NORD gratefully acknowledges Maureen Maciel, MD, Chief of Staff, Shriners Healthcare for Children, Florida; Affiliate Assistant Professor, Department of Orthopaedic Surgery and Sports Medicine, University of South Florida, for assistance in the preparation of this report.
Osteogenesis imperfecta (OI) is a rare disease affecting the connective tissue and is characterized by extremely fragile bones that break or fracture easily (brittle bones). The abnormal growth of bones is often referred to as a bone dysplasia. The specific symptoms and physical findings associated with OI vary greatly from person to person. The severity of OI also varies greatly, even among individuals in the same family. OI may be a mild disorder or result in severe complications.
Four main types of OI (the collagen types) have been identified based on clinical features and severity. These types account for 85-90 percent of OI cases and are caused by mutations (changes) in the COL1A1 or COL1A2 genes. These genes code for type 1 collagen, the most abundant collagen in the human body. It is found in bones, tendons and ligaments. OI type I is the most common and the mildest form of the disorder. OI type II is the most severe of the collagen types. OI types V through XXI (the non-collagen types), as well as unclassified types, make up the remaining 10-15 percent of OI cases. These types are caused by changes in genes that code for proteins that interact with collagen.
In all types of osteogenesis imperfecta, symptoms vary greatly from one individual to the next, even within the same type and the same family. Some affected individuals may not experience any bone fractures or only a few. Other affected individuals experience multiple fractures. The age of onset of fractures varies from person to person. OI is a collagen related disease, and as such, the arrangement and integrity of teeth (dentition), lung function, heart (cardiac) function, muscle strength and ligament flexibility may be affected as well.
Historically, OI has been classified into four main types according to clinical features and severity. Over the past decade, many new genes have been identified in individuals who have brittle bones as a component of their disease. The classification has been expanded beyond types I through IV to include these new and rarer types of OI. Types V through XXI are classified according to the causative genetic mutation. Just like the more common types of OI, the clinical features of affected individuals vary within these rare types. The types of OI and the causative gene (shown in parentheses) are described below.
Osteogenesis Type I (COL1A1)
Osteogenesis type I is the most common and usually the mildest form of OI. In most people, it is characterized by multiple bone fractures, usually occurring during childhood through puberty. A child with type I OI may fracture early in life with minimal trauma (falling from a standing position or when being pulled up by a caregiver), whereas others may fracture later on when participating in higher intensity physical activity. Fractures during the newborn (neonatal) period are rare. The frequency of fractures usually declines after puberty. Repeated fractures may result in slight malformation of the bones of the arms and legs (e.g., bowing of the tibia and femur).
A distinguishing feature associated with OI type I is a bluish discoloration of the whites of the eyes (blue sclera). Some individuals with OI type I may develop abnormalities affecting the middle and/or inner ears, contributing to, or resulting in hearing impairment. The incidence of hearing loss in patients with type I OI increases with age.
Individuals with OI type I may have a triangular facial appearance. Height is variable and most people are below average height for age in childhood, with an adult height shorter than that of unaffected family members. Between 10 and 40 percent of patients with OI type I develop a curved spine (scoliosis). The curve is often mild and progresses minimally over time.
Additional symptoms associated with OI type I include loose (hyper extensible) joints and low muscle tone (hypotonia). This may result in a predisposition to joint dislocations and ligament sprains. Some patients have skin that bruises easily. Brittle teeth (dentinogenesis) are uncommon in type I OI.
Osteogenesis Type II (COL1A1 or COL1A2)
OI type II is the most severe type of osteogenesis imperfecta. Affected infants often experience life-threatening complications at birth or shortly after. Infants with OI type II have low birth weight, abnormally short arms and legs and blue sclera. In addition, affected infants have extremely fragile bones and numerous fractures present at birth. The ribs and long bones of the legs are often malformed.
Infants with OI type II have underdeveloped lungs and an abnormally small upper chest (thorax) that may result in life-threatening respiratory insufficiency. Some affected infants may experience congestive heart failure.
Infants with OI type II may also have a small, narrow nose, small jaw (micrognathia) and abnormally large soft spots on the top of the skull (large fontanelle). Affected infants may also have thin, fragile skin and low muscle tone (hypotonia).
Osteogenesis Type III (COL1A1 or COL1A2)
Extremely fragile malformed bones and multiple fractures characterize OI type III. Fractures are often present at birth and x-rays may show signs of healing fractures that occurred prenatally.
Progressive malformations of various bones commonly result in short stature, spinal deformity (scoliosis, thoracic kyphosis and lumbar lordosis) and malformation of the junction where the bone in the back of the skull (occipital bone) and the top of the spine meet (basilar invagination). Approximately 70 percent of children with type III OI develop scoliosis. These curves have a high risk of progression during skeletal growth. Chest wall deformities are common, resulting in a barrel shaped rib cage. Frequent fractures and bone deformities of the upper and lower extremities may require multiple surgeries for stabilization as the child grows. Adult height is severely reduced. Individuals with type III OI may become more dependent on the use wheelchairs and other mobility aids by young adulthood.
Infants with OI type III may have a slight blue discoloration to the whites of the eyes at birth. In most patients, the bluish tinge fades during the first year of life. Affected infants often have a triangular facial appearance due to an abnormally prominent forehead (frontal bossing) and a small jaw (micrognathia). Hearing loss may develop during the first decade. Dentinogenesis imperfecta may also be present. Type III patients may develop pulmonary problems secondary to abnormal lung tissue and chest wall abnormalities.
Osteogenesis Type IV (COL1A1 or COL1A2)
The clinical severity of type IV OI (the moderate type) may resemble type I or type III. Fractures are more common before puberty. Affected individuals experience mild to moderate bone malformation and are usually shorter than average. Patients with type IV OI may also develop scoliosis.
Individuals with OI type IV may have a triangular facial appearance. In most patients, the sclera are normal or pale blue during infancy. As an infant ages, the pale blue discoloration of the sclera fades. Affected individuals may also experience hearing impairment and dentinogenesis imperfecta.
Osteogenesis Type V (IFITM5)
OI type V is moderate in severity, with a clinical picture similar to type IV. Individuals may develop an abundance of healing bone (hypertrophic callus) at fracture sites or where bones have been cut surgically. They may also have an abnormal bony connection between the two long bones of the forearm resulting in limitations of motion at the wrist and elbow.
Osteogenesis Type VI (SERPINF1)
Type VI OI is moderate in severity and affected individuals have a clinical picture similar to type IV. Children who have type OI type VI do not have fractures at birth, but develop them later. Vertebral compression fractures and scoliosis are common, as is progressive bowing of the bones in the arms and legs. Height is moderate to severely affected. The sclera of the eyes are white, teeth are normal and hearing loss has not been observed.
Osteogenesis Imperfecta Type VII (CRTAP)
Type VII OI is severe and affected individuals have clinical cases similar to type II.
Osteogenesis Imperfecta Type VIII (LEPREI)
Affected individuals have white sclera, severe growth deficiency and a clinical course similar to types either II or III.
Osteogenesis Imperfecta Type IX (PPIB)
Type IX OI is very rare and affected individuals have white sclera, proportionate limbs and moderate to severe clinical cases.
Osteogenesis Imperfecta Type X (SERPINH1)
Type X OI is extraordinarily rare and the bones are severely affected. Individuals with type X OI have a head that appears large for body size and blue sclera. Pulmonary complications, renal stones and muscle weakness have been reported.
Osteogenesis Imperfecta Type XI (FKBP10)
Type XI OI encompasses a spectrum of disorders that include variable severities of both brittle bones and abnormalities in joint mobility. Progressive scoliosis and kyphosis, abnormal hips and normal hearing are common features. Bruck syndrome type I is also caused by mutations in the FKBP10 gene and is characterized by severe OI and joint contractures (limited mobility).
Osteogenesis Imperfecta Type XII (BMP1)
Type XII OI includes several disorders that are characterized by recurrent fractures, poor bone density, muscle weakness, delayed tooth eruption, progressive hearing loss and white sclera. Bone density may be above normal.
Osteogenesis Imperfecta Type XIII (SP7)
Affected individuals have bone density just at or below normal and develop mild to moderate bone deformities. They have a small lower jaw, normal teeth, faint blue sclera and growth deficiency.
Osteogenesis Imperfecta Type XIV (TMEM38B)
The severity of symptoms in affected individuals varies widely. Some individuals have bowing of the bones in the legs and recurrent fractures, whereas others are asymptomatic. Muscle weakness and heart abnormalities have been reported in patients with type XIV OI.
Osteogenesis Imperfecta Type XV (WNT1)
Affected individuals have moderate to severe bowing of the long bones, scoliosis, vertebral fractures and muscle weakness. Some have blueish sclera and neurological problems have been reported.
Osteogenesis Imperfecta Type XVI (CREB3L1)
OI type XVI is severe. Fractures are present at the time of birth and the long bones of the upper arms and legs develop bowing.
Osteogenesis Imperfecta Type XVII (SPARC)
Type XVII is severe. Affected individuals have white sclera, no dental involvement, joint hypermobility and may develop scoliosis
Osteogenesis Imperfecta Type XVIII (FAM46A)
OI Type XVIII causes severe bony abnormalities, scoliosis, chest wall deformity and the sclera may be blue or white.
OI Type XIX (MBTPS2)
Type XIX OI is a severe type caused by a mutation on the X chromosome. It is characterized by prenatal fractures, growth deficiency, scoliosis and severe angulation of the lower leg bone (tibia).
OI Type XX (MESD)
OI type XX is severe. Features include fractures, severe bowing deformities of the long bones, and possible respiratory failure.
OI Type XXI (KDELR2)
Type XXI OI is moderate to severe and results in progressive bone deformities and multiple fractures. Growth deficiency and scoliosis are also reported.
Osteogenesis Imperfecta types I through IV are caused by mutations in the COL1A1 or COL1A2 genes. These genes carry instructions for the production of type 1 collagen. Collagen is the major protein of bone and connective tissue including the skin, tendons and sclera. The collagen protein is made up of three strands of proteins (two alpha 1 strands and one alpha 2 strand) that wind together in a helical fashion. These helical molecules then pack side by side to form characteristic bands that are linked together. This structure gives collagen enormous tensile strength. When a mutation occurs, the collagen that the mutated gene produces may be faulty or insufficient. In type I, the gene mutation results in a normal collagen protein, but only one-half of the normal amount is produced. Types II through IV are the result of mutations that affect the structure of the collagen protein. The precise location and type of mutation determines the severity of the resulting disease. The non-collagen types of OI (types V-XXI) are caused by mutations in genes that code for other proteins that play a pivotal role in the production of normal collagen.
Over 80 percent of the mutations that cause osteogenesis imperfecta are inherited in an autosomal dominant pattern. That means that an affected individual has only one copy of the mutated gene. The mutated gene dominates the normal gene such that the affected individual forms only abnormal collagen (as in types II-V) or only makes half the normal amount of collagen (as in type I). Autosomal dominant mutations can be passed down from parent to child. This autosomal dominant transmission accounts for about 60 percent of new diagnoses of OI cases each year. In another 20-30 percent of new cases annually, OI is caused by a spontaneous autosomal dominant mutation in the affected individual. This new dominant mutation can then be passed down to future generations. The risk of transmitting the autosomal dominant disorder from affected parent to offspring is 50 percent for each pregnancy and the risk is the same for males and females.
The rarer types of OI (except for type V and some type XVI) are recessive types that only occur when an individual has two copies of the mutated gene, one from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Osteogenesis imperfecta affects males and females in equal numbers. The incidence of cases recognizable at birth is 1:10-20,000. More mild types that are only recognized later in life occur at about the same incidence. It is estimated that 20,000 to 50,000 individuals in the United States have OI.
A diagnosis of osteogenesis imperfecta is made based upon a detailed patient and family history and a thorough clinical evaluation to identify characteristic signs and symptoms. Genetic testing is performed to detect the known genetic mutations that cause OI.
In some patients, the diagnosis of OI is made before birth (prenatally), based upon specialized tests such as ultrasound, amniocentesis and/or chorionic villus sampling (CVS). Ultrasound studies may reveal characteristic findings such as fractures and/or bowing of the long bones in the moderate to severe cases. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, a tissue sample is removed from a portion of the placenta. Genetic testing performed on this fluid or tissue sample may reveal a genetic mutation that causes OI.
Treatment
The treatment of OI is directed toward the specific symptoms that are apparent in each individual. Treatment is aimed at preventing symptoms, maintaining individual mobility, and strengthening bone and muscle. Attention to nutrition and overall physical and psychological well-being is also very important.
Exercise and physical therapy programs have proven beneficial in strengthening muscles, increasing weight-bearing capacity and reducing the tendency to fracture. Physical therapy in the water (hydrotherapy) has proven helpful since moving around in water lessens the chance of fracture. Individuals with OI should consult with their physicians and physical therapists to determine a safe and appropriate exercise program.
Bisphosphonate therapy (intravenous infusions with either pamidronate or zolendronate) is commonly used to treat children with OI who have frequent fractures, spinal compression fractures, bone pain and decreased bone density measured by DEXA scan. Bisphosphonates work by slowing down the resorption of existing bone while new bone is being formed. This allows bone mass and strength to increase. It does not, however, make the new bone normal. Adults with OI may be treated with oral or intravenous bisphosphonates. Other drugs used to treat osteoporosis may be used in adult patients with OI to prevent loss of bone mass. Denosumab decreases bone resorption and teriparatide has been shown to increase bone strength. The decision to initiate or alter drug therapy is dependent on multiple clinical factors and should be pursued under the direction of an experienced physician.
A surgical procedure in which metal rods are placed into the long bones of the upper and lower extremities (rodding) is used to treat some individuals with OI. This surgery may be necessary in patients where there is progressive deformity of a bone or if a bone fractures repeatedly. Rodding of the forearms is typically reserved for patients where deformities significantly impair function. The timing of surgery, type of rod used (expandable or non-expandable) and the aftercare is very individual and should be discussed thoroughly between the surgeon and parents or adult with OI.
Surgery to relieve compression between the base of the skull and the top of the spine (basilar invagination) may prove necessary in severe symptomatic patients. Specialized dental and orthodontic procedures may be necessary to correct abnormalities of the teeth and jaw.
Monitoring
Individuals with OI should undergo routine screenings to detect hearing loss. Regular dental care is also important. A consultation with an orthodontist should be obtained before age seven to assess jaw development and alignment. Pulmonary function should be measured using pulmonary function tests (PFTs) at approximately age 5 and then between ages 20 and 25. If normal, it should be repeated bi-annually. A baseline echocardiogram should be obtained in the late teens or early adulthood. Clinical evaluations for basilar invagination should be performed regularly and at least one lateral radiograph of the junction of the skull and the cervical spine obtained as a baseline. Serial screening for scoliosis should also be performed. If it is detected, regular x-rays may be necessary to monitor for curve progression.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXTBOOKS
The Skeletal Dysplasias. Chapter 7 In: Lovell and Winter’s Pediatric Orthopaedics. Seventh ed. Weinstein SL, Flynn JM eds. 2014 Lippincott Williams and Wilkins, Philadelphia, PA
JOURNAL ARTICLES
Doyard M, Bacrot S, Huber C, et al. FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta. J Med Genet. 2018; 55: 278-284.
Keller RB, Tran TT, Pyott SM, et al. Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively. Genet Med. 2018;20: 411-419.
Mendoza-Londono R, Fahiminiya S, Majewski J. Care4Rare Canada Consortium, et al. Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am. J Hum Genet. 2015;96: 979-985.
Apronen H, Makitie O, Waltimo-Siren J. Association between joint hypermobility, scoliosis, and cranial base anomalies in paediatric osteogenesis imperfecta patients: a retrospective cross-sectional study. BMC Musculoskelet Disord. 2014 Dec 13;15:428.
Marnini JC, Reich A, Smith SM. Osteogenesis Imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation. Curr Opin Pediatr. 2014; 26:500-507.
Anissipour AK, Hammerberg KW, Caudill A, et al. Behavior of scoliosis during growth in children with osteogenesis imperfecta. J Bone Joint Surg Am. 2014;96:237-43
Keupp K, Beleggia F, Kayserili H, et al. Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet. 2013; 92: 565-574.
Volodarsky M, Markus B, Cohen I, et al. A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. Hum Mutat. 2013;34: 582-586.
Martinez-Glez V, Valencia M, Caparros-Martin JA, et al. Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta. Hum Mutat. 2012;33: 343-350.
Marini JC et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. NEJM. 2006;26.
Antoniazzi F, et al. Osteogenesis imperfecta: practical treatment guidelines. Paediatr Drugs. 2000;2:465-88.
Byers PH. Osteogenesis imperfecta: perspectives and opportunities. Curr Opin Pediatr. 2000;12:603-09.
Glorieux FH. Bisphosphonate therapy for severe osteogenesis imperfecta. J Pediatr Endocrinol Metab. 2000;13:989-92.
Glorieux FH, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res. 2000;15:1650-58.
Kuurila K, et al. Hearing loss in children with osteogenesis imperfecta. Eur J Pediatr. 2000;159:515-19.
Glorieux FH, et al. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med.1998;339:947-52.
Pruchno CJ, et al. Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type I collagen. Hum Genet. 1991;87:33-40.
Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;16:101-116.
INTERNET
Marini JC, Dang AN. Osteogenesis Imperfecta. Endotext. Updated July 26, 2020. Available at: https://www.ncbi.nlm.nih.gov/books/NBK279109/. Accessed July 14, 2021.
Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University. Hammosh A, editor. Entry No:259440; Last Update:8/2/2018. Entry No:301014; Last Update:8/2/2018. Entry No:618644; Last Update:1/22/2020. Entry No:619131; Last Update:5/25/2021. Available at https://www.omim.org/ Accessed July 13, 2021.
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