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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. Bones: Structure and Types 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: Histology 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. Bones: Structure and Types 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 A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). 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 An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, 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 Deformity Examination of the Upper Limbs, and increasing ambulation. The prognosis Prognosis A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas 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.

Last updated: 8 Jan, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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: Histology 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. Bones: Structure and Types 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. Bones: Structure and Types 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 Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency:
    • 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 Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure encoding collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology type 1 Type 1 Spinal Muscular Atrophy (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 Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis 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. Bones: Structure and Types formation and homeostasis Homeostasis The processes whereby the internal environment of an organism tends to remain balanced and stable. Cell Injury and Death
Table: Major pathologic mutations, modes of inheritance, and phenotypes for OI types I-IV
Type I Type II Type III Type IV
Mutated gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics COL1A1, COL1A2 ( collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology type 1 Type 1 Spinal Muscular Atrophy alpha 1 and 2 chains) COL1A1, COL1A2, and CRTAP (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 recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are 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 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 Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology type 1 Type 1 Spinal Muscular Atrophy alpha 1 and 2 chains leading to decreased amounts of normal collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology Disrupted formation of the collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology triple helix structure, leading to little or no normal collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology 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 Type 1 Spinal Muscular Atrophy collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology:
    • Decreased amount of type 1 Type 1 Spinal Muscular Atrophy collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology (type I) 
    • Disruption of type 1 Type 1 Spinal Muscular Atrophy collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology triple helix (type II)
    • Structural protein defects of type 1 Type 1 Spinal Muscular Atrophy collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology (type III and IV)
  • Increased amounts of type III and IV collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology 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. Bones: Structure and Types tissue
  • Increased activity of osteoclasts Osteoclasts A large multinuclear cell associated with the bone resorption. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. Bones: Development and Ossification and abnormal osteoblast differentiation
  • Poor deposition of hydroxyapatite crystals Hydroxyapatite crystals A group of compounds with the general formula m10(PO4)6(OH)2, where m is barium, strontium, or calcium. The compounds are the principal mineral in phosphorite deposits, biological tissue, human bones, and teeth. They are also used as an anticaking agent and polymer catalysts. Calcium Hemostasis and Bone Metabolism 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. Bones: Structure and Types 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. Bones: Structure and Types 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. Bones: Structure and Types trabeculae and cortical thickness
  • Fractures with normal movement and very low-impact activities, with a normal healing process

Clinical Presentation

  • 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 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: Anatomy deformities (may cause nerve compression Nerve Compression Brachial Plexus Injuries)
    • 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: Anatomy)
    • Increased laxity of ligaments
    • Wormian bones (small bones near cranial sutures)
    • Easy bruising Easy bruising Chédiak-Higashi Syndrome
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 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 with normal sclerae
Severity Mild Perinatal lethal Severe Mild to moderate
Fractures < 100 > 100 > 100 > 100
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. Bones: Structure and Types deformity Deformity Examination of the Upper Limbs Uncommon Severe Moderate to severe Mild to moderate
Stature Normal to mildly reduced Severely reduced Reduced 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
Dentogenesis imperfecta 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 Common Common 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
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 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

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. Bones: Structure and Types fractures:
      • Olecranon Olecranon A prominent projection of the ulna that articulates with the humerus and forms the outer protuberance of the elbow joint. Arm: Anatomy process
      • Transverse humerus Humerus Bone in humans and primates extending from the shoulder joint to the elbow joint. Arm: Anatomy
      • Diaphyseal humerus Humerus Bone in humans and primates extending from the shoulder joint to the elbow joint. Arm: Anatomy 
    • 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 Easy bruising Chédiak-Higashi Syndrome
  • Family history Family History Adult Health Maintenance of the disease or findings suggestive of undiagnosed disease in relatives:
  • 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: Anatomy 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 Deformity Examination of the Upper Limbs (particularly bowing of the femur)
  • Extra-skeletal findings:
    • Prolonged bleeding from injured areas
    • Easy bruising Easy bruising Chédiak-Higashi Syndrome
    • Blue-colored sclera Sclera The white, opaque, fibrous, outer tunic of the eyeball, covering it entirely excepting the segment covered anteriorly by the cornea. It is essentially avascular but contains apertures for vessels, lymphatics, and nerves. Eye: Anatomy
    • Breathing problems/ fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • Hypoacusia that can be conductive, sensorineural, or mixed (deficient ossification Ossification The process of bone formation. Histogenesis of bone including ossification. Bones: Development and Ossification of the middle ear Middle ear The space and structures directly internal to the tympanic membrane and external to the inner ear (labyrinth). Its major components include the auditory ossicles and the eustachian tube that connects the cavity of middle ear (tympanic cavity) to the upper part of the throat. Acute Otitis Media)
    • Muscle weakness
    • Short stature (more common in severe cases)

Laboratory testing

  • Bloodwork:
    • Usually normal
    • Alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma 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. Bones: Structure and Types 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. Bones: Structure and Types resorption
  • Urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat: Hypercalciuria Hypercalciuria Excretion of abnormally high level of calcium in the urine, greater than 4 mg/kg/day. Nephrolithiasis with normal renal function may be present.
  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
    • Collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology: In vitro fibroblast culturing shows abnormal organization/structure. 
    • 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. Bones: Structure and Types 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. Bones: Structure and Types structure
      • Decreased size and number of bony trabeculae
      • Increased osteoblasts Osteoblasts Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. Bones: Development and Ossification and osteoclasts Osteoclasts A large multinuclear cell associated with the bone resorption. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in cementum resorption. Bones: Development and Ossification
  • Genetic studies:
    • No widely available commercial tests
    • Genomic DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure testing for mutations in COL1A1 and COL1A2
  • Prenatal testing:
    • Chorionic villus sampling
    • Amniocentesis Amniocentesis Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. Polyhydramnios

Imaging

  • Prenatal ultrasound: evidence of bony deformities
  • X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests 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. Bones: Structure and Types cortices and widened metaphysis Metaphysis Bones: Structure and Types 
    • 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. Bones: Structure and Types density
    • Bowed femurs
    • “Wormian” bones
    • “Codfish” vertebrae
    • Saber shins Shins Erythema Nodosum
    • Coxa vara
    • Kyphoscoliosis Kyphoscoliosis Osteomalacia and Rickets
    • Platyspondyly
Table: Radiographic findings of OI (types I-IV)
Type I Type II Type III Type IV
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: Anatomy radiographic findings Intra-sutural bones Undermineralization; calcified areas Intra-sutural bones Intra-sutural bones (sometimes)
Spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy radiographic findings Biconcave vertebrae (adults) Widened vertebral bodies (platyspondyly) Biconcave vertebrae; kyphoscoliosis Kyphoscoliosis Osteomalacia and Rickets Biconcave vertebrae
Extremity radiographic findings Thin cortices Severely deformed femurs Flared metaphyses, bowing, thin cortices Thin cortices
Other radiographic findings Osteopenia Osteopenia Osteoporosis Small, beaded ribs Ribs A set of twelve curved bones which connect to the vertebral column posteriorly, and terminate anteriorly as costal cartilage. Together, they form a protective cage around the internal thoracic organs. Chest Wall: Anatomy (pathognomonic) Thin ribs Ribs A set of twelve curved bones which connect to the vertebral column posteriorly, and terminate anteriorly as costal cartilage. Together, they form a protective cage around the internal thoracic organs. Chest Wall: Anatomy, 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 Protrusio Acetabuli Marfan Syndrome in a subset

Management

There is no definitive cure for OI.

Goals of therapy

  • Reduce pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • 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. Bones: Structure and Types deformity Deformity Examination of the Upper Limbs
  • 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. Bones: Structure and Types strength
  • Diet rich in calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes and vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies 
  • Avoidance of alcohol and caffeine Caffeine A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine’s most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. Stimulants
  • Steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors are contraindicated.
  • Avoidance of active or passive inhalation of cigarette smoke

Supportive management

  • Casts and splints
  • Braces 
  • Physical therapy Physical Therapy Becker Muscular Dystrophy
  • Implantation Implantation Endometrial implantation of embryo, mammalian at the blastocyst stage. Fertilization and First Week of rods in legs or arms
  • Dental workup
  • Hearing aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and 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: Anatomy
  • Mobility aids Mobility Aids Becker Muscular Dystrophy (e.g., crutches, canes, wheelchairs, walkers)
  • Supplemental oxygen Supplemental Oxygen Respiratory Failure 
  • Genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies for parents considering future pregnancies

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 ( pamidronate Pamidronate An aminobisphosphonate that inhibits bone resorption and is used for the treatment of osteolytic lesions, bone pain, and severe hypercalcemia associated with malignancies. Bisphosphonates)

  • 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. Bones: Structure and Types 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 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, deformity Deformity Examination of the Upper Limbs) is unclear.

Surgical therapy

  • 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 repair
  • Deformity Deformity Examination of the Upper Limbs correction

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

  • Severe functional limitation and decreased quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement 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 AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS, but can attain household and community ambulation skills.

Differential Diagnosis

  • 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: 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 Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. 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. Bones: Structure and Types 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. Bones: Structure and Types mineralization due to vitamin D deficiency Vitamin D Deficiency A nutritional condition produced by a deficiency of vitamin D in the diet, insufficient production of vitamin D in the skin, inadequate absorption of vitamin D from the diet, or abnormal conversion of vitamin D to its bioactive metabolites. It is manifested clinically as rickets in children and osteomalacia in adults. Fat-soluble Vitamins and their Deficiencies. Rickets Rickets Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. Osteomalacia and Rickets presents with recurrent fractures, limb deformities, increased alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma, and dental abnormalities in some cases, but does not display 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 and blue sclerae. 
  • Osteomalacia Osteomalacia Disorder caused by an interruption of the mineralization of organic bone matrix leading to bone softening, bone pain, and weakness. It is the adult form of rickets resulting from disruption of vitamin d; phosphorus; or calcium homeostasis. 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. Bones: Structure and Types 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 Disorder caused by an interruption of the mineralization of organic bone matrix leading to bone softening, bone pain, and weakness. It is the adult form of rickets resulting from disruption of vitamin d; phosphorus; or calcium homeostasis. Osteomalacia and Rickets shows fractures and increased alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma, but no 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 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. Bones: Structure and Types: 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. Bones: Structure and Types 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. Bones: Structure and Types deformity Deformity Examination of the Upper Limbs, bowing of long bones Long bones Length greater than width. Bones: Structure and Types, increased alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma, and conductive hearing loss Conductive hearing loss Hearing loss due to interference with the mechanical reception or amplification of sound to the cochlea. The interference is in the outer or middle ear involving the ear canal; tympanic membrane; or ear ossicles. Hearing Loss. However, 20% of cases are asymptomatic and diagnosis may be made incidentally as these patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are investigated for something else.

References

  1. Stankovits, L. M., M.D., & Lopyan, A.H., M.D., M.S. (2020). Genetic and metabolic conditions. Pediatric Clinics of North America, 67(1), 23-43. doi:http://dx.doi.org/10.1016/j.pcl.2019.09.005
  2. Marini, J. C. (2020). Osteogenesis imperfecta. In R. M. Kliegman MD, J. W. St Geme MD, N. J. Blum MD, Shah, Samir S., MD, MSCE, Tasker, Robert C., MBBS, MD & Wilson, Karen M., MD, MPH (Eds.), Nelson textbook of pediatrics (pp. 3736-3740.e1). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323529501007215
  3. Forlino, A., PhD., & Marini, J.C., Dr. (2016). Osteogenesis imperfecta. Lancet, The, 387(10028), 1657-1671. doi:http://dx.doi.org/10.1016/S0140-6736(15)00728-X
  4. Prockop, D. J., & Bateman, J. F. (2018). Heritable disorders of connective tissue. In J. L. Jameson, A. S. Fauci, D. L. Kasper, S. L. Hauser, D. L. Longo & J. Loscalzo (Eds.), Harrison’s principles of internal medicine, 20e (). New York, NY: McGraw-Hill Education. accessmedicine.mhmedical.com/content.aspx?aid=1160017759 
  5. Forlino, A., Cabral, W. A., Barnes, A. M., & Marini, J. C. (2011). New perspectives on osteogenesis imperfecta. Nature reviews. Endocrinology.
  6. Moscote-Salazar, L. R., Koller, O., Valenzuela, S., Narvaez-Rojas, A., Satyarthee, G. D., Mo-Carrascal, J., & Maraby, J. (2018). Neurosurgical Implications of Osteogenesis Imperfecta in a Child after Fall: Case Illustration. Journal of pediatric neurosciences, 13(4), 459–461.
  7. Dubowitz, H., & Lane, W. G. (2020). Abused and neglected children. In R. M. Kliegman MD et al., Nelson textbook of pediatrics (pp. 98-111.e1). https://www.clinicalkey.es/#!/content/3-s2.0-B978032352950100016X
  8. Greenbaum, L. A. (2020). Vitamin D deficiency (rickets) and excess. In R. M. Kliegman MD et al., Nelson textbook of pediatrics (pp. 375-385.e1). doi:http://dx.doi.org/10.1016/B978-0-323-52950-1.00064-X. Retrieved from https://www.clinicalkey.es/#!/content/3-s2.0-B978032352950100064X
  9. Ralston, S. H. (2020). Paget disease of bone. In L. Goldman MD, & A. I. Schafer MD (Eds.), Goldman-Cecil medicine (pp. 1623-1626.e2). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323532662002332
  10. Marini, J.C. (2004). Osteogenesis imperfecta: Comprehensive management. Adv Pediatr. 1988;35:391-426. PMID: 3055864.
  11. Niyibizi, C., Wang, S., Mi, Z. et al. (2004). Gene therapy approaches for osteogenesis imperfecta. Gene Ther 11, 408–416. https://doi.org/10.1038/sj.gt.3302199
  12. Steiner, R.D., Pepin, M.G., & Byers, P.H. (2005). Osteogenesis Imperfecta. Gene Reviews at GeneTests: Medical Genetics Information Resource.

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