newborn already has multiple broken bones at the time of birth. type ii infants also exhibit severe respiratory problems, and have severely deformed bones. sixty percent of infants die less than 24 hours after being born, and survival after the first year is extremely unlikely and normally requires mechanical ventilation. in the rare cases of infants who survive their first year of life, severe developmental and motor delays are seen; neither of two infants studied in 2019, both aged around two years, had achieved head control, and both required a ventilator to breathe. type ii is also known as the "lethal perinatal" form of oi, and is not compatible with survival into adulthood. due to similarly severely deformed bones, sometimes infants with severe type iii are wrongly initially classified as type ii; once long-term survival is shown, they are considered as having type iii instead.: 1511 type iii collagen quantity is sufficient, but is not of a high enough quality.: 1512 clinical differentiation between types iii and iv is not always simple, and is further confounded by the fact that an untreated adult with type iv may have worse symptoms than a treated adult with type iii;: 1511 features only found in type iii are its progressively deforming nature: 1511–1512 and the presence of a face with a "triangular" appearance. another differentiating factor between type iii and iv is blue sclerae; in type iii, infants commonly have blue sclerae that gradually turn white with age, but blue sclerae are not commonly seen in type iv,: 294–296 although they are seen in 10% of cases. oi type iii causes osteopenic bones that fracture very easily, sometimes even in utero, often leading to hundreds of fractures during a lifetime; early scoliosis that progresses until puberty; dwarfism (a final adult height frequently less than 4 feet or 120 centimetres); loose joints; and possible respiratory problems due to low rib cage volume causing low lung volumes.: 1512 due to the severity of the issues with the bones, neurological and seizure disorders are more likely to develop in type iii.: 1512 basilar invagination, which puts pressure on the brainstem, may cause or contribute to early death; surgical treatment of it is more complex in oi cases.: 1512 : 106–107 type iv collagen quantity is sufficient, but is not of a high enough quality.: 1512 type iv is for cases of variable severity, which do not fit into either types iii or i. while one of sillence's required characteristics for type iv was having normal sclerae,: 294–296 : 114 modern classification allows even those with blue sclerae to fit the criteria for type iv if they meet the other clinical requirements of the type. in type iv, bone deformity can be mild to severe, bones fracture easily (especially before puberty), dwarfism is common, vertebral collapse and scoliosis are evident, and hearing loss is possible, although uncommon. type iv oi is mostly defined in contrast to type iii and type i, being the clinical classification for patients somewhere in the middle ground between the two.: 1511 as such, type iv oi is often termed "variable" oi,: 111 with the severity of even those in the same family (so, with the same genetic mutation) differing. prepubertal bone fracture rates are another way of clinically assessing type iv oi—those with it tend to have fracture rates of ≈1 per year, compared to ≈3 per year for severe oi (type iii). as in type i, some further split type iv into types iv–a and iv–b, defined again by the absence (iv–a) or presence (iv–b) of dentinogenesis imperfecta.: 217 genetically defined types (types v–xxi) as of 2020, fifteen types of oi are defined genetically: x-rays of three people with oi type v: a newborn, a child, and an adult. evident are somewhat deformed long bones with widened metaphyses. type v – having the same clinical features as type iv, it can be clinically distinguished by observing a "mesh-like" appearance to a bone biopsy under a microscope. type v can be further distinguished from other types of oi by the "v triad": an opaque band (visible on x-ray) adjacent to the growth plates; hypertrophic calluses (abnormally large masses of bony repair tissue) which form at fracture sites during the healing process; and calcification of the interosseous membrane of the forearm, which may make it difficult to turn the wrist.: 429 other features of this condition may include pulled elbow, and, as in other types of oi, long bone bowing and hearing loss. cases of this type are caused by mutations in the ifitm5 gene on chromosome 11p15.5. the separation of type v from type iv oi, its clinical type, was initially suggested even before its genetic cause was known, by glorieux et al. in 2000. type v is relatively common compared to other genetically defined types of oi—4% of oi patients at the genetics department of the brazilian hospital de clínicas de porto alegre were found to have it. type vi – with the same clinical features as type iii, it is distinguished by bones which have an appearance similar to that seen in osteomalacia.: 168 type vi is caused by a loss-of-function mutation in the serpinf1 gene on chromosome 17p13.3.: 170 type vii – oi caused by a mutation in the gene crtap on chromosome 3p22.3; clinically similar to oi types ii and iii, depending on affected individual. type vii was the first recessive oi type confirmed, initially found among first nations people in quebec. type viii – oi caused by a mutation in the gene lepre1 on chromosome 1p34.2; clinically similar to oi types ii and iii, depending on affected individual. type ix – oi caused by homozygous or compound heterozygous mutation in the ppib gene on chromosome 15q22.31. type x – oi caused by homozygous mutation in the serpinh1 gene on chromosome 11q13. type xi – oi caused by mutations in fkbp10 on chromosome 17q21. the mutations cause a decrease in secretion of trimeric procollagen molecules. other mutations in this gene can cause autosomal recessive bruck syndrome, which is similar to oi. type xii – oi caused by a frameshift mutation in sp7 on chromosome 12q13.13. this mutation causes bone deformities, fractures, and delayed tooth eruption. type xiii – oi caused by a mutation in the bone morphogenetic protein 1 (bmp1) gene on chromosome 8p21.3. this mutation causes recurrent fractures, high bone mass, and hypermobile joints. type xiv – oi caused by mutations in the tmem38b gene on chromosome 9q31.2. this mutation causes recurrent fractures and osteopenia, although the disease trajectory is highly variable. type xv – oi caused by homozygous or compound heterozygous mutations in the wnt1 gene on chromosome 12q13.12. it is autosomal recessive. type xvi – oi caused by mutations in the creb3l1 gene on chromosome 11p11.2. the homozygous mutation causes prenatal onset of recurrent fractures of the ribs and long bones, demineralization, decreased ossification of the skull, and blue sclerae; it is clinically type ii or type iii. family members who are heterozygous for oi xvi may have recurrent fractures, osteopenia and blue sclerae. type xvii – oi caused by homozygous mutation in the sparc gene on chromosome 5q33, causing a defect in the protein osteonectin, which leads to severe disease characterized by generalized platyspondyly, dependence on a wheelchair, and recurrent fractures. type xviii – oi caused by homozygous mutation in the fam46a gene on chromosome 6q14.1. characterized by congenital bowing of the long bones, wormian bones, blue sclerae, vertebral collapse, and multiple fractures in the first years of life. type xix – oi caused by hemizygous mutation in the mbtps2 gene on chromosome xp22.12. thus far, oi type xix is the only known type of oi with an x-linked recessive pattern of inheritance, making it the only type that is more common in males than females. oi type xix disrupts regulated intramembrane proteolysis, which is critical for healthy bone formation. type xx – oi caused by homozygous mutation in the mesd gene on chromosome 15q25.1. initial studies of type xx indicate that it may cause global developmental delay, a first among oi types. oi type xx disrupts the wnt signaling pathway, which is thought to have a role in bone development. type xxi – oi caused by homozygous mutation in the kdelr2 gene on chromosome 7p22.1. causes disease clinically similar to types ii and iii, thought to be related to inability of chaperone protein hp47 to unbind from collagen type i, as to do so it needs to bind to the missing er lumen protein retaining receptor 2 protein encoded by kdelr2. given the rapid rate of type discovery, it is extremely likely that there are other genes associated with oi that have yet to be reported.: 491–492 genetics an α1 type i collagen protein osteogenesis imperfecta is a group of genetic disorders, all of which cause bone fragility. oi has high genetic heterogeneity, that is, many different genetic mutations lead to the same or similar sets of observable symptoms (phenotypes). the main causes for developing the disorder are a result of mutations in the col1a1 and/or col1a2 genes which are jointly responsible for the production of collagen type i. approximately 90% of people with oi are heterozygous for mutations in either the col1a1 or col1a2 genes. there are several biological factors that are results of the dominant form of oi. these factors include: intracellular stress; abnormal tissue mineralization; abnormal cell to cell interactions; abnormal cell-matrix interactions; a compromised cell matrix structure; and, abnormal interaction between non-collagenous proteins and collagen. previous research lead to the belief that oi was an autosomal dominant disorder with few other variations in genomes. however, with the lowering of the cost of dna sequencing in the wake of 2003's human genome project, autosomal recessive forms of the disorder have been identified. recessive forms of oi relate heavily to defects in the collagen chaperones responsible for production of procollagen and the assembly of the related proteins. examples of collagen chaperones that are defective in patients with recessive forms of oi include chaperone hsp47 (cole-carpenter syndrome) and fkbp65. mutations in these chaperones result in an improper folding pattern in the collagen 1 proteins which causes the recessive form of the disorder. there are three significant types of oi that are a result of mutations in the collagen prolyl 3-hydroxylation complex (components crtap, p3h1, and cypb). these components are responsible for the modification of collagen α1(l)pro986. mutations in other genes such as sp7, serpinf1, tmem38b and bmp1 can also lead to irregularly formed proteins and enzymes that result in other recessive types of osteogenesis imperfecta. defects in the proteins pigment epithelium-derived factor (pedf) and bone-restricted interferon-induced transmembrane protein (bril) are the causes of type v and vi osteogenesis imperfecta. defects in these proteins lead to defective bone mineralization which causes the characteristic brittle bones of osteogenesis imperfecta. a single point mutation in the 5′ untranslated region (5′ utr) of the ifitm5 gene, which encodes bril, is linked directly to oi type v. in the rare case of type xix, first discovered in 2016, oi is inherited as an x-linked genetic disorder, with its detrimental effects resulting ultimately from a mutation in the gene mbtps2. genetic research is ongoing, and it is uncertain when all the genetic causes of oi will be identified, as the number of genes that need to be tested to rule out the disorder continue to increase.: 491–492 in a study of 37 families, a 1.3% chance was found that oi recurs in multiple siblings born to two unaffected parents—this is a much higher rate than would be expected if all such recurrences were de novo. the cause is genetic mosaicism; that is, some of, or most of, the germ cells of one parent have a dominant form of oi, but not enough of their somatic cells do to cause symptoms or obvious disability in the parent—the parent's different cells have two (or more) sets of slightly different dna.: 1513 it has been clinically observed that ≈5–10% of cases of oi types ii and iii are attributable to genetic mosaicism.: 532 pathophysiology people with oi are either born with defective connective tissue, born without the ability to make it in sufficient quantities, or, in the rarest genetic types, born with deficiencies in other aspects of bone formation