testingpreventionpre-implantation genetic diagnosismanagementhealthy lifestyle (exercise, no smoking), metal rods through the long bonesmedicationbisphosphonatesprognosisdepends on the typefrequency1 in 15,000–20,000 people four x-rays of a 24-year-old american man, who had had more than one hundred bone fractures in his lifetime, and received a childhood clinical diagnosis of type iv–b oi. genetic diagnosis in 2018 identified a previously uncatalogued pathogenic variant in the gene which encodes proα2(i) chains of type i procollagen, col1a2, at exon 19, substitution c.974g>a. due to childhood neglect and poverty, subject never received surgery to implant intramedullary rods. malunions are evident as the humerus and femur were broken in adolescence but orthopedic care did not follow. severe scoliosis, as well as kyphosis, are also evident. the unavoidably low contrast in the film is due to a combination of subject's obesity and low bone mineral density (bmd). subject's bmd z-score was -4.1 according to results of a dual-energy x-ray absorptiometry (dxa) scan also done in 2018. the underlying mechanism is usually a problem with connective tissue due to a lack of, or poorly formed, type i collagen.: 1513 in more than 90% of cases, oi occurs due to mutations in the col1a1 or col1a2 genes. these mutations may be hereditary in an autosomal dominant manner but may also occur spontaneously (de novo). there are four clinically defined types: type i, the least severe; type iv, moderately severe; type iii, severe and progressively deforming; and type ii, perinatally lethal. as of september 2021, 19 different genes are known to cause the 21 documented genetically defined types of oi, many of which are extremely rare and have only been documented in a few individuals. diagnosis is often based on symptoms and may be confirmed by collagen biopsy or dna sequencing. although there is no cure, most cases of oi do not have a major effect on life expectancy,: 461 death during childhood from it is rare, and many adults with oi can achieve a significant degree of autonomy despite disability. maintaining a healthy lifestyle by exercising, eating a balanced diet sufficient in vitamin d and calcium, and avoiding smoking can help prevent fractures. genetic counseling may be sought by those with oi to prevent their children from inheriting the disorder from them.: 101 treatment may include acute care of broken bones, pain medication, physical therapy, mobility aids such as leg braces and wheelchairs, vitamin d supplementation, and, especially in childhood, rodding surgery. rodding is an implantation of metal intramedullary rods along the long bones (such as the femur) in an attempt to strengthen them. medical research also supports the use of medications of the bisphosphonate class, such as pamidronate, to increase bone density. bisphosphonates are especially effective in children, however it is unclear if they either increase quality of life or decrease the rate of fracture incidence. oi affects only about one in 15,000 to 20,000 people, making it a rare genetic disease. outcomes depend on the genetic cause of the disorder (its type). type i (the least severe) is the most common, with other types comprising a minority of cases. moderate-to-severe oi primarily affects mobility; if rodding surgery is performed during childhood, some of those with more severe types of oi may gain the ability to walk. the condition has been described since ancient history. the latinate term osteogenesis imperfecta was coined by dutch anatomist willem vrolik in 1849; translated literally, it means "imperfect bone formation".: 683 signs and symptoms orthopedic the main symptom of osteogenesis imperfecta is fragile, low mineral density bones; all types of oi have some bone involvement. in moderate and especially severe oi, the long bones may be bowed, sometimes extremely so. the weakness of the bones causes them to fracture easily; a study in pakistan found an average of 5.8 fractures per year in untreated children. fractures typically occur much less after puberty, but begin to increase again in women after menopause and in men between the ages of 60 and 80.: 486 joint hypermobility is also a common sign of oi, thought to be because the affected genes are the same as those that cause some types of ehlers–danlos syndrome.: 1513 otologic by the age of 50, about 50% of adults with oi experience significant hearing loss, much earlier as compared to the general population. hearing loss in oi may or may not be associated with visible deformities of the ossicles and inner ear. hearing loss frequently begins during the second, third, and fourth decades of life, and may be conductive, sensorineural, or a combination of both ("mixed"). if hearing loss does not occur by age 50, it is significantly less likely to occur in the years afterwards. mixed hearing loss is most common among those with oi of all age groups, while conductive hearing loss is most likely to affect older people, with sensorineural hearing loss most likely to affect children. although relatively rare, oi-related hearing loss can also begin in childhood; in a study of forty-five children aged four to sixteen, two were found to be affected, aged 11 and 15. in a different 2008 study, the hearing of 41 people with oi was checked. the results showed that 88% of those over 20 years of age had some form of hearing loss, while only 38% of those under 20 did. hearing loss is most common in type i oi; it is less common in types iii and iv.: 294–296 other parts of the inner ear may also be affected by oi. causing balance issues; however, only small studies have found links between vertigo and oi.: 308 oi may worsen the outcome of medical treatments which correct hearing loss. besides oi's association with sensorineural hearing loss, oi is associated with a number of neurological abnormalities, usually involving the central nervous system, due to deformities in the skeletal structures surrounding it. neurological complications, especially basilar invagination, may adversely affect life expectancy. in oi, this is most often due to upwards migration of the dens,: 106–107 a feature of the c2 vertebra. neurosurgery may be needed to correct severe abnormalities when they risk the patient's life or cause either great suffering or intolerable neurological deficits.: 106–107 systemic as its biological causes have been more precisely determined, it has become more widely recognized that while the primary disease process of oi happens in the bones, the most common types of oi—those caused by type i collagen gene mutations—affect virtually all of the human body's organs in some way. type i collagen is present throughout the circulatory and respiratory systems: from the ventricles of the heart itself, to the heart valves, to the vasculature,: 329 it is an integral part of the connective tissue of the lungs.: 336 as such, cardiovascular complications, among them aortic insufficiency, aortic aneurysm, and arterial dissections, are sometimes comorbid with oi,: 333 but not as frequently as they are comorbid with marfan syndrome.: 332 respiratory illnesses are a major cause of death in oi.: 335 the most obvious source of respiratory problems in oi is pulmonary insufficiency caused by problems in the architecture of the thoracic wall.: 341 however, respiratory tract infections, such as pneumonia, are also more fatal among those with oi than the general population. those with more severe ribcage deformities were found to have worse lung restriction in a small-scale 2012 study involving 22 italian patients with oi types iii and iv, plus 26 non-affected controls. oi—especially its severe form type iii—also has effects on the gastrointestinal system. it was found to be associated with recurrent abdominal pain and chronic constipation in two studies on patients affected by oi. chronic constipation is especially common,: 377 and is thought to be aggravated by an asymmetric pelvis (acetabular protrusion).: 377 especially in childhood, oi-associated constipation may cause a feeling of fullness and associated food refusal, leading to malnutrition.: 377 classification there are two typing systems for oi in modern use. the first, created by david sillence in 1979, classifies patients into four types, or syndromes, according to their clinical presentation, without taking into account the genetic cause of their disease.: 114–115 the second system expands on the sillence model, but assigns new numbered types genetically as they are found. therefore, people with oi can be described as having both a clinical type and a genetic type, which may or may not be equivalent. type i is the most common, and 90% of cases result from mutations to either col1a1 or col1a2. symptoms vary a lot between types, as well as vary from person to person, even in the same family. as of 2021, 21 types of oi have been defined: sillence's four types typedescriptiongeneomimmode of inheritanceincidence defined imildnull col1a1 allele 166200autosomal dominant, 34% de novo1 in 30,000 1979 iilethal in the perinatal period: 1511 col1a1, col1a2 166210autosomal dominant, ≈100% de novo1 in 40,000 to 1 in 100,000 iiisevere, progressive and deformingcol1a1, col1a2 259420autosomal dominant, 85% de novo1 in 60,000 ivvariable and deforming, but usually with normal sclerae: 294–296 col1a1, col1a2 166220autosomal dominant, 50% de novo1 in 30,000: 21 genetically defined types typegeneomimmode of inheritance defined v ifitm5 610967autosomal dominant 2000 vi serpinf1 613982autosomal recessive 2002 vii crtap 610682autosomal recessive 2006 viii lepre1 610915autosomal recessive 2007 ix ppib 259440autosomal recessive 2009 x serpinh1 613848autosomal recessive 2010 xi fkbp10 610968autosomal recessive 2010 xii sp7 613849autosomal recessive 2010 xiii bmp1 614856autosomal recessive 2012 xiv tmem38b 615066autosomal recessive 2012 xv wnt1 615220autosomal recessive 2013 xvi creb3l1 616229autosomal recessive 2013 xvii sparc 616507autosomal recessive 2015 xviii tent5a 617952autosomal recessive 2018 xix mbtps2 301014x-linked recessive 2016 xx mesd 618644autosomal recessive 2019 xxi kdelr2 619131 autosomal recessive 2020 sillence types jordanne whileyatticus shafferpeter radtketheresia haidlmayrosteogenesis imperfecta is highly variable, affecting all those above. sillence's four types have both a clinical and a genetic meaning; the descriptions below are clinical and can be applied to several genetic types of oi. when used to refer to a genetic as well as a clinical type, it indicates that the clinical symptoms are indeed caused by mutations in the col1a1 or col1a2 genes which are inherited in an autosomal dominant fashion. type i collagen is of normal quality but is produced in insufficient quantities.: 1516 bones fracture more easily than in the general public, but not as easily as more severe types of oi; there might be scoliosis, albeit mild compared to oi types iii and iv, with a lower cobb angle; the joints may be loose; blue sclerae may be apparent; hearing loss is likely to occur;: table 1 and there might be a slight decrease in height. because cases exist missing one or more of these symptoms, oi type i in some cases goes undetected into adulthood.: 1513–1514 some further split type i into types i–a and i–b, defined as being distinguished by the absence (i–a) or presence (i–b) of dentinogenesis imperfecta (opalescent teeth).: 217 people with type i generally have a normal lifespan. type ii collagen is fatally defective at its c-terminus.: 1512 most cases result in death shortly after birth, or within the first year of life, due to respiratory failure. another common cause of death is intracranial bleeds from skull fractures present at, or sustained during or shortly after, birth.: 1511 in many cases, the