The fundamental abnormality in OI is too little bone, resulting in extreme skeletal fragility. Other findings include blue sclerae caused by decreased collagen content, making the sclera translucent and allowing partial visualization of the underlying choroid; hearing loss related to a sensorineural deficit and impeded conduction due to abnormalities in the bones of the middle ear; and dental imperfections (small, misshapen, and blue-yellow teeth) secondary to a deficiency in dentin.
OI can be separated into multiple clinical subtypes that vary widely in severity. The type 2 variant is at one end of the spectrum and is uniformly fatal in utero or during the perinatal period. In contrast, individuals with the type 1 form have a normal life span despite a susceptibility to fractures, particularly during childhood.
Osteopetrosis, also known as marble bone disease, refers to a group of rare genetic diseases that are characterized by reduced bone resorption and diffuse symmetric skeletal sclerosis resulting from impaired formation or function of osteoclasts. The term osteopetrosis reflects the stonelike quality of the bones. However, the bones are abnormally brittle and fracture easily, like a piece of chalk. Osteopetrosis is classified into variants based on both the mode of inheritance and the severity of clinical findings.
Most of the mutations underlying osteopetrosis interfere with the process of acidification of the osteoclast resorption pit, which is required for the dissolution of calcium hydroxyapatite within the matrix. These include autosomal recessive mutations in the enzyme carbonic anhydrase 2 (CA2), or mutations in the TCIRG1 gene, which encodes a component of a vacuolar ATPase that helps to maintain acidic pH in osteoclasts, which is essential for breaking down bone. Bones involved by osteopetrosis lack a medullary canal, and the ends of long bones are bulbous (Erlenmeyer flask deformity) and misshapen. The neural foramina are small and compress exiting nerves. The primary spongiosa, which is normally removed during growth, persists and fills the medullary cavity, leaving no room for the hematopoietic marrow.
Severe infantile osteopetrosis is autosomal recessive and is often fatal because of leukopenia, despite extensive extramedullary hematopoiesis that can lead to prominent hepatosplenomegaly. The mild autosomal dominant form may not be detected until adolescence or adulthood, when it is discovered on radiographic studies for repeated fractures. These individuals also may have mild cranial nerve deficits and anemia.
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Abnormalitiesinasingleboneoralocalizedgroupofbonesarecalleddysostosesandarisefromdefectsinthemigrationandcondensationofmesenchyme.Theymanifestasabsent,supernumerary,orabnormallyfusedbones.Globaldisorganizationsofboneand/orcartilagearecalleddysplasias.Developmentalabnormalitiescanbecategorizedbytheassociatedgeneticdefect.
FGFR3mutationsareresponsibleforachondroplasiaandthanatophoricdysplasia,bothofwhichmanifestasdwarfism.
MutationsinthegenesfortypeIcollagenunderliemosttypesofosteogenesisimperfecta(brittlebonedisease),characterizedbydefectiveboneformationandskeletalfragility.
MutationsinCA2 andTCIRG1 resultinosteopetrosis(inwhichbonesarehardbutbrittle)andrenaltubularacidosis.