Brittle Bones
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Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of
genetic disorders A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are ...
that all result in
bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
s that
break Break or Breaks or The Break may refer to: Time off from duties * Recess (break), time in which a group of people is temporarily dismissed from its duties * Break (work), time off during a shift/recess ** Coffee break, a short mid-morning rest ...
easily. The range of symptoms—on the
skeleton A skeleton is the structural frame that supports the body of most animals. There are several types of skeletons, including the exoskeleton, which is a rigid outer shell that holds up an organism's shape; the endoskeleton, a rigid internal fra ...
as well as on the body's other
organs In a multicellular organism, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to a ...
—may be mild to severe. Symptoms found in various types of OI include whites of the eye (sclerae) that are blue instead,
short stature Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called ...
, loose joints,
hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spo ...
, breathing problems and problems with the teeth (
dentinogenesis imperfecta Dentinogenesis imperfecta (DI) is a genetic disorder of Human tooth development, tooth development. It is inherited in an autosomal dominant pattern, as a result of mutations on chromosome 4q21, in the dentine sialophosphoprotein gene (DSPP). It ...
). Potentially life-threatening complications, all of which become more common in more severe OI, include: tearing (
dissection Dissection (from Latin ' "to cut to pieces"; also called anatomization) is the dismembering of the body of a deceased animal or plant to study its anatomical structure. Autopsy is used in pathology and forensic medicine to determine the cause of ...
) of the major
arteries An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...
, such as the aorta; pulmonary valve insufficiency secondary to distortion of the
ribcage The rib cage or thoracic cage is an endoskeletal enclosure in the thorax of most vertebrates that comprises the ribs, vertebral column and sternum, which protect the vital organs of the thoracic cavity, such as the heart, lungs and great vessel ...
; and basilar invagination. The underlying mechanism is usually a problem with
connective tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...
due to a lack of, or poorly formed,
type I collagen Type I collagen is the most abundant collagen of the human body, consisting of around 90% of the body's total collagen in vertebrates. Due to this, it is also the most abundant protein type found in all vertebrates. Type I forms large, eosinop ...
. In more than 90% of cases, OI occurs due to
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in the ''
COL1A1 Collagen, type I, alpha 1, also known as alpha-1 type I collagen, is a protein that in humans is encoded by the gene. ''COL1A1'' encodes the major component of type I collagen, the fibrillar collagen found in most connective tissues, including ...
'' or ''
COL1A2 Collagen alpha-2(I) chain is a protein that in humans is encoded by the ''COL1A2'' gene. This gene encodes one of the chains for type I collagen, the fibrillar collagen found in most connective tissues. Mutations in this gene are associated with ...
'' genes. These mutations may be
hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...
in an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
manner but may also occur spontaneously (''
de novo De novo (Latin, , used in English to mean 'from the beginning', 'anew') may refer to: Science and computers * ''De novo'' mutation, a new germline mutation not inherited from either parent * ''De novo'' protein design, the creation of a protei ...
''). 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. , 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 A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...
or
DNA sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, thymine, cytosine, and guanine. The ...
. Although there is no cure, most cases of OI do not have a major effect on life expectancy, death during childhood from it is rare, and many adults with OI can achieve a significant degree of
autonomy In developmental psychology and moral, political, and bioethical philosophy, autonomy is the capacity to make an informed, uncoerced decision. Autonomous organizations or institutions are independent or self-governing. Autonomy can also be ...
despite
disability Disability is the experience of any condition that makes it more difficult for a person to do certain activities or have equitable access within a given society. Disabilities may be Cognitive disability, cognitive, Developmental disability, d ...
. Maintaining a
healthy lifestyle Health promotion is, as stated in the 1986 World Health Organization (WHO) Ottawa Charter for Health Promotion, the "process of enabling people to increase control over, and to improve their health." Scope The WHO's 1986 Ottawa Charter for He ...
by exercising, eating a balanced diet sufficient in
vitamin D Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...
and
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
, and avoiding
smoking Smoking is a practice in which a substance is combusted, and the resulting smoke is typically inhaled to be tasted and absorbed into the bloodstream of a person. Most commonly, the substance used is the dried leaves of the tobacco plant, whi ...
can help prevent fractures.
Genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. ...
may be sought by those with OI to prevent their children from inheriting the disorder from them. Treatment may include acute care of broken bones,
pain medication An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in so ...
,
physical therapy Physical therapy (PT), also known as physiotherapy, is a healthcare profession, as well as the care provided by physical therapists who promote, maintain, or restore health through patient education, physical intervention, disease preventio ...
,
mobility aids A mobility aid is a device designed to assist individuals with impaired movement. These devices help people walk, maintain balance, or get around more easily. Mobility aids include walking supports like canes, crutches, and walkers for those w ...
such as leg braces and
wheelchairs A wheelchair is a mobilized form of chair using two or more wheels, a footrest, and an armrest usually cushioned. It is used when walking is difficult or impossible to do due to illnesses, injury, disabilities, or age-related health conditions ...
, vitamin D supplementation, and, especially in childhood, rodding surgery. Rodding is an implantation of metal
intramedullary rod An intramedullary rod, also known as an intramedullary nail (IM nail) or inter-locking nail or Küntscher nail (without proximal or distal fixation), is a metal rod forced into the medullary cavity of a bone. IM nails have long been used to treat ...
s along the
long bones The long bones are those that are longer than they are wide. They are one of five types of bones: long, short, flat, irregular and sesamoid. Long bones, especially the femur and tibia, are subjected to most of the load during daily activities a ...
(such as the
femur The femur (; : femurs or femora ), or thigh bone is the only long bone, bone in the thigh — the region of the lower limb between the hip and the knee. In many quadrupeds, four-legged animals the femur is the upper bone of the hindleg. The Femo ...
) in an attempt to strengthen them.
Medical research Medical research (or biomedical research), also known as health research, refers to the process of using scientific methods with the aim to produce knowledge about human diseases, the prevention and treatment of illness, and the promotion of ...
also supports the use of medications of the
bisphosphonate Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed to treat osteoporosis. Evidence shows that they reduce the risk of fracture in ...
class, such as
pamidronate Pamidronic acid or pamidronate disodium or APD (marketed as Aredia among others), is a nitrogen-containing bisphosphonate used to prevent osteoporosis. It was patented in 1971 and approved for medical use in 1987. Medical uses It is used to pr ...
, to increase
bone density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although medicine#Clinical practice, clinically it is measured by ...
. Bisphosphonates are especially effective in children; however, it is unclear if they either increase
quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
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 Latin ( or ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally spoken by the Latins in Latium (now known as Lazio), the lower Tiber area around Rome, Italy. Through the expansion o ...
term ''osteogenesis imperfecta'' was coined by Dutch anatomist Willem Vrolik in 1849; translated literally, it means "imperfect bone formation". __TOC__


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 Bowed string instruments are a subcategory of string instruments that are played by a bow rubbing the strings. The bow rubbing the string causes vibration which the instrument emits as sound. Despite the numerous specialist studies devoted to t ...
, sometimes extremely so. The weakness of the bones causes them to
fracture Fracture is the appearance of a crack or complete separation of an object or material into two or more pieces under the action of stress (mechanics), stress. The fracture of a solid usually occurs due to the development of certain displacemen ...
easily—a study at the Endocrine Unit at the National Institute of Child Health in
Karachi, Pakistan Karachi is the capital city of the Administrative units of Pakistan, province of Sindh, Pakistan. It is the List of cities in Pakistan by population, largest city in Pakistan and 12th List of largest cities, largest in the world, with a popul ...
found an average of 5.8 fractures per year in untreated children. Fractures typically occur much less after
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...
, but begin to increase again in women after
menopause Menopause, also known as the climacteric, is the time when Menstruation, menstrual periods permanently stop, marking the end of the Human reproduction, reproductive stage for the female human. It typically occurs between the ages of 45 and 5 ...
and in men between the ages of 60 and 80.
Joint hypermobility Hypermobility, also known as double-jointedness, describes joints that stretch farther than normal. For example, some hypermobile people can bend their thumbs backwards to their wrists, bend their knee joints backwards, put their leg behind the ...
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 Ehlers–Danlos syndromes (EDS) is a group of 14 genetic connective-tissue disorders. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Co ...
. One OI mutation also causes combined Ehler–Danlos syndrome: "OIEDS1". ( Cabral, ''et al.'' 2005, Rasmussen 2020)


Otologic

By the age of 50, about 50% of adults with OI experience significant
hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spo ...
, much earlier as compared to the general population. Hearing loss in OI may or may not be associated with visible deformities of the
ossicles The ossicles (also called auditory ossicles) are three irregular bones in the middle ear of humans and other mammals, and are among the smallest bones in the human body. Although the term "ossicle" literally means "tiny bone" (from Latin ''ossi ...
and
inner ear The inner ear (internal ear, auris interna) is the innermost part of the vertebrate ear. In vertebrates, the inner ear is mainly responsible for sound detection and balance. In mammals, it consists of the bony labyrinth, a hollow cavity in the ...
. Hearing loss frequently begins during the second, third, and fourth decades of life, and may be
conductive In physics and electrical engineering, a conductor is an object or type of material that allows the flow of Electric charge, charge (electric current) in one or more directions. Materials made of metal are common electrical conductors. The flow ...
, 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. Other parts of the inner ear may also be affected by OI. causing
balance Balance may refer to: Common meanings * Balance (ability) in biomechanics * Balance (accounting) * Balance or weighing scale * Balance, as in equality (mathematics) or equilibrium Arts and entertainment Film * Balance (1983 film), ''Balance'' ( ...
issues; however, only small studies have found links between
vertigo Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...
and OI. 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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
, 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, a feature of the C2 vertebra.
Neurosurgery Neurosurgery or neurological surgery, known in common parlance as brain surgery, is the specialty (medicine), medical specialty that focuses on the surgical treatment or rehabilitation of disorders which affect any portion of the nervous system ...
may be needed to correct severe abnormalities when they risk the patient's life or cause either great suffering or intolerable neurological deficits.


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 a multicellular organism, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to a ...
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 A heart valve is a biological one-way valve that allows blood to flow in one direction through the chambers of the heart. A mammalian heart usually has four valves. Together, the valves determine the direction of blood flow through the heart. Hea ...
, to the
vasculature In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart an ...
, it is an integral part of the
connective tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...
of the
lungs The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory syste ...
. As such, cardiovascular complications, among them
aortic insufficiency Aortic regurgitation (AR), also known as aortic insufficiency (AI), is the leaking of the aortic valve of the heart that causes blood to flow in the reverse direction during ventricular diastole, from the aorta into the left ventricle. As a conse ...
,
aortic aneurysm An aortic aneurysm is an enlargement (dilatation) of the aorta to greater than 1.5 times normal size. Typically, there are no symptoms except when the aneurysm dissects or ruptures, which causes sudden, severe pain in the abdomen and lower back ...
, and arterial dissections, are sometimes
comorbid In medicine, comorbidity refers to the simultaneous presence of two or more medical conditions in a patient; often co-occurring (that is, concomitant or concurrent) with a primary condition. It originates from the Latin term (meaning "sicknes ...
with OI, but not as frequently as they are comorbid with
Marfan syndrome Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with dolichostenomelia, long arms, legs, Arachnodactyly, fingers, and toes. They also typically ha ...
. Respiratory illnesses are a major cause of death in OI. The most obvious source of respiratory problems in OI is
pulmonary insufficiency Pulmonary (or pulmonic) regurgitation (or insufficiency, incompetence) is a condition in which the pulmonary valve is incompetent and allows backflow from the pulmonary artery to the right ventricle of the heart during diastole. While a small am ...
caused by problems in the architecture of the
thoracic wall The thoracic wall or chest wall is the boundary of the thoracic cavity. Structure The bony skeletal part of the thoracic wall is the rib cage, and the rest is made up of muscle, skin, and fasciae. The chest wall has 10 layers, namely (from su ...
. However, respiratory tract infections, such as
pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
, are also more fatal among those with OI than the general population. Those with more severe
ribcage The rib cage or thoracic cage is an endoskeletal enclosure in the thorax of most vertebrates that comprises the ribs, vertebral column and sternum, which protect the vital organs of the thoracic cavity, such as the heart, lungs and great vessel ...
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 Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...
in two studies on patients affected by OI. Chronic constipation is especially common, and is thought to be aggravated by an asymmetric
pelvis The pelvis (: pelves or pelvises) is the lower part of an Anatomy, anatomical Trunk (anatomy), trunk, between the human abdomen, abdomen and the thighs (sometimes also called pelvic region), together with its embedded skeleton (sometimes also c ...
( acetabular protrusion). Especially in childhood, OI-associated constipation may cause a feeling of fullness and associated food refusal, leading to
malnutrition Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is a deficiency, excess, or imbalance of energy, protein and other nutrients which adversely affects the body's tissues a ...
.


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 A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek σύνδρομον, meaning "concurrence". When a syndrome is paire ...
, according to their
clinical presentation In a physical examination, medical examination, clinical examination, or medical checkup, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally consists of a series of questions ...
, without taking into account the genetic cause of their disease. 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 Collagen, type I, alpha 1, also known as alpha-1 type I collagen, is a protein that in humans is encoded by the gene. ''COL1A1'' encodes the major component of type I collagen, the fibrillar collagen found in most connective tissues, including ...
'' or ''
COL1A2 Collagen alpha-2(I) chain is a protein that in humans is encoded by the ''COL1A2'' gene. This gene encodes one of the chains for type I collagen, the fibrillar collagen found in most connective tissues. Mutations in this gene are associated with ...
''. Symptoms vary widely 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 types

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

Collagen is of normal quality but is produced in insufficient quantities. Bones fracture more easily than in the general public, but not as easily as more severe types of OI; there might be
scoliosis Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...
, albeit mild compared to OI types III and IV, with a lower
Cobb angle Cobb may refer to: People * Cobb (surname), a list of people and fictional characters with the surname Cobb * Cobb Rooney (1900–1973), American professional football running back Places New Zealand * Cobb River * Cobb Reservoir * Cobb Powe ...
; the joints may be loose; blue sclerae may be apparent; hearing loss is likely to occur; 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. 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 Dentinogenesis imperfecta (DI) is a genetic disorder of Human tooth development, tooth development. It is inherited in an autosomal dominant pattern, as a result of mutations on chromosome 4q21, in the dentine sialophosphoprotein gene (DSPP). It ...
(opalescent teeth). People with type I generally have a normal lifespan.


Type

Collagen is fatally defective at its
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...
. Most cases result in death shortly after birth, or within the first year of life, due to
respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a r ...
. Another common cause of death is intracranial bleeds from skull fractures present at, or sustained during or shortly after, birth. In many cases, the newborn already has multiple broken bones at the time of birth. Type II infants also exhibit severe
respiratory The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies gr ...
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 Mechanical ventilation or assisted ventilation is the Medicine, medical term for using a ventilator, ventilator machine to fully or partially provide artificial ventilation. Mechanical ventilation helps move air into and out of the lungs, wit ...
. 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 Prenatal development () involves the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal deve ...
" 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.


Type

Collagen quantity is sufficient, but is not of a high enough quality. 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; features only found in type III are its progressively deforming nature 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, 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 Dwarfism is a condition of people and animals marked by unusually small size or short stature. In humans, it is sometimes defined as an adult height of less than , regardless of sex; the average adult height among people with dwarfism is . '' ...
(a final adult height frequently less than ); loose joints; and possible respiratory problems due to low
rib cage The rib cage or thoracic cage is an endoskeletal enclosure in the thorax of most vertebrates that comprises the ribs, vertebral column and sternum, which protect the vital organs of the thoracic cavity, such as the heart, lungs and great ve ...
volume causing low
lung volumes Lung volumes and lung capacities are measures of the volume of air in the lungs at different phases of the respiratory cycle. The average total lung capacity of an adult human male is about 6 litres of air. Tidal breathing is normal, resting br ...
. Due to the severity of the issues with the bones, neurological and seizure disorders are more likely to develop in type III. Basilar invagination, which puts pressure on the
brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
, may cause or contribute to early death; surgical treatment of it is more complex in OI cases.


Type

Collagen quantity is sufficient, but is not of a high enough quality. 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, 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. As such, type IV OI is often termed "variable" OI, 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 Dentinogenesis imperfecta (DI) is a genetic disorder of Human tooth development, tooth development. It is inherited in an autosomal dominant pattern, as a result of mutations on chromosome 4q21, in the dentine sialophosphoprotein gene (DSPP). It ...
.


Genetically defined types (types –)

As of 2020, fifteen types of OI are defined genetically: * Type – Having the same clinical features as type IV, it can be clinically distinguished by observing a "mesh-like" appearance to a
bone biopsy A bone biopsy is a procedure in which a small bone sample is removed from the outer layers of bone for examination, unlike a bone marrow biopsy, which involves the innermost part of the bone. The bone biopsy sample retains the architecture of bon ...
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 Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...
calluses A callus (: calluses) is an area of thickened and sometimes hardened skin that forms as a response to repeated friction, pressure, or other irritation. Since repeated contact is required, calluses are most often found on the feet and hands, b ...
(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 The interosseous membrane of the forearm (rarely middle or intermediate radioulnar joint) is a fibrous sheet that connects the interosseous margins of the radius and the ulna. It is the main part of the radio-ulnar syndesmosis, a fibrous joint ...
, which may make it difficult to turn the wrist. Other features of this condition may include
pulled elbow A pulled elbow, also known as nursemaid's elbow or a radial head subluxation, is when the ligament that wraps around the radial head slips off. Often a child will hold their arm against their body with the elbow slightly bent. They will not mov ...
, 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 11 Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tota ...
p15.5. 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 – With the same clinical features as type III, it is distinguished by bones which have an appearance similar to that seen in
osteomalacia Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of b ...
. Type VI is caused by a
loss-of-function mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis ...
in the '' SERPINF1'' gene on
chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 84 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total DN ...
p13.3. * Type – OI caused by a mutation in the gene '' CRTAP'' on
chromosome 3 Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans more than 201 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA ...
p22.3; 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 First nations are indigenous settlers or bands. First Nations, first nations, or first peoples may also refer to: Indigenous groups *List of Indigenous peoples *First Nations in Canada, Indigenous peoples of Canada who are neither Inuit nor Mé ...
people in
Quebec Quebec is Canada's List of Canadian provinces and territories by area, largest province by area. Located in Central Canada, the province shares borders with the provinces of Ontario to the west, Newfoundland and Labrador to the northeast, ...
. * Type – OI caused by a mutation in the gene '' LEPRE1'' on
chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which a ...
p34.2; clinically similar to OI types II and III, depending on affected individual. * Type – OI caused by homozygous or compound heterozygous mutation in the '' PPIB'' gene on
chromosome 15 Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 99.7 million base pairs (the building material of DNA) and represents between 3% and 3.5% of the total DNA ...
q22.31. * Type – OI caused by homozygous mutation in the '' SERPINH1'' gene on chromosome 11q13. * Type – OI caused by mutations in ''
FKBP10 FK506-binding protein 10 is a protein that in humans is encoded by the ''FKBP10'' gene. The protein encoded by this gene belongs to the FKBP-type peptidyl-prolyl Cis-acting, cis/Trans-acting, trans isomerase family. It is located in endoplasmic r ...
'' 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 – OI caused by a
frameshift mutation A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet natur ...
in '' SP7'' on
chromosome 12 Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
q13.13. This mutation causes bone deformities, fractures, and delayed
tooth eruption Tooth eruption is a process in tooth development in which the teeth enter the mouth and become visible. It is currently believed that the periodontal ligament plays an important role in tooth eruption. The first human teeth to appear, the decidu ...
. * Type – OI caused by a mutation in the bone morphogenetic protein 1 (''BMP1'') gene on
chromosome 8 Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 146 million base pairs (the building material of DNA) and represents between 4.5 and 5.0% of the total DNA i ...
p21.3. This mutation causes recurrent fractures, high bone mass, and hypermobile joints. * Type – OI caused by mutations in the '' TMEM38B'' gene on
chromosome 9 Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of DN ...
q31.2. This mutation causes recurrent fractures and
osteopenia Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop o ...
, although the disease trajectory is highly variable. * Type – OI caused by homozygous or compound heterozygous mutations in the ''WNT1'' gene on chromosome 12q13.12. It is autosomal recessive. * Type – 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 – OI caused by homozygous mutation in the '' SPARC'' gene on
chromosome 5 Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 182 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. Ch ...
q33, causing a defect in the protein
osteonectin Osteonectin (ON) also known as secreted protein acidic and rich in cysteine (SPARC) or basement-membrane protein 40 (BM-40) is a protein that in humans is encoded by the ''SPARC'' gene. Osteonectin is a glycoprotein in the bone that binds calci ...
, which leads to severe disease characterized by generalized
platyspondyly Congenital vertebral anomalies are a collection of malformations of the spine. Most, around 85%, are not clinically significant, but they can cause compression of the spinal cord by deforming the vertebral canal or causing instability. This condit ...
, dependence on a wheelchair, and recurrent fractures. * Type – OI caused by homozygous mutation in the '' FAM46A'' gene on
chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans nearly 171 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total DNA i ...
q14.1. Characterized by congenital bowing of the long bones,
Wormian bones Wormian bones, also known as intrasutural bones or sutural bones, are extra bone pieces that can occur within a suture (joint) in the skull. These are irregular isolated bones that can appear in addition to the usual centres of ossification of the ...
, blue sclerae, vertebral collapse, and multiple fractures in the first years of life. *Type – 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 ''Main Article'': Sex linkage X-linked recessive inheritance is a mode of Mendelian inheritance, inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily hemizygous for ...
pattern of inheritance, making it the only type that is more common in males than females. OI type XIX disrupts
regulated intramembrane proteolysis Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral ...
, which is critical for healthy bone formation. *Type – 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 Global developmental delay is an umbrella term used when children are significantly delayed in two or more areas of development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech delay, spe ...
, a first among OI types. OI type XX disrupts the
Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...
, which is thought to have a role in bone development. *Type – OI caused by homozygous mutation in the '' KDELR2'' gene on
chromosome 7 Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 160 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total DN ...
p22.1. 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.


Genetics

Osteogenesis imperfecta is a group of genetic disorders, all of which cause bone fragility. OI has high
genetic heterogeneity Genetic heterogeneity refers to different genetic causes for the same disease and can be classified into three types: allelic heterogeneity, locus heterogeneity, and phenotypic heterogeneity. Allelic heterogeneity occurs when different mutations wi ...
, that is, many different genetic
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
lead to the same or similar sets of observable symptoms (
phenotypes In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological properti ...
). 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 Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
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 Matrix (: matrices or matrixes) or MATRIX may refer to: Science and mathematics * Matrix (mathematics), a rectangular array of numbers, symbols or expressions * Matrix (logic), part of a formula in prenex normal form * Matrix (biology), the m ...
interactions; a compromised cell matrix structure; and, abnormal interaction between non-collagenous
proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, re ...
and collagen. Previous research led to the belief that OI was an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
disorder with few other variations in genomes. However, with the lowering of the cost of
DNA sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, thymine, cytosine, and guanine. The ...
in the wake of 2003's
Human Genome Project The Human Genome Project (HGP) was an international scientific research project with the goal of determining the base pairs that make up human DNA, and of identifying, mapping and sequencing all of the genes of the human genome from both a ...
, 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 Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
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 Fold, folding or foldable may refer to: Arts, entertainment, and media * ''Fold'' (album), the debut release by Australian rock band Epicure * Fold (poker), in the game of poker, to discard one's hand and forfeit interest in the current pot *Abov ...
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 An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...
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. 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 A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo ...
of one parent have a dominant form of OI, but not enough of their
somatic cells In cellular biology, a somatic cell (), or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Somatic cells compose the body of an organism a ...
do to cause symptoms or obvious disability in the parent—the parent's different cells have two (or more) sets of slightly different DNA. It has been clinically observed that ≈5–10% of cases of OI types II and III are attributable to genetic mosaicism.


Pathophysiology

People with OI are either born with defective
connective tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...
, 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 Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in th ...
such as chaperone proteins, the
Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...
, the
BRIL Bril is a surname. Notable people with the surname include: * Ben Bril, Dutch boxer *Joel Bril, pen name of Joel Löwe * Matthaeus Bril, Flemish painter *Paul Bril Paul Bril (1554 – 7 October 1626) was a Southern Netherlands, Flemish painter ...
protein, et cetera. In type I the collagen's structure itself is normal, it is just its quantity that is low. Types II, III and IV are usually, but not always, related to a deficiency of
type I collagen Type I collagen is the most abundant collagen of the human body, consisting of around 90% of the body's total collagen in vertebrates. Due to this, it is also the most abundant protein type found in all vertebrates. Type I forms large, eosinop ...
. One possible deficiency arises from an
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
substitution of
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
to a bulkier amino acid, such as
alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group sid ...
, in the
collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...
protein's
triple helix In the fields of geometry and biochemistry, a triple helix (: triple helices) is a set of three congruent geometrical helices with the same axis, differing by a translation along the axis. This means that each of the helices keeps the same distan ...
structure. The larger amino acid side-chains lead to
steric effects Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape (conformational isomerism, co ...
that creates a bulge in the collagen
complex Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...
, which in turn influences both the molecular
nanomechanics Nanomechanics is a branch of '' nanoscience'' studying fundamental ''mechanical'' (elastic, thermal and kinetic) properties of physical systems at the nanometer scale. Nanomechanics has emerged on the crossroads of biophysics, classical mechanics, ...
and the interaction between molecules, which are both compromised. Depending on both the location of the substitution and the amino acid being used instead, different effects are seen which account for the type diversity in OI despite the same two collagen genes being responsible for most cases. Replacements of glycine with
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
or
cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
are seen less often in fatal type II OI, while replacements with
valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deproton ...
,
aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...
,
glutamic acid Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α- amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can ...
, or
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
are seen more often. At a larger scale, the relationship between the collagen
fibrils Fibrils () are structural biological materials found in nearly all living organisms. Not to be confused with fibers or filaments, fibrils tend to have diameters ranging from 10 to 100 nanometers (whereas fibers are micro to milli-scale stru ...
and
hydroxyapatite Hydroxyapatite (International Mineralogical Association, IMA name: hydroxylapatite) (Hap, HAp, or HA) is a naturally occurring mineral form of calcium apatite with the Chemical formula, formula , often written to denote that the Crystal struc ...
crystals to form bone is altered, causing brittleness. Bone fractures occur because 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 because the
homogeneous Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...
stress state normally found in healthy collagen fibrils is lost. OI is therefore a multi-scale phenomenon, where defects at the smallest levels of tissues (genetic, nano, micro)
domino Dominoes is a family of tile-based games played with gaming pieces. Each domino is a rectangular tile, usually with a line dividing its face into two square ''ends''. Each end is marked with a number of spots (also called '' pips'' or ''dots'' ...
to affect the macro level of tissues.


Diagnosis

Diagnosis is typically based on
medical imaging Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to revea ...
, including plain
X-rays An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...
, and symptoms. In severe OI, signs on medical imaging include abnormalities in all extremities and in the spine. As X-rays are often insensitive to the comparatively smaller bone density loss associated with type I OI, DEXA scans may be needed. An OI diagnosis can be confirmed through DNA or collagen protein analysis, but in many cases, the occurrence of bone fractures with little trauma and the presence of other clinical features such as blue sclerae are sufficient for a diagnosis. A
skin biopsy Skin biopsy is a biopsy technique in which a skin lesion is removed to be sent to a pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 day ...
can be performed to determine the structure and quantity of type I collagen. While DNA testing can confirm the diagnosis, it cannot absolutely exclude it because not all mutations causing OI are yet 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 visible. Relative to control, OI
cortical bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, an ...
shows increased porosity, canal diameter, and connectivity in micro-computed tomography. OI can also be detected before birth by using an ''in vitro'' genetic testing technique such as amniocentresis.


Genetic testing

In order to determine whether osteogenesis imperfecta is present, genetic sequencing of the most common problematic genes, ''COL1A1'', ''COL1A2'', and ''IFITM5'', may be done; if no mutation is found yet OI is still suspected, the other 10+ genes known to cause OI may be tested. Duplication and deletion testing is also suggested to parents who suspect their child has OI. The presence of frameshift mutations caused by duplications and deletions is generally the cause of increased severity of disease.


Differential diagnosis

An important differential diagnosis of OI is
child abuse Child abuse (also called child endangerment or child maltreatment) is physical abuse, physical, child sexual abuse, sexual, emotional and/or psychological abuse, psychological maltreatment or Child neglect, neglect of a child, especially by a p ...
, as both may present to a clinician with multiple fractures in various stages of healing. Differentiating them can be difficult, especially when no other characteristic features of OI are present. This can become an issue in court; in the United States, several child abuse cases were resolved with a finding that osteogenesis imperfecta was the true cause of a child's fractures, leading to lawsuits seeking redress such as ''Alice Velasquez, et al. v. United States''. Other differential diagnoses include
rickets Rickets, scientific nomenclature: rachitis (from Greek , meaning 'in or of the spine'), is a condition that results in weak or soft bones in children and may have either dietary deficiency or genetic causes. Symptoms include bowed legs, stun ...
and
osteomalacia Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of b ...
, both caused by
malnutrition Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is a deficiency, excess, or imbalance of energy, protein and other nutrients which adversely affects the body's tissues a ...
, as well as rare skeletal syndromes such as Bruck syndrome,
hypophosphatasia Hypophosphatasia (; also called deficiency of alkaline phosphatase, phosphoethanolaminuria, or Rathbun's syndrome; sometimes abbreviated HPP) is a rare, and sometimes fatal, inherited metabolic bone disease. Clinical symptoms are heterogeneous ...
, geroderma osteodysplasticum, and
Ehlers–Danlos syndrome Ehlers–Danlos syndromes (EDS) is a group of 14 genetic connective-tissue disorders. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Co ...
. Various forms of
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
, such as
iatrogenic Iatrogenesis is the causation of a disease, a harmful complication, or other ill effect by any medical activity, including diagnosis, intervention, error, or negligence." Iatrogenic", ''Merriam-Webster.com'', Merriam-Webster, Inc., accessed 27 ...
osteoporosis, idiopathic juvenile osteoporosis, disuse osteoporosis and exercise-related osteoporosis should also be considered as explanations when OI is suspected.


Treatment

There is no cure for osteogenesis imperfecta. Maintaining a healthy lifestyle by exercising and avoiding smoking can help prevent fractures. Treatment may include care of broken bones, pain medication,
physical therapy Physical therapy (PT), also known as physiotherapy, is a healthcare profession, as well as the care provided by physical therapists who promote, maintain, or restore health through patient education, physical intervention, disease preventio ...
, mobility aids such as braces or wheelchairs, and surgery. Judging the success or failure of treatment can be difficult in OI patients, as decreased bone fracture rates may just be coincidental. While these rates are often used in medical studies to judge treatment efficacy, a Norwegian study of fifteen people with OI emphasized that they feel doctors should consider the whole patient and not just fracture rates.


Acute bone fracture care

Bone fractures are treated in individuals with osteogenesis imperfecta in much the same way as they are treated in the general population—OI bone heals at the same rate as non-OI bone. A greater emphasis is placed on using lightweight materials to immobilize the fracture, as in moderate or severe types of OI, using heavy casts, such as hip spica casts, can cause fractures at the bones at the boundaries of the cast, as well as generalized
osteopenia Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop o ...
. The lightweight cast or splint is then replaced with a removable orthosis after a few weeks and once evidence of union is seen on X-ray. In order to prevent a
nonunion Nonunion is permanent failure of healing following a broken bone unless intervention (such as surgery) is performed. A fracture with nonunion generally forms a structural resemblance to a fibrous joint, and is therefore often called a "false jo ...
or
malunion A malunion is when a fractured bone does not heal properly. Some ways that it shows is by having the bone being twisted, shorter, or bent. Malunions can occur by having the bones improperly aligned when immobilized, having the cast taken off t ...
, all fractures should be immobilized, even if the fracture seems trivial ( microfracture), as people with OI are at greater risk of nonunion. Bone
infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
s secondary to fractures are treated as and when they occur with the appropriate
antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
and
antiseptics An antiseptic ( and ) is an antimicrobial substance or compound that is applied to living tissue to reduce the possibility of sepsis, infection, or putrefaction. Antiseptics are generally distinguished from ''antibiotics'' by the latter's abili ...
, as in the general population.


Medications


Bisphosphonates

In 1998, an initial observational trial demonstrated the effectiveness of intravenous
pamidronate Pamidronic acid or pamidronate disodium or APD (marketed as Aredia among others), is a nitrogen-containing bisphosphonate used to prevent osteoporosis. It was patented in 1971 and approved for medical use in 1987. Medical uses It is used to pr ...
, a
bisphosphonate Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed to treat osteoporosis. Evidence shows that they reduce the risk of fracture in ...
which had previously been used in adults to treat
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
. In severe OI, this trial showed that 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 Alendronic acid, sold under the brand name Fosamax among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone. It is taken by mouth. Use is often recommended together with vitamin D, calcium supplementa ...
and intravenous pamidronate, equivalent. In a 2013 double-blind trial of children with mild OI, oral
risedronate Risedronic acid, often used as its sodium salt risedronate sodium, is a bisphosphonate. It slows down the cells which break down bone. It's used to treat or prevent osteoporosis, and treat Paget's disease of bone. It is taken by mouth. It was p ...
increased bone mineral densities, and reduced nonvertebral fractures. However, it did not decrease new vertebral fractures. A ''Cochrane'' review in 2016 concluded that though bisphosphonates seem to improve bone mineral density, it is uncertain whether this leads either to a reduction in
bone fractures A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a ''c ...
or improvement in the
quality of life Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
of individuals with osteogenesis imperfecta. Even in trials with as many as 125 children, no causal link has been found between bisphosphonates and decreased fracture rates; placebo controlled trials were also unable to prove that they brought about increased strength,
motor control Motor control is the regulation of movements in organisms that possess a nervous system. Motor control includes conscious voluntary movements, subconscious muscle memory and involuntary reflexes, as well as instinctual taxes. To control ...
or lower pain levels. Bisphosphonates are not as effective at increasing the bone mineral density of adults.


Nutritional supplements

OI is a genetic disorder and is not caused by insufficient intake of any vitamin or mineral; supplementation cannot cure OI. Nevertheless, people with OI tend to be severely deficient in
vitamin D Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...
at much higher rates than the general population, and the cause of this is not well understood. The severity of the deficiency and the likelihood of its occurrence is thought to be related to severity of OI. Vitamin D supplementation may be recommended, at least until levels of 25(OH)D3 in a patient's blood return to normal.
Vitamin D deficiency Vitamin D deficiency or hypovitaminosis D is a vitamin D level that is below normal. It most commonly occurs in people when they have inadequate exposure to sunlight, particularly sunlight with adequate ultraviolet B rays (UVB). Vitamin D def ...
is also a concern as it may decrease the benefit of bisphosphanates.


Surgery

A
surgery Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery s ...
of any type inherently carries more risks when done on a patient who has (especially moderate to severe) OI. Skeletal deformities and dentinogenesis imperfecta may hinder access to the airway. Use of, and
weaning Weaning is the process of gradually introducing an infant human or other mammal to what will be its adult diet while withdrawing the supply of its mother's milk. In the United Kingdom, UK, weaning primarily refers to the introduction of solid ...
off of,
mechanical ventilation Mechanical ventilation or assisted ventilation is the Medicine, medical term for using a ventilator, ventilator machine to fully or partially provide artificial ventilation. Mechanical ventilation helps move air into and out of the lungs, wit ...
is also more challenging to carry out on patients with OI. During the procedure itself or the healing process, defective OI collagen may lead to bleeding diatheses. The safety of anesthesia is also of more concern among patients with OI, with anesthetic complications 5.6x more likely to occur when the patient has OI type III. A unique concern of anesthesia in OI is
perioperative The perioperative period is the period of a patient's surgical procedure. It commonly includes ward admission, anesthesia, surgery, and recovery. Perioperative may refer to the three phases of surgery: preoperative, intraoperative, and postoperat ...
fracture—fractures sustained due to patient transfer and airway access techniques that, while routine when a patient's bones are strong, may cause injury with brittle OI bones. As an example, due to a 1972 report of a
humerus The humerus (; : humeri) is a long bone in the arm that runs from the shoulder to the elbow. It connects the scapula and the two bones of the lower arm, the radius (bone), radius and ulna, and consists of three sections. The humeral upper extrem ...
fracture from a
sphygmomanometer A sphygmomanometer ( ), also known as a blood pressure monitor, blood pressure machine, or blood pressure gauge, is a device used to measure blood pressure, composed of an inflatable cuff to collapse and then release the artery under the cuff i ...
cuff sustained in an OI patient during surgery, blood pressure monitoring protocols are often modified for patients with OI, with
neonatal In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to Juvenile (orga ...
size cuffs and machine settings being used even in adults; further, the least deformed of the patient's limbs is preferred to receive the cuff.


Rodding

Metal rods can be surgically inserted in the long bones to improve strength, a procedure developed by Harold A. Sofield when he was Chief of Staff at Chicago's
Shriners Hospitals for Children Shriners Hospitals for Children, commonly known as Shriners Children's, is a network of non-profit children's hospitals and other pediatric medical facilities across North America. Children with orthopaedic conditions, burns, spinal cord inj ...
, a hospital that offers orthopedic care and surgery to children regardless of their family's ability to pay. Large numbers of children with OI came to Shriners, and Sofield experimented with various methods to strengthen their bones. In 1959, with Edward A. , Sofield wrote a seminal article describing a three-part surgery that seemed radical at the time: precisely breaking the bones ("fragmentation"), putting the resulting bone fragments in a straight line ("realignment"), then placing metal rods into the intramedullary canals of the long bones to stabilize and strengthen them ("rod fixation"). His treatment proved useful for increasing the mobility of people with OI, and it has been adopted throughout the world—it became standard surgical treatment for severe OI by 1979, in which year David Sillence found that ≈ of the patients he surveyed with OI type III had undergone at least one rodding surgery. Rodding surgery is often done with the hope that it will offer a path to ambulation,
walking Walking (also known as ambulation) is one of the main gaits of terrestrial locomotion among legged animals. Walking is typically slower than running and other gaits. Walking is defined as an " inverted pendulum" gait in which the body vaults o ...
, to patients with moderate or severe OI. A 2020 review in ''
The Journal of Bone and Joint Surgery ''The Journal of Bone and Joint Surgery'' is a biweekly peer reviewed medical journal in the field of orthopedic surgery. It is published by the non-profit corporation The Journal of Bone and Joint Surgery, Inc. It was established as the ''Transact ...
'' (''JB&JS'') found it remains broadly popular: ≈ of people with OI types III and IV (severe OI) have undergone some form of rodding surgery in their lives, at a mean age of and years respectively; one possible explanation for a tendency towards earlier intervention in type III is that one half of affected children could not walk at all without the surgery, as their limbs were more bowed, so surgery was sought sooner. In those with type III OI who had undergone rodding surgery, 79.5% had the femurs and tibias of both legs rodded. The most common form of rods used are intramedullary (IM) rods, some of which, such as the Fassier–Duval IM rod, are telescoping, meaning that they are designed to grow as the child grows, in an attempt to avoid the necessity of revision surgeries. Telescoping IM rods are widely used, and the common Fassier–Duval IM rod is designed to be used to rod the femur, tibia, and humerus. The surgery involves breaking the long bones in between one and three (or more) places, then fixing the rod alongside the bone to keep it straight. While telescoping IM rods are intended to grow along with both the femur and tibia in developing children; surgeons have a preference to use non-telescoping IM rods, such as Rush rods, in the tibia, which grows less comparatively—the ''JB&JS'' review found that while 69.7% of femurs were treated with telescoping IM rods, only 36.9% of tibiae were. While the review in the ''JB&JS'' was able to correlate receiving rodding surgery with greater mobility across all types of OI, in patients with type IV, the surgery did not decrease the incidence of broken bones as compared to non-rodded patients—while type IV patients with rodded tibiae experienced 0.93 tibia fractures per year, patients with natural tibiae experienced only 0.81. However, in patients with type III, rodding surgery decreased the average number of tibia fractures per year from 0.84 to 0.57.


Spinal

Spinal fusion Spinal fusion, also called spondylodesis or spondylosyndesis, is a surgery performed by Orthopedic surgery#Practice, orthopaedic surgeons or neurosurgeons that joins two or more vertebrae. This procedure can be performed at any level in the spine ...
can be performed either as a preventative measure or to correct existing
scoliosis Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...
, although the inherent fragility of OI bone makes this operation more complex in OI patients than it does with patients who have adolescent
idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause ...
scoliosis, but normal bone density. Despite the risks, however, three Nemours–duPont orthopedic surgeons who specialize in surgical intervention for osteogenesis imperfecta recommend operating if the curve is greater than 50° after a child is past peak height velocity, as the spine's curve can continue to worsen even into adulthood. Due to the risk involved, the same surgeons recommend that surgery for basilar impressions and basilar invaginations should only be carried out if the pressure being exerted on the
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
and
brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...
is causing actual neurological symptoms. Once basilar invagination has become symptomatic, only surgery can halt or reverse the progression of neurological deficits.


Physical therapy

Physical therapy Physical therapy (PT), also known as physiotherapy, is a healthcare profession, as well as the care provided by physical therapists who promote, maintain, or restore health through patient education, physical intervention, disease preventio ...
is generally recommended, however individualized protocols are required due to the variability of OI. Physical therapy is used to strengthen muscles, improve
motility Motility is the ability of an organism to move independently using metabolism, metabolic energy. This biological concept encompasses movement at various levels, from whole organisms to cells and subcellular components. Motility is observed in ...
, improve
flexibility Stiffness is the extent to which an object resists deformation in response to an applied force. The complementary concept is flexibility or pliability: the more flexible an object is, the less stiff it is. Calculations The stiffness, k, of a ...
, and help with
weight maintenance Weight management comprises behaviors, techniques, and physiological processes that contribute to a person's ability to attain and maintain a healthy weight. Most weight management techniques encompass long-term lifestyle strategies that promote ...
, although it must be done in a gentle manner to minimize the risk of bone fracture. In people with OI, exercise often involves
water aerobics Water aerobics (waterobics, aquarobics, aquatic fitness, aquafitness, aquafit) is the performance of aerobic exercise in water such as in a swimming pool. It is done mostly vertically and without swimming typically in waist deep or deeper water. ...
, light resistance exercises, and walking, if the patient is able. However, even in patients with mild OI,
contact sports A contact sport is any sport where physical contact between competitors, or their environment, is an integral part of the game. For example, gridiron football. Contact may come about as the result of intentional or incidental actions by the playe ...
, as well as activities likely to put unnecessary stress on the joints, such as
jumping Jumping or leaping is a form of locomotion or movement in which an organism or non-living (e.g., robotic) mechanical system propels itself through the air along a ballistic trajectory. Jumping can be distinguished from running, galloping and ...
, are contraindicated due to the risks they pose. Individuals with more limited mobility are encouraged to change positions regularly throughout the day; people who sit in a wheelchair most or all of the day are recommended to get out of it every two hours, as a form of exercise, to decrease stiffness, and to prevent
pressure ulcers Pressure ulcers, also known as pressure sores, bed sores or pressure injuries, are localised damage to the skin and/or underlying tissue that usually occur over a bony prominence as a result of usually long-term pressure, or pressure in comb ...
. Individuals with moderate to severe OI, who require assistive mobility devices and adapted vehicles, face significant barriers to access wheelchair-accessible pools or gyms—they either may not have any in their area, nor the means to get there.
Obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
may be more likely to present among those with severe OI, (especially after the age of 20,) and can, in some, cause further declines in mobility. Tilt table whole body vibration may also be done to increase the mobility of long-term immobilized (
bedridden Being bedridden is a form of immobility that can present as the inability to move or even sit upright. It differs from bed-rest, a form of non-invasive treatment that is usually part of recovery or the limitation of activities. Some of the more se ...
) patients with OI; in at least two cases it helped bedridden children to be able to sit upright.


Teeth

More than 1 in 2 people with OI also have dentinogenesis imperfecta (DI)—a congenital abnormality in the formation of
dentin Dentin ( ) (American English) or dentine ( or ) (British English) () is a calcified tissue (biology), tissue of the body and, along with tooth enamel, enamel, cementum, and pulp (tooth), pulp, is one of the four major components of teeth. It i ...
, one of the four major components of the
human tooth Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are great apes characterized by their hairlessness, bipedalism, and high intelli ...
. Dental treatment may pose as a challenge as a result of the various deformities, skeletal and dental, due to OI. Children with OI should go for a dental check-up as soon as their teeth erupt; this may minimize tooth structure loss as a result of abnormal dentine, and they should be monitored regularly to preserve their teeth and oral health. Many people with OI are treated with bisphosphonates, and there are several possible related complications with dental procedures, for example, medication-related osteonecrosis of the jaw (MRONJ). However, no report of bisphosphonate-related MRONJ in either a child or adult with OI was found in a 2016 ''Cochrane'' review of the safety and efficacy of bisphosphonates for OI.


In development


Monoclonal antibodies

Monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Mon ...
have long been considered for OI, but as of 2021, such therapy has not been approved for OI, neither in the European Union nor in the United States. Thus, it is unclear whether they are safe or effective. Among the monoclonal antibodies that have been studied are romosozumab (targets
sclerostin Sclerostin is a protein that in humans is encoded by the ''SOST'' gene. It is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative in neu ...
, by
Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical Corporation, company headquartered in Thousand Oaks, California. As one of the world's largest independent biotechnology companies, Amgen has a ...
), fresolimumab (
TGF-β Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
,
Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
), blosozumab (sclerostin, Lilly), and setrusumab (sclerostin, begun by
Novartis Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...
). Setrusumab, formerly known as BPS-804, is a monoclonal antibody that targets
sclerostin Sclerostin is a protein that in humans is encoded by the ''SOST'' gene. It is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative in neu ...
, and has been studied in OI specifically more than any of the others. In the body, sclerostin binds to the LRP5 and LRP6 receptors, resulting in inhibition of the
Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...
. This decreases bone formation, and is not a problem when a person has healthy bones. It is thought, though, that decreasing the concentration of sclerostin in the body may lead to the formation of more bone, and that is the premise as to why monoclonal antibodies that reduce the concentrations of naturally occurring sclerostin may help strengthen OI bone. While setrusumab was first developed at the pharmaceutical company Novartis, Novartis sold its rights to patent the drug to Mereo Biopharma in 2015, who has continued its development in conjunction with
Ultragenyx Ultragenyx Pharmaceutical Inc. is an American biopharmaceutical company involved in the research and development of novel products for treatment of rare and ultra-rare genetic diseases for which there are typically no approved treatments and hig ...
. In 2019, Mereo announced that it had concluded collecting data for its phase II-B trial of setrusumab; the study was completed on 12 November 2020. Despite the trial data failing to show improvements in bone density on QCT scans, its primary goal, there were improvements on DXA scans. In a September 2020 press release, Mereo said it was seeking to do a
phase III trial The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
in 2021, and had received a Rare Pediatric Disease (RPD) designation from the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA). Romosozumab, which also is a monoclonal antibody targeting sclerostin, is an approved drug in the US and EU for the treatment of
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
. The pharmaceutical industry analyst
Evercore Evercore Inc., formerly known as Evercore Partners, is a global independent investment banking advisory firm founded in 1995 by Roger Altman, David Offensend, and Austin Beutner. The firm has advised on over $4.7 trillion of merger, acquisitio ...
has remarked that "it could wipe out setrusumab's
economics Economics () is a behavioral science that studies the Production (economics), production, distribution (economics), distribution, and Consumption (economics), consumption of goods and services. Economics focuses on the behaviour and interac ...
", as romosozumab is priced more cheaply than a drug for a rare disease would be, claiming that it will be "vital" to Ultragenyx's
profit margins Profit margin is a financial ratio that measures the percentage of profit earned by a company in relation to its revenue. Expressed as a percentage, it indicates how much profit the company makes for every dollar of revenue generated. Profit margi ...
to prove its setrusumab is more efficacious than romosozumab for OI. A clinical trial evaluating romosozumab's efficacy in OI began in September 2020 and as of September 2021 is ongoing. Ultragenyx predicts that its phase 2/3 trials for setrusumab will be completed in 2026.


Prevention

As a genetic disorder, the mainstay of twenty-first century prevention of osteogenesis imperfecta is based on preventing affected individuals from being born in the first place.
Genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. ...
can help patients and their families determine what types of screening, if any, are right for their situation. Patients can consider
preimplantation genetic diagnosis Preimplantation genetic diagnosis (PGD or PIGD) is the genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal ...
after
in vitro fertilization In vitro fertilisation (IVF) is a process of fertilisation in which an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating the ovulatory process, then removing an ovum or ova (egg or eggs) from ...
to select fertilized embryos which are not affected. Common mutations which cause OI may be caught by
exome sequencing Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome (known as the exome). It consists of two steps: the first step is to select only the subs ...
and
whole genome sequencing Whole genome sequencing (WGS), also known as full genome sequencing or just genome sequencing, is the process of determining the entirety of the DNA sequence of an organism's genome at a single time. This entails sequencing all of an organism's ...
. If a pregnancy is already in progress, the procedure of
amniocentesis Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is ...
may be undergone to see if the fetus is affected. If affected, it is up to the family to consider whether or not they want to terminate the pregnancy and try again—raising questions of
medical ethics Medical ethics is an applied branch of ethics which analyzes the practice of clinical medicine and related scientific research. Medical ethics is based on a set of values that professionals can refer to in the case of any confusion or conflict. T ...
and a woman's right to choose. Without intervention, patients with the most common mutations causing osteogenesis imperfecta have a 50% chance per
gestation Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregn ...
of passing on the disorder, as these mutations are inherited in an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
pattern of
Mendelian inheritance Mendelian inheritance (also known as Mendelism) is a type of biological inheritance following the principles originally proposed by Gregor Mendel in 1865 and 1866, re-discovered in 1900 by Hugo de Vries and Carl Correns, and later popularize ...
. Those with the rare
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
forms of OI have a 25% chance of passing on the disorder. Genetic testing of the affected members of the family can be used to determine which inheritance pattern applies. As OI type I may be difficult to detect in a newborn child, the
cord blood Cord blood (umbilical cord blood) is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells, which can be used to treat hematopoietic and genetic disorders ...
of the child can be tested to determine if it has been passed on if the family has already rejected the more invasive genetic screening methods. In more severe cases, the diagnosis may be able to be done via ultrasound, especially if OI is already a possibility. An ethical concern with prenatal screening for OI often arises when parents inquire as to how severely affected their child will be—such questions are as yet difficult to answer conclusively. If a non-affected person has already had a child with OI, there is a greater likelihood (although still quite remote), that their future children will have OI due to genetic mosaicism. The
disability rights The disability rights movement is a global social movement that seeks to secure equal opportunities and equal rights for all disabled people. It is made up of organizations of disability activists, also known as disability advocates, around ...
critique of prenatal screening for OI, held by some
bioethicists Bioethics is both a field of study and professional practice, interested in ethical issues related to health (primarily focused on the human, but also increasingly includes animal ethics), including those emerging from advances in biology, medi ...
and some affected individuals, negatively compares it to
eugenics Eugenics is a set of largely discredited beliefs and practices that aim to improve the genetic quality of a human population. Historically, eugenicists have attempted to alter the frequency of various human phenotypes by inhibiting the fer ...
, with even those not opposed to abortion opposing selective abortions on the ethical ground that their existence betrays the belief that the lives of those with OI are "less worth living ndless valuable".


Prognosis

The
prognosis Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing"; : prognoses) is a medical term for predicting the likelihood or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) ...
of osteogenesis imperfecta depends entirely on its type (see ).


Life expectancy

In the mild form of the disorder, type I, the
life expectancy Human life expectancy is a statistical measure of the estimate of the average remaining years of life at a given age. The most commonly used measure is ''life expectancy at birth'' (LEB, or in demographic notation ''e''0, where '' ...
of patients is near that of the general population. In type II, however, patients only very rarely live past the age of two, and typically die in their first weeks of life. Assessment of the life expectancy of patients with types III and IV is more complicated, as lifestyle choices can cause fatally traumatic injuries that would not have otherwise occurred, or not been fatal in the general population. Life expectancy in type IV OI is thought to be close to normal, but in type III it is lower than in the general population. A 2016 study of data in Denmark's found that across all types of OI, all-cause mortality was three times higher, leading to a loss of around seven years in females and nine years in males. A 1996 study published in the ''
British Medical Journal ''The BMJ'' is a fortnightly peer-reviewed medical journal, published by BMJ Publishing Group Ltd, which in turn is wholly-owned by the British Medical Association (BMA). ''The BMJ'' has editorial freedom from the BMA. It is one of the world ...
'' found that mortality in type III OI is significantly higher, with many patients dying in their 20's, 30's, and 40's; patients who survive to the age of 10 were further found to have longer life expectancy than newborns.


Mobility

People with mild (type I) OI as adults need few pieces of adaptive equipment, although in infancy they reach motor milestones at a significant delay compared to the general population. With adaptive equipment such as
crutches A crutch is a mobility aid that transfers weight from the human leg, legs to the upper body. It is often used by people who cannot use their legs to support their weight, for reasons ranging from short-term injuries to lifelong disabilities. Hi ...
,
motorized wheelchair A motorized wheelchair, powerchair, electric wheelchair, or electric-powered wheelchair (EPW) is a wheelchair that is propelled by means of an electric motor (usually using differential steering) rather than human power, manual power. Motorized ...
s,
splints Splints is an ailment of the horse or pony, characterized by a hard, bony swelling, usually on the inside of a front leg, lying between the splint and cannon bone or on the splint bone itself. It may be "hot," meaning that it occurred recently an ...
, reach extenders, and/or modifications to the home, many individuals with moderate to severe OI can achieve or maintain a significant degree of
independence Independence is a condition of a nation, country, or state, in which residents and population, or some portion thereof, exercise self-government, and usually sovereignty, over its territory. The opposite of independence is the status of ...
. With treatment and physical therapy, the maximum levels of mobility are expected to be unassisted community walking for type I, household or exercise walking for type III, and household or community walking for type IV; due to the variability of OI between individuals, mobility achieved varies and may be below this expected maximum.


Epidemiology

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. The most common types are I, II, III, and IV, while the rest are very rare. Type I is the most common and has been reported to be around three times more common than type II. The prevalence of types III and IV is less certain. In a 1989 study in Denmark, type I was found to comprise 71% of cases and type II 12% of cases, with other types comprising the other 17%. In a 2015 study in Sweden, type I was nearly six times more common than type III and nearly four times more common than type IV. Most people with OI receive it from a parent, but in many cases, it is a brand new (''de novo'' or "sporadic") mutation in a family. Among a study of patients with survivable types of OI, OI type III is most often ''de novo'' (85%), followed by type IV (50%) and type I (34%). Some populations can have a higher incidence of OI than would be otherwise expected if they have a larger than average number of carriers of the recessive forms of the disease.


History

The condition, or types of it, has had various other names over the years and in different nations; " osteo
genesis Genesis may refer to: Religion * Book of Genesis, the first book of the biblical scriptures of both Judaism and Christianity, describing the creation of the Earth and of humankind * Genesis creation narrative, the first several chapters of the Bo ...
imperfecta" has, however, been the most widely accepted name for the condition since the late 20th century. Among some of the most common alternatives are " fragilitas ossium"; "Ekman–Lobstein syndrome", and "Vrolik syndrome", both
eponyms An eponym is a noun after which or for which someone or something is, or is believed to be, named. Adjectives derived from the word ''eponym'' include ''eponymous'' and ''eponymic''. Eponyms are commonly used for time periods, places, innovati ...
; and, the
colloquialism Colloquialism (also called ''colloquial language'', ''colloquial speech'', ''everyday language'', or ''general parlance'') is the linguistic style used for casual and informal communication. It is the most common form of speech in conversation amo ...
, "brittle bone disease".


Earliest recorded cases

OI has been identified in an
ancient Egypt Ancient Egypt () was a cradle of civilization concentrated along the lower reaches of the Nile River in Northeast Africa. It emerged from prehistoric Egypt around 3150BC (according to conventional Egyptian chronology), when Upper and Lower E ...
ian infant mummified in around 1000 BC, originally dismissed by archaeologists as containing the remains of a
monkey Monkey is a common name that may refer to most mammals of the infraorder Simiiformes, also known as simians. Traditionally, all animals in the group now known as simians are counted as monkeys except the apes. Thus monkeys, in that sense, co ...
. The Norse king
Ivar the Boneless Ivar the Boneless ( ; died ), also known as Ivar Ragnarsson, was a Viking leader who invaded England and Ireland. According to the '' Tale of Ragnar Lodbrok'', he was the son of Aslaug and her husband Ragnar Loðbrok, and was the brother of ...
, who lived , is speculated to have had OI as well. Nicolas de Malebranche is often credited as being the first person to describe the physical characteristics of OI in his 1688 book , in which he describes a man who has had his "bones broken in the places a murderer's would be" all his life. His confident description of the
pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
of the disorder, however, which creates what he termed «» ("monstrous children"), is scientifically void—he wrote that it was due to the mother's
antepartum Prenatal development () involves the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal deve ...
viewership of a
public execution A public execution is a form of capital punishment which "members of the general public may voluntarily attend." This definition excludes the presence of only a small number of witnesses called upon to assure executive accountability. The purpose ...
by
breaking wheel The breaking wheel, also known as the execution wheel, the Wheel of Catherine or the (Saint) Catherine('s) Wheel, was a torture method used for public execution primarily in Europe from antiquity through the Middle Ages up to the 19th century ...
. The earliest modern scientific studies of OI began in 1788 by Olof Jakob Ekman, who described the condition, which he termed "
osteomalacia Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of b ...
congenital", in his
doctoral thesis A thesis (: theses), or dissertation (abbreviated diss.), is a document submitted in support of candidature for an academic degree or professional qualification presenting the author's research and findings.International Standard ISO 7144: D ...
and mentioned cases of it going back to 1678, all in the same family, through three generations. Ekman's description of the condition mentioned dwarfism, bone fragility, and bowing of the long bones. In 1831, Edmund Axmann gave a detailed description of it in himself and his two brothers, being the first to mention blue sclerae as a characteristic sign of OI. Jean Lobstein first described the mild form of the condition, today known as type I, in 1833, calling it "osteo psathyrosis
idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause ...
a". It was not until 1912 that
hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spo ...
was positively recognized as a symptom of OI, first mentioned in a brief paper by the English physician Charles Allen Adair-Dighton.


Of the term

Willem Vrolik, a Dutch
anatomist Anatomy () is the branch of morphology concerned with the study of the internal structure of organisms and their parts. Anatomy is a branch of natural science that deals with the structural organization of living things. It is an old scien ...
who was also
curator A curator (from , meaning 'to take care') is a manager or overseer. When working with cultural organizations, a curator is typically a "collections curator" or an "exhibitions curator", and has multifaceted tasks dependent on the particular ins ...
of the "Museum Vrolikianum", which made him privy to many specimens of bodies having
birth defects A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
, coined the term "osteogenesis imperfecta" in his
bilingual Multilingualism is the use of more than one language, either by an individual speaker or by a group of speakers. When the languages are just two, it is usually called bilingualism. It is believed that multilingual speakers outnumber monolin ...
Latin Latin ( or ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken by the Latins (Italic tribe), Latins in Latium (now known as Lazio), the lower Tiber area aroun ...
and
Dutch language Dutch ( ) is a West Germanic languages, West Germanic language of the Indo-European language family, spoken by about 25 million people as a first language and 5 million as a second language and is the List of languages by total number of speak ...
book on
teratology Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology caused by ...
, ''Illustrations of Human and Mammalian
Embryogenesis An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...
'', first published in 1849. Included is a description of the remains of an infant who had what is now known as perinatally fatal OI type II (as verified in a 1998 re-examination of the remains by Baljet ''et al.''). The remains were first given to Vrolik's father, who could not make sense of them. Vrolik described poorly mineralized bones, bowed long bones, and fractures in various states of healing. Vrolik correctly determined that what he termed OI in the infant was not caused by secondary
rickets Rickets, scientific nomenclature: rachitis (from Greek , meaning 'in or of the spine'), is a condition that results in weak or soft bones in children and may have either dietary deficiency or genetic causes. Symptoms include bowed legs, stun ...
, but a congenital abnormality causing primary
osteopenia Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop o ...
; he theorized this was due to a lack of "intrinsic generative energy".


Of its classification

Classification of OI has also evolved as scientific understanding of it has improved. Before the advent of modern genetic testing, OI was classified in two broad groups: ''osteogenesis imperfecta congenita'', and ''osteogenesis imperfecta tarda'', a division first proposed by the German
physician A physician, medical practitioner (British English), medical doctor, or simply doctor is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through the Medical education, study, Med ...
E. Looser in 1906. ''Congenita'' was used to describe the modern clinical types II, III, and some cases of IV, where upon birth the condition was obvious, either due to bowing of the limbs or due to fractures sustained ''in utero''. ''Tarda'' was used to classify the modern OI type I and some cases of type IV, where the inherent fragility of the bones did not become clear until long after birth. The idea that these "late" and "prenatal" forms were manifestations of the same disorder was first proposed in 1897 by Martin Benno Schmidt; by the 1950s this fact was well accepted. The modern system of four types (I, II, III, IV), meanwhile, were introduced in a paper by David Sillence, Alison Senn, and David Danks in the ''
Journal of Medical Genetics The ''Journal of Medical Genetics'' is a monthly peer-reviewed medical journal covering all aspects of medical genetics, including reviews of and opinion on the latest developments. It was established in 1964 and is published by the BMJ Group. The ...
'' in 1979, and have since become standard terms among doctors, patients, and researchers. The modern genetic types, (those with numbers greater than IV,) have come into use as more and more recessively inherited forms of OI have been discovered since the discovery of the first one by Roy Morello ''et al.'' in 2006. In 2010, the International Nomenclature Group for Constitutional Disorders of the Skeleton (INCDS) "freed" the Sillence types from molecular reference, acquiescing to their new clinical-first role in the wake of what was to them a "surprising" increase in the number of genetic causes of OI. Writing for the ''
Annual Review of Genetics The ''Annual Review of Genetics'' is an annual peer-reviewed scientific review journal published by Annual Reviews. It was established in 1967 and covers all topics related to the genetics of viruses, bacteria, fungi, plants, and animals, includi ...
'' in 2012, Drs. Peter Byers and Shawna M. Pyott lamented how the expansion of the number of types to include genetic types has created a system that " grew like Topsy". They suggest that it may indeed be impossible to create a system which is useful for clinicians and which accurately describes the genetic cause of a person's OI, with attempts always prioritizing one use at the expense of the other.


Society and culture

Much
medical research Medical research (or biomedical research), also known as health research, refers to the process of using scientific methods with the aim to produce knowledge about human diseases, the prevention and treatment of illness, and the promotion of ...
has been done into the causes of osteogenesis imperfecta, benefiting not only those with OI but medicine more broadly; in the ten years between 2006 and 2016, the many discoveries of non-collagen related recessive gene mutations, which still led in those who have them to the clinical signs of OI, led to numerous breakthroughs in medical understanding of the process of healthy bone development.


Other animals

In dogs, OI is an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
condition, meaning that dogs with two copies of the allele will be affected. Many breed organizations and veterinarians offer OI tests to tell if a dog is a carrier of OI. To prevent OI, dogs who are
heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
for OI should only be bred to non-carriers. Naturally occurring mutations causing OI have been found in Golden Retrievers, Dachshunds, and Beagles. OI has also been identified in
zebrafish The zebrafish (''Danio rerio'') is a species of freshwater ray-finned fish belonging to the family Danionidae of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (an ...
and
mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
. Although dogs, mice, fish, and humans are not genetically identical, some of these
animal models A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Mod ...
have been officially recognized to represent the varying types of OI in humans. For example, homozygous ''oim''/''oim'' mice experience spontaneous bone fractures, small body size, and kyphosis, making them a model of OI type III. Meanwhile, heterozygous ''oim''/+ mice appear normal but have bones which are quite a bit weaker than wild mice, making them a model for OI type I. As in human OI, the location on the gene which is mutated affects the severity of resulting disease—the G859C ''Col1a1'' mouse is a model for OI type II as affected mice all die in the perinatal period.
Animal testing Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of animals, as model organisms, in experiments that seek answers to scientific and medical questions. This approach can be contrasted ...
on identified animal models may lead to human therapies for OI.


Explanatory notes


References


External links

* {{DEFAULTSORT:Osteogenesis Imperfecta Abnormalities of dermal fibrous and elastic tissue Skeletal disorders Collagen disease Rare diseases Wikipedia medicine articles ready to translate