Osteogenesis imperfecta

Osteogenesis imperfecta (OI)
Other names	Brittle bone disease,[1] Lobstein syndrome,[1]: 5  fragilitas ossium,[2] Vrolik disease,[1]: 5  osteopsathyrosis idiopathica[3]: 347
Blue sclerae are a classic non-pathognomonic sign of osteogenesis imperfecta.
Pronunciation	/ˌɒstioʊˈdʒɛnəsɪs ˌɪmpɜːrˈfɛktə/[4] OSS-tee-oh-JEN-ə-siss IM-pur-FEK-tə
Specialty	Pediatrics, medical genetics, orthopedics
Symptoms	Bones that break easily, blue tinge to the sclera (whites of the eye), short height, joint hypermobility, hearing loss[5]
Onset	Birth
Duration	Long term
Causes	Genetic (autosomal dominant or de novo mutation)[6]
Diagnostic method	Based on symptoms, DNA testing
Prevention	Pre-implantation genetic diagnosis
Management	Healthy lifestyle (exercise, no smoking), metal rods through the long bones
Medication	Bisphosphonates[7]
Prognosis	Depends on the type
Frequency	1 in 15,000–20,000 people[8]

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.

Osteogenesis imperfecta (IPA: /ˌɒstioʊˈdʒɛnəsɪs ˌɪmpɜːrˈfɛktə/;^[4] OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily.^{[1]: 85 [9]} The range of symptoms—on the skeleton as well as on the body's other organs—may be mild to severe.^[5]: 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^[10] and problems with the teeth (dentinogenesis imperfecta).^[5] 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;^{[1]: 333 [11]} pulmonary valve insufficiency secondary to distortion of the ribcage;^{[1]: 335–341 [12]} and basilar invagination.^{[13]: 106–107}

The underlying mechanism is usually a problem with connective tissue due to a lack of, or poorly formed, type I collagen.^[5]: 1513 In more than 90% of cases, OI occurs due to mutations in the COL1A1 or COL1A2 genes.^[14] These mutations may be hereditary in an autosomal dominant manner but may also occur spontaneously (de novo).^[9][15] 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.^[9] As of September 2021^[update], 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.^[16][17] Diagnosis is often based on symptoms and may be confirmed by collagen biopsy or DNA sequencing.^[10]

Although there is no cure,^[10] most cases of OI do not have a major effect on life expectancy,^{[1]: 461 [15]} death during childhood from it is rare,^[10] and many adults with OI can achieve a significant degree of autonomy despite disability.^[18] Maintaining a healthy lifestyle by exercising, eating a balanced diet sufficient in vitamin D and calcium, and avoiding smoking can help prevent fractures.^[19] Genetic counseling may be sought by those with OI to prevent their children from inheriting the disorder from them.^[1]: 101 Treatment may include acute care of broken bones, pain medication, physical therapy, mobility aids such as leg braces and wheelchairs,^[10] vitamin D supplementation, and, especially in childhood, rodding surgery.^[20] Rodding is an implantation of metal intramedullary rods along the long bones (such as the femur) in an attempt to strengthen them.^[10] Medical research also supports the use of medications of the bisphosphonate class, such as pamidronate, to increase bone density.^[21] Bisphosphonates are especially effective in children,^[22] however it is unclear if they either increase quality of life or decrease the rate of fracture incidence.^[7]

OI affects only about one in 15,000 to 20,000 people, making it a rare genetic disease.^[8] 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.^[15][23][24] 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.^[25] The condition has been described since ancient history.^[26] The Latinate term osteogenesis imperfecta was coined by Dutch anatomist Willem Vrolik in 1849; translated literally, it means "imperfect bone formation".^{[26][27]: 683}