Osteogenesis Imperfecta

Osteogenesis imperfecta (OI), or “brittle bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones disease,” is a rare genetic connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue disorder characterized by severe bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones fragility. Although OI is considered a single disease, OI includes over 16 genotypes and clinical phenotypes with differing symptom severity. Of these 16, types I–IV are the most common. Because of the rarity of OI, OI is considered an “orphan disease” in the United States. Diagnosis is made clinically, through history and examination, and is confirmed by radiologic findings and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure analysis. While there is no definitive cure, treatment is supportive, usually involving bisphosphonates Bisphosphonates Bisphosphonates are pyrophosphate analogs most well-known for treating osteoporosis by preventing bone loss. Bisphosphonates end in the suffix "-dronate" or "-dronic acid" (e.g., alendronate, risedronate, pamidronate) and bind to hydroxyapatite crystals in bone, inhibiting osteoclast-induced bone resorption. Bisphosphonates, and is focused on reducing pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, reducing fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures frequency, reducing bony deformity, and increasing ambulation. The prognosis is variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables, depending on the OI type.

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Overview

Definition

Osteogenesis imperfecta (OI) is an inherited connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue disorder characterized by impaired bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones formation and severe bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones fragility.

Epidemiology

  • Most common genetic cause of osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
  • Incidence:
    • Overall: 1 in 20,000 births
    • Type I: 1 in 15,000 to 1 in 20,000 births
    • Type II: 1 in 60,000 births
    • Types III and IV: unknown, very low
  • The distribution is similar worldwide.
  • Males and females are equally affected.

Etiology

  • Mutations in genes encoding collagen type 1 (COL1A1 and COL1A2): 
    • 90% of all cases
    • Classified as types I–IV 
  • Other mutations (10%):
    • Post-translational defects
    • 3-prolyl-hydroxylation complex defects
    • Other proteins involved in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones formation and homeostasis
Table: Major pathologic mutations, modes of inheritance, and phenotypes for OI types I-IV
Type I Type II Type III Type IV
Mutated gene COL1A1, COL1A2 (collagen type 1 alpha 1 and 2 chains) COL1A1, COL1A2, and CRTAP ( cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage-associated protein) COL1A1, COL1A2 COL1A1, COL1A2
Inheritance modality Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance AND autosomal recessive Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance
Defect Frameshift mutations in collagen type 1 alpha 1 and 2 chains leading to decreased amounts of normal collagen Disrupted formation of the collagen triple helix structure, leading to little or no normal collagen Mutations causing structural protein defects leading to severe pathology Mutations causing structural protein defects leading to minimal or mild pathology

Pathophysiology

  • Mutations in alpha 1 or alpha 2 chains of type 1 collagen:
    • Decreased amount of type 1 collagen (type I) 
    • Disruption of type 1 collagen triple helix (type II)
    • Structural protein defects of type 1 collagen (type III and IV)
  • Increased amounts of type III and IV collagen in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones tissue
  • Increased activity of osteoclasts and abnormal osteoblast differentiation
  • Poor deposition of hydroxyapatite crystals and paradoxic bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones hypermineralization
  • Globally abnormal bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones growth: decreased bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones trabeculae and cortical thickness
  • Fractures with normal movement and very low-impact activities, with a normal healing process

Clinical Presentation

  • Variable severity
  • Type II die in utero or early infancy.
  • Present to a variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables extent in types I, III, and IV:
    • Excess or atypical fractures
    • Short stature
    • Scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis
    • Basilar skull Skull The skull (cranium) is the skeletal structure of the head supporting the face and forming a protective cavity for the brain. The skull consists of 22 bones divided into the viscerocranium (facial skeleton) and the neurocranium. Skull deformities (may cause nerve compression)
    • Blue sclerae
    • Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    • Dentinogenesis imperfecta (opalescent teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth)
    • Increased laxity of ligaments
    • Wormian bones (small bones near cranial sutures)
    • Easy bruising
Table: Classification of OI (forms I-IV) based on inheritance pattern and clinical appearance
Type I Type II Type III Type IV
Description Non-deforming with blue sclerae Perinatally lethal Progressively deforming Variable with normal sclerae
Severity Mild Perinatal lethal Severe Mild to moderate
Fractures < 100 > 100 > 100 > 100
Bone deformity Uncommon Severe Moderate to severe Mild to moderate
Stature Normal to mildly reduced Severely reduced Reduced Variable
Dentogenesis imperfecta Variable Common Common Variable
Color of sclerae Blue Dark blue Blue Normal to gray
Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss Present in approximately 50% Frequent Variable

Diagnosis

History

  • History of fractures:
    • Multiple and recurrent fractures during very low-impact activities (e.g., diaper change)
    • Specific bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones fractures:
      • Olecranon process
      • Transverse humerus
      • Diaphyseal humerus 
    • Fractures before or during birth
  • History of extra-skeletal symptoms:
    • Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    • Easy bruising
  • Family history of the disease or findings suggestive of undiagnosed disease in relatives:
    • Family history of multiple fractures
    • Family history of extra-skeletal symptoms:
      • Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
      • Dentinogenesis imperfecta
    • Lack of family history does not rule out disease.
  • History of child abuse Child abuse Child abuse is an act or failure to act that results in harm to a child's health or development. The abuse encompasses neglect as well as physical, sexual, and emotional harm. Seen in all subsets of society, child abuse is a cause of significant morbidity and mortality in the pediatric population. Child Abuse: important to rule out in cases of fractures

Physical examination

  • Skeletal findings:
    • Dentinogenesis imperfecta: translucent teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth with amber, blue, or gray coloration
    • Genu varum Genu varum Genu varum is a deformation of the knee joint(s) that creates angulation of the lower limb(s) away from the midline in the coronal plane. Children ages 1-5 years are commonly affected. Genu Varum (bow legs): outward bowing at the knees 
    • Scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis
    • Loose joints
    • Limb deformity (particularly bowing of the femur)
  • Extra-skeletal findings:
    • Prolonged bleeding from injured areas
    • Easy bruising
    • Blue-colored sclera
    • Breathing problems/fatigue
    • Hypoacusia that can be conductive, sensorineural, or mixed (deficient ossification of the middle ear)
    • Muscle weakness
    • Short stature (more common in severe cases)

Laboratory testing

  • Bloodwork:
    • Usually normal
    • Alkaline phosphatase may be increased.
    • ↓ Markers of bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones formation, ↑ markers of bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones resorption
  • Urine: Hypercalciuria with normal renal function may be present.
  • Biopsy:
    • Collagen: In vitro fibroblast culturing shows abnormal organization/structure. 
    • Bone histology:
      • Shows disorganized bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones structure
      • Decreased size and number of bony trabeculae
      • Increased osteoblasts and osteoclasts
  • Genetic studies:
    • No widely available commercial tests
    • Genomic DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure testing for mutations in COL1A1 and COL1A2
  • Prenatal testing:
    • Chorionic villus sampling
    • Amniocentesis

Imaging

  • Prenatal ultrasound: evidence of bony deformities
  • X-ray findings suggestive of OI:
    • Multiple fractures in various states of healing
    • Thin bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones cortices and widened metaphysis 
    • Low bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density
    • Bowed femurs
    • “Wormian” bones
    • “Codfish” vertebrae
    • Saber shins
    • Coxa vara
    • Kyphoscoliosis
    • Platyspondyly
Table: Radiographic findings of OI (types I-IV)
Type I Type II Type III Type IV
Skull radiographic findings Intra-sutural bones Undermineralization; calcified areas Intra-sutural bones Intra-sutural bones (sometimes)
Spine radiographic findings Biconcave vertebrae (adults) Widened vertebral bodies (platyspondyly) Biconcave vertebrae; kyphoscoliosis Biconcave vertebrae
Extremity radiographic findings Thin cortices Severely deformed femurs Flared metaphyses, bowing, thin cortices Thin cortices
Other radiographic findings Osteopenia Small, beaded ribs (pathognomonic) Thin ribs, severe osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis Protrusio acetabuli in a subset

Management

There is no definitive cure for OI.

Goals of therapy

  • Reduce pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Reduce fractures
  • Reduce bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones deformity
  • Increase ambulation/independence

Lifestyle modifications

  • Controlled weight carrying
  • Safe exercises to improve muscle and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones strength
  • Diet rich in calcium and vitamin D 
  • Avoidance of alcohol and caffeine
  • Steroids are contraindicated.
  • Avoidance of active or passive inhalation of cigarette smoke

Supportive management

  • Casts and splints
  • Braces 
  • Physical therapy
  • Implantation of rods in legs or arms
  • Dental workup
  • Hearing aids
  • Crowns for brittle teeth Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. Teeth
  • Mobility aids (e.g., crutches, canes, wheelchairs, walkers)
  • Supplemental oxygen 
  • Genetic counseling for parents considering future pregnancies

Bisphosphonates (pamidronate)

  • Inhibit bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones turnover/resorption
  • Have been shown to reduce fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures rates
  • Long-term effect on other skeletal symptoms (scoliosis, deformity) is unclear.

Surgical therapy

  • Fracture repair
  • Deformity correction

Prognosis

  • Severe functional limitation and decreased quality of life 
  • Type I cases can attain a full lifespan.
  • Type II cases die prenatally or within the 1st year of life.
  • Type III and IV cases require walking aids, but can attain household and community ambulation skills.

Differential Diagnosis

  • Child abuse: defined by the U.S. government as “any recent act or failure to act on the part of a parent or caretaker, which results in death, serious physical or emotional harm, sexual abuse Sexual Abuse Sexual abuse and assault are major public health problems that affect many people from all walks of life, including people of all ages and genders, but it is more prevalent in women and girls, with reports of up to 1 in 3 experiencing sexual assault at some time in their life. Sexual Abuse or exploitation, or an act or failure to act which presents an imminent risk of serious harm.” Physically abused children may present with recurrent fractures and visits to the emergency department (ED). Old and recent signs of inflicted trauma are more indicative of the diagnosis of child abuse Child abuse Child abuse is an act or failure to act that results in harm to a child's health or development. The abuse encompasses neglect as well as physical, sexual, and emotional harm. Seen in all subsets of society, child abuse is a cause of significant morbidity and mortality in the pediatric population. Child Abuse
  • Rickets Rickets Rickets and osteomalacia are disorders of decreased bone mineralization. Rickets affects the cartilage of the epiphyseal growth plates in children. Although most cases of rickets are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Rickets commonly presents with skeletal deformities and growth abnormalities. Osteomalacia and Rickets: a disease of the growing bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones caused by inadequate bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones mineralization due to vitamin D deficiency. Rickets Rickets Rickets and osteomalacia are disorders of decreased bone mineralization. Rickets affects the cartilage of the epiphyseal growth plates in children. Although most cases of rickets are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Rickets commonly presents with skeletal deformities and growth abnormalities. Osteomalacia and Rickets presents with recurrent fractures, limb deformities, increased alkaline phosphatase, and dental abnormalities in some cases, but does not display hearing loss and blue sclerae. 
  • Osteomalacia Osteomalacia Rickets and osteomalacia are disorders of decreased bone mineralization. Osteomalacia affects the sites of bone turnover in children and adults. Although most cases are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Osteomalacia can present with bone pain, difficulty with ambulation and pathologic fractures. Osteomalacia and Rickets: a condition of decreased bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density in adults that tends to appear prior to the development of osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis. Osteomalacia Osteomalacia Rickets and osteomalacia are disorders of decreased bone mineralization. Osteomalacia affects the sites of bone turnover in children and adults. Although most cases are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Osteomalacia can present with bone pain, difficulty with ambulation and pathologic fractures. Osteomalacia and Rickets shows fractures and increased alkaline phosphatase, but no hearing loss or blue sclerae.
  • Paget’s disease of the bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones: a disorder characterized by increased and abnormal remodeling of bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones tissue that presents with fractures, bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones deformity, bowing of long bones, increased alkaline phosphatase, and conductive hearing loss. However, 20% of cases are asymptomatic and diagnosis may be made incidentally as these patients are investigated for something else.

References

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