Osteogenesis imperfecta

"Brittle bone disease" redirects here. For the etiologically distinct disease arising primarily from malnutrition rather than exclusively from genetic mutation, see rickets.

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}

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 (Fredrick Brennan), 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, Brennan 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 Brennan's obesity and low bone mineral density (BMD). His 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.^[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}

Signs and symptoms

Orthopedic

X-ray of the hips in osteogenesis imperfecta, showing low bone density

The main symptom of osteogenesis imperfecta is fragile, low mineral density bones; all types of OI have some bone involvement.^[5] In moderate and especially severe OI, the long bones may be bowed, sometimes extremely so.^[28] The weakness of the bones causes them to fracture easily—a study at the Endocrine Unit at the National Institute of Child Health in Karachi, Pakistan found an average of 5.8 fractures per year in untreated children.^[29] 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.^[1]: 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.^{[5]: 1513  [note 1][30][31]}

Otologic

By the age of 50, about 50% of adults with OI experience significant hearing loss, much earlier as compared to the general population.^[32] Hearing loss in OI may or may not be associated with visible deformities of the ossicles and inner ear.^[33] Hearing loss frequently begins during the second, third, and fourth decades of life, and may be conductive, sensorineural, or a combination of both ("mixed").^[34] If hearing loss does not occur by age 50, it is significantly less likely to occur in the years afterwards.^[32] 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.^[35]

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.^[36] 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.^[37]

Hearing loss is most common in type I OI; it is less common in types III and IV.^{[1]: 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.^[1]: 308 OI may worsen the outcome of medical treatments which correct hearing loss.^[35]

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,^{[38][13]: 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.^{[38][13]: 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.^[15]

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,^[1]: 329 it is an integral part of the connective tissue of the lungs.^[1]: 336 As such, cardiovascular complications, among them aortic insufficiency, aortic aneurysm, and arterial dissections, are sometimes comorbid with OI,^[1]: 333 but not as frequently as they are comorbid with Marfan syndrome.^[1]: 332

Respiratory illnesses are a major cause of death in OI.^{[12][1]: 335} The most obvious source of respiratory problems in OI is pulmonary insufficiency caused by problems in the architecture of the thoracic wall.^[1]: 341 However, respiratory tract infections, such as pneumonia, are also more fatal among those with OI than the general population.^[12][39] 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.^[12]

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.^[40][41] Chronic constipation is especially common,^[1]: 377 and is thought to be aggravated by an asymmetric pelvis (acetabular protrusion).^{[1]: 377 [41]} Especially in childhood, OI-associated constipation may cause a feeling of fullness and associated food refusal, leading to malnutrition.^[1]: 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.^{[42]: 114–115 [43]} The second system expands on the Sillence model, but assigns new numbered types genetically as they are found.^[44][43] Therefore, people with OI can be described as having both a clinical type and a genetic type, which may or may not be equivalent.^[43]

Type I is the most common, and 90% of cases result from mutations to either COL1A1 or COL1A2.^[9] Symptoms vary widely between types, as well as vary from person to person, even in the same family.^[45]

As of 2021, 21 types of OI have been defined:^[16][17]

Sillence's four types
Type	Description	Gene	OMIM	Mode of inheritance	Incidence	Defined[note 2]
I	mild	Null COL1A1 allele	166200	autosomal dominant, 34% de novo[6]	1 in 30,000[46]	1979[43]
II	lethal in the perinatal period[5]: 1511	COL1A1, COL1A2	166210	autosomal dominant, ≈100% de novo[6]	1 in 40,000[23] to 1 in 100,000[46]
III	severe, progressive and deforming	COL1A1, COL1A2	259420	autosomal dominant, 85% de novo[6]	1 in 60,000[46]
IV	variable and deforming, but usually with normal sclerae[1]: 294–296 [47]	COL1A1, COL1A2	166220	autosomal dominant, 50% de novo[6]	1 in 30,000[1]: 21
Genetically defined types
Type	Gene		OMIM	Mode of inheritance[note 3]		Defined[note 2]
V	IFITM5		610967	autosomal dominant[48][49]		2000[50][note 4]
VI	SERPINF1		613982	autosomal recessive[48]		2002
VII	CRTAP		610682	autosomal recessive[48]		2006
VIII	LEPRE1		610915	autosomal recessive		2007
IX	PPIB		259440	autosomal recessive		2009
X	SERPINH1		613848	autosomal recessive		2010
XI	FKBP10		610968	autosomal recessive		2010
XII	SP7		613849	autosomal recessive		2010
XIII	BMP1		614856	autosomal recessive		2012
XIV	TMEM38B		615066	autosomal recessive		2012
XV	WNT1		615220	autosomal recessive		2013
XVI	CREB3L1		616229	autosomal recessive		2013
XVII	SPARC		616507	autosomal recessive		2015
XVIII	TENT5A		617952	autosomal recessive		2018
XIX	MBTPS2		301014	X-linked recessive		2016
XX	MESD		618644	autosomal recessive		2019
XXI	KDELR2		619131	autosomal recessive		2020

Sillence types

Jordanne Whiley^[51]

Atticus Shaffer^[52]

Peter Radtke^[53]

Theresia Haidlmayr^[54]

Osteogenesis 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.^[16]

Type I

Collagen is of normal quality but is produced in insufficient quantities.^[5]: 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;^{[47]: 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.^{[5]: 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).^[47][55]